MBR 2019 - Physiology Handouts PDF

BLOOD PHYSIOLOGY
MA. ROSARIO F. CABANSAG, MD
BLOOD PHYSIOLOGY Growth factors: Early acting: SF, FLK2/FLT3

Multilineage – IL3
BLOOD Lineage specific – Erythropoietin -
- normal total circulating blood volume = about 8% stimulates erythropoiesis > 10x
of body weight or 70-80 ml/kg BW normal;
- plasma, liquid portion of blood = about 55% of 90% produced in the kidneys; 10% in the liver
whole blood (91% water; 7% proteins like
albumin, fibrinogens, globulins; solutes) Site of production: BM is prime hematopoietic
tissue and a major reticuloendothelial organ.
HEMATOPOIESIS
Role of Erythropoietin: The principal
RED BLOOD CELLS stimulus for red cell production in low oxygen
- lacks a nucleus or mitochondria states is the cytokine, erythropoietin. This
- 33% of its content is made up of a single protein, stimulates the production of proerythroblasts
hemoglobin from marrow stem cells and shortens the
maturation stages of erythroid cells. Its major
Functions of red blood cells effect appears to be at a level of the CFU-E
1. transport hemoglobin – major function during adult erythropoiesis. This is produced in
2. contains carbonic anhydrase, which catalyzes the peritubular interstitial cells of the kidney
the reversible reaction between CO2 & H2O (90%) and a little in the liver. Any condition that
3. excellent acid-base buffer reduces delivery of oxygen to the tissues causes
an increase erythropoietin secretion.
Production of Red Cells Androgens or male hormones affects
A. Sites of Production erythropoiesis in that they have the capacity to
Sites and periods of hematopoiesis: stimulate erythropoietin production and they can
characterized by sequential change in the major also directly induce differentiation of marrow
anatomic site for blood production. stem cells.
1. Mesoblastic period: fetal yolk sac is the
first site of primitive blood formation. Requirements for maturation of red blood
Although, some studies suggest that it cells
originated from the aorta-gonad- Role of Vitamin B 12 and folic acid:
mesonephros (AGM) region of the embryo. Cells with rapid cell turnover rate (rapidly
Starts at about 16 days age of gestation and growing and reproducing) such as red blood
starts to regress at about 6 weeks. cells require these 2 substances for proper
2. Hepatic period: the liver becomes the maturation. These 2 are essential for DNA
major site of blood production from the sixth synthesis as both are required for formation of
week age of gestation until shortly before the DNA base, thymidine triphosphate.
birth. Spleen and lymph nodes also sites of Therefore, lack of either vitamin B12 or folic
production. Characterized by an absolute causes abnormal and diminished DNA and
increase in the number of hematopoietic consequently a failure of nuclear maturation and
cells and a switch from primitive hemoglobin cell division. This results into fragile macrocytic
to fetal hemoglobin. red cells causing their shortened lifespan and
3. Myeloid period: the bone marrow found consequently causing anemia.
in the medullary cavity of bones become the
final site of hematopoiesis. Starts to function C. Regulation of Red Blood Cell Production -
at approximately 4 to 5 months age of depends on tissue oxygenation
gestation and becomes the only site of Factors that decrease tissue oxygenation:
normal hematopoiesis from the third week - anemia
postpartum and onwards - low blood volume
The bone marrow of essentially all - poor blood flow
bones produces blood cells until age 5. - cardiopulmonary disease
Thereafter, hematopoietically active (red) - high altitude
marrow continuously regresses such that
after age 20 it becomes focused only in the D. Hemoglobin Synthesis
lower skull, vertebrae, shoulder and pelvic - normal RBC contains approximately 32 pg of Hgb
girdles, ribs and sternum. Fat cells replace (32+/-2 pg).
hematopoietic red marrow turning it to - normal hemoglobin synthesis requires an adequate
yellow marrow. Fat occupies approximately supply of iron and normal production of both
50% of the space of the red marrow in protoporphyrin and globin.
adults. Further fatty metamorphosis 1. Protoporphyrin synthesis - initiated in the
continues slowly with aging. mitochondria with the formation of -ALA
from glycine and succinyl-CoA.
B. Genesis of Blood Cells 2. Globin chains - assembled by the
Stem cells: Pluripotent hematopoietic stem cells cytoplasmic ribosomes under the control of
Committed stem cells – CFU-E; CFU- 2 clusters of closely linked genes:
GM, CFU-M
UST FMS MEDICAL BOARD REVIEW 2019 1 | PHYSIOLOGY
BLOOD PHYSIOLOGY
a. -genes on chr 16 b. Non- genes - , ,

 on chr 11 A. Embden-Meyerhoff Pathway
- non-oxidative or anaerobic pathway
 Final globin molecule - a tetramer of 2  - responsible for the generation of
globin and 2 non  -globin 90% ATP needed by RBC
- metabolism of glucose results in net
 Final assembly of the hemoglobin molecule - generation of 2 molecules of ATP
occurs in the cell cytoplasm - also generates NADH from NAD,
important in other pathways
The pairing of these several globin chains - defect: associated with increased
produces 3 types of hemoglobin: cell rigidity and decreased survival
a. Hemoglobin A (2 2)
b. Hemoglobin A2 (2 2) B. Phosphogluconate pathway (HMP
c. Hemoglobin F (2 2) Shunt)
- where another 5-10% of glucose is
3. Iron metabolism metabolized
Total quantity of iron in the body = 4-5 gms - produces pyridine nucleotide NADPH
- 65% in hemoglobin, 4% in myoglobin, 1% from NADP.
in various heme compounds, 15-30% - NADPH, together with reduced
stored as ferritin glutathione, provides the main line
Ferritin – storage iron of defense for the RBC against
Hemosiderin – iron in the storage pool that oxidative injury.
is extremely insoluble. - prevents globin denaturation
- Deficiency of either G6PD or GSH
Total body iron is largely regulated by altering causes denatured hemoglobin to
the rate of GI absorption: precipitate as aggregates (Heinz
1. Transferrin when almost fully bound with bodies) on the inner surface of the
iron accepts almost no new iron from the RBC membrane, resulting in
mucosal cells of the intestines. Excess iron membrane damage and hemolysis.
in the mucosal cells depresses active GI
absorption. C. Methemoglobin Reductase Pathway
2. When the body has excess iron stores, the - maintains heme iron in its reduced
liver decreases the rate of formation of (ferrous) functional state.
apoferritin, thus reducing its concentration - absence of methemoglobin
in the plasma and bile. reductase enzyme results in an
inability to counteract oxidation of
Life Span of Red Blood Cells - has a normal life hemoglobin to methemoglobin.
span of 120 days.
D. Luebering-Rapoport Pathway
Crucial area of RBC survival and function - responsible for the production of 2,3
1. Integrity of RBC cellular membrane DPG important for its effect on
RBC membrane cytoskeleton - maintains the hemoglobin’s affinity for O2.
shape, stability and deformability of RBC.
Chemical composition: 40% lipids, 52% Destruction of Red Cells
proteins and 8% carbohydrates
1. Extravascular Hemolysis
2. Hemoglobin structure - 90% of destruction of senescent RBCs occurs
Abnormal hemoglobin - e.g. Hemoglobin S by the process of extravascular hemolysis;
old or damaged RBCs are phagocytized by
3. Cellular energetics & metabolic pathways RES cells and digested by their lysosomes
Cell metabolism- red cells have cytoplasmic
enzymes that: Iron - salvaged & returned by transferring to
a. Metabolize glucose and form small the erythroid precursors in the bone
amounts of adenosine triphosphate. marrow.
b. Maintain the pliability of the cell Globin – broken down into amino acids and
membrane redirected to the amino acid pool of the
c. Maintain membrane transport of ions body.
d. Keep the iron of the cell's hemoglobin in Protoporphyrin ring – disassembled, its alpha
the ferrous form carbon exhaled in the form of CO; the
e. Prevent oxidation of the proteins in the opened tetrapyrrole, biliverdin, is
red cells converted to bilirubin.
The stability of the red cell membrane and the 2. Intravascular hemolysis
solubility of the intracellular hemoglobin depend on - only 5-10% of normal RBC destruction occurs
4 glucose-supported metabolic pathways. through intravascular hemolysis

BLOOD PHYSIOLOGY
Disorders of Red Cell - more than 600 RBC antigens belonging to

20 systems have been described.
1. Anemias
- Most of the antigens are weak, are of
Anemia of underproduction- megaloblastic
importance principally for studying the
anemia, iron deficiency anemia, aplastic anemia
inheritance of genes
Anemia of increased destruction (hemolysis) –
- ABO and Rh systems are more important -
membrane defects, enzyme deficiency,
the only groups routinely determined before
abnormal hemoglobin structure, immune and
blood transfusion.
non-immune hemolytic anemias
- ABO blood group system - the only one in
Anemia of blood loss – acute or chronic, overt or
which antibodies are found regularly in the
occult
plasma without prior host exposure to red
cell A or B antigens.
2. Polycythemias
Secondary – e.g. high altitude, cardiac failure
Many blood group antigens are also found on non-
Primary – e.g. polycythemia vera
erythroid cells
Ex: A, B, Fya, Fyb, Kna, Inb, Oka, and the
WHITE BLOOD CELLS OR LEUCOCYTES
Cromer-related antigens
Leucocytes - mobile units of the body's protective
Erythroid specific antigens Ex: Rh-related
system.
antigens
- formed partially in the bone marrow
(granulocytes, monocytes and few lymphocytes)
O-A-B Blood Groups
and partially in the lymph tissue (lymphocytes
- The ABO, H, P, I, and Lewis blood group
and plasma cells).
antigens reside on structurally related
- 3x times as many WBCs are stored in the
carbohydrate molecules that carry sugars.
marrow as circulate in the entire blood.
The antigens arise from the action of
Life span:
specific glycosyltransferases that add
Granulocytes – 4-8 hours circulating; 4-5 days in
individual sugars sequentially to sites on
the tissues
oligosaccharides.
Monocytes - 10-20 hours transit time; live for
- The added sugars are called
months in the tissues
immunodominant because they confer
Lymphocytes - continual circulation (lymph –
specific antigenic activity on the
blood – tissues - lymph); life span of weeks
oligosaccharide chains.
or months
- Blood types with their genotypes and
constituent agglutinogens and agglutinins
PLATELETS
- round or oval discs 1-4 micrometers in Genoty Blood Aggluti Agglutinins Relative
diameter cytoplasmic fragment; anucleate. pe types nog fre
- replaced in the blood about once every 10 s ens que
days; thus about 30,000 platelets/mL of ncy
blood are formed each day. OO O - Anti A & 47%
Anti-B
- play a role in maintaining hemostasis.
OA or A A Anti B 41%
- Platelet count – 300,000/mm3 (150,000-
AA
450,000/mm3); about 30% are sequestered in OB or B B Anti A 9%
the microvasculature or spleen as functional BB
reserves AB AB A&B - 3%
- Life span: 8-12 days and eliminated mainly
by tissue macrophages, esp liver and spleen
Genetic Determination of the Agglutinogens
- Two genes, one on each of the 2 paired
Megakaryopoiesis and thrombopoiesis
chromosomes, determine the O-A-B blood
type. These 2 genes can be any one of the
Megakaryocytes - formed in the bone marrow.
3 types but only 1 type on each
- proliferate and then fragment their
chromosome: type O, type A or type B.
cytoplasm into platelets or thrombocytes.
- Type O gene- either functionless or almost
- its maturation involves endoreduplication (or
functionless, causing no significant type O
endomitosis), where the nuclear material
agglutinogen on the cells.
reduplicates but the nucleus does not divide.
- Type A and type B genes do cause strong
- After megakaryocyte maturation is
agglutinogens on the cells.
complete, the entire megakaryocyte
cytoplasm fragments and thrombopoiesis
Rh BLOOD TYPES
occurs.
Six common types of Rh antigens, each of which is
called Rh factor: C, D, E, c, e
BLOOD GROUPS
Type D antigen is widely prevalent in the population
Erythrocyte blood group antigens - and is considerably more antigenic than the
polymorphic, inherited, structural characteristics other Rh antigens.
located on proteins, glycoproteins, or glycolipids Rh positive - presence of D antigen
on the outside surface of the RBC membrane.
BLOOD PHYSIOLOGY
Rh negative - absence of D antigen, though other Endothelial surface of the blood vessel
Rh antigens can still cause transfusion reactions. - usually inert to coagulation factors and
platelets due to the ff:
Formation of anti-Rh agglutinins 1. Smoothness of the endothelial surface
- spontaneous agglutinins almost never occur 2. Layer of glycocalyx on the endothelium
- Anti Rh agglutinins develop slowly, the which repels clotting factors and platelets
maximum concentrations occurring about 2- 3. Contain an ecto-ADPase, CD 39, which
4 months after an Rh negative person was destroys ADP and limits platelet activation
exposed to the Rh factor. 4. Produce 2 potent anti-platelet compounds,
prostacyclin and nitric acid.
Erythroblastosis fetalis – (hemolytic Disease of the
NB) Endothelial cells also modulate the coagulation
- Set-up: The mother is Rh (-) and the father system and life span of fibrin clots by the ff ways:
is Rh (+) with the baby inheriting the Rh (+) 1. Binds, inactivates and cleaves thrombin
antigen from the father. 2. Expresses thrombomodulin, which is a thrombin-
- The mother develops anti-Rh agglutinins binding glycoprotein. Thrombin-thrombomodulin
from the fetus Rh antigens, which diffuse complex activates Protein C, the latter degrades
through the placenta into the fetus causing Factor Va & VIIIa.
red cell agglutination 3. Expresses heparin SO4 which catalyzes binding
- 1st born usually not affected, about 3% of of antithrombin III & heparin cofactor II to
the 2nd and 10% of the 3rd Rh (+) babies thrombin thereby inactivating thrombin.
exhibit the disease 4. Releases tissue plasminogen activator (tPA), the
- Clinical picture: jaundice, usually anemia at major intravascular activator of the fibrinolytic
birth, hepatosplenomegaly, many circulating system.
nucleated red cells
- Treatment and prevention: Exchange B. FORMATION OF PLATELET PLUG
transfusion; the use of Rh immunoglobulin
to the expectant mother Platelet Function in Hemostasis
1. Maintenance of vascular integrity - platelets are
Transfusion reactions after mismatched blood types incorporated into the vessel wall, releasing
- Hemolysis of the donor’s red cells – platelet derived growth factor (PDGF) that
immediate intravascular hemolysis or nurtures EC, maintaining normal vascular
delayed integrity and promoting vascular healing
2. Initial arrest of bleeding by platelet plug
HEMOSTASIS AND BLOOD COAGULATION formation
3. Stabilization of hemostatic plug by contributing
Systems Involved in Maintaining Hemostasis to fibrin formation
Major Systems Minor Systems Platelet Plug Formation

Vascular system Kinin System A. Platelet Adhesion
Platelets Serine protease inhibitors
Coagulation system Complement system This is the formation of an initial one-cell-
Fibrinolytic system thick “carpet” of platelets at the site of injury in
the vascular tree. This occurs due to:
PHASES OF HEMOSTASIS a. Exposure of the injured vascular sub
endothelium which is rich in adhesive
I. PRIMARY HEMOSTASIS proteins.
b. Presence of platelet glycoprotein receptors
A. VASCULAR SPASM
1. Vasoconstriction and reflex stimulation of
adjacent vessels from nervous reflexes, local
myogenic spasm, & local humoral factors
from traumatized tissues and platelets such
as thromboxane A2 and serotonin
(vasoconstrictors)
2. Diversion of blood flow around damaged
vasculature
3. Initiation of contact activation of platelets
with subsequent adhesion, release reaction,
and aggregation
4. Contact activation of the coagulation system
leading to fibrin formation
Adhesion of platelets to the vascular

subendothelium

BLOOD PHYSIOLOGY
Depending on the vascular bed, available adhesive II. SECONDARY HEMOSTASIS

glycoprotein & shear conditions, it is likely that
various combinations of vascular of platelet Function: To support and reinforce the
receptors such as GPIb,GPIa/IIa,GPIV, and GP platelet plug and to solidify blood that
IIb/IIIa act in concert to transform the tethering and remains in the wound channel.
slow translocation of platelets initiated by GPIb with
vWF into stable platelet adhesion. Clotting takes place in 3 essential steps:
A. A complex cascade of chemical reactions
B. Release Reaction (Secretion) involving more than a dozen coagulation
* Platelet release reaction and platelet factors is set into play in response to vessel
aggregation are intimately related and may injury or damage to blood itself. The net
sometimes occur almost simultaneously. result of which is the formation of a complex
- release reaction from dense granules involves of activated substances collectively called
the secretion of ADP, serotonin, and calcium prothrombin activator.
- ADP, responsible for both initial and further B. Conversion of prothrombin to thrombin
aggregation of platelets by the catalytic action of the prothrombin
- elevation of intracellular Calcium further activator.
amplifies the process by activating more C. Thrombin acts as an enzyme converting
calcium-sensitive phospholipases, leading to fibrinogen to fibrin fibers that enmesh
further formation of thromboxane A2 (TXA2) platelets, blood cells and plasma to form the
C. Aggregation clot.
- follows adhesion in the presence of sufficient
activation or stimulus Formation of the Fibrin Clot
- platelet-to-platelet interaction is a process of
Ca++ dependent ligand formation between The mechanisms that initiate the clotting
membrane bound fibrinogen molecules; process is markedly complex and these are set
fibrinogen binding to divalent cation complex into play by the ff:
of platelet membrane glycoproteins IIb/IIIa. 1. trauma to the vascular wall
and adjacent tissues
Prostaglandin synthesis 2. trauma to the blood
3. contact of blood to
damaged endothelial cells
or with collagen and other
tissue elements outside the
blood vessel.
In each instance a prothrombin activator is

formed which causes the conversion of
prothrombin to thrombin. The prothrombin
activator is generally considered to be formed in
2 ways, the intrinsic and the extrinsic pathways.
Sequence of events in primary hemostasis In both the extrinsic and intrinsic pathways,
a series of different plasma proteins called
blood-clotting factors play major roles. Most of
these are inactive forms of proteolytic enzymes.
When converted to the active forms, their
enzymatic actions cause successive, cascading
reactions to the clotting process.
Most of the clotting factors are designated

by Roman numerals. To indicate the activated
form, a small letter “a” is added after the Roman
numeral.
Blood Coagulation Factors
Category and Hemostatic Plasma

Name Function concentrat
ion
(ug/ml)
Contact Activation
Factors Activates F
XI & PK 30
FXII (Hageman Brings FXI & 70
Factor) PK to a 45
BLOOD PHYSIOLOGY
HMW Kininogen surface 4 Interaction between the Extrinsic and

Prekallikrein Activates Intrinsic Pathways
F XI (PTA) FXII
(plasmathromb Activates FIX 1. Intrinsic pathway: begins with trauma to
oplastin the blood itself or exposure of blood to
antecedent) collagen from a traumatized tissue. It is
Vitamin K- Precursor of called such because everything necessary
Dependent thrombin 150 for it is “in” the blood.
Proenzymes Activates 8
Prothrombin prothrombi 4 2. Extrinsic pathway: begins with trauma to
(FII) n 0.5 the vascular wall and surrounding tissues. It
FX (Stuart- Activates F X 3.5 is so named because a cellular element
Prower Activates F outside the blood is needed for activation.
Factor) IX & F X
FIX (Christmas Inactivates These 2 pathways do not actually act in
Factor) VIIIa & Va parallel but are actually brought into play
FVII sequentially. The extrinsic pathway, with its
(Proconvertin tissue factor, is the usual way of initiating
) clotting in the body. This is an explosive
Protein C reaction, once initiated its speed of
Cofactors occurrence is limited only by the amount of
Tissue factor (F Cofactor for - tissue factor released from the traumatized
III) FVII & - tissues and by the quantities of Factors X,
Platelet VIIIa VII, and V in the blood. This can occur in as
procoagulant Cofactor for 0.1 little as 15 seconds.
phospholipid FIXa & Fxa 7 Tissue factor is not a plasma protein. These
(PF3) 35 are glycoprotein receptors which are located
F VIII Cofactor for in the outer plasma membrane of various
(antihemophil FIXa tissue cells including fibroblasts and other
ic factor) Cofactor for cells in the walls of blood vessels below the
FV Fxa endothelium. Exposure of the tissue factor
(proaccelerin) Cofactor for causes it to bind with circulating F VII
Protein S activated causing F VII activation. The complex of TF-
protein C FVIIa catalyzes activation of FX. It also
Factors of Fibrin activates FIX of the intrinsic pathway.
Deposition Precursor of 2500 The thrombin initially formed by the
Fibrinogen (FI) Fibrin 8 extr0069nsic pathway is too small to
FXIII (fibrin Crosslink produce adequate or sustained coagulation.
stabilizing Fibrin But it is large enough to trigger thrombin’s
factor) stimulatory effect on the activation of F XI,
VIII and platelets. This triggers the intrinsic
Contact activation factors – proteins that initiate pathway independent of FXII activation.
clotting when blood is exposed in vitro to a Thrombin generated from here is large
negatively charged activating surface such enough for adequate coagulation to occur.
as glass.
Action of thrombin on fibrinogen
Vitamin K-dependent proenzymes or zymogens – to form fibrin. Thrombin acts on
these are serene protease proenzymes fibrinogen to remove 4 low molecular weight
possessing residues of a unique amino acid, peptides from each molecule of fibrinogen,
-carboxyglutamic acid (Gla). Vitamin K acts forming a molecule of fibrin monomer that
as a cofactor for activation of these has the automatic capability to polymerize
proenzymes creating strong calcium binding with other fibrin monomers forming fibrin.
sites. Binding of calcium to these sites Therefore, many fibrin monomer molecules
confers a tertiary structural conformation polymerize within seconds into long fibrin
they need for hemostatic function. fibers that then constitute the reticulum of a
clot.
Cofactors – required to form enzyme – cofactor In the early stages of this polymerization,
complexes, which provide specificity & the fibrin monomer molecules are held
kinetic efficiency for several enzymatic together by weak noncovalent hydrogen
reactions of blood coagulation. bonding, and the newly forming fibers are
not cross-linked with one another;
therefore, the resulting clot is weak and
maybe broken with ease.

BLOOD PHYSIOLOGY
Role of platelets. Platelets play an

important role in the conversion of
prothrombin to thrombin because much of
the prothrombin first attaches to the
prothrombin receptors on the platelets that
have already bound to damaged tissue.
Then this binding accelerates the formation
of still more thrombin from prothrombin, but
this time occurring in the specific tissue
where the clot is needed.
PATHWAYS FOR INITIATING BLOOD

CLOTTING
CROSSOVER SCHEME OF COAGULATION
SCHEMA FOR CONVERSION OF

PROTHROMBIN AND POLYMERIZATION OF
FIBRINOGEN TO FORM FIBRIN FIBERS
III. TERTIARY HEMOSTASIS
A. CONSOLIDATION AND GRADUAL

DISSOLUTION OF THE FIBRIN CLOT
Conversion of soluble fibrinogen to insoluble cross-
linked fibrin is the central event in the coagulation
system, where thrombin removes small polar
peptides (termed fibrinopeptides A & B) from the
fibrinogen molecule forming fibrin.
These fibrin molecules noncovalently interact with

each other to form a fibrin web. FXIIIa causes fibrin
stabilization by introducing numerous covalent
cross-links between these fibrin molecules. The
resulting fibrin web is able to capture platelets and
red blood cells, thus effectively sealing the wound
and stemming plasma loss.
B. ACTIVATION OF THE FIBRINOLYTIC

SYSTEM- LYSIS OF BLOOD CLOTS
- large amount of plasminogen is trapped in the
clot along with other plasma proteins when a
clot is formed.
- Plasminogen is activated to plasmin by tissue
plasminogen activator (tPA) from injured
tissues and vascular endothelium.
- Plasmin digests fibrin fibers and some other
protein coagulants reopening blood vessels to
allow blood flow.
BLOOD PHYSIOLOGY
Hemostatic Tests:
KININ SYSTEM Bleeding time – tests the integrity of platelets/blood
- important in inflammation, vascular permeability, vessel
and chemotaxis Platelet Count
- activated by both the coagulation and fibrinolytic Prothrombin time - reflects overall efficiency of
system extrinsic system; useful in monitoring effect of
- HMWK is important in both the fibrin-forming and coumarin-type agents (warfarin); screening for
fibrin-lysing systems Vit. K deficiency
- Kalllikrein can act on kininogens, both low and Partial thromboplastin time - screening test of the
high MWK, and convert them to kinins like kallidin intrinsic system; prolonged in deficiency of
and bradykinins common pathways (def in FV, FX and FII; lesser
extent fibrinogen) and in the presence of
SERINE PROTEASE INHIBITORS inhibitors incl heparin and FDPs
Two major mechanisms are responsible for
preventing the generation of thrombin and fibrin
from extending beyond the site of injury:
1. neutralization of activated coagulation proteases
by circulating and endothelial cell bound
antiproteases.
a. Antithrombin III – also called heparin
cofactor or FXa inhibitor
- major inactivator of thrombin and FXa
- considered the most important physiologic
anticoagulant because possibly more than
90% of the antithrombin activity of normal
human plasma is derived from AT-III.
b. Tissue factor pathway inhibitor – inhibits
FXa and TF-FVIIa complex
c. Alpha-2-antiplasmin – rapid inhibitor of
plasmin
d. Alpha-2-macroglobulin – slower inhibitor of
plasmin
e. Alpha-1-antitrypsin – inhibits FXa, FXIa,
thrombin, and plasmin
f. C1 esterase inhibitor – inhibits FXIa, FXIIa,
Kellikrein, and plasmin
2. limited proteolysis of factors Va and VIIIa by

activated Protein C in the presence of its
cofactor free Protein S
- Protein C is activated by thrombin when it is
bound to thrombomodulin, thrombin-
thrombomodulin complex
- Thrombin in the thrombin-thrombomodulin
complex loses its ability to convert fibrinogen
to fibrin and activate platelets
COMPLEMENT SYSTEM
- Plasmin activates complement by cleaving C3
into C3a and C3b
- C1 esterase inhibitor inactivates complement
EFFECTS OF SOME DRUGS ON HEMOSTASIS

1. Aspirin - induces irreversible acetylation and
inactivation of platelet cyclooxygenase, leading
to inhibition of endoperoxide, and TXA2
synthesis, thus preventing platelet aggregation.
2. Warfarin or Coumadin – an oral anticoagulant
that has structural similarity with Vitamin K
- inhibits the regeneration step of reduced
Vitamin K, thus blocking the final synthesis step
of the Vit K dependent proteins
3. Heparin – transforms AT-III into a powerful
inhibitor of thrombin, FXa, FXa, and FXIa in
order of decreasing frequency

REVIEW TEST
CHOOSE THE BEST ANSWER:

_____12. Which metabolic pathway is the main
_____1. Approximate volume of blood in a normal source of energy of the red cell?
healthy individual A. Embden Meyerhoff
A. 40-50mL/kg BW B. Hexose monophosphate shunt
B. 50-60mL/kg BW C. Luebering rapaport
C. 60-70 mL/kg BW D. Pentose phosphase pathway
D. 70-80mL/kg BW
_____13. Which is the terminal sugar in the RBC
_____2. The first site of blood formation that makes it Type A?
A. Yolk sac A. Galactose
B. Liver B. Glucose
C. Spleen C. Fructose
D. Bone marrow D. N-acetyl galactosamine
_____3. Of the above, for the most part of fetal life, _____14. The platelet glycoprotein that initially
which is the major site of blood formation? attaches to the vWF at the start of adhesion
A. GP IIb/IIIa
_____4. Which is in early-acting hematopoietic B. GP Ib
growth factor? C. GP IV
A. Stem cell factor D. GP Ia/IIa
B. IL2
C. GCSF _____15. Platelet agonist or activator generated
D. GMCSF from arachidonic acid
A. Thromboxane A2
_____5. Conditions that can stimulate erythropoietin B. Thrombospondin
production C. Epinephrine
A. ↓Ph D. Prostacyclin
B. COPD
C. Renal failure _____16. True of the extrinsic pathway of
D. Decreased temperature coagulation EXCEPT
A. Results in generation of thrombin
_____6. Vitamin B12 is required for formation of B. Initiates the clotting cascade by way
which DNA base? of the tissue factor
A. Thymidine C. Able to generate significant amounts
B. Cytosine of thrombin for adequate coagulation
C. Adenine D. Uses Vitamin K-dependent clotting
D. Guanine factors
_____7. Major oxygen carrying protein in _____17. Intrinsic pathway of coagulation involves
erythropoietin the ff clotting factors EXCEPT
A. Haptoglobulin A. VIII
B. Hemoglobin B. XI
C. Hemosiderin C. VII
D. Methemoglobin D. IX
_____8. Most sensitive and specific test for iron _____18. Which of the following stabilizes the fibrin
deficiency: clot?
A. Serum protophorphyrin A. FVIII
B. Ferritin B. Vw
C. Serum iron C. FXIII
D. TIBC D. Fibrinogen
_____9. The basic structure of adult hemoglobin: _____19. Which is a powerful initiator of clot lysis?
A. α2β2 A. tPA
B. α2δ2 B. Plasminogen
C. α2ϒ2 C. Protein C
D. α2ε2 D. Protein S
_____10. How many oxygen molecules does each _____20. The following prevents extension of clot
hemoglobin molecule contain? formation EXCEPT:
A. 2 C. 6 A. Protein C
B. 4 D. 8 B. TFPI
C. Plasmin
_____11. Insoluble storage form of iron
D. Anti-thrombin III
A. Hemosiderin
B. Ferritin
C. Apoferritin
D. Apotransferrin
UST FMS MEDICAL BOARD REVIEW 2019 | PHYSIOLOGY

GASTROINTESTINAL PHYSIOLOGY
REMEDIOS DEE-CHAN, M.D. MHPEd
ANITA Q. SANGALANG, MD, MHPEd
The gastrointestinal (GI) system includes the GI

ORGAN EXOCRINE FUNCTIONS
tract (mouth, pharynx, esophagus, stomach, small
SECRETIONS
intestine, and large intestines) plus several
II. ACCESSORY GLANDS/ORGANS
accessory glands and organs that add secretions to
these hollow organs. Each of these organs, Salivary Salt and water  moisten food
separated from each other at key locations by Glands
sphincters, has evolved to serve specialized function. Mucus  lubricates
Amylase  polysaccharide-
Parts of the GI System and their Functions digesting
enzyme
Pancreas  secretes
enzymes and
ORGAN EXOCRINE FUNCTIONS bicarbonate
SECRETIONS  nondigestive
I. GI TRACT endocrine
Mouth,  chewing begins; functions
Pharynx  initiate swallowing Enzymes  digest
reflex carbohydrates,
Esophagus  moves food to fats, proteins,
stomach by nucleic acids
peristaltic waves Bicarbonate  neutralizes HCl
Mucus  lubricates entering small
Stomach  stores, mixes, intestines from
dissolves, and stomach
continues Liver  secretes bile
digestion of food;  nondigestive
 regulates functions
emptying of Bile salts  solubilize
dissolved food water-insoluble
into small fats
intestines Bicarbonate  neutralizes HCl
HCl  solubilizes food entering small
particles; intestines from
 kills microbes; stomach
 activates Organic waste  elimination in
pepsinogens to products & feces
pepsins trace metals
Pepsins  protein-digesting Gallbladder  stores and
enzymes concentrates
Mucus  lubricates and bile between
protects meals
epithelial surface
Small  digests and LAYERS OF THE GI TRACT
Intestine absorbs most
(SI) substances; 1. Mucosa (Innermost layer)
 mixes and propels A. Epithelium- single layer of specialized cells
contents that line the lumen
Enzymes  food digestion  enterocytes
Salt and water  maintain fluidity enteroendocrine cells
of luminal mucin-producing cells
contents  columnar epithelial cells are linked
Mucus  lubricates together by tight junctions
Large  stores and  surface area of the epithelium is
Intestine concentrates arranged into villi and crypts
(LI) / Colon undigested B. Lamina propria
matter;  loose connective tissue
 absorbs salt and  glands, capillaries and nerve fibers
water; C. Muscularis Mucosae
 mixes and propels  thin innermost layer of intestinal
contents smooth muscle
Mucus  lubricates  gives rise to the folds and ridges of the GI
tract
Rectum  defecation

2. Submucosa 2. Secretion - refers to the processes by which

 loose connective tissue the glands associated with the GI tract
 Some glands are present. release water and substances into the tract.
 larger nerve trunks, blood vessels and lymph 3. Digestion - involves the processes by which
vessels food and large molecules are chemically
 submucosal plexus (Meissner’s plexus) which
degraded to produce smaller molecules that
is part of the enteric nervous system (ENS)
3. Muscle Layer can be absorbed across the wall of GI tract.
 muscularis externa or muscularis propia 4. Absorption - refers to the processes by which
 Two layers: nutrient molecules are absorbed by cells that
a. Inner circular muscle layer line the GI tract and enter the bloodstream
b. Outer longitudinal muscle layer
 between these layers is the myenteric plexus
(Auerbach’s) – which is part of the ENS REGULATION OF GI FUNCTION
4. Serosa or Adventitia (outermost layer) A. Endocrine / Hormonal
 squamous mesothelial cells B. Paracrine
 part of the mesentery C. Neurocrine
 Mesenteric membrane secrete a thin viscous
fluid. A. Endocrine Mechanism / Hormonal
 A sensing cell, an enteroendocrine cell
ROLES OF THE GI SYSTEM (EEC), responds to a stimulus (chemical or
1. Digestion and absorption of dietary calories mechanical) by secreting a hormone that
and nutrients travels via the bloodstream to a target cell.
Nutritional Requirement:  can be stimulated by neural input or other
Sedentary individual = 30 kcal/kg/day factors not associated with meal
 normally acquired via oral route of food B. Paracrine Mechanism
 assimilated by GI tract (small intestines)  A chemical messenger is released from a
 Intravenous route - other means of caloric sensing cell, EEC in the GI wall that acts
intake on a nearby target cell by diffusion
 I.V. alimentation / total parenteral through the interstitial space
nutrition  Paracrine agents exert their actions on
2. Maintenance of overall fluid & electrolyte balance several different cell types in the wall of the
 Dietary fluid intake = 1.2 – 2 L/day GI tract, including:
 Total fluid secreted by GIT & accessory a. smooth muscle cells
organs = 7– 8.5L/day b. absorptive enterocytes
 Total fluid absorbed by small intestine c. secretory cells in glands
~ 8-9 L/day d. other EEC’s
 Total fluid in feces ~100 ml/day 1. Histamine
3. Excretion of waste materials (feces)  produced by the enterochromaffin-like
a. nondigested / nonabsorbed food cells in the gastric mucosa.
b. colonic bacteria and metabolic products  It mediates hydrochloric acid (HCl)
c. excretory products - secretion by gastric parietal cells.
• heavy metals i.e. iron, copper 2. Serotonin (5-hydroxytryptamine [5-HT]}
 It is released from enteric neurons, mucosal
• organic anions & cations (drugs)
mast cells, and specialized EEC’s called
d. dead and dying epithelial cells
enterochromaffin cells .
e. water
 It regulates smooth muscle function and
4. Immune functions
water absorption across the intestinal wall.
 gut-associated lymphoid tissue (GALT)
3. GI Immune System
a. protects against microbial pathogens
b. permits immunologic tolerance  It includes mesenteric lymph nodes,
Peyer’s patches, immunocytes
Non-immunologic defenses (intraepithelial lymphocytes, B & T
a. gastric acid secretion lymphocytes, plasma cells, mast cells,
b. intestinal mucin macrophages, eosinophils).
c. peristalsis  It secretes antibodies & inflammatory
d. epithelial cell permeability barrier mediators (histamine, prostaglandin,
leukotrienes, cytokines) in response to
PHYSIOLOGIC FUNCTIONS OF THE GIT specific food antigens and mounts an
 processes needed to perform its roles immunologic defense against many
pathogenic microorganisms.
1. Motility - is the movement that mixes and 4. Hormones
circulates the GI contents and propels them  These include cholecystokinin, secretin,
along the length of the tract. GI contents are peptide YY, proglucagon-derived peptides ½
usually propelled in the orthograde direction. (GLP-1/2).

GASTROINTESTINAL PEPTIDE HORMONES
Cranial divisions – vagus
HORMONE SOURCE TARGET ACTION
Sacral divisions (S2, S3, S4) T5-L2 (SC)
I cells in Pancreas  Enzyme – pelvic nerve
Cholecystokinin duodenum & Gallbladder secretion
jejunum;  Contraction
Innervation to:
neurons in 1. esophagus 1. Distal half of large
ileum & colon 2. stomach, intestine
Gastric- K cells in Pancreas Exocrine: 3. pancreas 2. anus
Inhibitory duodenum ↓ fluid 4. small intestine
peptide and absorption 5. proximal half of large
jejunum Endocrine: intestine
 insulin Directly innervates GIT No direct innervation
release
Preganglionic fibers Preganglionic (SC) →
G cells, Parietal cells  H secretion
+
(vagus nerve) → Postganglionic (Prevertebral
Gastrin antrum of in body of
stomach stomach Postganglionic fibers (ENS) ganglia) → Effector cells
→ effector cells a. Celiac ganglia
Gastrin- Vagal nerve G cells in  Gastrin release
Releasing endings antrum of b. Superior mesenteric
peptide stomach ganglia
 cells of Liver  Glycogenolysis
b. Inferior mesenteric
Glucagon pancreatic  Gluconeogenesis ganglia
islets of Neurotransmitter: Neurotransmitter:
Langerhans Acetylcholine Norepinephrine
Guanylin Ileum & colon Small & large  Fluid absorption Actions: Actions:
intestine Stimulatory Inhibitory
Endocrine Esophageal  Smooth- - stimulates the following - inhibits the
Motilin cells sphincter muscle functions of the GIT following functions of
in upper GI Stomach contracti 1. secretory the GIT
tract Duodenum on
2. motor 1. secretory
Endocrine Intestinal Vasoactive 2. motor activity (except
Neurotensin cells, smooth stimulation of
submucosal muscles)
wide-spread muscle histamine
in GI tract release 3. Local blood flow
(vasoconstriction)
Endocrine Stomach  Vagally mediated
Peptide YY cells in ileum acid secretion
& colon Pancreas  Enzyme & 2. Intrinsic Nervous System
fluid  Enteric Nervous System (“little brain of the
secretion
gut”)
S cells in Pancreas  HCO3- & fluid
Secretin small
 primary neural control of GI function
secretion by
intestine pancreatic ducts  100 M neurons
Stomach  Gastric-acid  lies entirely in the wall of the gut
secretion  can be modified by input from the brain
D cells of Stomach /  Gastrin release  nervous connections with
Somatostatin stomach & Intestine  Fluid absorption / parasympathetic and sympathetic
duodenum,  secretion
 cells of  Smooth-muscle nerve fibers
pancreatic contraction  receives afferent fibers from sensory nerve
Pancreas
islets  endings located in the epithelium or gut wall
Endocrine/exocrine
Liver secretions
 Bile flow
Substance P Enteric Enteric Neurotransmitter a. Myenteric (Auerbach’s) Plexuses
neurons neurons  outer layer
Vasoactive ENS neurons Small  Smooth-  located between the muscle layers of
Intestinal intestine muscle proximal esophagus to rectum
Peptide relaxation  Actions: motor effects
 Secretion by
small • increase tonic contraction
Intestine • increase intensity of rhythmic
Pancreas  Secretion by contraction
pancreas
• increase velocity of excitatory waves
C. Neurocrine Mechanism b. Submucosal (Meissner’s) Plexuses
 involves the release of neurotransmitters from a  inner layer
nerve terminal located in the GI tract. The  submucosa of intestines only
neurotransmitter then influences the motor & / or  Action: regulate the secretory activities of
secretory activities of the GI tract glandular, endocrine, epithelial cells
Innervation of the GI Tract
1. Extrinsic Nervous System – nerves that innervate the

gut with cell bodies located outside the gut wall.
a. Parasympathetic NS
b. Sympathetic NS
PARASYMPATHETIC NS SYMPATHETIC NS
GASTROINTESTINAL MOTILITY Action Potentials

 Action potentials (AP’s) in GI smooth muscles are
more prolonged (10 - 20 msec) than those of
The primary functions of the motor activity of the skeletal muscle.
GI tract are:  have little or no overshoot
1. GI motility produces peristalsis or  The rising phase of the AP is caused by ion flow
propulsive contractions - moving through channels that conduct both Ca2+ and
Na+ and are relatively slow to open.
rings of contractions that propel luminal
 Ca2+ that enters the cell during the AP helps to
contents along the GI tract in a caudal initiate contraction by activating the openings of
direction. K + channels.
 result in the elimination of nondigested,  When the membrane potential of GI smooth
nonabsorbed material. muscle reaches the electrical threshold, a train of
 occurs in the pharynx, esophagus, gastric action potential is fired. These AP’s enhance the
antrum and the small and large intestines. contractile force of the smooth muscles cells.
2. It produces segmental contractions, which Stronger contractions are produced by AP’s that
produce narrow areas of contracted segments are intermittently triggered near the peaks of the
between relaxed segments. slow waves. The greater the number of AP’s that
occur, the more intense is the muscle
 result in the increased mixing or churning
contraction.
of luminal contents that enhances the
• Between trains of AP’s, the tension
digestion and absorption of dietary nutrients.
developed by the GI smooth
3. It allows the stomach and large intestines
muscle fails but not to zero. This baseline
to act as reservoirs for holding the tension is called tone.
luminal contents.
 made possible by sphincters that separate the
organs of the GI tract.
ELECTROPHYSIOLOGY OF THE GI SMOOTH

MUSCLE
 The electrical and mechanical properties
of GI smooth muscle needed to perform
its functions include: Relationship between Action Potential and
1. Rhythmic contraction - alternating Smooth Muscle Tension
contraction and relaxation of individual
muscle cells.  These activities are regulated, in large part, by
 allows the movement of the GI tract from both neural and hormonal stimuli. Modulation
orad to caudad of GI smooth muscle contraction is largely a
2. Tonic contraction - sustained contraction of function of [Ca 2+].
each individual muscle cells. Agonists regulate [Ca2+] by
 allows some of the GI organs to function as 1. activating G-protein-linked receptors which
reservoirs. results in the formation of IP3 and release
of Ca2+ from intracellular stores
Electrical Activity of the GI Smooth Muscle 2. opening and closing plasma-membrane Ca
2+
 Resting Membrane Potential / Slow Waves / channels
Basic Electrical Rhythm  Acetylcholine (Ach) and substance P
 The RMP of the GI smooth muscle cells ranges • predominant neurotransmitter of excitatory
from approximately - 40 to - 80 mV. motor neurons.
 The Na+K+-ATPase contributes significantly to the  Vasoactive intestinal peptide (VIP) and nitric
RMP of the GI smooth muscle. oxide (NO)
 In GI smooth muscle, the RMP characteristically • inhibitory.
varies or oscillates. These oscillations are called • hyperpolarize the smooth muscle cells and
slow waves or basic electrical rhythm (BER). may diminish or abolish action potential
 The frequency of slow waves varies from the spikes.
stomach to the large intestine.  Different neural or hormonal inputs increase or
 generated by the interstitial cells of Cajal (ICCs), decrease the frequency with which membrane-
located between the circular and longitudinal voltage Vm exceeds threshold and produces an
layers of the muscularis externa & other places AP and thus increases muscle contractility.
in the wall of the GI tract. ICCs are the  Smooth muscle activity is also regulated by
“pacemaker” cells of the GI smooth muscle luminal food and digestive products. They
 modulated by hormones, paracrine substances, activate mucosal chemical and mechanical
and neurocrine mediators receptors, thus inducing hormone release or
stimulating the ENS and controlling smooth
muscle functions.

Differences Between a Slow Wave from adjacent muscle in the distal end of the
and a Spike Potential esophagus and proximal portion of the stomach
• Primary Functions of the LES:
SLOW WAVE SPIKE POTENTIAL a. permit coordinated movement of ingested
Not an action potential food into the stomach from the esophagus
slow undulating changes in True action potential after swallowing or deglutition
the RMP b. prevent reflux of gastric contents into the
Basic electrical rhythm
esophagus
excited by slow wave
caused by interstitial cells potential when it reaches 3. Pyloric Sphincter
of Cajal (intestinal the RMP threshold (more • a ring of smooth muscle and connective tissue
pacemaker) positive than -40mv) between the antrum and the duodenum
NV: -50 to -60 mv • The pressure of the pyloric sphincter regulates,
does not elicit contractions causes muscle
in part, gastric emptying and prevents duodenal
contractions
gastric reflux.
Intensity: 5-15 mv
Frequency: • quite short and is a relatively poor barrier (i.e.
Stomach: 3/min it can resist only a small pressure gradient).
Duodenum: 10-13/min • The stomach, duodenum, biliary tract, and
Ileum: 8-9/min pancreas – which are closely related
Colon: 6-8/min embryologically -- function as a unit.
Depolarization by: • Coordinated contraction and relaxation of the
stretch antrum, pylorus, and duodenum (referred to as
acetylcholine “antroduodenal cluster unit”) are probably more
parasympathetic NS
important than simply the pressure produced by
Hyperpolarization by:
the pyloric smooth muscle per se.
Norepinephrine 4. Sphincter of Oddi
Sympathetic NS • regulates the movement of the contents of
the common bile duct into the duodenum
GI SPHINCTERS
5. Ileocecal Sphincter
 specialized circular muscles that separate • separates the ileum and the cecum
segments of the GI tract through which food • distention of the ileum results in relaxation of
products pass the sphincter, whereas, distention of the
 function as barriers to flow by maintaining a proximal (ascending) colon causes
positive resting pressure that serves to separate contraction of the ileocecal sphincter.
the two adjacent organs, in which lower Consequently, ileal flow into the colon is
pressures prevail. Thus, they regulate both regulated by luminal contents and pressure,
antegrade (forward) and retrograde (reverse) both proximal and distal to the ileocecal
movement. sphincter.
 As a general rule, stimuli proximal to a sphincter
cause sphincteric relaxation, whereas, stimuli 6. Internal Anal Sphincter
distal to a sphincter induce sphincteric • both circular and longitudinal smooth muscle.
contraction. • under involuntary control.
 effectively serve as one-way valves • The high resting pressure of the overall anal
 The location of a sphincter determines its sphincter predominantly reflects the resting
function. tone of the internal anal sphincter. It
 Changes in sphincter pressure are coordinated contributes 70-80 of anal tone at rest.
with the smooth muscle contractions in the • Distention of the rectum initiates the
organs on either side. rectosphincteric reflex by relaxing the internal
This coordination depends on both the anal sphincter.
Intrinsic properties of sphincteric smooth 7. External Anal Sphincter
muscle and neurohumoral stimuli. • encircles the rectum
 All GI sphincters are under the control of the • contains only striated muscles
enteric nervous system, vagus nerve, and • controlled by both voluntary and involuntary
sympathetic nerves. mechanisms
• produces 20-30% of anal tone at rest
1. Upper Esophageal Sphincter (UES)
• separates the pharynx from the upper part of MASTICATION (CHEWING)
the esophagus  a voluntary and but more frequently, a reflex
• striated muscle behavior
• has the highest resting pressure of all the GI  controlled by the somatic nerves to the skeletal
sphincters muscles of the mouth and jaw
2. Lower Esophageal Sphincter (LES) Functions of Chewing

• separates the esophagus from the stomach 1. lubricates food by mixing it with salivary
• specialized smooth muscle that is both mucus
anatomically and pharmacologically distinct 2. initiates digestion of starch through salivary
amylase Types of Peristalsis in Esophagus

3. mechanically chops food into smaller pieces
1. Primary peristalsis - continuation of peristaltic
so that it can be easily swallowed and
waves from the pharynx
propelled more easily and more readily
2. Secondary peristalsis - results from distention of
mixed with the digestive secretions of the
the esophagus
stomach and duodenum.
Motor Functions of the Esophagus
 Although chewing prolongs the subjective
 conduit that moves food from the pharynx to the
pleasure of taste, it does not appreciably
stomach
alter the rate at which food is digested and
 Innervation : vagus nerve
absorbed. On the other hand, attempting to
1. somatic fibers - striated muscles
swallow a large particle of food can lead to
2. visceral fibers (preganglionic
choking if the particle lodges over the trachea,
parasympathetic) – smooth m.
blocking the entry of air into the lungs.
 Sphincters:
1. UES – prevents the entry of air
The Chewing Reflex
2. LES – prevents the entry of gastric contents
Bolus of food → initiates reflex inhibition of muscle
GASTRIC MOTILITY
of mastication → allows the lower jaw to drop →
stretch reflex of the jaw muscles that lead to Functions of Gastric Motility
rebound contraction → raises the jaw to cause
1. The receipt of ingested material represents the
closure of the teeth → bolus of food
reservoir function of the stomach and occurs
DEGLUTITION (SWALLOWING)
as smooth muscle relaxes.
- occurs primarily in the proximal portion of
 A rigidly ordered sequence of events that propel
the stomach.
food from the mouth to the stomach
2. Ingested material is churned and altered to
 Initially voluntary, later, a reflex
a form that rapidly empties from the
 Swallowing center: medulla, lower pons (CN V, IX,
stomach through the pylorus and facilitates
X, XII)
normal jejunal digestion and absorption.
3. The antrum, pylorus, and proximal part of
Phases of Swallowing
the duodenum function as a single unit for
emptying into the duodenum the modified
1. Oral Phase (Voluntary)
gastric contents (“chyme”), consisting of
 food broken down, moistened to form a bolus
both partially digested food material and
that is moved toward the oropharynx
gastric secretions.
 accomplished by pressing food against the hard
palate with the tongue
Electrophysiology of the Stomach
2. Pharyngeal Phase  electrical rhythm of the stomach lasts 10x
 touch receptors in pharynx stimulated by food longer and does not overshoot.
to initiate swallowing reflex  produces gastric smooth muscle contraction
 occurs in <1 second when the depolarization exceeds the threshold
 respiration is inhibited for contraction.
 the greater the extent of depolarization and the
3. Esophageal phase longer the muscle cell remains depolarized
 respiration resumes above the threshold, the greater is the force of
a. Primary peristalsis contraction.
b. Secondary peristalsis – frequently
repetitive Regulation of Gastric Contractions
1. Endocrine
Note: Swallowing induces relaxation (receptive
 stimulate gastric contractility
relaxation) of LES and proximal stomach
Substance P
Gastrin
ESOPHAGEAL MOTILITY
 inhibits gastric contractility
Esophagus Norepinephrine
 18 - 26 cm hollow muscular tube 2. Neurocrine
 lined with a stratified squamous epithelium a. Extrinsic Neurons
Parasympathetic NS - vagus
 no serosa
 excitatory to gastric smooth muscle
motility and gastric secretions
Parts:
Sympathetic NS - celiac plexus;
 Upper 1/3 – striated muscles  inhibitory
 Middle 1/3 – striated & smooth muscle b. Intrinsic Neurons
 Lower 1/3 – smooth muscle Neurons of ENS produce
acetylcholine and substance P

which are stimulatory to gastric

contractions. C. Retropulsion - particles larger than 2 mm are
propelled back into the body of the stomach for
Gastric Filling and Accomodation pulverization and shearing.
 Gastric accommodation is the active dilatation
of the fundus
 Receptive relaxation of the fundus and body
occurs after the relaxation of LES
 The stomach can receive volume as large as 1.5
liters without an increase in intragastric pressure
 Relaxation in the fundus is primarily regulated by
 Propulsion, grinding, and retroplusion are
a vagovagal reflex.
repeated multiple times until the gastric
 Vagotomy abolishes a major portion of gastric
contents are emptied.
accommodation, so increases in intragastric
 Particles larger than 2 mm are initially
volume produce greater increases in intragastric
retained into the stomach but are eventually
pressure.
emptied into the duodenum by migrating
myoelectric complexes during the
Mixing and Emptying of Gastric Contents
interdigestive period that begins two hours or
 When food enters the stomach, they settle in the more after eating.
fundus and body.
 The muscle layers in the fundus and body are Functions of the Gastroduodenal Junction
thin; As a result, the contents of the fundus and
the body settle into layers based on the density 1. allows the carefully regulated emptying of
of the contents. gastric contents at a rate consistent with the
 Gastric contractions begin in the middle of the ability of the duodenum to process the chyme.
body of the stomach and travel toward the 2. prevents regurgitation of the duodenal contents
pylorus. They increase in force and velocity as back into the stomach.
they approach the gastroduodenal junction, and
emptied into the duodenal bulb. Regulation of Gastric Emptying
1. Liquids flow around the mass of food 1. Extrinsic Neurons

contained in the body of the stomach and a. Parasympathetic NS - both excitatory &
are emptied more rapidly into the inhibitory to the pyloric sphincter
duodenum. b. Sympathetic NS - stimulates constriction of
a. Water and isotonic saline are the the pyloric sphincter
substances most rapidly emptied.
b. Acidic and caloric fluids are emptied 2. Intrinsic Neurons - ENS
more slowly. a. Ach - stimulates constriction of the pyloric
2. Fats tend to form an oily layer on top of the sphincter
other gastric contents. They are emptied b. VIP - inhibit constriction of the pyloric
later than are the other gastric contents. sphincter
3. Solids do not leave the stomach as such. c. NO - inhibit constriction of the pyloric
They must first be reduced in size (< 2mm). sphincter
4. Large (> 2 mm) or indigestible particles
cannot pass through the pyloric ring. They 3. Hormones – stimulate constriction of the pyloric
are retained in the stomach for even longer sphincter
periods. a. cholecystokinin (CCK)
b. gastrin
Mechanical Actions of Stomach and its Content c. gastric inhibitory peptide (GIP)
d. secretin
A. Propulsion - movement of solid particles
toward the antrum that is accomplished by
Gastric Emptying is slowed by
the interaction of propulsive gastric contractions
and occlusion of the pylorus. 1. Duodenal pH < 3.5 - acid in the duodenum
releases secretin  inhibits antral
contraction + stimulates contraction of the
pyloric sphincter
2. Fatty acids or monoglycerides in the duodenum
B. Grinding – churning of a bolus of material is  release of CCK and GIP from the duodenum
trapped near the antrum to help reduce the size and jejunum  decrease gastric emptying
of the particles 3. Hypertonic solutions in the duodenum
 hyperosmotic solutions in the duodenum
and jejunum  release an unidentified
hormone  slows rate of gastric emptying

4. Amino acids and peptides in the duodenum -  effectively mixes chyme with digestive
release: secretions.
a. gastrin - increases the strength of antral  regulated by neural pathways (ENS) and
contractions + constriction of pyloric hormonal mediators (CCK)
sphincter
b. CCK - constrict pyloric sphincter
c. GIP - constrict pyloric sphincter
Segmentation
2. Peristalsis
 progressive contraction of successive
sections of circular smooth muscle.
 moves along the GI tract in an orthograde
direction.
 occurs in the small intestines but usually
Control of Gastric Emptying involves only a short length of small
intestines.
SMALL INTESTINAL MOTILITY  regulated by neural and hormonal controls:
(a) released orad to a site of intestinal
Functions of Small Intestinal (SI) Motility distention - stimulatory
Acetylcholine
1. serves to mix chyme with digestive secretions. Substance P
2. brings chyme into contact with the absorptive (b) released caudad to a site of
surface of the microvilli, intestinal distention; inhibitory:
3. propels chyme toward the colon. VIP
Nitric oxide
Basic Electrical Rhythm of the Duodenal Bulb
MIGRATING MYOELECTRIC COMPLEX
 10-13 slow waves /minute
 The basic electrical rhythm (BER) of the  In the fasting state, the small intestine is
duodenal bulb is influenced by the BER of relatively quiescent but exhibits synchronized,
both the stomach and the postbulbar rhythmic changes in both electrical and motor
duodenum. activity.
 The duodenal bulb contracts irregularly. The  consists of bursts of intense electrical and
contractions of the antrum and duodenum contractile activity of the stomach and small
are coordinated: when the antrum intestine in the fasting state
contracts, the duodenal bulb relaxes.  more propulsive than in the fed state
 repeats every 75-90 minutes unless a meal is
Electrophysiology of the SI Muscle ingested, in which case the migarting
myoelectric comples (MMC) is suspended
 The BER of the smooth muscles of the small  housekeeper of the small intestines
intestines occurs regularly.
 It is highest in the duodenum and declines Phases of MMC
along the length of the small intestines.
 Duodenum - 10-13 slow waves/minute 1. Prolonged quiescent period
 Terminal ileum –8-9 slow waves/minute 2. Period of increasing action potential frequency
 Regulation: The BER of the small intestinal and contractility
smooth muscle is entirely intrinsic but the 3. Period of peak electrical and mechanical activity
autonomic nervous system modulates  lasts about 10 minutes
contractile activity.  large contractions that propagate along the
length of the intestines are stimulated by
Types of Movement of the Small Intestine motilin and sweep any remaining gastric
and intestinal contents out into the colon
1. Segmentation  pylorus and ileocecal valve open fully during
 most frequent type this phase, so even large undigested items
 characterized by closely spaced contraction of can eventually pass.
the circular muscle layer. 4. Period of declining activity that merges into the
 divides the small intestines into small next quiescent period
neighboring segments.

Motilin - a 22-amino-acid peptide synthesized  In contrast, the longitudinal muscle of the

in duodenal mucosa and released just before the rectum and anal canal is substantial and
initiation of phase 3 of the MMC cycle continuous.
 After a meal motilin levels fall and the MMC
cannot be resumed until they rise again. Functions of the Large Intestine
1. reabsorbs remaining fluid and electrolytes

that were used during movement of the meal
along the GIT. It converts the liquid content of
Ileocecal materials to solid and semi-solid
stool containing only about 50-100 ml of
water per day
2. digests and absorbs the components of the
meal that cannot be digested and absorbed
more proximally
3. avidly absorbs the short chain-fatty acids
formed by the catabolism (or fermentation) of
. Phases of Migrating Myoelectric Complex dietary carbohydrates that are not absorbed
in the small intestines
Reflex Control SI Motility 4. communicates with other GI segments to
optimally integrate function (ie.gastrocolic
 Law of the intestine - when a bolus of reflex)
material is placed in the small intestines, the 5. serves as a reservoir. It stores the waste
intestines typically contract behind the bolus products of the meal
and relax ahead of it. This action propels the 6. eliminates its contents in a regulated and
bolus in an orthograde direction. controlled fashion, largely under voluntary control
 Intestinointestinal reflex – overdistention of
one segment of the intestine relaxes the Functional Parts of the Large Intestine
smooth muscle in the rest of the intestine
 Gastroileal reflex, increased motor and 1. Proximal part
secretory activities in the stomach increase the  cecum, ascending colon, transverse colon
motility of the terminal part of the ileum and  where most of the fluid and electrolyte
accelerate the movement of material through absorption occurs
the ileocecal sphincter.  where bacterial fermentation takes place
2. Distal part
Emptying of the Ileum  descending colon and rectosigmoid
 provides final dessication
 The ileocecal sphincter valve separates the  serves as storage organ for colonic material
terminal end of the ileum from the cecum. before defecation
Normally this valve is closed.
 Distention of the distal ileum promotes Electrophysiology of the Colon
peristalsis in the ileum and thus the opening of
the ileocecal sphincter. 1. Circular Muscle
 Ileal emptying occurs at a rate that allows the Types of interstitial cells of colon
colon to absorb most of the salts water in the a. Those near inner border of the circular
chyme. muscle layer - produce 6-8 slow waves /
minute, high amplitude
b. Those near the outer border of the
LARGE INTESTINAL MOTILITY circular muscle layer
Parts of the Large Intestine  produce myenteric potential oscillations
 higher frequency, low amplitude
1. ascending colon  The circular muscle layer of the colon does
2. transverse colon not usually fire action potentials.
3. descending colon  Acetylcholine enhances contractions by
4. sigmoid colon increasing the duration of some of the slow
5. rectum waves.
6. anus
2. Longitudinal Muscle - fires AP at the peaks of
 The longitudinal muscle layer of the muscularis the myenteric potential oscillations.
externa is concentrated into three bands called
taenia coli. Regulation of Large Intestinal Motility
 The longitudinal muscle layer between the taenia
coli is thin. 1. Extrinsic Neurons - modulates the control of
colonic motility by the ENS (except defecation
reflex)

a. Parasympathetic NS: small intestinal transit times are

Vagus nerve - causes segmental relatively constant in healthy adults, the
contractions of proximal colon contents may be retained in the large
intestines anywhere from hours to days
Pelvic nerve - causes expulsive movements
without significant dysfunction.
of the distal colon and sustained
contractions of some segments.
Reflex Control of Large Intestinal
b. Sympathetic NS – inhibits colonic moveme Motility
 Colonocolonic reflex - distention of one
2. Intrinsic Neurons part of the colon causes a relaxation in other
ENS - directly controls the contractile behavior parts of the colon . Partly mediated by the
of the colon sympathetic fibers.
Acetylcholine stimulatory  Gastrocolic reflex - after a meal enters
Substance P the stomach, there is an increase in the
VIP motility of proximal and distal colon and the
Nitric oxide inhibitory frequency of mass movements. This reflex
depends on the autonomic innervation to
Types of Movements of the Large Intestine the colon, hormones such as CCK and
gastrin may also be involved.
1. Short-duration contraction  Orthocolic reflex is activated on rising
 It originates in the circular muscle. from bed and promotes a morning urge to
 stationary pressure waves that persist defecate.
for 8 seconds
RECTUM AND ANAL CANAL
2. Long-duration contraction
 It is produced by the taeniae coli. DEFECATION REFLEX
 It lasts for 20-60 seconds.  expulsion of indigestible residues from the GI
 It may propagate over short distances. tract.
 The propagation may move orally as  both a reflex and a voluntary action.
well as aborally, particularly in the more  Stimulus: rectal filling
proximal segments of the colon.  Reflex center: sacral spinal cord
 Innervation :
 The BER that governs the rate and  Parasympathetic (pelvic nerve) - relaxation of the
origination sites of smooth muscle internal anal sphincter
contraction in the small intestine does  Skeletal motor nerve – voluntary action;
not traverse the ileocecal valve to relaxation of the external anal sphincter
continue in the colon.  Note: The role of the sympathetic nervous
 The two predominant motility system is not significant in normal defecation.
patterns of the large intestine are  The rectum is usually empty.
directed not to propulsion of the colonic  The anal canal is kept tightly closed by the anal
contents but rather to mixing of the sphincters. Just before defecation a mass
contents and retarding their movement, movement in the sigmoid causes the rectum to
thereby providing them with ample time fill.
in contact with the epithelium. Both these  Distention of the rectum with feces initiates the
patterns originate largely in response to rectosphincteric reflex by relaxing the internal
local conditions, such as distention. anal sphincter via the release of VIP and the
generation of nitric oxide.
2. “High-amplitude propagating contraction”  Relaxation of the internal anal sphincter permits
 It is a motility pattern that is of high the anal sampling mechanism which can
intensity distinguish whether the rectal contents re solid,
 It produces mass movement of liquid, or gaseous in nature.
feces exclusively in an aboral  After toilet training, sensory nerve endings in the
direction, along the length of the anal mucosa then generate reflexes that initiate
large intestine from the cecum to appropriate activity of the external anal sphincter
the rectum. to either retain the rectal contents or permit
 It is designed to clear the colon of its voluntary expulsion (e.g. flatus).
contents. However, although such  If defecation is not desired, continence is
motility pattern can clearly be associated maintained by an involuntary reflex – via the
with defecation, it does not necessarily spinal cord - that contracts the external anal
result in defecation. sphincter.
 It occurs approximately 10x/day in  If defecation is desired, a series of both voluntary
healthy individuals. and involuntary events occurs that include the
 There is considerable variability among voluntary relaxation of the external anal
individuals with respect to the rate at sphincter.
which colonic contents are transported
from the cecum to the rectum. Although
 Evacuation is preceded by deep breath which  increased blood flow, increased metabolism (both
moves the diaphragm downward. The glottis are proportional to saliva formation)
then closes, and contractions of the respiratory
muscles on full lungs elevate both intrathoracic Neural Control of Salivary Secretion
and intrabdominal pressures.
1. Parasympathetic NS
 primary neural control
 Contractions of abdominal wall muscles further
 salivatory nuclei CN 7 & 9
increase intraabdominal pressure. The increase in
 stronger, long-lasting effects
pressure helps to force feces through the relaxed
 affects both acinus and ducts
sphincters.
Effects:
 Adoption of a sitting or squatting position alters a. ↑ synthesis of amylase & mucins
the relative orientation of the intestines and b. contraction of myoepithelial cells
surrounding muscular structures by straightening c. enhances transport activities of ductular
the path for the exit of feces. epithelium
d. ↑ blood flow (ACH and VIP cause
 After voluntary relaxation of the external anal vasodilatation)
sphincter, rectal contractions move the feces out e. stimulates metabolism & growth
of the body,
2. Sympathetic NS
 superior cervical ganglion
 If a delay in defecation is needed or desired,
 travels along the surfaces of blood vessel wall
voluntary contraction of the external anal
to the salivary glands
sphincter is usually sufficient to override the
 slight increase in salivary secretions
series of reflexes initiated by rectal distention.
STOMACH
GASTROINTESTINAL SECRETION Glandular Regions of the Stomach
1. Cardiac glandular region

SALIVARY GLANDS
 surface epithelial cells (HCO3-)
Types of Salivary Glands
 mucus neck cells (mucus)
1. Parotid – serous secretions 2. Oxyntic glandular region
2. Sublingual – mainly mucous  surface epithelial cells (HCO3-)
3. Submandibular – mixed  mucus neck cells (mucus)
4. Buccal glands – mucus only  parietal cells (HCl, intrinsic factor)
 chief cells (pepsinogen)
Major Types of Salivary Secretions  ECL cells (histamine)
1. Serous secretion (ptyalin or α amylase) –  D cells (somatostatin)
digesting starches 3. Pyloric glandular region
2. Mucus secretion (mucin) – lubricating and  surface epithelial cell (HCO3-)
surface protective purposes  mucus neck cells (mucus)
 chief cells (pepsinogen)
Functions of Saliva  G cells (gastrin)
1. maintaining healthy oral tissues  D cells (somatostatin)
2. digestion
3. neutralization of refluxed gastric contents
4. mucosal growth and protection of the GI tract
 The final salivary secretion is hypotonic, slightly
alkaline
 Salivary amylase works best at a neutral pH.
 large salivary flow rate, low osmolality, high
potassium
Composition of Saliva
1. Proteins/Enzymes (amylase/lipase) Functional Parts of the Stomach
2. Glycoproteins (mucin)
3. Lysozymes Ionic Composition of Gastric Juice
4. Electrolytes (Na, K, HCO3, Ca, Mg, Cl-, Flouride)
5. Water  the higher the rate of secretion, the higher the
[H+]
Metabolism & Blood Flow of Salivary Glands  at high flow rates, Na decreases H increases
 maximal rate of saliva production 1 mL/min/g of  at high flow rates, approaches isotonic HCl
gland  K+ always > than in plasma

 Cl- is major anion 2. Gastrin

 H+ & Cl- secreted against electro-chemical  an endocrine agonist
gradient  produced by G cells in the mucosa of the
antrum
 Mechanism:
 binds to CCK-B receptors to elevate
intracellular concentration of Ca++
 activating basolateral K+ channels to
hyperpolarize cell  causing more
H+K+ATPase & Cl- channels to be
inserted into the apical membrane.
3. Histamine
 paracrine agonist
 produced by ECL cells when stimulated by
Ionic Composition of Gastric Acid Juice gastrin
 strongest agonist of HCl secretion
GASTRIC ACID SECRETION  Mechanism:
 binds to H2 receptors on parietal cells
 Basal rate of secretion: 1-5 mEq/hr plasma membranes hence:
 Maximal rate of secretion: 6-40 mEq/hr  activating adenyl cyclase and elevating
 Parietal cell release acid at pH 1- 2 the cytosolic concentration of cAMP:
 The parietal cells release acid against a  activating basolateral K+ channels 
concentration gradient (pH7 in the parietal hyperpolarizes cell, activating apical Cl-
cytosol, pH1 in the lumen of the gastric gland). channels  causing more H+,K+ATPase
 Cl- enters the gastric lumen against both molecules and Cl- channels to be
chemical and electrical potential differences. inserted in the apical plasma membrane
 H+ and Cl- are actively transported (energy-
requiring) by separate pumps in parietal cells Endogenous Antagonists of Acid Secretion
against gradient.
 H+K+-ATPase - primary H+ pump; - exchanges 1. Somatostatin
H+ for K+  released by D cells near the bases of the
 Cl-,HCO3- countertransporter - mediates HCO3- gastric glands. D cells are found both in the
efflux out of the parietal cell across its basolateral corpus and the antrum
membrane.  most important antagonist of HCl secretion
2. Prostaglandin E & I
Mechanism: It inhibits parietal cell HCl
secretion
Misoprostol – prostaglandin analogue
3. Epidermal Growth Factor
Mechanism: It stimulates Gαi - inhibit adenylyl
cyclase hence suppressing HCl secretion by
parietal cells.
Phases of Gastric Acid Secretion

1. Basal / Interdigestive Phase
Control of Gastric Acid Secretion  rate of acid secretion between meals is low
Agonists of Gastric Acid Secretion  follows a circadian rhythm: acid secretion is
lowest in the morning before awakening and
1. Acetylcholine highest in the evening.
 a neurocrine agonist  Acid secretion is a direct function of thr
 released by cholinergic nerve terminals number of parietal cells.
 Mechanism:
 The number of parietal cells is influenced,
binds to M3 muscarinic receptors and
at least in part; by body weight.
opens Ca++ channels in the apical
membrane hence activating the  Men have higher rates of basal acid secretion
phospholipase C pathway. This leads to than women.
elevation of intracellular Ca++  Considerable variability in basal acid secretion
concentration which enhances HCl is also seen among normal individuals.
secretion by:  Resting intragastric pH = 3 - 7 Basal
(a) activation of basolateral K+ channels (unstimulated) rate of secretion: 1 – 5
 causing more H+ and K+ATPase mEq/hour
molecules and Cl- channels to be  Maximal rate of secretion : 6 – 40 mEq/hr
inserted into the apical plasma
membrane 2. Cephalic phase
(b) inhibits release of somatostatin by  elicited by the sight, smell, and taste of
D cells food
 accounts for 30% of acid secreted 4. Intestinal Phase

a. Vagus nerve
 mediates the cephalic phase. It
stimulates the enteric NS.
 Acetylcholine - directly stimulates
parietal cell to secrete HCl
 directly stimulates release of
gastrin from G cells and histamine
from ECL cells.
b. Others:
 low glucose level
 neuropeptides in the brain
 The cephalic phase is self-regulated: low pH in
the gastric lumen inhibits HCl secretion by Intestinal Phase of Gastric Acid Secretion
parietal cells
a. Stimulation
3. Gastric Phase  when gastric lumen pH 3
 elicited by the presence of food in the  duodenal distension  vagovagal
stomach. reflexes  stimulate parietal and
 accounts for 50-60% of acid secreted antral G cells
 Amino acids and peptides - stimulate
Stimuli: duodenal & jejunal G cells  release
a. Gastric distention gastrin
 stimulates cholinergic mechanoreceptors in  release of entero-oxyntin which
the gastric wall released onto the parietal stimulates HCl secretion
cells which directly stimulates them to
secrete HCl, and onto antral G cells, which b. Inhibition
are stimulated to release gastrin.
 acid (pH<3) in the antrum of the
b. Amino acid (tryptophan,phenylanlanine),
stomach
peptides
 acid in duodenum – inhibits parietal cell
 stimulates gastrin release from antral
release of HCl
G cells
c. Others : Ca++, caffeine, alcohol - effects are  fat digestion products - release
enhanced by gastric distension hormones that inhibit acid secretion by
parietal cells
 Once the buffering capacity of the gastric  Hyperosmotic solutions in the duodenum -
contents is saturated, gastric pH falls rapidly release enterogastrones that inhibit
and inhibits further acid release. In this way, gastric acid secretion
the acidity of gastric contents regulates
itself PEPSINOGEN
 major digestive constituent of gastric secretion
 stored in cytoplasm inside zymogen granules in
chief cells and released by exocytosis
 secreted as an inactive proenzyme converted to
pepsin by:
1. cleavage of linkages by HCl
2. Pepsin - acts proteolytically (pH<3) on
pepsinogens to form more pepsins
 initiates protein digestion by splitting certain
amino acid linkages in proteins to create short
amino acid chains.
 may digest 20% of the protein in a typical meal
 inactivated by neutral pH of duodenum
Gastric Phase of Gastric Acid Secretion
Agonists of Pepsinogen Secretion
 Most agents that stimulate gastric acid secretion
also release pepsinogen from chief cells
1. Acetylcholine
2. Gastrin
3. HCl
4. Secretin
5. CCK

INTRINSIC FACTOR 2. Exocrine pancreas

 a glycoprotein secreted by the parietal cells in - secretes pancreatic juice
response to the same stimuli that elicit HCl
- contains microscopic, blind-ended tubules that
are surrounded by polygonal acinar cells and
secretion
are organized into lobules (acini) which drain
 needed for absorption of vitamin B12 in the
into intercalated ducts  intralobular ducts 
terminal ileum
 Intrinsic factor secretion is the only gastric extralobular ducts  main pancreatic duct
function that is essential to life.  Both neural and hormonal signals control
pancreatic exocrine secretion
Pernicious anemia – a condition wherein the  Innervation:
erythrocyte production is defective caused by parasympathetic NS – stimulation
autoimmune attack against parietal cell sympathetic NS – inhibition
PANCREATIC JUICE
MUCUS Components of Pancreatic Juice
secretion that contains the glycoprotein mucin. 1. Aqueous component
 a tetramer linked together by disulfide bonds, It  secreted by the epithelial cells of the ducts
is 80% carbohydrates. of the pancreas.
 subject to proteolysis by pepsins.  nearly isotonic to plasma at all flow rates
 secreted by mucus neck cells located in the necks  Na+ and K+ - similar to those in plasma
of gastric glands and surface epithelial cells of  HCO3- - above those in plasma major
the stomach. anions
 secretion is stimulated by acetylcholine.  Cl- - vary reciprocally w/ HCO3-
 protects gastric mucosa:  serves to buffer HCl-
 lubricating property  HCO3- in the blood is the major source of
 inhibits pepsin the HCO3- secreted into the lumen of the
 alkalinity protects against self-digestion extralobular duct.
 Stimulated by secretin
BICARBONATE
 The gastric epithelial cells secrete a
watery fluid that contains HCO3- that is
higher in amount than plasma making the
mucus layer alkaline
 Stimulus : acetylcholine
Gastric Mucosal Barrier

 the protective mucus gel layer that forms on
the luminal surface of the stomach
Feedback Loop that Responds to a Fall in
 0.2mm thick
 separates the HCO3- -rich secretions of the pH in the Duodenum
epithelium from the acidic contents of the 2. Enzyme component
gastric lumen.  secreted by the acinar cells of the pancreas
 allows the pH of the epithelium to be  for digestion of food.
maintained at nearly neutral pH despite a  Stimulated bv CCK.
luminal pH 2.  CCK is the product of I cells of the small
 slows the diffusion of HCl & pepsin to the intestinal epithelium. Its release is regulated
epithelial cells. by:
a. Amino acids, fatty acids
Aspirin, NSAIDs - inhibit secretion of both mucus & b. Releasing factor - CCK-releasing factor
HC03-can cause gastritis and gastric ulcer or peptide (CCK-RP) – secreted by
Adrenergic agonists - diminish HCO3- secretion; can paracrine cells within the epithelium into
cause stress ulcers the SI lumen
PANCREAS
 The pancreas weighs < 100 grams , secretes 1
kg/day of pancreatic juice.
1. Endocrine pancreas – Islet of Langerhans. It

secretes
a. insulin
b. glucagon
c. somatostatin
d. pancreatic polypeptide
CCK- Induced Pancreatic Acinar Cell Secretion
2. Brush border digestion

GASTROINTESTINAL
 disaccharides are hydrolyzed to their
DIGESTION AND ABSORPTION component monomers through brush border
digestion
 mediated by a family of membrane-bound,
CARBOHYDRATE ASSIMILATION heavily glycosylated hydrolytic enzymes
synthesized by SI epithelial cells.
 The small intestine is critical not only for
absorption of macronutrients into the body but
also for the final stages of digestion into
molecules that are simple enough to be
transported across the intestinal epithelium.
 Phases of Carbohydrate Digestion
1. Luminal - in the lumen of the SI

2. Brush border digestion – surface of
enterocytes
 Molecular Classes of Dietary

Carbohydrates
1. Starch - mixture of both straight-chain

(amylose) and branched-chain
(amylopectin) polymers of glucose. ABSORPTION OF CARBOHYDRATES
2. Dietary fiber – consists of carbohydrate
polymers that cannot be digested by human  Water soluble monosaccharides resulting from
enzymes. These polymers are digested by digestion must be transported across the plasma
colonic bacteria, allowing salvage of their membrane.
caloric value.  Sodium/glucose transporter 1 (SGLT 1) – a
3. Disaccharides symporter that takes up glucose and galactose
a. Sucrose - glucose + fructose against its concentration gradient by coupling its
b. Lactose – glucose + galactose transport to that of Na+.
 GLUT 5 - transport protein through which
DIGESTION OF CARBOHYDRATES fructose is taken across the apical membrane.
 GLUT 2 – transport protein through which
1. Luminal glucose, galactose, and fructose exit the cell via
a. Salivary amylase the basolateral membrane.
 Starch digestion is initiated in the oral
cavity via salivary amylase.
 Salivary amylase, however, is not
essential for starch digestion (except in
neonates or in patients whom the output
of pancreatic enzymes is impaired by
disease).
b. Pancreatic amylase
 most significant contributor to the
luminal digestion of starch
 Both salivary and pancreatic amylase
hydrolyze internal α1,4 bonds in both Absorption of Glucose, Galactose, and Fructose
amylose and amylopectin but not in the Small Intestine
external bonds nor the α 1,6 bonds that
form the branch points in the
amylopectin molecule PROTEIN ASSIMILATION
A. D segmentation
 Proteins are water soluble polymers that must be
 igestion of starch by amylase is
digested into their smaller constituents before
incomplete and results in glucose
absorption is possible.
oligomers including dimers (maltose),
 Their absorption is more complicated than that of
trimers (maltotriose), and α limit
carbohydrates because they contain 20 different
dextrins, the simplest branching structure
amino acids and short oligomers of these amino
 to allow absorption of its constituent
acids (dipeptides, tripeptides, and perhaps even
monosaccharides, starch must also
tetrapepides) can also be transported by
undergo brush border digestion
enterocytes.

 The liver has substantial ability to interconvert their C-terminal and thus are resistant to
various amino acids subject to the body’s needs. carboxypeptidase A or B.
 Essential amino acids – amino acids that cannot
be synthesized by the body either de novo or 3RD PHASE
from other amino acids and thus must be  takes place at the brush border.
obtained from the diet.  mature enterocytes express a variety of
peptidases on their brush borders including both
DIGESTION OF PROTEINS aminopeptidases and carboxypeptidase that
 Proteins can be hydrolyzed to long peptides generate products suitable for uptake across the
simply by virtue of the acidic pH that exists in the apical membrane.
gastric lumen.  SI can take up not only single amino acids
but also peptides.
Phases of Protein Assimilation  peptides that are taken up into the enterocytes in
their intact form are then subjected to a final
1ST PHASE stage of digestion in the cytosol of the
 occurs in the gastric lumen, mediated by pepsin. enterocyte to liberate their constituent amino
 pepsinogen - in acidic pH, is autocatalytically acids for use in the cell or elsewhere in the body.
cleaved to pepsin.
 pepsin cleaves proteins at sites of neutral ABSORPTION OF PROTEINS
amino acids, with preference for aromatic or  Peptide transporter 1 (PepT1) – primary
large aliphatic side chains. transporter responsible for uptake of products
 pepsin is not capable of digesting protein fully of protein digestion. It is a proton-coupled
into a form that can be absorbed by the symporter that carries peptides in conjunction
intestines with proteins.
 yields a mixture of intact protein, large peptides  Peptides taken up into enterocytes are then
and a limited number of free amino acids. immediately hydrolyzed by a series of cytosolic
peptidases into their constituent amino acids.
 Amino acids not required by the enterocyte are
2ND PHASE in turn exported across the basolateral
 occurs in the lumen of the small intestine, membrane and enter blood capillaries to be
mediated by proteases of pancreatic juice. transported to the liver via the portal system.
 these enzymes are secreted in the inactive forms.
Their activation is delayed until they are in the
lumen by virtue of the localized presence of an
activating enzyme, enterokinase, only on the
brush border of small intestinal epithelial cells.
Uptake of Peptides and Amino Acids

by Enterocytes
Activation of Pancreatic Proteases
 Enterokinase – cleaves trypsinogen to yield active LIPID ASSIMILATION

trypsin
 Trypsin - cleaves all the other protease Forms of Lipids
precursors secreted by the pancreas 1. Dietary:
 Chymotrypsin & Elastase – are also a. triglycerides – predominant form of lipid in
endopeptidases, similar mechanism of action as the human diet. Majority of these have long-
trypsin but cleave at sites of neutral amino acids. chain fatty acids ( carbon chains > 12
 Carboxypeptidase A / B – are ectopeptidases. carbons) esterifed to the glycerol backbone.
They act on the peptides that result from b. phospholipids
endopeptidase activity. They cleave single amino c. cholesterol
acids from the end of a peptide chain of neutral 2. Lipids from bile – exceeds cholesterol from diet
(carboxypeptidase A) or basic (carboxypeptidase 3. Fat-soluble vitamins A, D, E, K
B) amino acids situated at the C-terminal.
 The products that result after digestion of a
protein meal by gastric and pancreatic secretions
include neutral and basic amino acids, as well as
short peptides that have acidic amino acids at
EMULSIFICATION AND SOLUBILIZATION OF the portal circulation, the products of lipolysis are
LIPIDS reesterified in the endoplasmic reticulum (ER) of
 When a fatty meal is ingested, the lipid enterocyte to form triglycerides, phospholipids,
becomes liquefied at body temperature and and cholesterol esters.
floats on the surface of the gastric contents.  Concurrently, the enterocyte synthesizes a series
 an early stage in the assimilation of lipids is of proteins known as apolipoproteins in the rough
emulsification. The mixing action of the ER. These proteins are then combined with the
stomach churns the dietary lipid into a re-synthesized lipids to form chylomicrons
suspension of fine droplets, which vastly  chylomicrons consist of a lipid core
increases the surface area of the lipid phase. (predominantly triglyceride, much less
cholesterol, phospholipid, and fat-soluble
DIGESTION OF LIPIDS vitamins) coated by apolipoproteins.
 It begins in the stomach via the action of  chylomicrons are then exported from the
gastric lipase. enterocyte through exocytosis then taken up into
 Gastric lipase is released in large quantities the lymphatics and bloodstream.
from gastric chief cells. It adsorbs to the
surface of fat droplets dispersed in the gastric
contents and hydrolyzes component
triglycerides to diglycerides and free fatty acids
(FFAs).
 Little lipid assimilation takes place in the
stomach because of acidic pH
 Majority of lipolysis occurs in the small
intestines.
 Pancreatic lipolytic enzymes:
1. Pancreatic lipase -
 capable of hydrolyzing both 1 and 2
positions of triglyceride to yield large
quantities of FFAs and monoglycerides.
 lipase activity is sustained by a cofactor,
colipase, which is a bridging molecule
that binds to both bile acids and to
lipase. It anchors lipase to the oil droplet Products of Fat Digestion by Lipase are held in
even in the presence of bile acids Solution in the Micellar State
2. Phospholipase A2 - hydrolyzes phospholipids
secreted as an inactive pro-form that is
activated only when it reaches the small
intestines.
3. Cholesterol esterases – break down esters
of cholesterol and fat-soluble vitamins and
triglycerides.
 this enzyme requires bile acids for
activity and is related to an enzyme
produced in breast milk that plays an
important role in lipolysis in neonates.
 as lipolysis proceeds, the products are abstracted
from the lipid droplet, first into a lamellar or
membrane phase and subsequently into mixed
micelles composed of lipolytic products and bile
acids.
 the amphiphatic (both having a hydrophobic and
hydrophilic face) bile acids serve to shield the
hydrophobic regions of lipolytic products from Fat Absorption Across Walls of Small Intestine
water while presenting their own hydrophilic
faces to the aqueous environment.
 Micelles increase the solubility of lipid in the WATER AND ELECTROLYTE
intestinal contents. They increase the rate at SECRETION AND ABSORPTION
which molecules such as fatty acids can diffuse
to the absorptive epithelial surface.  The fluidity of intestinal contents, especially in
the small intestine, is important in allowing the
ABSORPTION OF LIPIDS meal to be propelled along the length of the
 The products of fat digestion are capable of intestine and to permit digested nutrients to
crossing cell membrane readily because of their diffuse to thie site of absorption.
lipophilicity.
 Unlike monosaccharides and amino acids, which
leave the enterocyte in molecular form and enter
SECRETION OF WATER & ELECTROLYTES

 Dietary fluid intake ~ 2 Liters/day
Lumen Blood
 Total amount of fluid secreted by the GI tract
and its accessory organs = 8 L/day
 Saliva - 1500 ml.day
 Gastric secretions - 2500 ml.day
 Bile - 500 ml.day
 Pancreatic juices - 1500 ml/day
 Intetsinal secretions - 1000 ml/day
 Total amount of fluid for absorption by the SI
~9 L/day (99%)
 Total amount of fluid passed onto the LI ~ 2 L
 Total amount of fluid lost in the feces = 100 -
200 ml/day
ABSORPTION OF WATER & ELECTROLYTES

 During the postprandial period, absorption of Mechanism of Cl- Secretion
fluid is promoted in the small intestines Small Intestine and Colon
predominantly via the osmotic effects of nutrient
absorption.  Some segments of intestine may engage in
 an osmotic gradient is established across the additional secretory mechanisms such as
intestinal epithelium that simultaneously drives secretion of HCO3- ions
the movement of water across the tight  This local HCO3- protects the epithelium,
junctions. particularly in the most proximal portions of the
 in the period between meals, when nutrients are duodenum immediately downstream from the
absent, fluid absorption can still occur via the pylorus, from the damage caused by acid and
coupled uptake of Na+ and Cl- mediated by Na+ pepsin.
H+ antiporter and Cl-HCO3- antiporter.
Lumen Blood
Lumen Blood
Mechanism of HCO3- Secretion in

Mechanism of NaCl Absorption the Duodenum
in the Small Intestine
Changes that represent the intestinal phase of
the response to meal
SECRETION OF WATER & ELECTROLYTES 1. increased pancreatic secretion
 Secretion of water and electrolyte is regulated in 2. increased gallbladder contraction
response to signals derived from the 3. relaxation of the sphincter Oddi
 luminal contents , and/or 4. regulation of gastric emptying
 deformation of the mucosa or intestinal 5. inhibition of gastric acid secretion
distention 6. interruption of the migrating myoelectric
 Secretagogues: Ach, VIP, prostaglandins, complex (MMC)
serotonin
 Secretion makes sure that the intestinal contents
are appropriately fluid while digestion and HEPATOBILIARY PHYSIOLOGY
absorption are still ongoing and may be LIVER
important to lubricate the passage of food
particles along the length of the intestine. Structural Features of the Liver
 The majority of the intestinal secretory flow of  largest organ of the body
fluid into the lumen is driven by the active  2% total body weight
secretion of Cl- ions.  Hepatocyte – major cell type
 Hepatic lobule
 functional unit of liver; human liver contains 5. Stellate cells

50,000-100,000 individual lobules  serves as storage sites for retinoids
 composed of hepatocytes arranged in plates  source of key growth factors for hepatocytes
that radiate from the central vein like spokes  site of synthesis of excessive collagen during
in a wheel. disease states  hepatic fibrosis  cirrhosis
Hepatic Sinusoids
Hepatic Lobule Hepatic Vascular and Lymph System
Hepatic portal vein – drains into liver from small

Hepatic / Portal Triad intestine
 consists of (HaPv Bday) Hepatic arteries – bring oxygenated blood to liver
1. Hepatic artery from descending aorta.
2. Hepatic portal vein Central veins – drain the lobules and merge to form
3. Bile duct the hepatic veins into vena cava
Hepatic Sinusoids 1. High blood flow and low vascular resistance

 capillaries that are surrounded by hepatocytes  1050 mL of blood that flows from portal vein
supplied by branches of both portal vein and into liver sinusoids/minute + 300 mL of
hepatic artery. Nutrients and other substances blood that flows into sinusoids from the
present are taken up by hepatocytes hepatic artery each minute = 1350 mL/min
or 27% resting cardiac output
Features of Hepatic Sinusoids  resistance to blood flow through the hepatic
1. Low resistance cavities sinusoids low (9 mmHg)
 blood flow through liver can increase 2. Blood reservoir
considerably without concomitant increase in  liver is a large expandable venous organ
pressure.  Its normal blood volume including that in
 during fasting, many sinusoids are collapsed. hepatic veins and sinuses is 450 mL or 10%
During postprandial period more sinusoids total blood volume.
are recruited allowing absorbed nutrients to  can expand to 0.5-1 L especially in cardiac
be transported to liver. failure with peripheral congestion
2. Endothelial cells- with specialized openings - 3. High lymph flow
fenestrations - allowing passage of molecules  Very permeable pores in hepatic sinusoids
as big as albumin; lack basement membrane – and high permeability of liver sinusoid
allow access of albumin-bound substances to epithelial cells allows passage of fluid and
hepatocytes that will eventually take them up proteins into space of Disse.
3. Kupffer cells (or reticuloendothelial cells)  Half of all lymph formed in body under
 resident macrophages that line the resting conditions arises in the liver.
sinusoids. 4. Regeneration
 involved in the liver's response to infection,  Hepatic growth factor (HGF) – secreted by
toxins, ischemia, resection and other mesenchyme cells in the liver after partial
stresses. hepatectomy; promotes hepatic cell division
 able to phagocytize bacteria and other and growth
foreign matter in the hepatic sinus blood.  Transforming growth factor-β – cytokine
4. Space of Disse (perisinusoidal spaces) secreted by hepatic cells; potent inhibitor of
 thin layer of loose connective tissues liver cell proliferation;
beneath sinusoidal endothelium and  main terminator of liver regeneration after
separating endothelium from hepatocytes liver has returned to its original size.
 provides little resistance to movement of
large molecules like albumin.

Zones of the Liver 4. Other metabolic functions:

1. Zone 1 a. Storage of vitamins
 Periportal Zone i. Vitamin A stores can prevent
 consists of hepatocytes lying closest to deficiency for 10 months
hepatic triad ii. Vitamin D stores can prevent
 greatest supply of 02 and nutrients deficiency for 3-4 months
 most active in detoxification functions iii. Vitamin B12 stores can prevent
 more sensitive to oxidative injury deficiency for at least 1 year
b. Stores iron as ferritin – hepatocytes contain
2. Zone 2 – Intermediate Zone apoferritin capable of combining reversibly
3. Zone 3 with iron. The apoferritin-ferritin system of
the liver act as blood iron buffer.
 Pericentral Zone c. Forms blood substrates used in coagulation
 most active in bile synthesis  Vitamin K - required by the metabolic
 more sensitive to ischemia processes of liver for formation of clotting
factors: prothrombin, Factors VII, IX, and X.
B. Detoxification
First Pass Metabolism
 This is a process where absorbed
substances in intestines are metabolized by
liver before making it to systemic circulation.
Little or none of absorbed substances make
it to the systemic circulation.
 Liver limit entry of toxic substances into the
bloodstream.
 It has unusual blood supply. Majority of
blood draining into liver is venous in nature
via portal vein from the intestines. Thus,
liver absorbs not only nutrients but
Zones of the Liver
potentially harmful absorbed molecules ex:
drugs and toxins
Functions of the Liver
1. Metabolic
Levels of Detoxification
2. Detoxification
1. Physical - involves the Kupffer cells, which are
3. Excretion of protein-bound lipid-soluble waste
phagocytic cells
products
2. Biochemical
 Hepatocytes are endowed with a broad array
A. Metabolic Functions
of enzymes that metabolize and modify both
1. Carbohydrate Metabolism
endogenous and exogenous toxins so that the
a. Storage of large amount of glycogen
products are more soluble and less
b. Conversion of galactose and fructose to
susceptible to reuptake by the intestines.
glucose
c. Gluconeogenesis
Metabolic reactions:
d. Formation of many chemical compounds from
a. Phase I reactions
intermediate products of carbohydrate
 oxidation, hydroxylation, other reactions
metabolism
catalyzed by cytochrome p450 enzymes
2. Fat Metabolism
b. Phase II reactions
a. Oxidation of fatty acids to supply energy for
 conjugate the resulting products with
other body functions
another molecule such as glucoronic acid,
b. Synthesis of large quantities of cholesterol,
sulfate, amino acids, or glutathione to
phospholipids, and most lipoproteins
promote their excretion.
c. Synthesis of fat from proteins and
carbohydrates
C. Excretion
3. Protein Metabolism
 Small water-soluble catabolites are excreted
a. Deamination of amino acids
by the kidneys.
b. Formation of urea for removal of ammonia
 Larger water-soluble catabolites and
from the body fluids
molecules bound to plasma proteins (lipophilic
c. Formation of plasma proteins
metabolites, xenobiotics, steroid homones,
d. Interconversion of the various amino acids
and heavy metals) cannot be filtered by the
and synthesis of other compounds from amino
process of glomerular filtration.
acids
 These substances are taken up by basolateral
membrane transporters that will metabolize
them at the level of microsomes and in the
cytosol.
 These substances ultimately exported through

bile across the canalicular of hepatocytes via a Pathway of Bile
different transporters. They are then
Bile from hepatocytes  cannaliculus  biliary
excreted into the intestine and into the feces.
ductules bile ducts  right and left hepatic duct
 common hepatic duct  cystic duct 
BILIARY SYSTEM
gallbladder  common bile duct  duodenum
BILE
 excretory fluid of the liver important in lipid
digestion
 micellar solution with major solutes
Composition of Bile
1. bile acids
2. phosphatidylcholine
3. cholesterol
* In ratios of 10:3:1, respectively
Bile Acid
 Bile acids are produced by hepatocytes as end

products of cholesterol metabolism. Pathway of Bile
 Cholesterol 7 -hydroxylase – catalyzes the rate-
limiting step of bile acid synthesis. ENTEROHEPATIC CIRCULATION
 Actively reabsorbed conjugated bile acids
A. Primary Bile Acids travel the portal blood back to the hepatocyte,
where they are efficiently taken up by
1. Chenodeoxycholic acid -a dihydroxy bile acid
basolateral transporters that may be Na+
2. Cholic acid - trihydroxy bile acid
dependent or independent
The primary bile acids are acted upon by colonic
bacteria to yield secondary bile acids.  Bile acids that are deconjugated in the colon
also return to the hepatocytes, where they are
B. Secondary Bile Acids reconjugated to be secreted into bile.
1. ursodeoxycholic acid  A pool of circulating primary and secondary bile

2. deoxycholic acid acids, and daily synthesis is then equal only to
3. lithocholic acid – formed from bacterial enzymes the minor fraction ( 10%/day or 200-400 mg)
acting on chenodeoxycholic acid; relatively
that escapes uptake and lost in stool.
cytotoxic
Role of the Gallbladder
 Both primary and secondary bile acids can be  Gallbladder - a muscular sac lined with high
conjugated with either glycine or taurine. resistance epithelial cells
 In the postprandial period, bile enters the ducts
 Conjugated bile acids are retained in the and is conveyed toward the SI.
intestinal lumen until they are actively  In the period between meals, bile outflow is
absorbed in the terminal ileum. blocked by constriction of the sphincter of Oddi,
and bile is redirected to the gallbladder.
 Conjugated bile acids that escape this uptake are
deconjugated by bacterial enzymes in the colon,
then passively reabsorbed across the colonic
epithelium because they are no longer charged.
Regulation of Bile Acid Syntesis
 Bile acid synthesis can be up- or down

regulated, depending on the body’s
requirements
 If bile acid levels are reduced in the blood
flowing to the liver, synthesis can be
increased up to 10-fold.
 feeding of bile acids suppresses the new
synthesis of bile acids by hepatocytes Enterohepatic Circulation

Stimuli to Hepatic Secretion of Bile and

Gallbladder Emptying
BILE CONCENTRATION IN THE GALLBLADDER 1. Cholecystokinin via blood stream causes:
(STANDING OSMOTIC GRADIENT a. Gallbladder contraction
MECHANISM) b. Relaxation of sphincter of Oddi
2. Secretin via blood stream - stimulates liver
 During gallbladder storage, bile becomes ductal secretion
concentrated because Na+ ions are actively 3. Bile acids via blood - stimulate hepatic
absorbed in exchange for protons and bile acids parenchymal secretion of bile
as the major anions are too large to exit across 4. Vagal stimulation (Ach) – causes weak
the gallbladder epithelial tight junction. contraction of gallbladder
 Actively absorbed Na+ are pumped into the
BILIRUBIN
lateral interstitial spaces. Cl- follows through
 a tetrapyrole pigment, is a metabolite of heme
basolateral Cl- channels.
 About 70-80% derived from the breakdown of
 The resultant hyperosmotic interstitial space hemoglobin in senescent RBCs
induces osmotic flow of water from the  Formation of bilirubin occurs in RES primarily in
gallbladder lumen through the chalangiocyte or the spleen and liver.
through the lateral intercellular spaces.  Bilirubin formed in the RES is unconjugated
(UCB) and insoluble in water.
 Hydrostatic pressure in the intercellular spaces
 To be transported in blood, UCB must be
elevates forcing fluid to the capillaries.
solubilized. This is accomplished by its reversible,
 Although concentration of bile acids can rise noncovalent binding to albumin.
more than 10-fold, bile remains isotonic because
a single micelle acts as only one osmotically
active particle.
 Any additional bile acid monomers are
immediately incorporated into existing mixed
micelles reducing the risk that cholesterol will
precipitate from bile.
 in the ER, bilirubin is conjugated with glucoronic

acid.
Mechanism of Bile Concentration

in the Gallbladder
Comparison Between Bile in the Liver and

in the Gallbladder
Gallbladder
Liver Bile Bile
Water 97.5 g/dl 92 g/dl
Congugation of Bilirubin
Bile salts 1.1 g/dl 6 g/dl
Bilirubin 0.04 g/dl 0.3 g/dl  Conjugated bilirubin (CB) excreted into bile
Cholesterol 0.1 g/dl 0.3 to 0.9 g/dl drains into the duodenum and passes unchanged
Fatty acids 0.12 g/dl 0.3 to 1.2 g/dl through the proximal small intestines.
Lecithin 0.04 g/dl 0.3 g/dl
Na+ 145 mEq/L 130 mEq/L  When CB reaches the distal ileum and colon 
K+ 5 mEq/L 12 mEq/L hydrolyzed to unconjugated CB by bacterial
Ca++ 5 mEq/L 23 mEq/L glucoronides.
Cl- 100 mEq/L 25 mEq/L
pH 7.5 6.0  Unconjugated bilirubin is reduced by normal gut
bacteria  urobilinogens

 ~ 80-90% excreted in feces  stercobilins
 ~10% of urobilinogens passively absorbed

enter portal venous blood  reexcreted by the
liver. A small fraction (< 3 mg/dl) escapes
hepatic uptake, filters across the renal
glomerulus excreted in urine  urobilin
Urea Cycle (Krebe-Henseleit Cycle)
_______________________
REFERENCES
Fate of Bilirubin in the Large Intestine
 Berne, R., Levy, M., Koeppen, B., Stanton, B.
Physiology (Updated Version) , 6th edition, 2010
AMMONIA HANDLING  Boron, W., Boulpaep, E. Medical Physiology, 1st
edition, 2003
 Ammonia (NH3) is a small metabolite that arises  Guyton, A., Hall, J., Textbook of Medical Physiology,
from protein catabolism and bacterial activity and 12th edition, 2011
is highly membrane permeant.  Ganong, W. Review of Medical Physiology, 23rd
edition, 2010
Widmaier, Raff & Strang, Vander’s Human
 It is toxic to the central nervous system.
Physiology, 12th edition.
Sources of Ammonia
1. Colon – 50%
2. Kidney – 40%
3. Liver deamination of amino acids
10%
4. Metabolic processes in muscles
5. Release of glutamine from senescent RBC’s
 The liver eliminates ammonia from the body by

converting it to urea via the urea or Krebe-
Henseleit cycle.
 The liver is the only tissue in the body that can

convert NH3 to urea.
 If the metabolic capacity of the liver is

compromised acutely, coma and death can
rapidly ensue due to accumulation of both
ammonia and other toxins that cannot be cleared
by the liver  hepatic encephalopathy.

REVIEW TEST
REMEDIOS DEE-CHAN, M.D. MHPED
ANITA Q. SANGALANG, M.D. MHPED

_____10. Destruction of parietal cells as seen in
_____1. Stimulation of the myenteric nerve plexus chronic gastritis is accompanied by decreased
of the enteric nervous system results in: production of HCl and:
A. local intestinal secretion A. intrinsic factor
B. contraction of submucosal muscles B. pepsin
C. increased tone of gut wall C. bicarbonate
D. local intestinal absorption D. gastrin
_____2. Slow waves of the GI smooth muscles _____11. Promotes gastric acid secretion:
A. are action potentials A. somatostatin
B. represent changes in resting B. gastrin
membrane potentials C. prostaglandins
C. lead to muscle contraction D. EGF
D. occur in similar frequencies throughout
the GIT _____12. Which phase of gastric acid secretion
accounts for the most acid secreted?
_____3. Respiratory center in the medulla is inhibited A. cephalic
during this phase of swallowing: B. gastric
A. oral C. intestinal
B. pharyngeal D. pancreatic
C. esophageal
D. gastric _____13. Promotes secretion of bicarbonate-rich
pancreatic juice:
_____4. Movement of solid particles toward the A. acetylcholine
antrum is accomplished by the interaction of B. cholecystokinin
gastric contractions and occlusion of the pylorus C. secretin
A. receptive relaxation D. gastrin
B. propulsion
C. grinding _____14. A patient with genetic mutation in SGLT1
D. retropulsion transporter in the intestinal brush border
membrane will develop abdominal pain and diarrhea
_____5. Factor that lead to increased gastric due to malabsorption of:
emptying: A. fructose
A. cholecystokinin B. B. galactose
B. gastrin C. C. amino acids
C. acidic duodenal chyme D. D. Fatty acids
D. hypotonic fluids in duodenum
_____15. Essential for intestinal absorption of
_____6. Predominant movement of the small products of lipolysis:
intestines: A. apolipoprotein
A. haustrations B. B. bile acids
B. mass movements C. C. co-lipase
C. segmentation D. D. chylomicron
D. peristalsis
_____16. Which segment of the gastrointestinal tract
_____7. Effective defecation is: absorbs sodium via active transport in the
A. mediated by local enteric myenteric presence of sugar and amino acids?
nervous system in rectal wall A. duodenum
B. by way of parasympathetic nerve fibers B. B. jejunum
in the pelvic nerve C. C. ileum
C. initiated by contraction of abdominal D. D. colon
wall muscles
D. promoted by tonic contraction of _____17. What transport mechanisms allow the
internal and external anal sphincters absorption of nutrients across the small -
intestinal epithelial brush borders by secondary active
_____8. Stimulation of sympathetic nervous system transport with Na?
in the gastrointestinal tract results in which A. fructose
gastrointestinal movement? B. B. glucose
A. vomiting C. C. fatty acids
B. gastric emptying D. D. vitamin K
C. constipation
D. migrating myoelectric complexes
_____9. True of salivary secretion:

A. contains more HCO3 than plasma
B. inhibited by parasympathetic
C. Cl- is the major anion
D. isotonic with plasma

REVIEW TEST
REMEDIOS DEE-CHAN, M.D. MHPED
ANITA Q. SANGALANG, M.D. MHPED
_____18. True about the structural features of the

liver:
A. has low vascular resistance
B. Zone 2 is most active in detoxification
C. liver sinusoid epithelial cells are tightly
packed
D. majority of blood flowing to the liver
is arterial in origin
_____19. The most abundant substance secreted in

the bile:
A. Bile salts
B. Bilirubin
C. Cholesterol
D. Lecithin
_____20. Enterohepatic circulation of bile acids:

A. Conjugated bile acids are passively
reabsorbed in terminal ileum
B. Deconjugated bile acids in colon are
actively reabsorbed
C. Absorbed bile acids from small
intestines and colon are brought to
kidneys for excretion
D. Daily hepatic synthesis of bile acid is
equal to amount of bile acids lost in
stool

MUSCLE PHYSIOLOGY
FRANCIS MARIE A. PURINO, MD
JAN TYRONE CABRERA, MD
SKELETAL
ADP and Pi are released producing the A-M
1. How is skeletal muscle cell fiber activated? complex. The power stroke of the myosin head
from 90° to 45° configuration caused the actin
Acetylcholine is released by the presynaptic filament to be drawn closer to the center of the
nerve terminal and binds to ionotropic (nicotinic) sarcomere. When ATP binds the A-M, actin is
Ach receptors at the NMJ. The Ach receptors released. The myosin ATPase cleaves the
open, allowing Na+ channels to open, attached ATP forming M·ADP·Pi returning the
depolarizing the membrane and if the threshold head to a 90° configuration ready to bind again
is exceeded, an action potential result. to actin.
Overview of the Cross Bridge Cycling
2. What is the arrangement of myofibrils in a

skeletal muscle fiber?
S1
Each skeletal muscle cell contains parallel

myofilbrils which in turn consist of repeating
sarcomeres. Sarcomeres are stacked end to end S4 Power
S2
from one Z disc to another and are made up of Stroke
smaller interdigitating filaments of 2 types actin ADP
Pi
(at both ends) and myosin (at the middle), ATP REQ.
arranged in an orderly fashion imparting a S3
striated appearance.
6. What are the sources of energy for
skeletal muscle contraction?
The energy sources include:
a) Direct phosphorylation – rapid generating
capacity, immediate, few seconds duration,
anaerobic.
b) Glycolysis – rapid, few minutes duration, low
efficiency, anaerobic
c) Oxidative phosphorylation – slow generating
capacity, indefinite duration of supply, high
efficiency, aerobic
7. What are the types of skeletal muscle

fibers based on rapidity of hydrolyzing
ATP?
3. Describe excitation-contraction coupling
in a skeletal muscle fiber.
Type 1 Type 2A Type 2B
Slow (Avian) (Bilis) Fast
Upon depolarization of a skeletal muscle
Oxidative Fast Glycolytic
fiber, the action potential travels along the
Oxidative
sarcolemma and T tubule. The depolarized T
Myosin Slow Fast Fast
tubule, via Dihydropyridine voltage sensors
Isoenzyme
signals the sarcoplasmic reticulum to release
calcium via the ryanodine channels. Calcium Contraction Slow Fast Fast
enters the sarcoplasm and binds to troponin C, velocity
uncovering the active site on actin, triggering Sarcoplasmic Moderate High High
cross bridge cycling. Reticulum
Pumping
4. Contrast the regulation of actin and Capacity
myosin interaction between a skeletal and Main Source Oxid. Both Glycolysis
smooth muscle fiber. of ATP Phos.
Fatigable No No Yes
The regulatory protein that is activated by Glycolytic Moderate High High
calcium to effect actin and myosin interaction in Capacity
a skeletal muscle is troponin. In a smooth Oxidative High High Low
muscle cell, calmodulin is activated, which in Capacity:
turn activates myosin light chain kinase. myoglobin;
CAP. Density
5. Describe the states of myosin in a skeletal Other name Red Red White
muscle cell. Diameter Moderate Small Large
When the active site of actin is uncovered,

M·ADP·Pi binds to actin to form A-M·ADP·Pi.

MUSCLE PHYSIOLOGY
8. How is contraction terminated in a 12. How does exercise influence a muscle’s

skeletal muscle fiber? strength and susceptibility to fatigue?
Calcium has to be removed from the Low intensity and long duration exercise
sarcoplasm in order for contraction to stop. It is increases the number of mitochondria and blood
either extruded at the cell membrane by a Na-Ca vessels of a muscle. The capacity for ATP
exchanger or a Ca++ pump or re-uptaken into the SR production by oxidative phosphorylation is
by a SERCA-type Ca++ pump. The latter is more increased and endurance is enhanced.
important mechanism. High intensity short duration exercise
increases fiber diameter due to enhanced actin
9. What is skeletal muscle fatigue? and myosin synthesis. This results in increased
strength.
This is the gradual decrease in force
generated by the muscle if it is stimulated to 13. Tabulate the biophysical relationship in
exert maximal force continuously. Contributing skeletal muscle.
factors are AP conduction failure due to K Biophysical Relationship in Skeletal Muscle
depletion, lactic acid accumulation and inhibition Cause Effect Relationship

of cross-bridge cycling from ADP and Pi build-
Intensity Force Direct (T->M)
up. Additionally depletion of fuel substrates (i.e.
glycogen) and central command fatigue (failure Frequency Force Direct (S-CT)
of cortex to send excitatory signals to motor Muscle Length Passive Tension Direct
neuron) may contribute to fatigue. Muscle Length Active Tension Biphasic (RL)
Parallel Fibers Force Direct (STUBMR)
10. What is the relationship between skeletal
Fibers in Series Velocity Direct (STUBMR)
muscle length and tension generated?
Load Velocity Inverse
With increased stretch, the passive tension Load Power Biphasic (30% ML)
(dependent on elastic property) of a relaxed
fiber increases. As a relaxed muscle is stretched, NON-SKELETAL
the active tension (tension developed during
contraction) increases until the optimal length is
reached. With increasing length beyond this 1. Contrast role of intracellular with
optional length, the active tension decreases. extracellular calcium in cardiac muscle
contraction.
Below 60% and beyond 175% of optimal length,
no tension is generated.
Calcium mainly released from the
sarcoplasmic reticulum (SR) functions as the
ECC complex in cardiac muscle by combining
with troponin. Extracellular calcium will act as a
second messenger to trigger the release of SR
calcium.
2. What is the effect of increasing cytosolic

calcium on the strength of cardiac muscle
contraction?
The amount of calcium released does not

usually saturate all troponin binding sites, so the
number of active cross bridges can increase if
cytosolic calcium increases still further.
11. How can skeletal muscle tension be
3. Why is tetanic contraction not observed in
increased? cardiac muscle?
Increase in skeletal muscle tension is Because of its longer absolute refractory
controlled primarily by recruitment or by
period, which ends during the relaxation phase
increasing the number of active units in a
of the mechanical response. It can generate a
muscle. Slow oxidative motor units are
new action potential only during the relaxation
recruited first during weak contraction, followed
phase.
by fast-oxidative motor units and lastly, fast-
glycolytic motor units during very strong
contractions.

MUSCLE PHYSIOLOGY
maximally, it generates more tension (termed total

tension – TT). The difference between total tension
and resting tension at any given length is the force
produced by contraction (e.g. active tension – AT).
The bell-shaped dependence of active tension on
muscle length is consistent with the sliding filament
theory of cardiac and skeletal muscle. It is, however,
Temporal Relationship: Action Potential & Response difficult to stretch cardiac muscle beyond its optimal
sarcomere length, as evidenced by the rapid rise in
Incomplete Tetanization Complete Tetanization resting tension in the middle of the bell-shaped AT
curve.
ARF
6. Describe activation of crossbridge cycling

in smooth muscle.
Excitation Contraction Coupling is Different
Cardiac Muscle
Ca-Calmodulin-Myosin Kinase Myosin Phosphatase
4. Enumerate factors that will decrease
Response during the relaxation & contraction phase? Myosin Regulatory
myocardial contraction: Light Chain (MLC)
a. Stimulation of active calcium pump will

decrease the amount of calcium Fast Velocity Slow Velocity
intracellularly therefore decrease

contraction. Increased myoplasmic calcium will activate
b. Stimulation of NaK pump will decrease the the calmodulin. The active Ca2+ calmodulin will
amount of sodium intracellularly thereby activate the myosin light chain kinase. This will
allowing the Na-Ca pump to increase its phosphorylate cross bridges, thus driving them
extrusion of calcium in exchange for the Na. to bind with the thin filament. Only
phosphorylated myosin can bind to actin and
5. Contrast the length tension relationship of undergo cross bridge cycling.
skeletal & cardiac muscle
Slow Cross Bridge Cycling Velocity
S1
+1 Before
Reattachment
S4 +1 Before the
* Power Stroke
* Long Duration S2
*
S3
Dephosphorylated MLCK-Low Ca- 6 Steps- Tonic Contraction
Rapid Cross Bridge Cycling Velocity
S1
S4 S2
Cardiac muscle (panel A) has high resistance to

stretch when compared with skeletal muscle (panel S3
B). When either cardiac or skeletal muscle is Phosphorylated MLCK-High Ca- 4 Steps
stretched, there is an increase in resting tension

(RT). If the muscle is then stimulated to contract

MUSCLE PHYSIOLOGY
7. How is relaxation of smooth muscle 10. Summarize and compare the properties of
brought about by? skeletal, cardiac and smooth muscle
It is brought about by activation of the Skeletal Cardiac Smooth

myosin phosphatase and deactivation of the Mechanis o MNT o Pacemak o Synaptic
CCMK due to low myoplasmic calcium. m of er Transmissi
Excitation potentials on
8. Enumerate the sources of calcium for spreading o Receptor
smooth muscle contraction. via gap Activation
junctions o Pacemaker
Two sources of the cytosolic calcium ions potentials
that initiate smooth muscle contraction are the Electrical o Action o Action o Action
sarcoplasmic reticulum calcium and extracellular Activity of potential potential potential
calcium. the spikes plateaus spikes,
muscle o Action
9. What are the types of crossbridge cycling cell potential
velocity in smooth muscle? plateaus
o Graded
a. Rapid velocity - MLC is maintained membrane
phosphorylated prerequisite – high potential
myoplasmic calcium. Ca++ o Troponin o Troponin o Calmoduli
b. Slow velocity – MLC is dephosphorylated sensor n
and rephosphorylated during each cycle, Excitation o DHP o Ca2+ o Ca2+ entry
prerequisite – lower myoplasmic calcium. – stimulate entry via via
contractio s Ca DHP o voltage-
n coupling release receptor gated
from SR triggers o ligand-
Ca2+ gated
release o IP3-
from SR mediated
SR Ca2+
release
Regulatio o Frequenc o Regulatio o Balance
n of force y n of between
o Intensity calcium MLCK
entry phosphory
lation
o Latch
State
Metabolis o Oxidative o Oxidative o Oxidative
m ,
o glycolytic
 Handout courtesy of Dr. Elizabeth L. Roasa & Dr.
Ma. Carole Lisa C. Sibulo

CARDIOVASCULAR PHYSIOLOGY
AILEEN CYNTHIA DE LARA, MD
The resting membrane potential is determined by

conductance to K+ and approaches K+ equilibrium
potential
Ionic basis of the Fast response

 Ions move across membrane along its
concentration and electrical gradient
 When ion channels open up
Similarities of cardiac muscles to skeletal muscles –  Na and Ca influx – (+) generating event
both are striated with myofibrils that contain actin called depolarization
and myosin  K efflux - (-) generating event
Differences – cardiac muscles possess intercalated hyperpolarizing membrane potential
discs allowing it to act as syncytium  Ion channels involved
 Fast Na channels – open and close very
Types of Cardiac Cells fast
Type of  Calcium channels – remains open for a
Type Function Found action longer period of time
potential  K channels – open abruptly but closes
Contractile contract Free wall of Fast gradually
or working and pump atrium and
cell blood ventricles Other Names Primary Ion Negativity
Conducting transmit Purkinje Fast Ions flow of
action conduction channels membrane
potential system involved potential
Pacemaker Generate SA and AV Slow
an action node 0 Depolarization Opening of Na Decreasin
potential Na influx g
channels
VENTRICULAR ACTION POTENTIAL
1 Rapid Closing of K Increasing
Presence of plateau causes ventricular contraction to repolarization Na efflu
last as much as 15 times longer when compared to channels x
skeletal muscle and
maximum
opening of
K channels
2 Plateau Opening of K No
calcium efflu significant
channels, x change
while the K and
channels Ca
are open influx
3 Gradual Non K Increasing

repolarization permeabilit efflu
y of x
protein
anion
IONIC BASIS OF RESTING POTENTIAL 4 RMP NA-k

pump ( 3
Na effluxer
ION Extracellular Intracellular Equilibrium
and 2K
concentration concentration potential
influxer)
Na 145 10 70
Permeabilit
K 4 135 -94 y of K leak
channels
Ca 2 10 132
Phase 0 – upstroke of AP, Na+ channels open

Sodium is the predominant extracellular ion resulting in Na+ influx and depolarization
Potassium is the predominant intracellular ion

Phase 1 – brief period of initial repolarization
caused by K+ going out of the cell and decreased Fast Response Slow Response
Na+ conductance 40
Phase 2 – plateau phase, inward Ca++ current and

outward K+ currents are approx. equal
Millivolts
0
Phase 3 – Repolarization, Ca++ conductance

decreases, K+ conductance predominates
-40
Phase 4 – RMP -80
Comparison of Fast and Slow Action Potential -120

ERP RRP ERP RRP
0 100 200 300 0 100 200 300
Time (ms)
Three periods of the action potential (based

on response to a stimulus)
Period Correspondi Responsivene Na

ng Phases ss to stimulus channels
configuratio
n
Resting potential of slow response fiber is less
Absolute Phase 0 till Unresponsive All of Na
negative; upstroke is less steep; amplitude of AP
smaller and phase 1 is absent refractor part of to any type of channels
y phase 3 stimulus are open
Slow Response AP seen in the SA node (normal wherein the and
pacemaker of the heart), also seen in the AV node Vm becomes unexcitable
and His Purkinje systems (latent pacemakers) -50mv
Intrinsic rate of phase 4 depolarization (heart rate)
is fastest in the SA node >AV node> His-Purkinje Relative Phase 3 Responsive to Some of
refractor wherein the a the Na
For Slow Response AP
y Vm is -50mv suprathreshol channels
Phase 0 – upstroke, caused by increased Ca++
conductance till the start d stimulus are open
Phase 3 – repolarization caused by increased K+ of phase 4 and
conductance therefore
Phase 4 – slow depolarization, responsible for unexcitable
pacemaker activity or automaticity; due to increased
Na+ conductance Non Phase 4 Responsive to All of the
refractor a threshold Na
Note: Phase 1 &2 are not present
y stimulus channels
Compared to fast AP, slow response AP are close
o Less steep phase 0 slope and
o Lower overshoot excitable
o No phase 1
o Less sustained plateau phase
o More gradual phase 3
o Less negative phase 4
o Longer refractory period which extends to
phase 4
Unique features of the slow response cells

 Lacks the fast Na channel (less steep phase
0 slope and lower overshoot)
 Slow Ca channel generates phase 0 (less
steep phase 0 and lower overshoot)
Less leaky to K efflux during phase 4 (less negative
RMP)
Excitability Conducting system

- ability of cardiac cells to initiate AP in  Sinoatrial node- spontaneous action
response to depolarizing current potential transmitted to surrounding atrial
- changes in excitability are described by muscle which triggers contraction
refractory periods • Internodal pathway

 AV node
 Common bundle of His Factors that affect conduction velocity
• Left and right His Bundle’
 Purkinje system
 Ventricular Muscle
Sinoatrial node
• Pacemaker of the heart, which
generates impulses at the greatest
frequency
• Steepest phase 4 slope
• Least negative RMP
 Overdrive suppression – hyperpolarization of Conditions that alter conduction velocity

the cells due to repeated stimulation of the  Sympathetic activity
Na-K pump • Increased conduction velocity
 Rationale for automaticity of other cells: • Increases amplitude of AP and
backup pacemaker phase 0
 Parasympathetic activity
ATRIOVENTRICULAR CONDUCTION • Decreases the phase 0
 Same components as that of the SA node • Decreases conduction velocity
but less abundant round cells and more  Hyperkalemia
elongated cells • Makes RMP less negative
 3 functional regions: • Decreases conduction velocity
• AN region – longest length  Coronary ischemia
• N region – slowest conduction • Decreases the activity of NA+K+
velocity pump therefore increasing
• AN and N region - site of the extracellular K
principal delay in AV node • Decreases conduction velocity
 Only pathway along which cardiac impulse  Hypercalcemia
travels from atria to ventricles • Increases amplitude of AP and
phase 0
DEPOLARIZATION/CONTRACTION OF THE • Increases conduction velocity
VENTRICLE
 Septal Factors that affect conduction velocity
 Apical
 Ventricular free wall
• Greatest electrical potential
 LV posterobasal, PA conus (SRA)
 Repolarization (ILP)
Natural excitation of the Heart

 AUTOMATICITY
o Ability to initiate its own beat
o Ability to generate spontaneous action
potential
o Ionic events responsible for pacemaker
potential (slow diastolic depolarization
throughout phase 4)
 Leaky Na channels
 Leaky Ca channels
 Tight K channels
Factors that increase automaticity

1. Less negative RMP
CONDUCTION VELOCITY 2. More negative threshold potential
 Ability of cardiac cell to conduct an action 3. Increased phase 4 slope
potential
 Factors that determines conduction velocity Conditions that alter automaticity
• Amplitude of action potential  Decreases automaticity ( decreases phase 4
• Slope of phase 0 )
• Negativity of the RMP
• Hypoxemia  T wave – ventricular repolarization
• Increased parasympathetic activity  PR interval – beginning of the P wave to the
• Hyperkalemia beginning of the QRS complex
 Increases automaticity ( increase phase 4 )  QT interval – beginning of the Q wave to the
• Increased sympathetic activity end of T wave
• Cardiac dilatation  ST segment – segment from end of S wave to
• Hyperthermia beginning of T wave
• Hypercalcemia
• hypercapnia
ELECTROCARDIOGRAPHY
 Galvanometer which measures the potential
difference between two electrodes
 Depolarization and repolarization can be
imagines as a wave of positivity and
negativity
Electrocardiography leads
NAME OF ELECTRODE PLACEMENT
LEAD
Standard limb Reference (-) Recording (+)

leads electrode electrode
Lead I Right arm Left arm
Lead II Right arm Left leg
Lead III Left arm Left leg
Augmented
limb leads
Left arm and Right arm
aVR left leg  Transports and distributes essential
Left arm substances to tissues
aVL Right arm  Removes by products of metabolism
and left leg Left leg  Participates in homeostatic mechanisms
aVF such as body temperature regulation and
Right arm fluid maintenance
and left arm
 BLOOD
Precordial
 formed elements (cells and
(chest) leads
Combined 4th
intercostal fragments) suspended plasma
V1 limb leads space, right of  RBC, WBC, and platelets
sternum
V2 Combined HEART
limb leads 4th
intercostal Anatomy
V3 space, left of  Muscular organ enclosed in the pericardium
Combined sternum  Three layers
V4 limb leads  Epicardium
5th intercostal  Myocardium
V5 Combined space, left of  Endocardium
limb leads sternum
V6
Combined 5th intercostal
limb leads space, centered on
clavicle
Combined
limb leads 5th intercostal
space, left of V4
5th intercostal
space, under left
arm
Electrocardiography
 P wave – atrial depolarization
 QRS – ventricular depolarization
Cardiac output of the left heart equals cardiac  Ventricular pressure rapidly decreases with
output of the right heart constant volume
CO of left heart – systemic blood flow  When ventricular pressure becomes less
CO of right heart – pulmonary blood flow than atrial pressure, mitral valve opens
CARDIAC CYCLE  Rapid filling

 Ventricular pressure falls below that of left
atrium
 Mitral valve opens
 Left ventricular volume begins to increase

rapidly
Atrial Contraction  Aortic pressure continues to decrease as
 Preceded by P wave blood continues to run off into small arteries
 At rest, contributes 25% of SV
 During heavy exercise can increase rise to  Diastasis
40%  Longest phase of cardiac cycle
 Slight rise in atrial pressure seen as a wave  Period of decreased filling
in JVP  Mitral valve is open but little blood flows
 produces the 4th heart sound which is not from left atrium to the left ventricle;
audible in adults ventricular volume slowly rises then plateau
 P wave in the ECG occurs at the end of this
 Isovolumetric Ventricular Contraction phase
 Begins after onset of QRS
 When ventricular pressure exceeds atrial
pressure AV valves close (causing 1st heart THE HEART SOUNDS
sound)
 Ventricular pressure rises with no change in
volume
 Both semilunar and AV valves are closed
 Rapid ejection
 Ventricular pressure reaches maximun
 When ventricular pressure exceeds aortic
pressure aortic valves open
 Pressure gradient between ventricle and
aorta leads to rapid ejection of blood
 Reduce ventricular volume
 Atrial filling begins
 Onset of T wave
 Slow ejection (Reduced ventricular

ejection) CARDIAC OUTPUT
 Ejection of blood continues but slower  The volume of blood each ventricle pumps
 Ventricular pressures start to decrease  Expressed in liters per minute
 Aortic pressure decreases due to runoff of  Volume of blood flowing through either the
blood systemic or the pulmonary circuit per minute
 Atrial filling continues  Product of heart rate and stroke volume
 Isovolumetric Ventricular Relaxation CONTROL OF THE HEART RATE

 Repolarization complete (end of T wave)  Under constant influence of nerves and
 Aortic valve closes followed by pulmonic hormones
valve  Resting state- more parasympathetic
(2nd heart sound) • The greater the heart rate from 0 to
 AV valves remain closed 170-180, the greater is the CO &
MAP.

• Due to limited ventricular filling SYMPATHETIC PARASYMPATHETIC
time, the relationship becomes NERVES NERVES
inverse at a heart rate greater than AREA (norepinephrine (ACh on muscarinic
170-180/min. AFFECTED on -adrenergic receptors)
receptors)
OTHER FACTORS AFFECTING HEART RATE SA node Increased heart Decreased heart
 Epinephrine – increases HR rate rate
 Changes in body temperature – increase AV node Increased Decreased
temperature increases HR that’s why conduction rate conduction rate
patients who are febrile are tachycardic Atrial Increased Decreased
muscle contractility contractility
CONTROL OF STROKE VOLUME Ventricular Increased No significant effect
 Volume of blood each ventricle ejects during muscle contractility
each contraction
 Three Determinants Ejection Fraction
• Preload( ventricular end diastolic  Fraction of EDV ejected in each SV
volume)  Related to contractility
• Afterload( arterial pressure)  Normally at least 55%
• Contractility  EF = SV
EDV
FRANK STARLING MECHANISM HEMODYNAMICS
 physical law that governs blood flow with
 Increase in venous return (EDV) increases respect to pressure and resistance
stroke volume and cardiac output  addresses property of both the content
 Based on length tension relationship, (blood) and its container (blood vessel)
increase in EDV increases centricular fiber • properties of the blood
length which produces increased tension • arteries as distribution system, the
microcirculation as a diffusion and
filtration system and the veins as a
collection system
Pressure, Flow and Resistance

 Hemodynamics
• Blood flow ( F ) determined by
pressure difference between two
ends of vessel (pressure gradient)
and impediment to blood flow or
resistance R
SYMPATHETIC NERVES
OHM’S LAW
 Distributed to the entire myocardium Q=∆ P
 Norepinephrine acts on beta adrenergic R
receptors to increase cardiac contractility Q = Blood Flow
• Strength of contraction at any given ∆ P = Pressure Difference between P1 and P2
end diastolic volume (Mean arterial pressure – right atrial pressure)
R = Resistance
DETERMINANTS OF RESISTANCE
 Viscosity
• Function of the friction between
molecules of a flowing fluid
• The greater the friction ,the greater
the viscosity
 Length of the tube
 Radius of the fluid
FACTORS AFFECTING VISCOSITY

 Fibrinogen concentration
• Major protein and key element in
coagulation
• Eliminates shear stress in its
absence in blood
•
 Hematocrit
EFFECT OF AUTONOMIC NERVES ON THE • Elevates blood viscosity in 2
HEART mechanism
• The greater percentage of cells,  Fluid molecules touching wall do not move
greater friction occurs because of adherence to the wall
 Vessel Radius – FAHREUS – Linquist effect  Second layer of molecules slips over these,
 Linear velocity – inverse relationship with third layer over second, fourth over the
viscosity third, so on and so forth
 Temperature  Therefore, fluid in middle move rapidly
because many layers of slipping molecules
VELOCITY OF BLOOD FLOW exist
 V = Q/A REYNOLD’S NUMBER

Where: V = velocity in cm/sec Re = VDp
Q = blood flow in mL/min n
A = cross sectional area in cm2 V = velocity of blood flow
Velocity is directly proportional to blood flow and D = diameter
inversely proportional to cross sectional area n = viscosity
p = density
POISEUILLE’S LAW
 Blood flow is laminar when Re is below 2000
 most fundamental law that governs the flow and turbulent when Re exceeds 3000
of fluids through rigid cylindrical tubes  Turbulence occurs when r is large (aorta); v
 applies to a steady, laminar flow of is high(arterial stenosis); low viscosity
Newtonian fluids (anemia)
• Newtonian signifies absence of
variations of flow in time TURBULENCE
 Means blood flows crosswise in the vessel
Q= π (Pi- Po)r4/8η1 and along the vessel, forms whorls in the
blood – EDDY CURRENTS
 Poiseuille-Hagen Equation
R = 8nl
Πr4
Where R - resistance
n – viscosity of blood
l – length of blood vessel
r – radius of blood vessel
 Importance: 4th POWER

 Systemic circulation – 2/3 resistance is in
the small arterioles
• Internal diameter ranges from 4
micrometers to 25 micrometers
• Have very strong vascular walls
which allows changes to occur
 Fourth power law relates blood flow to
diameter of the vessel, which would
increase flow
Capacitance or Compliance
 Steady Flow- absence of variation of flow
in time  Describes distensibility of blood vessels
 Laminar Flow- type of motion in which the  Inversely related to elastance or stiffness
fluid moves as a series of individual layer  C=V
with each layer moving at different velocity P
where C = compliance in mL/mmHg
V = volume in mL
P = pressure in mmHg
 Greater for veins than for arteries
 Capacitance of arteries decrease with age
(as a person ages, arteries become stiffer
and less distensible)
THE VASCULAR SYSTEM

 functional and structural characteristic of the
blood vessels change with successive branching
 smooth, single- celled layer of endothelial cells
LAMINAR FLOW

• Decrease in capacitance with aging

increases PP
CO X TPR = MAP
HR X SV
Preload Contractility 1/ Afterload
Blood Volume
Returning to
the Heart
Venous Total Water Intake (GIT)

Tone Blood = --------------------
Volume Water Output (Kidneys)
• Mean Arterial Pressure

• Average arterial pressure with respect to
time
• DBP + 1/3PP
• SBP + 2(DBP)/2
Vessel
 Aorta VENOUS PRESSURE
 Small Arteries  Very low due to the high capacitance of
 Arterioles veins allowing it to hold large volumes of
 Capillaries blood at low pressure
 Venules
 Small Veins ARTERIES
 Venae Cavae - thick wall containing large quantities of
Cross Section (CM2) elastic tissue
 2.5 - smooth elastic tubes
 20 - Large radii, serve as low resistance vessel
 40 - Act as “ pressure reservoir”
 2500
 250 Major Determinants of Tissue Blood Flow
 80  Local Control
 8 • Autoregulation – blood flow remains
constant over a wide range of perfusion
pressure (brain, heart and kidney)
- pressure change and myogenic
• Active hyperemia – blood flow is
proportional to metabolic activity (exercising
skeletal muscles)
 Local Control
• Active hyperemia – metabolic activity
• Flow autoregulation- pressure change
Arterial Pressure and myogenic
• Systolic Pressure • Reactive hyperemia – extreme form of
• highest arterial pressure during a cardiac flow autoregulation
cycle • Response to injury- inflammation
• measured after the heart contracts  Extrinsic Control
• Diastolic Pressure • Sympathetic nerves- norepinephrine
• Lowest arterial pressure • Parasympathetic nerves
• measured when the heart is relaxed and • Noncholinergic, nonadrenergic-
blood has returned to the heart autonomic neurons and hormones (
• Pulse Pressure angiotensin II, epinephrine, vasopressin,
• Difference between SBP and DBP ANP)
• Most important determinant is the stroke  Endothelial Cells and Vascular smooth
volume muscle
• EDRF ( nitric oxide) , prostacyclin,
endothelin

Metarterioles
 blood enters from the arterioles to the
capillaries
 connect arterioles to venules
 contain scattered smooth muscle cells
Precapillary Sphincter
 site at which a capillary exits from a
metaarteriole which relaxes or contracts in
response to local metabolic factors.
Exchanges of nutrients and metabolic end products
 Diffusion
 Vesicle transport
 Bulk flow
 Mediated transport
Diffusion
 Lipid soluble- easily absorbed
 Ion and polar substance are poorly soluble
• Water filled channels – intercellular
clefts and water fused vesicle
 varies from organ to organ

 thin walled tube of endothelial cells one
layer thick resting on a basement
membrane, without any surrounding
smooth muscle or elastic tissue.
 In other organs, ( brain), a second set
of cells that surround the basement
membrane
 Flat cells in the endothelial tube are Diffusion
separated by intercellular clefts  Lipid soluble- easily absorbed
 Fluid vesicle channels- fusion of  Ion and polar substance are poorly soluble
endocytotic and exocytotic vesicles • Water filled channels – intercellular
clefts and water fused vesicle
 “ Leakiness” of capillaries
• Brain- tight junctions
 Carrier mediated transport
• Liver – large intercellular clefts
Starling Equilibrium
 Amount of fluid filtered from arterial end
almost equals amount returned by
absorption
 NET FILTRATION PRESSURE= (Pc + II if)

- (P if - II c)
o Pc – capillary hydrostatic pressure
o πif- - interstitial oncotic pressure
o Pif – interstitial hydrostatic pressure
o πc – capillary oncotic pressure

VENOUS SYSTEM av wave - Relaxation of the right atrium closure of

 last set of tubes that blood flows towards the tricuspic value
the heart C-peak - Pressure rise in the right ventricle
 in the systemic circulation, force during this - Bulging
venous return, pressure difference between X-minimum – contracting ventricle
the peripheral veins and right atrium V peak – Right atrial filling
 10=15 mm Hg – peripheral venous pressure Y-minimum – Right atrial pressure fall
 0 mm Hg- RAP
LYMPHATIC SYSTEM
Main function
 act as a low resistance conduits for blood  is a network of small organs and tubes
flow from tissues to the heart through which lymph- fluid derived from
 blood reservoir- important determinant of interstitial fluid flows
stroke volume  Lymphatic capillaries- single layer of
Determinants of venous pressure endothelial cells resting on a basement
- volume of fluid within it membrane but have large water filled
 compliance of its walls channels that are permeable to all interstitial
 60% of total blood volume fluid constituents/
 10 mm Hg – average venous pressure
 Mechanisms that can increase venous
pressure
 sympathetic system , hormones and
paracrine substances
 skeletal muscle pump
 respiratory pump
SYSTEMIC VEINS
 Jugular vein
• 3 maxima or peaks – a, c, v
• 3 minima or dips - av, x, y
 Reasons for occurrence
• Retrograde action of the heart beat
during the cardiac cycle
• Respiratory cycle
• Skeletal muscle contraction
The labels reflect events in the cardiac cycle

a – wave - Right atrial contraction

CHOOSE THE BEST ANSWER: ______11. The heart sound produced during rapid
diastolic filling is:
______1. What type of action potentials does A. First heart sound
conducting cells have? B. Second heart sound
A. Slow type of action potential C. Third heart sound
B. Fast type of action potential D. Fourth heart sound
C. Both slow and fast action potential ______12. Also known as end diastolic volume:
D. None of the above A. Preload
______2. Most abundant ion intracellularly: B. Afterload
A. Na C. Contractility
B. K D. Arterial pressure
C. Ca ______13. It is a measure of friction that impedes
D. Mg flow:
______3. What is a positive generating event that A. Hydrostatic pressure
produced depolarization of the membrane:
A. K efflux B. Velocity
B. Na influx C. Resistance
C. Ca influx D. Flow
D. K efflux and Ca influx ______14. The law that governs the movement of
______4. During the plateau phase of the action fluid in a cylindrical tube:
potential, what gates are open: A. Ohm’s Law
A. Na channels B. Poiseuille’s Law
B. K channels C. Frank Starling Law
C. Ca channels D. Law of Laplace
D. K & Ca channels ______15. Which condition will produce an increase
______5. Compared to ventricular muscle action in Reynold’s number?
potential, the pacemaker action potential has: A. Vessel diameter is decreased
A. more steep phase 0 slope B. High viscosity
B. more sustained plateau phase
C. lower overshoot C. Velocity of blood flow is increased
D. shorter refractory period D. Laminar flow is present
______6. Absolute refractory period means that the ______16. Highest cross sectional area in the blood
cell will not be responsive to any kind of stimulus. At vessels:
what phase in the action potential does it occur? A. Arteries
A. Phase 4 B. Veins
B. Phase 3 until start of phase 4 C. Venules
D. Capillaries
C. Phase 0 until phase 3 ______17. Most important vasodilators in the
D. All phases in the action potential arterial system:
______7. A 55 year old male has acute coronary A. Oxygen
syndrome. He was given beta blocker. After a week, B. Bradykinin
his electrocardiogram showed a PR interval of 0.28: C. Change in osmolarity
A. Decrease in phase 0 slope D. Adenosine
B. More negative RMP ______18. The Starling’s forces in the capillaries
C. Increase Calcium particularly the oncotic pressure is dependent on:
D. Sympathetic activation A. Protein concentration in the plasma and
______8. A 24 year old female has fever. You noted in the interstitium
that her heart rate is 108/min. Her HR is increased B. Changes in the capillary hydrostatic
because of hyperthermia: pressure
A. makes resting membrane potential less C. Water concentration in the capillary and
negative interstitium
B. increases phase 4 slope D. Distribution of the cellular elements
C. makes threshold potential more ______19. Venous return increase due to:
negative A. Increase in parasympathetic respond
D. increases amplitude of action potential B. Increase in the skeletal pump
______9. This wave represents ventricular C. During expiration
depolarization: D. Decrease in blood volume
A. P wave C. T wave ______20. The y descent coincides with:
B. QRS wave D. U wave A. Right atrial filling
______10. Which part of the diastolic phase in the B. Right atrial contraction
cardiac cycle? C. Fall in right atrial pressure
A. Isovolumetric contraction D. Bulging of the tricuspid valve
B. Rapid ventricular filling
C. Rapid ejection phase
D. Opening of the semilunar valves
RENAL PHYSIOLOGY
DEXTER CLIFTON C. PE, MD
 secrete prostaglandin &

The functions of the kidneys are divided into: proinflammatory cytokines
1. Excretory- excretion of metabolic waste  increase glomerular arteriolar
products that were either ingested or resistance
produced by metabolism.
2. Regulatory- regulate the balance between
intake & output for the regulation of body
fluid osmolality & volume and electrolytes’
concentration. Acid-base balance & arterial
blood pressure are also controlled by the
kidneys.
3. Endocrine- production of erythropoietin,
renin & calcitriol
4. Metabolic- production of glucose via
gluconeogenesis
Nephrons are the functional units of the kidneys.

Each kidney contains approximately 1.2M
nephrons. A nephron consists of:
1. Renal corpuscle or glomerulus- is made

up of the glomerular capillaries surrounded
by the Bowman’s capsule.
a. Glomerular capillaries- a tuft of
capillaries supplied by the afferent
arteriole & drained by the efferent
arteriole.
b. Bowman’s capsule-is formed by the
2. Renal tubules – proximal tubules (PT),
epithelial cells called podocytes which
descending thin limb, loop of Henle
form the visceral layer. Visceral cells
(LH), ascending thin limb, thick
face outward at the vascular pole (area
ascending limb (TALH), distal tubules
where the afferent arteriole enters &
(DT) and the collecting ducts (CD).
efferent arteriole exits) to form the
parietal layer of the Bowman’s capsule.
The space between the visceral &
parietal layers is the Bowman’s space,
which at the urinary pole of the
glomerulus, becomes the lumen of the
proximal tubule.
 Macula densa - a specialized group

of epithelial cells in the TALH
that comes in close contact
with the afferent & efferent
arterioles.
- monitors the composition of
the fluid in the tubular lumen, at
the point where TALH continues
as the distal tubule.
c. Mesangium - consists of mesangial cells  Juxtaglomerular apparatus-consists

& mesangial matrix which have the of the macula densa,
following functions: extraglomerular mesangial cells &
 give structural support to the juxtaglomerular cells of the afferent
glomerular capillaries arteriole that produce renin.
 secrete extracellular matrix - is one component of the
 exhibit phagocytic activity tubuloglomerular feedback
mechanism that is involved in
the autoregulation of renal
RENAL PHYSIOLOGY
blood flow & GFR; modulation Vascular supplies of the nephrons are
of Na+ balance & systemic arranged in-series & separated by efferent
blood pressure indirectly. arterioles. Long efferent arterioles that extend
from glomeruli down into the outer medulla
continue to become the:
1. peritubular capillaries- supply the tubules of
the cortical nephrons
2. vasa recta - are specialized peritubular
capillaries that extend downward into the
medulla supplying the loop of Henle of the
juxtamedullary nephron.
A. Urine Formation
Three processes involved in the formation of
urine:
1. Glomerular filtration- is the ultrafiltration
of protein-free plasma in the
glomerulus.
- is the initial event in the formation
of urine which results in the
movement of a large volume of fluid
from the glomerular capillaries to
Two types of nephron depending on its location the Bowman’s space.
within the kidney mass: 2. Tubular reabsorption - is the regulated
1. Cortical nephron (75%) - glomeruli are transport of substances out of the
located in the outer cortex which has a short tubular urine to be returned to the
loop of Henle that penetrates only a short capillary blood.
distance into the medulla. It is involved in 3. Tubular secretion - is the transport of
the reabsorption & secretion of solutes, but substances from capillary blood into the
do not contribute to the creation of a tubular urine.
hypertonic medullary interstitium.
2. Juxtamedullary nephron (25%) - glomeruli
lie deep in the renal cortex near the
medulla which has a long LH that dip deep
into the medulla. It generates a
hyperosmotic gradient for the reabsorption
of water.
Two capillary beds of the renal vasculature:

1. Glomerular capillaries - high pressure
capillaries where fluid is filtered.
2. Peritubular capillaries - low pressure
capillaries where solutes & fluid are
absorbed from the interstitial spaces.
Four ways on how the kidneys handle

substances:
1. substance is freely filtered by the
glomerular capillaries, but is neither
reabsorbed nor secreted. Its excretion
rate is equal to filtration rate, e.g.
inulin, creatinine.
2. substance is freely filtered but is also
partly reabsorbed from the tubules back
into the blood. The rate of excretion is
less than the rate of filtration, hence,
excretion rate is equal to filtration rate -
reabsorption rate, e.g. many of the
electrolytes of the body.
3. substance is freely filtered but is not
excreted into the urine because all the
filtered substance is reabsorbed, e.g.
amino acids & glucose.
4. substance is freely filtered and not
reabsorbed but is secreted from the
RENAL PHYSIOLOGY
peritubular capillary blood into the renal 2. basement membrane-have properties

tubules. The excretion rate is equal to that prevent filtration of plasma protein
filtration rate + tubular secretion rate, a. a porous matrix of negatively
e.g. organic acids & bases. charged protein making the filtration
barrier a “charge-selective filter”
b. gel-like structure formed from
collagenous & non-collagenous
glycoprotein called proteoglycans
3. foot processes of the podocytes-
a. have long finger-like processes that
completely encircle the outer
surface of the capillaries
b. interdigitate to cover the basement
membrane
c. separated by filtration slits making
the barrier a “size-selective filter”
that keeps protein &
macromolecules that cross the
basement membrane from entering
the Bowman’s space.
The ability of macromolecules to permeate

C. Properties of the glomerular capillaries the filtration barrier is determined by their
The glomerular capillaries have 3 major layers: size & valence or charge:
1. endothelium of the capillaries 1. Neutral molecules with a smaller radius
2. basement membrane are filtered freely while molecules with a
3. podocytes - a layer of epithelial cells greater radius are not filtered.
surrounding the outer (visceral) Molecules with size between 20-42
surface of the capillary basement Angstrom are filtered variably depending
membrane. on their charge.
2. Positively charged molecules are filtered
Properties of the filtration barrier: much more readily than negatively
1. endothelial cells of the capillaries- charged molecule. Anionic molecules
a. are fenestrated making it freely have reduced filtration rate due to the
permeable to water, small solutes presence of negatively charged
(Na+, urea, glucose) but glycoprotein (glycocalyx) on the surface
impermeable to red blood cells, of the basement membrane &
white blood cells & platelets. podocytes that impede passage of
b. express negatively charged negatively charged macromolecules by
glycoprotein on their surface which electrostatic repulsion.
may slow down the filtration of very 3. Some low molecular weight substances,
large anionic proteins into the e.g. Ca++ & fatty acids, are not freely
Bowman’s space. filtered because they are partially bound
c. synthesize vasoactive substances, to plasma protein.
such as the vasodilator nitric oxide
& vasoconstrictor endothelin, that
are important in controlling renal
blood flow

RENAL PHYSIOLOGY
D. Dynamics of ultrafiltration
Starling’s forces drive ultrafiltration across
the glomerular capillaries, filtration barrier &
Bowman’s space. The glomerular capillaries
have a much higher filtration rate than most
other capillaries because of higher PGC &
large kf.
Glomerular Filtration Rate (GFR):

- is the rate at which plasma is filtered by
the glomerulus per unit time
- is equal to the sum of the filtration
rates of all functioning nephrons
- is an index of kidney function;
evaluates the severity & course of
kidney disease
Determinants of ultrafiltration:
- is proportional to body size, hence, is
1. PGC – glomerular capillary hydrostatic
lower in females.
pressure
- decreases with age & with renal
- promotes movement of fluid from
disease.
the glomerular capillary into the
- normal GFR = 80-120 ml/min or
Bowman’s space.
180L/day
2. PBS – Bowmans’s space hydrostatic
pressure; opposes filtration.
Criteria of a substance that can be used to
3. GC –glomerular capillary oncotic
measure GFR:
pressure; opposes filtration.
1. Must be freely filtered across the
4. BS – Bowman’s space oncotic pressure;
glomerulus into the Bowman’s space.
nearly 0
2. Must not be reabsorbed nor secreted by
- does not influence filtration because
the nephrons.
concentration of protein in the
3. Must not be metabolized nor produced
glomerular filtrate is very low.
by the kidneys.
4. Must not alter the GFR; physiologically
* Net ultrafiltration pressure =Kf x ( PGC - PBS - GC)
inert (not toxic & without effect on renal
function).
Ultrafiltration coefficient (Kf) - is the intrinsic
permeability of the glomerular capillary & the
With a substance having these criteria, the
glomerular surface area.
amount of the substance that appears in the
urine per unit time is the same as the
GFR is proportional to the sum of the Starling’s
amount that the glomerulus filters per unit
forces that exist across the capillary multiplied by
time. Therefore, GFR can replace clearance
the ultrafiltration coefficient (kf).
of a substance (Cx).
GFR can be altered by changing the kf or any of
the Starling’s forces, specifically the PGC, which is the
primary means for regulating the GFR.
Changes in arterial pressure usually exert much

less effect on urine volume due to:
1. renal autoregulation that prevents large
changes in GFR
2. glomerulotubular balance- adaptive
mechanism by tubules to increase
reabsorption rate when GFR is increased.
Autoregulation maintains the PGC & GFR at a

relatively constant values over a wide range of
systolic BP (arterial BP of 80-180 mmHg). BP of less
than 80 mmHg decreased the PGC & GFR. GFR
ceases & urine output decreases at BP of 40-50
mmHg.
RENAL PHYSIOLOGY
Inulin - is an ideal substance that can be whereas the renal vein &
used to measure GFR because it is ureters constitute the 2 output
freely filterable by the glomerulus; routes:
not reabsorbed or secreted by the
tubules; not synthesized, Px a x RPFa = (Pxv x RPFv ) + (Ux x V)
metabolized or stored in the kidneys
& is non-toxic. Px a & Pxv are the
 it is NOT used clinically because it is concentrations of substance X
inconvenient as it has to be infused in the renal artery & renal vein
intravenously. RPFa & RPFv are renal plasma
flow rates in the artery & vein
Creatinine- can be used to measure GFR Ux is the concentration of
although it overestimates filtration rate substance X in the urine
because it is secreted to a small extent V is the urine flow rate
(10%) in the proximal tubule. (GFR x Pcr
= Ucr x V  GFR=Ucr x V) Renal blood flow
 Average RBF is 1.2L/min or 4ml/min/g tissue
Pcr which is approximately 20% of the CO.
 it is an endogenous substance, being an  The high blood flow supplies enough plasma
end-product of muscle metabolism that necessary for a high GFR.
has stable plasma value.  Cortical blood flow is greater than medullary
 inversely proportional to GFR. blood flow to permit high rate of filtration in
the glomerulus for the regulation of body
fluid volume & solute concentration.
 Relatively lower (1-2%) blood flow in the
medulla via vasa recta helps maintain a
hyperosmolar environment in the formation
of concentrated urine.
 The kidneys account for ~8% of the total
body oxygen consumption due to the
metabolic cost of the many transport
processes such as high rate of active Na+
reabsorption by the tubules.
 Renal O2 consumption varies in proportion
to renal tubular Na+ reabsorption, which in
turn is closely related to GFR & the rate of
Na+ filtered.
Renal clearance - assesses renal function by

evaluating the ability of the
kidneys to handle solutes &
water.
- compares the rate at which the
glomeruli filter a substance
with the rate at which the
kidneys excrete it into the
urine, so that an estimate of
the amounts reabsorbed or
secreted by the renal tubules
can be made from the
difference between amounts
filtered & excreted.
- can be used to estimate GFR.
- is based on Fick’s principle, Autoregulation
i.e., mass balance or - is the phenomenon whereby RBF &
conservation of mass: for any GFR are maintained relatively
substance that is neither constant as arterial blood pressure
synthesized nor metabolized, changes between 80-180 mmHg.
the amount that enters the - is achieved by changes in vascular
kidneys is equal to the amount resistance mainly through the
that leaves the kidneys in urine afferent arteriole, an intrinsic
plus the amount that leaves property of the kidneys, thereby
the kidneys in the renal venous minimizing the impact of changes in
blood. -arterial pressure on Na+ excretion
- the renal artery is the single by maintaining GFR.
input source to the kidney,
RENAL PHYSIOLOGY
Two mechanisms involved in autoregulation are: decreased ECFV (e.g. dehydration,

1. Myogenic – pressure-sensitive mechanism hemorrhage)
that responds to changes in arterial pressure
 related to the intrinsic property of 2. Angiotensin II- constricts both afferent
vascular smooth muscle to contract & efferent arterioles, but the efferents
when stretched: When arterial are more sensitive. With low
pressure increases & the renal afferent concentration, efferent arteriole
arteriole is stretched, the smooth constricts, increasing PGC & GFR while
muscle contracts (due to increase influx decreasing RBF which reduces flow
of Ca++), increasing the resistance of through peritubular capillaries,
the afferent arteriole that offsets the increasing tubular reabsorption of Na+ &
increased in pressure. H2O leading to the restoration of blood
 decreased pressure of the renal artery volume & blood pressure. Afferent
decreases its stretched which will be arterioles are relatively protected from
sensed by the afferent arteriole which in angiotensin II- mediated
turn directs the JG cells to increase vasoconstriction due to release of NO &
renin release to increase the blood prostaglandin. Stimulus are decreased
pressure. Therefore, RBF & GFR remain BP and/or volume.
constant.
2. Tubuloglomerular feedback - NaCl-

dependent mechanism that responds to
changes in NaCl concentration in the tubular
fluid
 links changes in NaCl concentration at
the MD with the control of renal
arteriolar resistance.
 main purpose is to ensure a constant
delivery of NaCl to the DT where final
processing of the urine takes place.
 NaCl concentration in tubular fluid is
sensed by macula densa of the JG
apparatus:
a. When GFR is increased, NaCl in the
tubular fluid at MD increases,
causing increased in NaCl entry into
MD cells via Na+K+2Cl- symporter.
This causes increased formation &
release of ATP & adenosine by the
MD cells leading to constriction of
afferent arteriole, decreasing GFR to
normal. (*Adenosine is a
vasodilator in most vascular beds
but constricts the afferent arteriole.)
b. When GFR decreases, it slows the TUBULAR REABSORPTION
flow rate in the LH, increasing - includes passive and active renal solute
reabsorptiion of NaCl in the LH transport mechanisms
causing a decreased in the 1. Passive Transport
concentration of NaCl at the MD  DIFFUSION - Channels – Na+, K+
cells. This will reduce NaCl entry  FACILITATED DIFFUSION
into MD cells with decreased  Uniport – Glucose (GLUT1)
formation of ATP & adenosine  SOLVENT DRAG
causing dilation of the
afferent arteriole, increasing GFR to
normal. 2. Active Transport – moves a solute against
electrochemical gradient and requires
Aside from myogenic & tubuloglomerular energy derived from metabolism
feedback mechanisms, major hormones also
influence the GFR & RBF:
1. Sympathetic nerves- release NE & E
from the adrenal medulla causes
constriction of afferent arteriole via
alpha1 receptor decreasing GFR & RBF.
Sympathetic stimulation also enhances
Na+ reabsorption of the proximal tubule
& renin secretion. Stimulus is a
RENAL PHYSIOLOGY
 Primary active transport – coupled  Reabsorbs calcium, K+, bicarbonate & Mg by

directly to energy source ex. Na+,K+- paracellular diffusion
ATPase  Has Na-H antiporter causing Na

Secondary active transport – reabsorption and H secretion
coupled indirectly to energy  Tubular fluid becomes dilute or hypoosmotic
source such as an ion gradient e  “Diluting segment”
Antiport – Na+-H+
DISTAL TUBULE (DT)
Symport – Na+-glucose
o First portion forms part of JGA
 Active transport mechanism for o Next portion – highly convoluted – distal
absorption of protein ex. Endocytosis convoluted tubule (DCT)
 Avidly reabsorbs Na+, K+, Cl-
Transport maximum for substance that are  Is virtually impermeable to water and urea
actively absorbed – there is a limit to the  dilute tubular fluid
rate at which solute can be transported due  Reabsorbs 5% filtered NaCl via Na-Cl
cotransporter which is blocked by thiazide
to saturation of specific transport system
diuretic
when tubular load exceeds capacity of
carrier proteins i.e. transport maximum for LATE DISTAL TUBULE & CORTICAL
glucose is 375 mg/min. COLLECTING TUBULE
- reabsorbs 3% filtered water under control of
Reabsorption of filtered water and solutes from ADH, controls degree of dilution or
tubular lumen concentration of urine
1. Transcellular route – through cell membrane - is impermeable to urea
2. Paracellular route – through junctional and - 2 cell types:
intercellular spaces 1. Principal cells
3. Ultrafiltration (bulk flow) – mediated by  Reabsorbs Na+ & H20 from lumen and
hydrostatic and colloid osmotic forces secrete K+ into lumen via individual Na+
& K+ channels
PROXIMAL TUBULE (PT)  Aldosterone regulates Na+ reabsorption
1. Reabsorbs 2/3 (67%) of fluid filtered by & K+ secretion. Aldosterone increases
glomeruli activity of the Na+ channels.
- preferentially reabsorbs solutes useful  Diuretics like amiloride – blocks Na+
for metabolism and secretes by- channel; spirinolactone – an aldosterone
products of metabolism antagonist, competes with aldosterone
2. Demonstrates isosmotic volume for receptor sites in principal cells.
reabsorption 2. Intercalated cells
3. Preferentially reabsorbs solutes (glucose,  Reabsorb K+ ions and secrete H+ into
amino acids) by secondary active transport tubular lumen
driven by Na co-transport down its  Uses active H+-ATPase – able to secrete
electrochemical gradient. H+ against a large concentration
4. Protons are actively secreted via Na-H gradient
antiport using the energy from downhill Na  Plays key role in acid-base regulation
entry across luminal membrane
5. Actively secretes metabolic by products, MEDULLARY COLLECTING DUCT
drugs and potential toxins in second half of - Reabsorbs <10% filtered water & Na+
PT - Final site for processing urine – determines final
urine output of water & solutes
LOOP OF HENLE - Permeability to water controlled by ADH.  ADH
1. Thin descending limb of loop of Henle (dLH)   urine volume  concentration
 Surrounded by medullary interstitial fluid - Permeable to urea – reabsorbs urea into
which can have osmolality up to 1200 medullary interstitium raising its osmolality and
mOsm/Kg H20 in the papilla its ability to concentrate urine
 Has aquaporin-1 water channels – very - Secretes H+ against a large concentration
water permeable but less permeable to gradient
solutes
 Reabsorbs 15% water TUBULAR SECRETION
2. Thin ascending loop of Henle  Means for excreting by-products of metabolism.
 Reabsorbs NaCl by a positive mechanism  Eliminates exogenous anions and bases (drugs),
 Is impermeable to water pollutants and organic compounds
3. Thick ascending limb of loop of Henle (TALH)
 Reabsorbs 25% filtered Na+, Cl- & K+ by Regulation of Tubular Reabsorption
NaK2Cl co-transporter which is blocked by 1. Glomerulotubular balance
powerful “loop” diuretic (furosemide)  ability of tubules to increase Na+ & water
 Is impermeable to water reabsorption in response to increased
filtered Na+ load
RENAL PHYSIOLOGY
 a constant fraction of filtered Na+ & water is through the vasa recta (countercurrent
reabsorbed from PT despite variations of exchanger).
GFR  Solute concentration in the loop of Henle ranges
 helps prevent overloading of distal tubule from 300-1200 mOsm.
when GFR increases  Dissipation of the medullary osmotic gradient is
prevented because the blood in the vasa recta
2. Peritubular capillary and renal interstitial fluid equilibrates with the interstitial fluid.
physical forces – Starling forces
 Starling forces regulate NaCl & water
reabsorption across PT into the capillaries
 Starling forces favoring movement of solutes
& water to capillaries:
Capillary oncotic pressure (c)
Interstitial space hydrostatic
pressure (Pif)
Opposing forces: Interstitial oncotic
pressure (if) The Loop of Henle:
Capillary hydrostatic 1. Descending Limb is permeable to water but not to
pressure (Pc) solutes.
 Starling forces do not affect transport by LH, 2. Ascending limb is impermeable to water.
DT, CD because these segments less
permeable to water than PT Steps in Countercurrent Multiplication
1. Na is pumped out of the TALH with a
URINE CONCENTRATION AND DILUTION maximum gradient of 200 mOsm/L –
Understanding urine concentration and dilution “SINGLE EFFECT”
requires understanding three basic processes that 2. Water flows out of the descending tubule
work in concert: raising tubular osmolality to 400 mOsm/L
 The function of the loops of Henle as 3. Osmolality between tubular fluid and
countercurrent multipliers to establish an interstitium is equilibrated
interstitial osmotic gradient that increases from 4. Fluid shifts along loop
the cortex to the tip of the papilla
 The function of the vasa recta as countercurrent
exchangers to help maintain this gradient.
 The function of antidiuretic hormone to alter the
permeability of the late distal tubule (connecting
tubule) and cortical and medullary collecting
ducts to water.
OBLIGATORY URINE VOLUME

 Maximum urine concentrating ability is 1200
mOsm/L to 1400 mOsm/L
 Normal 70 kg person must excrete 600 mOsm of ANTIDIURETIC HORMONE
solute/day ■ Antidiuretic hormone or vasopressin is a nine-
 Minimal volume of urine: 600 mOsm/day = amino acid peptide secreted from the posterior
0.444 L/day obligatory water loss pituitary.
1400 mOsm/L ■ Its most important effect is the conservation of
water to decrease urine output.
FACTS ABOUT OSMOLALITY OF TUBULAR ■ It binds to receptors in the distal and collecting
FLUIDS tubules to promote water reabsorption.
 Proximal tubule (PT) – regardless of final urine ■ It stimulates insertion of water channels or
osmolality – reabsorbs 2/3 filtered fluid aquaporins into the membranes of said tubules.
isosmotically ■ These channels transport solute-free water
 Descending limb of Henle (dLH) – permeable to through the tubular cells and back to the blood.
water; relatively impermeable to solute ■ It lowers the plasma osmolality and increases
 Thick ascending Loop of Henle (TALH) – urine osmolality.
impermeable to water; reabsorbs salt in excess
of water UREA
 Distal convoluted tubule (DCT) – impermeable ■ Low molecular weight compound resulting from
to water; hypoosmotic protein break-down in liver.
 CCT and IMCD – permeability to water depends ■ Enters tubular fluid by glomerular filtration.
upon ADH ■ Permeable in MCD especially under ADH
■ Moves from interstitium back to tubules (UREA
COUNTERCURRENT MECHANISM RECYCLING).
 It is the interaction between the flow of the ■ A major osmole in urine.
tubular filtrate through the loop of Henle
(countercurrent multiplier) and the flow of blood
RENAL PHYSIOLOGY
■ Contributes 40-50% of the osmolarity of the  It is highly permeable to water and solutes
renal medullary interstitium. which equilibrate across the capillary wall as it
courses through the medulla.
UREA RECYCLING  In addition to maintaining the osmotic gradient,
it provide nutrients and O2 to the medullary
tissues and remove the excess water and
solutes being reabsorbed in the cortical and
medullary nephron segments.
 The ability to maintain the medullary interstitial
gradient is flow dependent.
UREA HANDLING AND REGULATION ALONG RENAL

TUBULAR SEGMENTS
SEGMENT RENALUREA REGULATION

HANDLING
Glomerulus Freely filtered None
Proximal 50% Unrelated to H20
tubule reabsorbed reabsorption
Loop of Thin Loops
Henle - recycled: urea
from
interstitium
enters passively Note: Goal of countercurrent multiplier and
Thick ascending exchanger; maintenance of hyperosmotic
Limb interstitium.
-impermeable
Distal - FORMATION OF CONCENTRATED URINE
tubule impermeable
Collecting Cortical With ADH – As the tubular fluid reaches the thin and
duct collecting ducts remaining 50% thick ascending loop of Henle, active Na
- reabsorbed and reabsorption occurs. The reabsorbed NaCl
impermeable recycled thru Loop accumulates in the medullary interstitium raising its
(Urea is not of Henle thin limb osmolality. Tubular filtrate becomes diluted as it
reabsorbed) reaches the DCT AND CCT. Under the influence of
Medullary Without ADH – little ADH, there is increased water reabsorption. 99% of
collecting ducts or no urea is the water in the filtrate is reabsorbed thus
- Urea reabsorbed by the increasing tubular osmolality.
reabsorption collecting duct Interstitial fluid osmolality progressively
is proportional increases from the corticomedullary junction down
to the levels to the papilla. Under the influence of ADH, urea
of ADH permeability of the last portion of the IMCD
increases causing urea to diffuse out further
increasing interstitial fluid osmolality.
ROLE OF VASA RECTA (COUNTERCURRENT
EXCHANGER)
FORMATION OF DILUTE URINE
 Vasa recta are capillaries whose structure is
critical to the maintenance of the
As the tubular fluid reaches the thin and
corticopapillary osmotic gradient set up by
thick ascending loop of Henle, active Na
the countercurrent multiplication in the loop
reabsorption occurs. Filtrate is diluted in the
of Henle.
ascending limb of the loop of Henle. Dilute urine is
 Its specialized hairpin (i.e. countercurrent)
formed by allowing this filtrate to continue into the
structure permit it to function as countercurrent
renal pelvis. This will happen as long as ADH is not
exchangers.
secreted. Collecting ducts remain impermeable to
 Its loop structure allows blood flow to reach the
water. No further water reabsorption occurs. Urine
inner medulla but does not wash out the
osmolality can be as low as 50 mOsm.
osmotic gradient.

RENAL PHYSIOLOGY
FACTORS NECESSARY FOR EXCRETION OF Addition of Water

SOLUTE-FREE WATER:
Addition of Water
1. Absent ADH Intracellular Extracellular
2. Normally functioning tubular segments
which separate solute from water: 270 mOsm/kgH20 270 mOsm/kgH20
- Ascending thin LH
- TALH – most important K = 135mEq/L Na = 135 mEq/L
- DT
- CD
25.9 liters 17.6 liters
3. Reduced delivery of tubular fluid to above
nephron segments – impairs ability of
kidneys to maximally excrete solute-free
water ex.  GFR,  proximal tubular
reabsorption - osmolality of ECF decreases
- ECF water diffuses into cell
FACTORS NECESSARY TO EXCRETION OF - both intracellular & extracellular volume
MAXIMALLY CONCENTRATED URINE: Increases
1. Maximal ADH level with normally responsive
CD Addition of Isotonic Saline
2. Normal NaCl tubular reabsorption – TALH
Addition of Isotonic Saline
most important Intracellular Extracellular
3. Adequate delivery of tubular fluid to
nephron segments involved in separation of 280 mOsm/kgH20 280 mOsm/kgH20
solute and water ex.  GFR,  proximal
K = 140 mEq/L Na = 140 mEq/L
tubular reabsorption
4. Hyperosmotic medullary interstitium which is
maintained by NaCl reabsorption by Henle’s 25 liters 18.5 liters
loop and by effective accumulation of urea.
FLUIDS AND ELECTROLYTES

- osmolality of ECF unchanged
EXCHANGE OF WATER BETWEEN ICF & ECF: - no osmosis through
Osmotic cell membranes
and Volume Effects of
CONTROL STATE - only increase in ECF volume seen
Control State Addition of NaCl, Water &
Osmotic and Volume Effects of Addition of NaCl,
Intracellular Extracellular Isotonic Saline
Water & Isotonic Saline
280 mOsm/kgH20 280 mOsm/kgH20
Substances added
K = 140 mEq/L Na = 140 mEq/L
NaCl H20 Isotonic Saline
Plasma Osmolality 0
25 liters 17 liters
Plasma Na 0
Extracellular volume
Intracellular volume 0
Addition of Hypertonic NaCl Urine Na
Addition of Hypertonic NaCl
Intracellular Extracellular EXCHANGE OF WATER BETWEEN PLASMA &
290 mOsm/kgH20 290 mOsm/kgH20 INTERSTITIAL SPACE:
Starling’s Law of Capillaries
K = 145 mEq/L Na = 145 mEq/L Favors filtration (movement of water from
plasma to interstitial fluid)
 capillary hydrostatic pressure
24.1 liters 17.9 liters  interstitial oncotic pressure
Favors reabsorption (movement of water from
interstitial fluid to plasma)
 capillary oncotic pressure
 Extracellular osmolality increases and  interstitial hydrostatic pressure
causes osmosis of water out of cells into
extracellular compartment Net equation = k (P cap + O if) – (O cap + P if)
 Net effect: increase in extracellular FILTRATION =
volume, decrease in intracellular volume ALGEBRAIC SUM (+)
and rise in osmolality in both ABSORPTION =
compartments ALGEBRAIC SUM (-)

RENAL PHYSIOLOGY
CONTROL OF OSMOLALITY: exits across the basolateral membrane,

resulting in net absorption of water.
All solutes contribute to OSMOLALITY 5. With removal of ADH, AQP2 are internalized
Total osmolality = effective osmoles + ineffective into the cells, making the apical membrane
osmoles impermeable to water again.
Effective osmoles – restricted only to ECF
- contributes to total ACID BASE PHYSIOLOGY
osmolality & tonicity ex: Na+, glucose, mannitol
Blood pH is normally maintained within a narrow
Total Osmolality = 2 Na+ + (Glucose / 18) + range (7.35-7.45) by extracellular and intracellular
(BUN / 2.8) + (every solute/mol. wt.) buffering processes through respiratory and renal
Estimation of Osmolality = 2 x (plasma regulatory mechanisms to provide an optimal
[Na+]) chemical environment for cellular function. These
processes dispose of the body's normal physiological
Control of ECF Osmolality load of carbonic acid (as CO2), non-volatile (fixed)
1. Osmoreceptor-ADH system acids and defend against occasional
2. Thirst mechanism addition/accumulation of abnormal quantities of
acids and alkalis.
OSMORECEPTOR-ADH SYSTEM
Acid - Hydrogen (H+) ion donor.
High Plasma Osmolality – plasma osmolality of >270 e.g. HCl, H2C03, acetic acid, uric acid
mOsm/kg H2O
1. Stimulates hypothalamic osmoreceptors Base – Hydrogen ion acceptor.
2. Osmoreceptors activate the hypothalamic e.g. HCO3- = accepts H+ form H2CO3
neurosecretory cells that synthesize and HPO4-- = accepts H+ to form H2PO4
release ADH Proteins = its aminoacids bind with H+
3. Nerve impulses liberate ADH from axon
terminals in the posterior pituitary gland into Strong acid - has very strong tendency to
the bloodstream discharge H+ into the solution. e.g. HCl
4. Kidneys retain more water, which decreases
urine output; Sweat glands decrease water Weak acid - has less tendency to discharge H+ into
loss by perspiration from the skin; Arterioles solution. e.g. H2CO3
constrict, which increases blood pressure
Strong base - removes H+ strongly from solution.
Low Plasma Osmolality e.g. OH-
1. Inhibits hypothalamic osmoreceptors
2. Reduces or stops ADH secretion Weak base - reacts less avidly with H+. e.g. HCO3-
Action of ADH on the collecting duct cell: Buffer – any substance that reversibly consumes or
releases H+ and helps to minimize pH changes
Buffering ability - capacity of a weak acid and

base to resist a change in pH on addition of a
strong acid and base.
pH = symbol used for expressing H+ concentration

using the formula:
pH = log 1/(H+) = -log H+ conc.
= varies inversely with H+ concentration
Low pH = high H+ conc. = ACIDOSIS
High pH = low H+ conc. = ALKALOSIS
Hydrogen Regulation Consist of:

1. Chemical buffering by extracellular and
intracellular buffers
1. ADH binds to vasopressin 2 (V2) receptor at - acts within a fraction of a second.
the basolateral membrane of the cell.
2. Binding increases cAMP. 2. Respiratory regulation
3. Intracellular cAMP activates protein kinase A - altering rate of breathing affecting rate of CO2
(PKA), causing insertion of aquaporin-2 removal
(AQP2) water channels into the apical - acts within 1-12 mins to days
membrane of the cell, as well as synthesis
of more AQP2 channels. 3. Renal regulation
4. AQP3 and AQP4 channels, are present in the - excreting either an acid or alkaline urine
basolateral membrane, so any water that - acts within many hours to several days
enters the cell through the apical membrane - full renal compensation may take 1 to 3 days
RENAL PHYSIOLOGY
TITRATION CURVE FOR BICARBONATE free acid radicals that can dissociate to form
BUFFER SYSTEM: base + H+
Assumes a sigmoidal curve but there is a linear

midregion (pH = 5.1-7.1) in which large amounts of
acid or base can be added without much change in II. Intracellular
pH. Thus a buffer is most efficient when the pH of Buffers
the solution is within  1.0 pH units of its pkA.
1. Organic and
inorganic
TITRATION CURVE FOR BICARBONATE phosphates –
most
Buffering Power is determined by: important
1. pH within + 1.0 from buffer; large
pkA amounts are
2. Concentration of found intracellularly
buffer substances
2. Hemoglobin in erythrocytes
BUFFER SYSTEMS: Chloride Shift - process of exchanging
bicarbonate formed in the
RBC with a chloride ion
from plasma makes
possible CO2 to be
buffered in RBC then
carried as bicarbonate in
plasma.
I. Extracelllular buffers Hemoglobin also contains an unusually large
amount of histidine.
1. Bicarbonate buffer - most important buffer
of ECF because of its high concentration, 3. Tissue protein
CO2 concentration can be regulated by 4. Bone buffers – important source of
ventilation and HCO3 concentration by the bicarbonate
kidneys. - an acid load causes uptake
of excess H+ by bone in
C.A. exchange for surface Na
H+ + HCO3-  H2CO3  CO2 + H20 and K and dissolution of
bone mineral resulting in
- Ability to maintain pCO2 at constant level release of buffer
increases efficiency of bicarbonate buffer compounds CaCO3 and
by 11-fold. CaHPO4 to ECF.
- contributes to 40% of
2. Phosphate buffer - pK is 6.8 which is not buffering of acute acid load
far from 7.4 but since concentration of
phosphate in the ECF is only 1/12 of THE ISOHYDRIC PRINCIPLE
HCO3 it is still not as good as bicarbonate. Any condition that causes H+ concentration
to change, it causes the balance of all buffer
HPO4-2 + H+  H2PO4- system to change at the same time because the
buffer system actually buffers each other by
- Important in renal tubular fluids because shifting H+ from one to the other.
phosphate is concentrated in the tubules where
pH is acidic (pH 7.13 - close to its pk) improving H+ = k1 x pCO2/HCO3 = k2 x H2PO4-/HPO4-- = k3 x
its buffering capacity. HA/A-
- Important in ICF where phosphate is
abundant, and where cell pH is closer to Significance: simply studying the behavior of
pK of phosphate buffer. one buffer system is adequate
3. Protein buffer - most plentiful in the body,

most powerful buffer because pK of proteins RESPIRATORY REGULATION
(amino acids) are not far from 7.4. Proteins
contain multiple negative charges because  Physiological type of buffer – because it acts
of dissociated carboxyl groups on the acidic rapidly
amino acids.  One to two times as great as chemical buffers
H+ + Pr--12  H Pr-11 1. Effect of alveolar ventilation on pH of ECF -

assuming that rate of metabolic formation of
Example: Histidine (pKa = 7.0) – contains CO2 is constant, changes in alveolar ventilation
RENAL PHYSIOLOGY
causes reciprocal changes in H+ concentration DISTAL ACIDIFICATION

and direct relation with pH.
 alveolar ventilation   CO2   [H+] -  Occurs primarily in the intercalated cells found in
 pH the late distal convoluted tubule, the connecting
tubule, cortical and outer medullary collecting
duct.
 Specific H+ secretory pumps (H+-ATPase pumps)
are responsible for the movement of H+ into the
tubular lumen rather than the Na+-H+
countertransport.
 Important in forming a maximally acidic urine
2. Effect of H+ concentration on alveolar

ventilation - by stimulating the respiratory center
in the medulla, increased H+ concentration will
activate the respiratory system, increasing
alveolar ventilation.
 pH   [H+]   alveolar ventilation   pCO2
  Ph
BICARBONATE REABSORPTION
 90% of filtered HCO3- is reabsorbed in the

proximal tubule
 Mediated by Na+-H+ exchangers and HCO3
permeability and H+-ATPase
 10% is absorbed in the more distal tubules
 Remember: HCO3- lost is H+ gain in the body
FACTORS AFFECTING BICARBONATE

TRANSPORT
The change in ventilation rate per unit pH a)  pH -  HCO3- reabsorption
change is much greater at reduced levels of pH b)  pCO2 -  HCO3- reabsorption
compared with increased levels of pH. c)  K+ -  HCO3- reabsorption
d) extracellular volume status
RENAL REGULATION  ECFV -  HCO3- reabsorption
The kidneys regulate extracellular fluid hydrogen

ion concentration through these fundamental
mechanisms:
1) secretion of hydrogen ions
2) reabsorption of filtered bicarbonate ions
3) production of new bicarbonate ions
PROXIMAL ACIDIFICATION
 Energy for H+ secretion is primarily the result of

Na+ pump which transports Na+ across cell’s
basolateral membrane (Na+,K+-ATPase pump)
creating a gradient across the luminal PRODUCTION OF NEW BICARBONATE IONS
membrane favoring entry.
 Since luminal membrane contains Na +-H+ linked The kidney cannot excrete acid as free H+.
transport system (Na+,H+ exchanges), influx of A typical acid intake is 70 mmoles/day. If urine
Na+ results in H+ secretion to the lumen volume is 0.7 liter, then the acid concentration
 The presence of carbonic anhydrase on the would have to be 100 mmole/liter or pH 1. The
brush border of proximal tubules facilitates the kidney is unable to achieve H+ concentration
bulk reabsorption of HCO3- gradients which are this high. Minimum urine pH is

RENAL PHYSIOLOGY
4.5 (0.03 mmoles H+/liter). Thus the H+ must be

excreted with urine buffers.
Role of renal tubule in excreting acid-

containing urine:
1. Removal (reabsorption) of all filtered
HCO3- from tubular fluid
2. Addition of additional H+ in tubular fluid
for elimination in urine
Combination of excess H+ with urine buffers – a
mechanism for generating new bicarbonate ions.
Urine Buffers:
1. Phosphate buffers - major urinary buffer in its
travel from plasma to urine, 5 mmoles of
phosphate can take up 4 mmoles of H+. In the
process, tubular fluid becomes acidified from 7.4
to 5.
Na2HPO4 + H2CO3  Na2HPO4 (excreted) + Renal NH4+ excretion is regulated by:
NaHCO3 (reabsorbed) 1.  pH   H+ secretion
- has little regulation of acid excretion. Urinary 2.  pCO2   H+ secretion
phosphate excretion follows phosphate intake 3.  K+   renal ammonic production
and not the requirement of acid-base balance, so 4. Mineralocortical/Aldosterone stimulates H+
it cannot increase in response to acid load. secretion
ACID-BASE DISORDERS
Classification:
I. Simple Disturbance
a. Respiratory
1. Acidosis
2. Alkalosis (acute, chronic)
b. Metabolic
1. Acidosis
2. Alkalosis
II. Mixed Disturbances

2. Ammonia – more important quantitatively; it is Combination of a and b
the major mechanism by which the kidney
increases urinary H+ excretion; ordinarily RESPIRATORY ACIDOSIS AND ALKALOSIS
accounts for about 2/3 of excreted H+
- In contrast to phosphate buffers, ammonia Dec. alveolar ventilation, inc. pCO2, dec. pH -
synthesis controls urinary acid excretion. It RESPIRATORY ACIDOSIS
increases under conditions when net acid Inc. alveolar ventilation, dec. pCO2, inc. pH -
excretion is required. i.e. acidosis is a RESPIRATORY ALKALOSIS
stimulus for renal ammoniagenesis.
Na2SO4 + 2 H+ + 2 NH3  (NH4)2SO4
(excreted) + 2 Na+ (reabsorbed) RESPIRATORY ACIDOSIS:
- most of the ammonia produced migrate to
the most acidic region of the kidney i.e.  pH = 6.1 + log HCO3 _
collecting duct.  pCO2
- each time an NH3 enters the tubular lumen,
it will bind (1:1) with H+ making the tubular
fluid more alkaline, while still remaining in Etiology -
an acceptable pH range. 1. Inhibition of medullary respiratory center
2. Disorders of respiratory muscles and chest
Process of Ammonium excretion takes place in 3 wall
steps: 3. Disorders of gas exchange across the
1. Ammonium formation (proximal tubule) alveolar capillaries
2. Ammonium reabsorption (TALH) – medullary
recycling: prevent loss of NH4+ Compensation: Renal and Buffers
3. Non-ionic diffusion and Ammonium trapping
(collecting tubule) Tissues and RBC generate HCO3- by taking
+
up H in exchange for Na+ and K+. This acts to

RENAL PHYSIOLOGY
increase HC03- and K+. In time, renal HCO3- 4. Loss of HCO3- from body via gastrointestinal
synthesis will further augment serum HCO 3-. tract or kidney
1. Acute respiratory acidosis: Duration of < 24 Compensation:

hours. No time for renal compensation. 1. ICF buffers and ECF buffers - instantaneous
Tissue and RBC rarely elevate serum HC03-. 57% = ICF buffers
43% = ECF buffers
2. Chronic respiratory acidosis: Duration of >
24 hours. Serum HCO3- rises further due to 2. Respiratory
compensatory synthesis by kidney. Elevated - Metabolic acidosis stimulates both
pCO2 stimulates renal tubular H+ secretion central and peripheral chemoreceptors
and ammonia production. More acid is resulting in increased alveolar
excreted; more HCO3- is synthesized and ventilation (Kussmaul's respiration) and
returned to the blood. fall of pCO2. This will raise the pH
toward normal.
- Compensation begins 1 to 2 hours and
reaches maximum level at 12 to 24
RESPIRATORY ALKALOSIS: hours. However, protective effect lasts
 pH = 6.1 only for few days.
+ log HCO3__
3. Renal
 pCO2 - increased urinary excretion of H+
The Anion Gap

Etiology:
1. Hypoxemia - high altitude If only the three major charged constituents of
2. Psychiatric disorders plasma are considered, there is much more
3. Severe central nervous system diseases positively-charged (Na+) than negatively-charged
4. Aspirin overdose (Cl- and HCO3-) ions.
5. Hypermetabolic states e.g. fever, anemia, Na+ = 140 MEq/L
thyrotoxicosis Cl- = 105 MEq/L
HCO3- = 25 MEq/L
Compensation: Renal & Buffers
The difference between cations (Na+) and
Tissues and RBC act to lower serum HCO3 - anions (Cl- and HCO3-) is called ANION GAP.
by exchanging intracellular H+ for ECF Na+ and K+.
Acts to lower serum HCO3- and K+. In time, there Anion Gap = Na+ - (Cl- + HCO3-)
will be renal retention of acid which further lowers
HCO3-. It is also equal to the difference between
unmeasured anions and cations. The unmeasured
1. Acute respiratory alkalosis: Duration of < 24 anions consist mainly of albumins. The normal
hours. No renal compensation acutely. anion gap is 8-12 MEq/L. It is helpful in the
Metabolic acid production (lactate) increases differential diagnosis of metabolic acidosis.
slightly.
Unmeasured cations = K+, Ca++, Mg++
2. Chronic respiratory alkalosis (CRALK): Unmeasured anions = PO4-3, SO4-2, proteins,
Duration of > 24 hours. Kidney's ability to organic acids
excrete acid is impaired. Fall in buffer
excretion. Retained acid serves to lower When concentrated HCl is added to plasma:
serum Na+. CRALK of <2 weeks is
associated with alkalemia. CRALK of greater
duration may elicit normal pH.
METABOLIC ACIDOSIS AND ALKALOSIS The chloride concentration will increase and the
bicarbonate concentration will fall by the same
amount. The "anion gap” will be unaltered. Normal
METABOLIC ACIDOSIS: anion gap acidosis is also referred to as
“hyperchloremic” acidosis.
 pH = 6.1 + log  HCO3_
pCO2 If a non-chloride acid (e.g. lactic acid, as in
lactic acidosis) is added:
Etiology: H-Lac + Na + HCO3-  Na+ + Lac + H+ + HCO3-
1. Increased acid intake
2. Increased metabolic production of acid H2CO3  CO2
3. Decreased acid excretion by the kidney (excreted by
lungs)
RENAL PHYSIOLOGY
The bicarbonate concentration will fall, while the

chloride concentration will not change. The anion
gap is increased by lactate concentration.
Anion Gap in Major Causes of Metabolic Acidosis
High Anion Gap:
M ethanol intoxication
U remia
L actic acidosis
E thylene glycol intoxication
P Aldehyde intoxication
K etoacidosis
S alicylate intoxication
Normal Anion Gap (hyperchloremic

acidosis):
A. Gastrointestinal loss of HCO3-

1. Diarrhea
B. Renal HCO3- loss
1. Type 2 (proximal) renal tubular
acidosis
C. Ingestions
1. Ammonium chloride
D. Hypoaldosteronism
METABOLIC ALKALOSIS:
 pH = 6.1 + log  HCO3_

pCO2
Etiology:
1. Loss of gastrointestinal secretions
e.g. vomiting or gastric drainage (loss of
HCl)
2. Diuretics - loss of Na+, K+, Cl-
in the urine leaving bicarbonate-rich fluid
in the ECF -"contraction alkalosis"
3. Rapid correction of chronic hypercapnea
4. Increased mineralocorticoid activity
5. Profound K depletion
6. Milk-alkali syndrome - intake of large
quantities of absorbable alkali and calcium
(milk and CaCO3)
Compensation:
1. ICF buffers – immediate exit of ICF H+
derived from PO4-3 and proteins
Small increase in lactic acid production
References:
2. Respiratory - Rose,B.D. Clinical Physiology of Acid-Base and Electrolyte
PaCO2 must be raised to return pH to Disorders. 5th Edition. McGraw-Hill. 2001.
normal therefore, hypoventilation  Guyton,A.C. Textbook of Medical Physiology. 12th
decreased PaCO2 (this adaptation is limited Edition. Saunders. 2011.
by requirement of O2 - decreased PaCO2 Vander, A.J. Renal Physiology. 12th Edition. McGraw-
stimulates chemoreceptors  increased Hill. 2011.
ventilation Berne, Robert M., Physiology, Mosby, 6th edition updated,
2010
3. Renal - increased excretion of HCO3-
Boron, Walter F, Medical Physiology, Saunders, 2nd
updated edition 2011

RENAL PHYSIOLOGY
DEXTER CLIFTON C. PE, M.D.
ADDITIONAL NOTES ON RENAL PHYSIOLOGY:  Aldosterone (RAAS)

 inhibition of ANP & Urodilatin from distal tubule
ACTION OF ADH: cells   water + Na+ excretion
• Primary action is to increase the
permeability of the collecting duct to water Renal response to volume contraction:
• Increases permeability of the medullary  decreased GFR
portion of the collecting duct to urea  increased Na+ reabsorption in proximal tubule
• ADH stimulates reabsorption of NaCl by
 increased Na+ reabsorption in collecting duct
TALH, distal tubule and collecting duct
VOLUME EXPANSION / HYPERVOLEMIA
CONTROL OF ECF VOLUME:
 decreased activity of renal sympathetic
Extracellular Fluid Volume – directly proportional to
nerves
total amount of Na+ in the body
Volume of ECF is determined by Na+ balance.  release of ANP & Urodilatin from distal
A positive Na+ balance = VOLUME EXPANSION tubule cells
A negative Na+ balance = VOLUME DEPLETION  inhibition of ADH from posterior pituitary
 decreased Renin   Angiotensin II
EFFECTIVE CIRCULATING VOLUME
 is the portion of ECF volume contained within Renal response to volume expansion:
the vascular system that is “effectively”  increased GFR
perfusing tissues.  decreased Na+ reabsorption in proximal tubule
 it is directly related to: and collecting duct
 ECF volume (arterial & venous)
 arterial BP
 cardiac output
 Terminologies
 Euvolemia – a state of normal body fluid
volume or ECV
 Volume contraction – may also be referred
to as dehydration clinically
 Volume expansion – may also be referred to
as congestion or fluid overload clinically
EUVOLEMIA
– Na+ excretion by kidneys matches the amount of
Na+ ingested in the diet.
– Na+ reabsorption in proximal tubule (PT), loop
of Henle (LH) & distal tubule (DT) is regulated,
so that Na+ load delivered to collecting duct
(CD) remains constant.
– CD is the main segment where Na+ reabsorption
is adjusted.
VOLUME CONTRACTION / HYPOVOLEMIA

 stimulation / increased activity of renal
sympathetic nerves.
 stimulation of ADH from posterior pituitary  
water permeability DT, CD   reabsorption
 increased Renin   Angiotensin II 

RENAL PHYSIOLOGY
DEXTER CLIFTON C. PE, M.D.
COMPARISON OF RENAL SODIUM HANDLING

DURING EUVOLEMIA,
VOLUME CONTRACTION & VOLUME
EXPANSION
In Euvolemia – normal renal Na+ excretion,
approximately 1% of ingested Na+ load.
In volume contraction – decreased renal Na+
excretion  0%
In volume expansion – increased renal Na+ excretion
– 6%

REVIEW TEST

_____8. This is the ability of the tubules to increase
_____1. These are specialized capillaries that extend Na+ and water reabsorption in response to increased
downward into the medulla supplying the loop of Na+ load:
Henle: A. Renal clearance
A. Vasa recta B. Ultrafiltration
B. Peritubular capillaries C. Autoregulation
C. Capillaries of Bellini D. Tubuloglomerular balance
D. Juxtamedullary capillaries
_____9. Starling’s force that will promote Na+ and
_____2. This is how the kidney handles creatinine: water reabsorption in the proximal tubule:
A. Freely filtered and not reabsorbed, but is A. Increased peritubular capillary hydrostatic
secreted into the tubules. pressure
B. Freely filtered and reabsorbed, but not B. Decreased peritubular capillary oncotic
excreted in the urine. pressure
C. Freely filtered and partially absorbed back C. Increased interstitial hydrostatic pressure
into the blood. D. Decreased interstitial oncotic pressure
D. Freely filtered and neither absorbed or
secreted by the tubules. _____10. Tubular segment that contains a
hypoosmotic fluid compared to plasma:
_____3. This is how the kidney handles amino acids: A. Proximal tubule
A. Freely filtered and not reabsorbed, but is B. Descending limb of the loop of Henle
secreted into the tubules. C. Distal convoluted tubule
B. Freely filtered and reabsorbed, but not D. Inner medullary collecting duct
excreted in the urine.
C. Freely filtered and partially absorbed back _____11. A regulatory hormone that increased Na+
into the blood. and water reabsorption in the different tubular
D. Freely filtered and neither absorbed or segments:
secreted by the tubules. A. Angiotensin II
B. Atrial natriuretic peptide
_____4. GFR ceases and urine output start to C. Dopamine
decrease below this systolic BP: D. Uroguanylin
A. 50 mmHg
B. 60 mmHg _____12. TRUE of the loop of Henle:
C. 70 mmHg A. Reabsorbs majority of the filtered Na+ and
D. 80 mmHg water.
B. Known as the countercurrent exchanger.
_____5. The ideal substance that can be used to C. Permeability to water depends on the
measure GFR because it is freely filtered by the presence of ADH.
glomerulus, neither absorbed or secreted by the D. Responsible for increasing osmotic gradient
tubules: in the interstitium.
A. Creatinine
B. Inulin _____13. Infusion of large amounts of isotonic
C. PAH saline will cause an increase in:
D. Glucose A. Plasma osmolality
B. Plasma Na+ level
_____6. The phenomenon whereby RBF and GFR C. Extracellular volume
are maintained relatively constant as arterial blood D. H+ ion level (acidosis)
pressure changes from 80-180 mmHg:
A. Renal clearance _____14. Action of ADH include/s:
B. Ultrafiltration A. Increases permeability of the loop of Henle
C. Autoregulation to water
D. Tubuloglomerular feedback B. Increases permeability of the medullary
collecting duct to urea.
_____7. Tubular segment that reabsorbs most (2/3) C. Inhibits the absorption of Na+ and water in
of the filtered load of the glomerulus: the loop of Henle.
A. Proximal tubule D. Inhibits reabsorption of water in the
B. Loop of Henle collecting duct.
C. Distal tubule
D. Collecting duct

REVIEW TEST
_____15. Renal adaptation to cases of volume

contraction include/s:
A. Inhibition of the renal sympathetic nerves.
B. Inhibition of the release of ADH from the
pituitary gland.
C. Inhibition of the RAAS.
D. Inhibition of ANP and urodilantin from the
tubule cells.
_____16. This is the most potent stimulus for the

release of ADH:
A. 5% blood loss
B. 5% drop in blood pressure
C. 5% increase in urine volume
D. 5% increase in plasma osmolality
_____17. This causes an decrease in the secretion

of H+ in the proximal tubule:
A. Inhibition of carbonic anhydrase
B. Increasing filtered load of HCO3-
C. Increasing pCO2
D. Decreasing intracellular Na+
_____18. Metabolic acidosis occurs in this situation,

EXCEPT:
A. Rapid addition of acid in the plasma
B. Poor exchange of gases between the blood
and alveolar air
C. Diarrhea
D. Chronic renal failure
_____19. The renal response to metabolic acidosis is

to:
A. Increase in titrable acid and ammonium
excretion
B. Renal excretion of bicarbonate
C. Generation of new phosphate buffer
D. Conservation of hydrogen
_____20. The most important extracellular buffer in

the regulation of acid-base disturbances:
A. Bone buffers
B. Protein buffers
C. Phosphate buffers
D. Bicarbonate buffers

ENDOCRINE PHYSIOLOGY
ELAINE C. CUNANAN, M.D.
ENDOCRINE PHYSIOLOGY 2. Hormonal communication is slower than

neurotransmission.
Objectives: At the end of the lecture, the 3. Neuronal response to NT is all-or-none: Response
REVIEWEE is expected to: to hormones can be graded - minimal to major
effects.
1. Explain the general principles of endocrine 4. Can more easily voluntarily control many neural
physiology. events, but not hormonal ones.
2. Differentiate between the Neural and
Endocrine control systems. A TYPICAL ENDOCRINE SYSTEM:
3. Name the different endocrine glands and
enumerate their hormones and describe Endocrine Gland → Hormone → Target Cell
their major functions in the body. → Receptor → Physiologic effects
4. Explain the mechanisms of control in the
endocrine system. TYPES OF GLANDS:
5. Enumerate and explain the functions of the
ENDOCRINE glands. 1. Endocrine - hormones released reach cells via the
6. Describe and explain the general signs and blood stream.
symptoms of dysfunction of the Endocrine 2. Exocrine- substances are released by cells onto a
system. duct which connects to a surface (local effects)
3. Paracrine - products of the cells diffuse in the
PART I: ENDOCRINE GENERALITIES ECF to affect neighboring cells that may be some
Endocrine Cellular Communication distance away without entering the circulation.
4. Autocrine - acts on the cell in which it is
Cells communicate by chemical signals. produced.
5. Juxtacrine - hormone on one cell can interact
 Neurotransmitters- chemicals secreted from directly with a receptor on a juxtaposed cell as in
a neuron into a synapse causing changes in hemopoeitic growth factors.
postsynaptic neuron.
HORMONE
 Hormones- chemicals secreted by A substance released by an endocrine gland and
specialized cells into the bloodstream where transported through the blood stream to another
they are carried to other parts of the body. tissue where it acts to regulate the function of the
target tissue.
 Endocrine glands - contain specialized cells
that secrete hormones TYPES OF HORMONES:
1. Amines - derived from a single amino acid
TWO MAJOR CONTROL SYSTEMS IN THE tyrosine (or tryptophan)
BODY: 2. Peptide or proteins- derived from chains of amino
1. NERVOUS CONTROL acids
2. HUMORAL or HORMONAL CONTROL 3. Steroids - derivatives of cholesterol
HORMONES AND NEUROTRANSMITTERS THE PROTEIN HORMONES:

(NTs) - formed by the granular ER
- initial protein is almost never the final hormone
Similarities itself usually larger: preprohormone cleaved into
1. Hormones are produced in endocrine cells, and a prohormone  transported to the Golgi apparatus
may be stored there for later release (NT stored in and packaged into secretory vesicles contains
neurons) enzymes cleaves it further into the active hormone
2. Hormone release (or synthesis) must be and copeptides
stimulated by receptor activation (NT activate - Stored in secretory vesicles until stimulus causes
receptors) exocytosis and secretion (water-soluble)
3. Hormones bind with specific receptors (NT bind
with specific receptors) THE AMINE HORMONES:
4. Hormones bind with receptors on surface or • formed by the actions of enzymes in the
inside cells (NT: surface membrane) cytoplasmic compartments of the glandular cells.
5. Binding triggers activities within the cell. • The Adrenal medullary hormones (E and NE) are
6. Some overlap between cells and substances that then absorbed into preformed vesicles and stored
release/serve as hormones and as until secreted (levels regulated by secretion of
neurotransmitters. hormones after stimulus; water-soluble)
7. Drugs/chemicals, diet, behavior can alter • The Thyroid hormones are formed as part of a
hormone levels and effects. large thyroglobulin molecule and then stored
extracellularly in large follicles in the thyroid gland.
Differences
1. NTs travel over synaptic space to receiving THE STEROID HORMONES:
neuron: Hormones travel in blood to different • hormones of the adrenal cortex, the ovaries and
locations throughout body where receptors exist. the testes, and calcitriol.
• Only small amounts stored, however, there are 5. Adrenal (Cortex) – Cortisol, Aldosterone,
large amounts of the precursor molecule DHEAS, androstenedione
cholesterol 6. Adrenal (Medulla) - Epinephrine and NE
• hormone levels regulated at the level of gene 7. Gonads (Testes) – Testosterone, Inhibin
expression of enzymes involved in synthesis of these 8. Gonads (Ovaries) – Estrogen; Progesterone,
hormones (fat-soluble) Relaxin
9. Pancreas – Insulin; Glucagon, Somatostatin;
Hormones, their Receptors and Functions. Pancreatic polypeptide; GI- VIP, gastrin
HORMONE RECEPTORS: Endocrine Feedback systems:

1) Response-driven feedback- circulating
• Normally each cell has 2,000 to 100,000 receptors. component/ physiologic effect causes the
• highly specific for a single hormone. feedback directly
• Locations of these receptors are: 2) Endocrine axis-driven- negative feedback
1. In or on the surface of the cell membrane caused by hormone produced by end target
2. In the cell cytoplasm organ (hypothalamus-pituitary-organ axis)
3. In the cell nucleus long, short, and ultra-short loops
• Receptors must:
1. Distinguish the hormone from all the other PART 2: THE HYPOTHALAMUS AND
millions of molecules to which the cells are PITUITARY GLAND
exposed
2. Transmit the binding information into post- Role of Hypothalamus – Anterior Pituitary
receptor events  The hypothalamus receives signals from the
rest of the brain and body (information on
STRUCTURE OF THE HORMONE RECEPTOR: circadian rhythms, chemical sensors, etc),
and is able to coordinate patterns of its
1. Hydrophilic/Water-soluble hormones hormones’ secretions and triggers
(protein and catecholamines) – receptors  Hormones from hypothalamus travel in
localized on the cell surface with one or special blood system (hypothalamic-
several different subunits and 3 domains: hypophyseal portal vessels) to anterior
a. extracellular domain pituitary
b. transmembrane domain  Bind with receptors in anterior pituitary
c. intracellular domain gland
2. Lipophilic/Fat-soluble hormones (steroid and  Secretion of anterior pituitary hormones is
thyroid)- receptors for Vitamin D, retinoids increased or decreased
and retinoic acid. Receptors are intracellular  anterior pituitary hormones then travel in
(transcription factors) and transported to blood and find receptors on target organs
the nucleus after their binding to the
hormone also having 3 domains: Role of Hypothalamus-Posterior Pituitary
a. Amino (N-) terminal - Axons from hypothalamus travel to Posterior
b. DNA binding domain Pituitary (hypothalamo-hypophyseal tracts, not
c. Carboxy (C-) terminal vessels direct neural connection).
- The hormones ADH/vasopressin and oxytocin are
HORMONE FUNCTIONS: produced in the magnocellular neurons of the
1. Reproduction paraventricular and supraoptic nuclei of the
a. regulate growth and structure hypothalamus, then stored in secretory granules.
maintenance of reproductive organs - Secretory granules with the hormones are
b. produce gametes and continue the transported from the neuron cell body axons
species axonal ends at posterior pituitary (storage only)
c. regulate patterns of sexual behavior - With the stimuli, exocytosis and secretion to
d. establish phenotypic differences bloodstream of the hormones occurs
between sexes
2. Growth and Development (for body size and Anterior Lobe Hormones:
for individual tissues) 1. Prolactin
3. Maintenance of Homeostasis  stimulates the development of mammary
4. Regulation of Energy Availability glands and the production of milk
 inhibits the reproductive axis
THE CLASSICAL ENDOCRINE GLANDS: 2. Growth Hormone (GH)
1. Pituitary (Anterior Lobe) – LH; FSH; Prolactin;  accelerates body growth & stimulates
Growth Hormone; ACTH secretion of IGF-1; has metabolic effects
- -endorphin 3. Luteinizing Hormone (LH)
-(Intermediate Lobe) - Melanocyte stimulating  stimulates ovulation and luteinization of
-endorphin ovarian follicles in the female
-(Posterior Lobe) – Vasopressin or ADH; Oxytocin  stimulates testosterone in male
2. Thyroid – T3; T4 (thyroxine); Calcitonin 4. Follicle Stimulating Hormone (FSH)
4. Parathyroid – Parathormone (PTH)
 stimulates ovarian follicle growth in female In Children: DWARFISM

& stimulates spermatogene-sis in male There is: decreased growth velocity
5. Thyroid Stimulating Hormone (TSH) retarded skeletal development
 stimulates thyroid secretion & gland growth poorly developed musculature
6. Adrenocorticotropic Hormone (ACTH) excess subcutaneous fat
 stimulates secretion and growth of the zona In Adults: Increased insulin sensitivity
fasciculata and reticularis of adrenal cortex Increased body fat
7. -lipotropin Decreased muscle mass
 unknown physiologic role Decreased bone density
Intermediate Lobe Hormones: GROWTH HORMONE EXCESS

1. Melanocyte Stimulating Hormone (MSH) - Causes: Functional Tumor of the pituitary
stimulates melanin synthesis Ectopic Tumors producing GH
2. - endorphin - alleviates pain
In Children: GIGANTISM
Posterior Lobe Hormones: There is increased growth velocity (tall!)
1. Vasopressin - promotes water retention In Adults: ACROMEGALY
decreased serum osmolality and increased BP There is: connective tissue proliferation
2. Oxytocin - causes milk ejection and uterine dermal overgrowth
contraction enlarged extremities
skull deformities
peripheral neuropathies
GROWTH HORMONE insulin resistance (diabetes)
 Stored in vesicles and secreted in pulsatile
fashion by a process of exocytosis OTHER HORMONES INFLUENCING GROWTH
 Diurnal secretion 1. Thyroid Hormones (hypothyroid with stunted
 The surge in GH secretion is found during growth)
deep sleep 2. Androgens – accelerate linear growth (pubertal
 Approximately 1 - 2 mg. are secreted daily growth)
with values higher in puberty.  increase muscle mass (anabolic)
 promotes epiphyseal closure (initially taller
Target Effects than peers but eventually shorter due to earlier
tissues peak)
Bone Proliferation of epiphyseal 3. Estrogens - decrease somatic growth
cartilage, increased synthesis  promotes epiphyseal closure (as above)
Connective Stimulation of proliferation  increase plasma GH levels
Tissue  decrease somatomedin release
Viscera Stimulation of growth 4. Insulin - stimulates fetal somatic growth
Adipose Increase lipolysis higher  increases somatomedin production
Tissues serum fatty acids; anti-insulin 5. Glucocorticoids - inhibit somatic growth
Muscle Increase amino acid entry
protein synthesis; anti-insulin SOMATOSTATIN
Liver Increase glucose output, fatty
acid oxidation, ketogenesis Same chemical substance as the Growth Hormone
Inhibitory Hormone in the hypothalamus. Also
Direct Effects: produced in the delta (D) cells of the pancreatic
Adipose Tissue (increased lipolysis) islets.
Muscle and Liver (insulin antagonism)
Actions:
Indirect Effects - Somatomedins 1. decreases stomach motility
Skeletal growth 2. decreases secretion and absorption in the GIT
Increased protein synthesis 3. decreases insulin and glucagon secretion
Increased cell proliferation
PROLACTIN (PRL)
Outside of endocrine axis (GHRH GH IGF-1): - Actions:
- stimulated by: high serum amino acid content, 1. Development of Mammary glands
hypoglycemia, sleep exercise and ACUTE stress, 2. Milk synthesis/production
estrogen 3. inhibits GnRH and thus the reproductive axis
- inhibited by: somatostatin, hyperglycemia, high
serum free fatty acids, steroids, hypothyroidism, - chronically inhibited by dopamine (prolactin
chronic stress inhibitory factor) from the hypothalamus) secreted
in small amounts throughout life in both genders
GROWTH HORMONE DEFICIENCY - elevated during pregnancy (for mammary gland
Causes: hypothalamic dysfunction development)
primary pituitary lesion

- during breast stimulation (e.g. infant suckling),

neural afferents inhibit hypothalamic dopamine
•Hormone-responsive Tissues are:
Pituitary, Liver, Kidney, Heart, Skeletal Muscle,
release increased PRL milk production
Lung and Intestine, brain
- no “feedback mechanism”
- PRL also increased by exercise and stress (central •Hormone-unresponsive Tissues are:
amenorrhea), hypothyroidism (TRH), serotonin, and Spleen, Testes (previously brain included)
pituitary stalk compression and lesions that interfere
with portal circulation Sites of Action:
1. In the Nucleus - T3 binds with receptors in
VASOPRESSIN or Antidiuretic Hormone /ADH the nuclear chromatin increasing RNA
(Posterior Pituitary) synthesis and increasing cell and enzyme
• Binds to specific receptor (V2) on the serosal activity.
surface of cells of the distal convoluted tubules 2. In the Membrane - T3 binds with a receptor
inducing adenyl cyclase activity (cAMP) protein and increases the uptake of glucose
and amino acids into the cell.
• insertion of pure water channels (aquaporin-2) on 3. Mitochondria - T3 binds with receptors in
luminal membrane of renal DCT and CCT the inner mitochondrial membrane and
reabsorption of solute-free water regulates energy metabolism (direct) and
protein synthesis (indirect).
• Other ADH actions (secondary):
1. acts on V2 receptors on vascular smooth ACTIONS:
muscle (vasoconstriction) 1. Regulation of Growth and Development
2. lower body temperature  through control of protein synthesis
3. facilitates memory consolidation and  important role in development of nervous
retrieval system as in axonal/ dendritic networks and
4. potentiates the release of ACTH in response myelinization
to CRH
2. Calorigenic Effects (mechanism poorly
OXYTOCIN (Posterior Pituitary) understood)
• Detectable during ovulation, parturition, lactation  increases BMR and regulates temperature
and in mild stress (male and female)  increased Na+ - K+ ATPase activity
 enhanced lipolysis (prolonged action) and
• Actions: (primary) lipogenesis (early, plateaus) in adipose
1. stimulates milk ejection by contracting the
myoepithelial cells surrounding the 3. Cardiovascular Effects
mammary gland alveoli and ducts  positive inotropic effects due to increased
2. stimulates rhythmic myometrial contractions number of myocardial beta-adrenergic
in the uterus to aid in the expulsion of the receptors
fetus (labor)  enhanced Ca-ATPase activity in the myosin
• Actions: (secondary) 4. Metabolic Effects

1. has some renal and vascular actions  on FAT - stimulates cholesterol metabolism
mimicking Vasopressin in terms of to bile acids
potentiating ACTH release  enhance lipolytic responses of fat cells to
2. has amnestic and maternal behavioral other hormones
effects through CNS  on CHO - increased CHO utilization due to
3. may act directly on lactotroph for prolactin increased caloric demand
secretion  T3 increases gluconeogenesis (Sandler, et
al, 1983)
PART 3: THE THYROID GLAND HORMONES
PART 4: PARATHYROID AND BONE (Calcium
The Major steps in synthesis are: and Phosphate Balance)
1. iodide uptake by the gland (iodide trapping)
2. oxidation of iodide and iodination of tyrosyl PARATHYROID HORMONE
groups of thyroglobulin (iodide • Initially synthesized as a prohormone, it has
organification) a half-life of 2-5 minutes and is cleared by
3. conversion of iodotyrosyl residues to the liver and kidney to 90%.
iotyrosyl residues in thyroglobulin • Actions:
4. proteolysis of thyroglobulin and release of 1. Bone – dual action: increased resorption if
T4 and T3 in the blood continuous secretion, increased formation if
5. conversion of T4 to T3 in peripheral tissues intermittent
 higher levels of T4 produced and more bound to 2. Kidney - increases tubular reabsorption of
proteins in blood (TBG) than T3 Calcium
 T3 (active hormone) has higher physiologic o inhibits tubular reabsorption of
activity than T4 phosphate, AA, Na, Cl and bicarbonate

o enhances the conversion of calcidiol to • On Fat Metabolism

calcitriol  increases fatty acid mobilization from fat
3. GIT - acts indirectly (via calcitriol) to cells
increase intestinal absorption of Ca++ and  increases free FA concentration in plasma
phosphate.  increases FA oxidation
4. Decreases the Ca++ concentration in milk,  decreases glucose transport into fat cells
saliva and lens blood  promotes ketogenesis
5. Recently, has been found to be vasoactive  fat distribution - buffalo hump and moon
and cardioprotective. facies
Feedback Mechanism: Negative feedback from high • Increases Resistance to STRESS

calcium and calcitriol, as well as low phosphorus • Causes bone resorption
levels • RBC Changes
 diminished eosinophils
CALCITONIN  increases RBC, neutrophils and platelets
• Secreted by the parafollicular/C cells of the  decreases lymphocytes
thyroid gland • Decreases the immune response due to atrophy
• Essentially a HYPOCALCEMIC hormone of lymphoid tissue and decrease in T-cell and
antibodies, also decreased neutrophil function
• Actions: • Increases vascular reactivity
1. Bone - inhibits bone resorption • Anti-inflammatory activity due to:
2. Kidney - inhibits reabsorption of Ca++ and  stabilization of the lysosomal membrane
phosphate  decreases capillary permeability
 inhibits chemotaxis
The NET Effect: Decreased serum concentration of  inhibits fibroblastic activity - so no “walling
Ca and phosphate off” of infection
 lyses fever due to pyrogen release inhibition
PART 5: ADRENALS in granulocytes
 Has mineralocorticoid effects when in excess
THE ADRENAL HORMONES: ADRENAL CORTEX
• From the Zona Glomerulosa (via PATHOLOGIC EFFECTS OF GLUCOCORTICOIDS
ReninAngiotensin II causes direct stimulation,
also hyperK) 1. CUSHING’S Syndrome
 Mineralocorticoid (aldosterone): for ECF Characterized by:
volume regulation and Na+ and K+ balance, a. weakness and loss of muscle mass
secondarily acid-base balance b. thinning of the skin with striae formation
c. osteoporosis
• From the Zona Fasciculata (stimulated by ACTH) d. poor wound healing
 Glucocorticoid (cortisol) - glucose and e. increase in facial hair and acne
protein metabolism f. buffalo hump, moon facies
 Sex Steroids g. hypertension
h. insulin resistance
• From the Zona Reticularis
 Glucocorticoids (cortisol) 2. GIT Effects (steroid Ulcers)
 Sex Steroids (DHEA, androstenedione) - a. interferes with prostaglandin synthesis (which
gonadal supplement inhibits acid secretion)
b. increases gastric acid and pepsin secretion
GLUCOCORTICOIDS (Cortisol)
3. Increased capillary fragility (easy bleeding and
Actions and Effects: bruising)
• On Carbohydrate Metabolism (anti-
insulin/counter-regulatory hormone) MINERALOCORTICOID (Aldosterone)
 stimulates gluconeogenesis
 decreased glucose utilization by other cells A. Stimulates Sodium (Na+) reabsorption in the:
 increased blood glucose concentration -  kidneys
adrenal diabetes  sweat glands
 salivary glands
• On Protein Metabolism  stomach
 reduces protein stores in all cells except B. Stimulates Potassium (K+) excretion in the:
hepatic cells  kidneys
 increases plasma proteins and liver proteins  sweat glands
 increases deamination rate of amino acids  salivary glands
by hepatocytes
 increases conversion of amino acids to C. Stimulates hydrogen ion (H+) excretion in the:
glucose  kidneys

PATHOLOGIC EFFECTS OF - favors gluconeogenesis from fatty acids

MINERALOCORTICOIDS - inhibits lipogenesis (FA formation)
On CHON - favors protein catabolism, inhibits
Adrenal Insufficiency Aldosterone anabolism
excess - promotes gluconeogenesis from amino acids
hyponatremia hypernatremia Therefore: Overall a catabolic and counter-
hyperkalemia hypokalemia regulatory hormone, making energy (glucose)
acidosis alkalosis available for use by important (non-insulin-requiring)
decrease in ECF volume hypertension organs
ADRENAL MEDULLARY HORMONES INSULIN

Notes:
Epinephrine - from epinephrine secreting cells which • A polypeptide composed of 2 AA chains
make up 90% and are larger with less dense connected by a disulfide link.
granules; • It starts as a PREproinsulin after appropriate
mRNA translation and then it is cleaved in the
Norepinephrine - from NE secreting cells which ergastoplasm to PRO insulin.
make up 10% and are smaller with more dense • PROinsulin divides into 3 parts: A, B and C
granules. peptides.
• In the secretory granules packed in the Golgi
Notes: apparatus, the C-peptide is cut off from the rest
 Both hormones are sourced from Tyrosine and co-secreted with insulin.
 The rate limiting step is the conversion of • The C-peptide therefore, when measured by
tyrosine to DOPA radioimmunoassay, becomes an index of insulin
 Both are released from the adrenal medullary secretion and b-cell function.
cells by exocytosis initiated by AcH from
preganglionic neurons innervating the secretory  Take note of tissues which require insulin
cells for glucose entry: primarily muscle and fat
 Metabolism is by: Methylation (COMT) and  Insulin does not facilitate glucose uptake in:
Oxidation (MAO) (KRIB)
 50%- 80% are reuptaken by active transport o Kidney
o Intestinal mucosa
PART 6: THE ENDOCRINE PANCREAS o RBC
The pancreas is made up of two types of tissues, o Brain
namely:
1. ACINAR tissue - concerned with pancreatic INSULIN EFFECTS: (Carbohydrate
exocrine function, and - Metabolism)
2. ISLET OF LANGERHANS - concerned with  STIMULATES GLYCOGENESIS AND GLYCOLYSIS
endocrine function  INHIBITS GLUCONEOGENESIS
through:
The Islets of Langerhans has 4 cell types:  increase in cell permeability to CHO
Alpha cells - secrete GLUCAGON  increase in cell trapping of CHO via activation of
Beta cells - secrete INSULIN glucokinase
Delta cells - secrete SOMATOSTATIN  inhibition of glucose release via inhibition of
E cells - secrete Pancreatic Polypeptides phosphatase
 stimulation of glycogenesis via activation of
GLUCAGON glycogen synthetase and inhibition of
phosphorylase
It is a single chain polypeptide (unlike insulin) with  stimulation of glycolysis via activation of
29 AAs. phosphofructokinase
Mechanism of Action: Mediated through 2 second INSULIN EFFECTS: (Protein Metabolism)

messengers:  STIMULATES PROTEIN ANABOLISM
1. cAMP - promotes glycogenolysis and inhibits  INHIBITS PROTEIN CATABOLISM AND
glycolysis GLUCONEOGENESIS
2. Inositol Triphosphate - release of intracellular through:
Ca++  Increase in cell permeability to amino acids
- promotes glycogenolysis  Increase in transcription of DNA
 Increase in translation of mRNA
Effects:  Inhibition of transamination of amino acids into
On CHO - promotes glycogenolysis and pyruvate
gluconeogenesis
- inhibits glycolysis INSULIN EFFECTS: (Fat Metabolism)
 increased serum glucose  STIMULATES LIPOGENESIS (Triglyceride
On Fats - favors lipolysis - increased Synthesis)
cholesterol/ketone formation  INHIBITS LIPOLYSIS and GLUCONEOGENESIS
through:
 increase in cellular permeability to fatty acid
 stimulation of Lipoprotein lipase
 conversion of excess CHO to glycerophosphate
and acetyl CoA
 inhibition of Hormone sensitive Lipase
 inhibition of Carnitine transport
 inhibition of glycerol conversion to glycerol
phosphate
INSULIN PECULIARITIES:
• Insulin can be used in hyperkalemia as it
increases cellular permeability to K+, Mg
and phosphates.
• HgbA1c, a derivative of adult Hgb has a terminal
Valine chain irreversibly attached to glucose,
hence this Hgb can reflect blood sugar level of a
subject for the past 4 - 6 weeks.
SOMATOSTATIN
Same chemical substance as the Growth Hormone
Inhibitory Hormone in the hypothalamus
Actions: Requirements:
1. decreases stomach motility 1) Intratesticular testosterone
2. decreases secretion and absorption in the GIT 2) LH→ Leydig cells
3. decreases insulin and glucagon secretion 3) FSH→ Sertoli cells
4) GH
Theoretically: 5) estrogen?
1. It extends time period wherein food is
assimilated from the GIT into the blood so Negative feedback:
pancreas can control absorption of nutrients Testosterone, inhibin
from GIT according to its secretory capability.
2. Regulates islet cell secretion to adjust pattern of ANATOMY
hormone secreted in response to various stimuli.
PANCREATIC POLYPEPTIDE
It is a linear polypeptide with 36 amino acid
residues.
Actions:
1. inhibits pancreatic enzyme secretion
2. inhibits gall bladder contraction
3. inhibits gut motility and gastric emptying
Its exact physiologic function is presently unknown.
PART 7: REPRODUCTION
MALE REPRODUCTIVE SYSTEM

SPERMATOGENESIS
TESTOSTERONE
Actions:
- in reproduction: role in spermatogenesis, penile
growth, prostate growth and seminal fluid
secretion, development of other secondary
sexual organs (with 5-dihydrotestosterone)
- male physique/physical features: increased
muscle mass (strength and volume), thicker skin
and subcutaneous tissue, hair loss and balding,
sebum production (acne)
- others: libido and aggression, liver synthesis of
serum proteins, increased bone density and
basal metabolic rate, erythropoietin production,
bone marrow stem cell production, linear bone
growth and epiphyseal closure.

FEMALE REPRODUCTIVE SYSTEM ESTROGEN ACTIONS

OOGENESIS
- Growth and development of internal and external
genitalia (puberty)
- Thicker endometrium and fallopian tube lining,
more functional cilia
- Female breast development
- Bone- inhibits osteoclasts (via OPG), epiphyseal
closure
- Slight increase in protein
- Increased BMR (<testosterone), female fat
distribution (buttocks, thighs)
- Minimal on hair (adrenal androgens)
- Soft smooth skin
- Sodium and water retention
- Cognition
PROGESTERONE ACTIONS
- Secretory uterine endometrium (for implantation)
- Increase secretion in fallopian tube lining
- Proliferation and enlargement of lubules and
alveoli of breasts, swelling
FEEDBACK MECHANISMS
ANATOMY
Testosterone, estrogen, progesterone inhibits
Ovary LH>FSH
Fallopian Tubes Inhibin from ovaries and testes inhibit FSH
Uterus
Cervix
Vagina
THE MENSTRUAL CYCLE

REVIEW TEST
ELAINE C. CUNANAN, MD

______12. Decreased ACTH secretion would be
______1. Which of the following hormones is a expected in which condition?
glycoprotein? A. Addison’s Disease
A. Triiodothyronine B. Chronic exogenous steroid use
B. Tetraiodothyonine C. Cushing’s Disease
C. Thyroid stimulating hormone D. Primary adrenal insufficiency
D Thyrotropin releasing hormone ______13. Which of the following hormone is
______2. Which of the following hormones is a important for milk-letdown?
transcription factor? A. Melatonin
A. Cortisol B. Oxytocin
B. Glucagon C. Prolactin
C. Insulin D. Vasopressin
D. Epinephrine _____14. Which of the following effects are
______3. Which of the following hormones uses stimulated by growth hormone?
inositol 1,4,5- triphosphate (IP3) second messenger A. glycolysis
system? B. glycogenesis
A. Aldosterone C. lipogenesis
B. Calcitriol D. protein synthesis
C. Tetraiodothyonine _____15. Which of the following is true of luteinizing
D. Thyrotropin releasing hormone hormone?
______4. Which of the following hormones has the A. It is primarily regulated by inhibin.
slowest metabolic clearance rate (longest half-life)? B. It is not controlled by negative
A. Cortisol feedback.
B. Growth Hormone C. It can be stimulated by a steroid
C. Thyroxine hormone.
D. Parathyroid D. Its hypothalamic hormonal controller is
______5. Which of the following leads to an mainly inhibitory.
increase in free T4 level in plasma? ______16. Which of the following hormones
A. Pregnancy enhances insulin secretion?
B. Hypopituitarism A. ADH
C. Hyperalbuminemia B. ANP
D. Exogenous thyroxine intake C. IGF-1
______6. Intake of which of the following will D. GLP-1
increase the secretion of aldosterone? ______17. Which of the following hormones
A. Corticosteroids decreases in response to exercise?
B. Potassium rich meal A. Insulin
C. Angiotensin-receptor blocker B. Cortisol
D. Angiotensin-converting enzyme inhibitor C. Glucagon
______7. Which of the following occurs with D. Growth hormone
hyperthyroidism? _____18. Which of the following can occur as an
A. increased heart rate effect of high prolactin levels?
B. increased catecholamine levels A. hyperthyroidism
C. increased serum glucose levels B. pituitary stalk compression
D. decreased basal metabolic rate C. amenorrhea
______8. Which of the following stimulates secretion D. milk ejection
of growth hormone? _____19. Which of the following biochemical
A. IGF-1 processes is stimulated by glucagon?
B. Arginine A. Glycolysis
C. Glucose B. Glycogenesis
D. Somatostatin C. Ketogenesis
_____9. Which of the following stimulates D. Lipogenesis
conversion of 25-hydroxycholecalciferol to _____20. Which of the following hormones inhibits
1,25 dihydroxycholecalciferol? bone resorption?
A. PTH C. Calcitriol A. Cortisol
B. Calcitonin D. RANK-ligand B. Calcitonin
_____10. This hormone is synthesized from tyrosine. C. Thyroxine
A. Aldosterone C. Prolactin D. Aldosterone
B. Epinephrine D. Vasopressin
______11. Which of the following Inhibits prolactin
secretion?
A. Dopamine
B. Estrogen
C. Serotonin
D. Thyrotropin-releasing hormone

RESPIRATORY PHYSIOLOGY
TIM S. TRINIDAD, MD
CELESTE MAE CAMPOMANES, MD
QUESTION QUESTION
Which of the following occurs to atmospheric air during ascent to high altitude? Which of the following explains why the PaO2 is much lower than PAO2?
A- Atmospheric pressure increases A- Upper airway humidification of air
B- FIO2 remains constant B- Low atmospheric pressure
C- Nitrogen concentration remains constant C- VQ relationship in the normal lung
D- PIO2 increases D- Left to right shunt due to bronchial circulation
1) Gas Composition of Atmospheric Air at Sea Level 2) Changes in O2 tension from Atmosphere to Mitochondria
a) Dalton’s Law of Partial pressures
i) Total pressure of a mixture of gases is the sum of their individual partial Compartment Mean Comments
pressures PO2
ii) Partial pressure of a particular gas is equal to its fractional concentration Atmosphere PIO2 160 O2 is 21% of room air
times the total pressure of all the gases in the mixture
b) Composition of Inspired Air Airway 150 Humidification of inspired air decreases
(dilutes) O2
Fractional Gas pressure Volume in Alveoli PAO2 104 Dependent on the delivery of O2 from the
Concentration of at sea level 500 cc of air atmosphere (input) & diffusion across the
Inspired air (Fix) (760mm hg) AC membrane (output)
Nitrogen 78% 593 390
Oxygen 21% (FiO2) 160 105 End Capillary PcO2 104 Dependent on the VQ relationship of the
respiratory unit
CO2 0.03 0.2 0.2
Others 0.97 7.4 4.8 Arterial PaO2 100 Lower than PcO2 due to the presence of
Sum 100 760 500 physiologic shunts
Tissue PtO2 23 Due to the metabolism of the cells
c) Relationship between PIO2 and Altitude Venous PvO2 40 Mixture of all deoxygenated blood coming
i) Atmospheric pressure decreases (less than 760) during ascent from the different tissues of the body
ii) FiO2 remains constant
iii) PIO2 decreases QUESTION
d) Relationship between PIO2 and Deep Sea Diving Which the following is equal to function residual capacity?
i) Atmospheric pressure increases (more than 760) during descent A- IRV + TV
ii) FiO2 remains constant B- ERV + RV
iii) PiO2 (and PiN2) increases C- TLC – VC
iv) More O2 and Nitrogen dissolved in plasma D- VC- IC
v) Rapid ascent may cause decompression sickness

TIM S. TRINIDAD, MD
(1) To better retain the diff. lung volumes, students are advised to memorize
3) L the word ITER (IRV + TV + ERV + RV)
TOTAL LUNG CAPACITY (TLC) VITAL CAPACITY (VC) ung
volum
INSPIRATORY es and
IRV I I I CAPACITY Capaci
(IC) ties
TV T T T Lung Capacity: Combinations of 2 or more lung volumes
FUNCTIONAL
ERV E E E Therefore:
RESIDUAL
CAPACITY v) TLC = IC + FRC
RV
R (FRC) vi) TLC = VC + RV
R
vii) VC = IC + TV
viii) FRC = TLC-IC
ix) IC = TLC- FRC
x) And many more the examiner can think of
QUESTION
Which of the following is equal to the difference between alveolar and atmospheric
pressure?
A- Trans pulmonary pressure
IRV TV ERV RV B- Trans airway pressure
Inspiratory Capacity IC X X C- Trans chest wall pressure
Functional Residual Capacity FRC X X D- Trans respiratory pressure
Vital Capacity VC X X X
Total Lung Capacity TLC X X XP X 4) Distending Pressure of the
a) Lung Respiratory Organs (Trans Pressures)
Volumes
i) Total Volume (TV or VT) - the amount of air that goes in and out of our
lungs during normal quiet respiration. It has two points, the PEAK TIDAL
POINT or END INSPIRATION and END TIDAL or END EXPIRATION.
ii) Inspiratory Reserve Volume (IRV) - the volume of air that can be
additionally inspired maximally from end inspiration.
iii) Expiratory Reserve Volume (ERV) - the volume of air that can be
additionally expired maximally from end expiration.
iv) Residual Volume (RV) - the amount of air remaining in the lungs after
maximal expiration.

TIM S. TRINIDAD, MD
b) Origin of Lung Elastance
a) There are several pressures that influence the configuration (shape) of the i) Elastic tissue content (1/3) of the lungs elastic property.
respiratory organs ii) Surface tension (2/3)
i) Pressure in the different compartments (1) Due to the water lining the alveolar lumen
(1) Atmospheric Pressure (Patm) (2) Decreased by the surfactant secreted by the type 2 pneumocytes
(2) Airway opening pressure (PAO) c) How Compliance is Measured
(3) Alveolar Pressure (Palv) i) Compliance = Change in Lung Volume / Change in Pressure
(4) Pleural Pressure (Pip) (1) During inspiration we needed to generate a pleural pressure from 5 to
ii) Pressure between 2 different compartments 7.5 cm H2O to increase or inflate the lung by 500 cc.
(1) Transairway pressure (PAW)= (PAO) - (Patn) (2) Compliance = 500 cc / (7.5- 5) = 500 /2.5 = 200 ml/ cm H2)
(2) Transpulmonary (Translung) pressure (Ptp)= (PAlv) - (Pip)
(3) Transthoracic pressure (Pcw)= (PP) - (Patm)
(4) Transrespiratory pressure (PRS)= (PA) - (PAtm)
b) Significance of the Trans pressure
500
i) Trans pressure represents the elastic property of structure EXPIRATION
ii) If positive the structure has a tendency to collapse LUNG

iii) If negative the structure has a tendency to expand VOLUME
INSPIRATION
QUESTION 0
Which of the following statements best describe the elastic property of the respiratory 5 7.5
system? At FRC PLEURAL PRESSURE
A- The lungs have a natural tendency to expand

B- The chest wall has a natural tendency to contract d) Compliance of the Respiratory System
C- The respiratory system is most compliant
D- The respiratory system is most elastic
4) Elastic Properties of the Respiratory System

a) Elastance VS Compliance
i) Elastance
(1) Narrative Definition
(a) Tendency to recoil back to its original configuration
(b) Resistance to deformation
(c) Collapsibility
(2) Mathematical Definition: Change in pressure/ Change in volume
ii) Compliance
(1) Narrative Definition
(a) Ability to be deformed
(b) Inflatability
(2) Mathematical Definition: Change in volume/ Change in pressure (CVP)

TIM S. TRINIDAD, MD
ii) Due to the opposing elastic properties, a negative intrapleural pressure is
e) Elastic Properties of the Respiratory System generated.
i) Characteristics of the Compliance Curve/Line b) Why is the FRC the relaxed lung volume?
(1) It is tri-phasic in characteristics i) At FRC, Ptp = PCW
(2) Less compliant from 0 to 25% of VC (near RV) c) What is the significance of the FRC as being the relaxed lung volume?
(3) Very compliant from 25% to 75% of VC (at FRC) i) If a person inspires above FRC and relaxes his inspiratory muscle, the
(4) Less compliant from 75% to 100% of VC (near TLC) respiratory system will passively collapse back to FRC.
ii) Shifting of the Compliance Curve ii) If a person expires below FRC and relaxes his expiratory muscle, the
(1) Right shift: means diminished compliance (ARDS or pulmonary fibrosis) respiratory system will passively recoil back to FRC.
(2) Left shift: means increased compliance (Emphysema)
QUESTION
The alveolar pressure is most negative at which part of the tidal breathing?
A- Start of inspiration
B- Mid inspiration
C- End of inspiration
D- Mid expiration
6) Events During Tidal Breathing (normal conditions)

a) Principles
i) Air moves from greater to lesser pressure
ii) It is the pressure difference between PAO & PA which governs flow
f) Elastic Properties of the Respiratory System iii) The proper sequence of events are as follows:
i) Lungs has the tendency to (1) Pressure change
(1) Collapse from RV (0% of the vital capacity) to TLC (100% of the vital (2) Flow of air
capacity) (3) Volume change
ii) Chest wall has the tendency to b) Events
(1) Expand from RV to 60% of the vital capacity FRC Mid Mid Expiration
(2) Contract from 60% of the vital capacity to TLC Inspiration
iii) Respiratory system (lungs and chest wall combined)
(1) Expand from RV to FRC Mouth Pressure 0 0 0
(2) Contract/Collapse from FRC to TLC
5) FRC: Relaxed Lung Volume Alveolar Pressure 0 -1 +1
a) Origin of the Negative Intrapleural Pressure
i) At FRC Intrapleural Pressure -5 -7.5 -5
(1) Chest wall wants to expand
(2) Lungs want to contract

TIM S. TRINIDAD, MD
QUESTION
0 0 0 Which of the following is accurate with regards small airway resistance?
A- Contributes highest to the total airway resistance
B- Highest at TLC
0 0 -1 -1 +1
-5
+1 C- Not dependent on bronchial smooth muscle contraction
-5 -7
D- Inversely related with lung elastance
FRC INSPIRATION EXPIRATION
i) Inspiratory Phase 7) Respiratory System’s Airway Resistance

(1) Inspiratory muscle contracts increases the pleural cavity volume a) The frictional resistance offered by the airways is known as the resistance of the
(2) Intrapleural pressure becomes more negative (Boyle’s law: volume and airway.
pressure are inversely related) b) Ohm’s law
(3) Distends the alveoli (increased volume) & makes the alveolar pressure Driving pressure
negative (Boyle’s law) Flow = -------------------------
(4) Air flows into the alveoli (PAO > PA) Airway Resistance
(5) Lung volume increases i) The greater the driving pressure, the greater is the flow.
ii) Expiratory Phase ii) The greater the airway resistance, the lower is the flow
(1) Inspiratory muscles relax c) The amount of resistance offered by airway depends on
(2) Respiratory system passively collapse back to FRC (due to its elastic i) Type of flow pattern
property) (1) Flow Pattern
(3) Intrapleural pressure becomes less negative & alveolar pressure (a) Movement of air
becomes positive (i) Nose till terminal bronchioles: Bulk flow
(4) Air flows from the alveoli in the atmosphere (PA > PAO) (ii) Respiratory zone: Diffusion
(5) Lung volume decreases (b) Types of Bulk Flow: Bulk flow has 3 patterns, which is determined by the
iii) Apnea Phase Reynolds Number
(1) Airflow ceases and nothing happens Density X Velocity X Diameter
(2) As the respiratory center shifts command from expiration to inspiration Reynolds Number = -----------------------------------------
c) Relative Duration Viscosity
i) Apnea is considered as part of expiration and therefore the Inspiratory to (i) Turbulent (RN > 2000) pattern
Expiratory (duration) ratio is 1 is to 2-3 (1:2-3). 1. Occurs in the trachea
Expiratory is usually 2 to 3 times longer than inspiration 2. Large airway diameter and rapid airflow velocity
(ii) Laminar (RN < 1000) pattern
QUESTION 1. Occurs in the bronchioles
Which of the following causes a turbulent airflow pattern? 2. Small airway diameter and slow airflow velocity.
A- Low gas density (iii) Transitional (RN 1000-2000)
B- Slow airflow velocity 1. Occurs in the large airways
C- A low Reynolds number (c) Quantity of Resistance offered by different airflow patterns
D- A large luminal airway diameter (i) Laminar (bronchioles) – least resistance

TIM S. TRINIDAD, MD
(ii) Transitional (large airways) -
(iii) Turbulent (trachea) – highest resistance i) The greater airway resistance, the lesser the ventilation
ii) Physical Attributes of the Airways & Gas (Pouiselle’s law) ii) The greater the compliance, the greater the ventilation (during inspiration)
Viscosity x length of the tube (1) Right shift of the compliance (pressure volume) curve
Airway resistance = ------------------------------ (a) Means less compliant lungs
Radius of the tube (b) Leading to less ventilation
(1) Radius of the Tube is dependent on (2) Left shift of the compliance (pressure volume) line
(a) Mucosal Thickness (a) Means more compliant lungs
(b) Smooth Muscle Tone (b) Leading to greater ventilation (during inspiration) but with airflow limitation
(c) Tethering Effect (Elastic Pull) of the Surrounding Lung Parenchyma during expiration
(i) The higher the lung volume  greater is the elastance  b) Regional Distribution of Ventilation in an Upright Lung
greater luminal diameter  lower small airway resistance (1) Factors that determine compliance of the Alveoli
(2) Factors which can decrease airway caliber (a) Transpulmonary pressure (Ptp)= (Palv) - (Pip)
(a) Smooth muscle contraction (i) PL is the distending pressure of the alveoli.
(b) Parasympathetic tone (ii) The greater the PL, the more distended the alveoli.
(c) Mucosal edema (iii) Alveolar pressure (PA) is not affected by gravity.
(d) Mucus hypersecretion (iv) Intrapleural pressure (PIP) is affected by gravity
(e) Bronchial gland hyperplasia (v) Upper lung zone has a more negative PIP
(f) Decrease lung elastance (vi) Upper lung zone has greater transpulmonary
d) Distribution of Total Airway Resistance (TAR) (vii) Upper lung zone alveoli is more distended
i) Nose: 50%
ii) Pharynx till large airways: 30% (b) Configuration of the Alveoli
iii) Small (peripheral) airways: 20% (i) Moderately distended alveoli: most compliant
(1) Reason despite a small radius it accounts only 20% (ii) Almost collapse alveoli: less compliant
(a) Large surface area (dichotomous branching system of the small airways). (iii) Almost fully distended: less compliant
(b) Laminar flow pattern TRANS- INTRA- ALVEOLAR
PULMONARY PLEURAL PRESSURE
PRESSURE PRESSURE
QUESTION
FRC-TLC
Which of the following most accurately described inhalation from RV to TLC? +10 -10 O
LUNG
VOLUME
A- The bases are ventilated from RV to FRC (L)
B- The apices are ventilated from FRC to TLC +5 -5 O
C- AT RV, the lower lung zones are more compliant upper lung zone O
RV-FRC
D- AT FRC, the lower lung zones are more moderately distended **** +2 -2
8) Ventilation TRANSPULMONARY
PRESSURE (CM H20)
a) Factors that Determine Ventilation
Compliance (2) Alveoli Configuration/ Compliance at Residual Lung Volume
--------------------------- = Ventilation
Airway Resistance

TIM S. TRINIDAD, MD
Zone Alveoli Configuration Compliance
CELESTE MAEVentilation
CAMPOMANES, MD
Upper Moderately distended Higher Greater
Lower Almost collapse
(3) Alveoli Configuration/ Compliance at Functional Residual Capacity b. WOB during normal tidal breathing
Zone Alveoli Configuration Compliance Ventilation

Upper Almost fully distended
Lower Moderately distended Higher Greater
(2)Summary of Regional Ventilation: As a person inhales from RV to TLC, the regional i. Only 5% of the total energy expended
ventilation differs ii. Person is not aware not aware of the work of breathing
(a) From RV to FRC: Upper lung zone are better ventilated c. Increase WOB
(b) From FRC to TLC: Lower lung zone are better ventilated i. Increase Viscous Resistance (Addition of non elastic tissue in
(c) Since a person’s tidal breathing is done above FRC, the person’s lower are 8X the lungs)/ Elastic
better ventilated compared to the upper lung zone 1. Exudates in Pneumonia
2. Transudates in CHF
QUESTION 3. Fibrotic Tissue in Pulmonary fibrosis
Which work of breathing component increases in a patient with pneumonia? ii. Increase Airway Resistance: Asthma
A- Elastic iii. Increase Elastance: Hyaline Membrane of the new born
B- Non-elastics
C- Airway resistance QUESTION
D- Viscous tissue resistance Which of the following constricts the pulmonary arterioles?
A- Oxygen
2) Work of breathing B- Nitric oxide
a)Method of Measurement C- Prostaglandin
ii) Conventionally, work is equal to force times distance. D- Thromboxane A2
iii) In pulmonary physiology, pressure and volume are used as surrogate
markers for force and distance respectively. (3) Blood Flow in the Lungs
iv) Work of breathing is equal product of pressure & volume. a. Bronchial Circulation
v) The pressure volume loop reflects the work of breathing. i. The bronchial artery is a branch of the aorta.
b)The respiratory muscles contract to generate driving pressures that propel a volume of ii. The deoxygenated blood in the bronchial vein leaving the airways
air in and out of the lungs. drains into the pulmonary veins (which contains the oxygenated blood)
i) The greater the airway resistance and elastance therefore producing an (R  L) anatomic shunt.
ii) The greater will be the contraction of the muscles to generate the necessary iii. The connection between the bronchial and pulmonary vein is one of
driving pressure the normal anatomic shunts in the circulation. The other shunt is the
a. Work of breathing is divided into the following: The besian vein draining into the left ventricle.
i. Non-elastic work: 35%
1. Viscous resistance: 7% b. Pulmonary Microcirculation
2. Airway resistance: 28% i. Pulmonary capillaries are the site wherein exchanges of solutes and
ii. Elastic work: 65% liquid occur between blood, lung interstitum and alveolar cells.

TIM S. TRINIDAD, MD
ii. The exchange is governed by Starling’s Law (Forces) Function Blood flow supply Blood oxygenation and CO2
Flux = K (Pc-Pi) -  (c -i) regulation elimination
Abbreviation Symbolize Favors Resistance High Low

K Hydraulic Conductivity
Pc Capillary Hydrostatic Pressure Filtration Pressure High Low
Pi Interstitial Hydrostatic Pressure Absorption
Response Vasodilatation Vasoconstriction (compensatory
 Average Colloid Osmotic Reflection Coefficient
to Hypoxia mechanism for VQ abnormality)
C Capillary Oncotic Pressure Absorption
I Interstitial Oncotic Pressure Filtration
iii. Significance of a FLUX QUESTION
(1) Positive flux Which following best describe the pulmonary vascular resistance (PVR)?
a. Filtration forces > Absorption forces (congestive heart failure, A- PVR due to extra alveolar vessels is highest at TLC
hypoalbuminemia) B- PVR due to alveolar vessels is highest at RV
b. Transudation of fluid is favored C- Total PVR is higher in RV than FRC
(2) Negative flux D- Total PVR is higher in FRC than TLC
(a) Absorption forces > Filtration forces
(b) Absorption of fluid is favored a) Types of Pulmonary Vessels
(3) Flux under Normal Conditions i) Alveolar Blood Vessels: Includes capillaries within the alveolar septa and
(a) It is positive. larger vessels in the corner of the alveolar walls
(b) Fluid does not accumulate in the interstitum because it is immediately drained ii) Extra-alveolar Blood Vessels: Includes arteries and veins that run through
by the lymphatic. the lung parenchyma, generally have larger caliber
c) Edema Formation b) Pulmonary Vascular Resistance (PVR)
i) Pulmonary edema: abnormally accumulation of fluid in the interstitum or i) How is it computed?
alveoli. (1) Based on Ohm’s Law
ii) This condition can be brought about fluid that forms in the interstitial and Driving Pressure
alveolar space cannot be adequately drained by the lymphatics. This Flow = ------------------------
condition may arise from Resistance
(1) Abnormally High Positive Flux
(a) High capillary hydrostatic pressure (left heart failure) Input Pressure (Mean Pul. Art) - Output Pressure (Left Atrial)
(b) Low interstitial hydrostatic pressure (re-expansion pulmonary edema) PVR = --------------------------------------------------------------------------------
(c) Low capillary oncotic pressure (Hypoalbuminemia) Cardiac Output
(2) Normal Flux
(a) Low colloid osmotic reflection coefficient (ARDS) ii) Factors that control PVR
(b) Lymphatic obstruction Based on Pouiselle’s Equation
d) Differences between Pulmonary and Systemic Circulation
Systemic Pulmonary Length X Viscosity
Resistance = -----------------------------
Radius
TIM S. TRINIDAD, MD
(1) Blood viscosity is directly dependent on hematocrit 1. The greater the lung volume
(2) Factors that Control Blood Vessel Radius 2. The greater the lung elastance
(a) Smooth Muscle Tone 3. The greater is the EAV radius
Vasodilators Constrictor 4. The lower is the vascular resistance
High PAO2 Low PaO2 (v) AV resistance and lung volume
High CO2 1. The greater the lung volume
Nitric Oxide 2. The greater the alveolar pressure
Prostacyclin Thromboxane A2 3. The lower is the AV radius
Prostaglandin 4. The higher is the vascular resistance
Leukotriene (vi) Since the effect of lung volume are opposite on the resistance of
Bradykinin Neuropeptides the 2 types of blood vessels, the effect of lung volume on total
Serotonin pulmonary vascular resistance is bi-phasic
1. From RV to FRC: PVR decreases
Dopamine Endothelin
2. From FRC to TLC: PVR increases
Angiotensin
Acetylcholine Histamine
Beta Adrenergic catecholamine Alpha Adrenergic catecholamine
(b) Perfusion Pressure

(i) Pulmonary circulation is a very compliant. Within limits, it can
accommodate increase in blood flow/ perfusion pressure without
increase in pulmonary vascular resistance or pressure.
(ii) This very compliant characteristic is due to
1. Recruitment of previously collapse blood vessels
2. Accommodation of non maximally distended blood vessels
(c) Lung Elastance
(i) The greater the lung elastance, the greater is the extra-alveolar
vessel radius.
(d) Alveolar Pressure
(i) The greater the alveolar pressure, the lower is alveolar vessel
radius.
(e) Lung Volume
(i) Alveolar pressure and lung elastance are both directly dependent
on lung volume
(ii) There two types of blood vessels.
1. Extra-alveolar vessel’s (EAV)
2. Alveolar vessels (AV)
(iii) Total Pulmonary Vascular Resistance is sum of the resistance
offered by EAV and AV.
(iv) EAV resistance and lung volume
TIM S. TRINIDAD, MD
10th to 16th Non  Small or Peripheral
lower airway Respiratory Airways (<1 mm)
4.Blood Flow Lung Zones (based on J. West) generation  Collapsible due to the
a. Basis of the Lung Zones Bronchioles absence of cartilages.
i. Pulmonary artery (PPA) and pulmonary venous (PPV) pressure  Patency is
(1) PA is always higher than PV maintained by the
(2) Both are affected by gravity: Highest in the lower lung zone pull of the
ii. Alveolar pressure (PA) surrounding
(3) Not affected by gravity parenchyma
(4) Equal throughout the lungs (Tethering Effect)
iii) Due to the differential effect of gravity, 3-4 Blood Flow Lung Zones are 17th to 19th Respiratory  Contains some alveoli
brought about generation
Bronchioles Respiratory
QUESTION 20th to 23rd Alveolar Ducts Zone

The respiratory zone starts at which anatomic structure? lower airway
A- Part of the airway wherein the cartilage disappears & Sacs
generation
B- 10th generation of the lower airway
C- 17th generation of the lower airway
D- 20th generation of the lower airway
b. Physiologically the tidal volume distributes into 2 spaces
5. Distribution of the Tidal Volume Zone Relative Comments
a. Anatomic/ Physiologic Compartments Distributed Pressure
i. Inspired volume of air is distributed into the following compartments
Anatomic Compartment Histological features Physiologic 1 PA>PPA>PPV  This zone does not exist in a normal lung.
 Low blood pressure or high alveolar pressure
Classification during mechanical ventilation support gives rise to
this zone.
Upper airway Nasal Cavity 2 PPA>PA>PPV  Usually seen in the upper 1/3 of the lung.
Conducting  There is damming of blood in the pulmonary
Pharynx artery, which gives rise to the waterfall effect.
Zone 3 PPA>PPV>PA
Larynx
or Anatomic 4 PPA>PPV>PA  Some books include this zone.
st th
1 to 9 Bronchus  Large Airways (>1 Dead Space  The extra-alveolar blood vessels are partially
lower airway mm) collapsed due to the low tethering effect (less
generation  Cartilaginous support negative intrapleural pressure).
which maintains its Gas Anatomic Structures
patency Exchange

TIM S. TRINIDAD, MD
Physiologic Dead VD Absent  Anatomic dead space or Conducting zone iii. We can derive
Space Volume  Respiratory Units (zones) which have a VQ 1. VE dot = (VA x RR) + (VD X RR)
relationship of either 2. VE dot = VA dot + VD dot
o High 3. VA dot = VE dot – VD dot
o Infinity 4. VA dot = (TV X RR) – VD dot
iv. Therefore
Alveolar Space VA Present  Respiratory Zone 1. At constant VD dot, an increase in VE dot is accompanied by
Volume an increase in VA dot.
2. At constant VE dot, an increase in VD dot is accompanied by
c. Relative Volume Distribution a decrease in VA dot.
i. Under Normal Condition:
1. VT: 5-7ml/ IBW (Ideal body weight in Kg) QUESTION
 Some references use 8-10 or 5 to 10 ml/ IBW Which of the following is both seen in the alveolar ventilation and alveolar gas equation?
2. VD: 2.2 cc/ ABW (Actual body weight in Kg) A- PACO2
ii. VT = VA + VD B- PAO2
1. VA= VT-VD C- VCO2 dot
2. VD= VT-VA D- RQ
iii. In a normal 70Kg
1. VT= 500 ml (using the 7-8 ml/Kg) 7. Alveolar ventilation process for O2 uptake and CO2 elimination
2. VD = 150 ml (using 2.2 ml/Kg) a. Alveolar ventilation is the process whereby
3. VA = 500- 150 = 350 i. O2 is delivered from the atmosphere into the alveoli (blood)
4. VD/ VT (physiologic dead space ratio) = 150/ 500 or 0.3 ii. CO2 is eliminated from the alveoli (blood) into the atmosphere.
iv. In a 70 Kg respiratory patient (abnormal respiratory system),
1. VT maybe higher or lower than 500 cc b. Equations Relating VA, PACO2 & PAO2
2. VD may increase due to increased alveolar dead space i. Alveolar Ventilation Equation
secondary to some respiratory units having a high VQ or
infinity VQ (brought about by VQ mismatching) VCO2 dot (ml/min): CO2 production of the body per min
3. Therefore the VA and VD/VT will vary depending on the VA (dot) = -----------------------------------------------------------------------------
changes in the VD and VT. PACO2 (mm Hg)
1. This equation can be interpreted bi-directionally

6. Concept of minute ventilation and alveolar ventilation a. At constant VCO2 dot, the greater the VA dot the
a. Minute Ventilation (VE dot) is the volume of air that goes in and out lung per lower is the PACO2.
minute. Therefore VE dot = VT X RR b. If VCO2 increases, to maintain PACO2 at a constant
b. Alveolar Ventilation (VA dot) is the volume of air that goes to the alveoli per level the VA dot must increase
minute. Therefore VA dot = VA X RR
c. Relationship between VE dot and VA dot ii. Alveolar Gas Equation
i. VE dot = VT X RR
ii. VT = VA X VD PACO2

TIM S. TRINIDAD, MD
PAO2 = PIO2 - ---------------------------------- 3. Solubility of Gas (S)
R (Respiratory Quotient) 4. Molecular Weight (MW)
5. Thickness of the Membrane (T)
The greater the PACO2, the lower is the PAO2  Although CO2 has a greater MW than O2, it is more soluble and
therefore diffuses 20 X faster along the ACM compared to O2.
QUESTION d. Diffusion & the Pulmonary Capillary Blood Transit Time (PCBTT)
Which of the following is accurate with regards the gas exchanges along the alveolo i. The blood pulmonary capillary transit time is 0.70 sec.
capillary membrane? Under normal conditions, ii. It takes only 0.23 sec. (1/3 of PCBTT) for O2 to diffuse into the
A- Blood stays in the pulmonary capillary 4 X longer than necessary for CO2 to be pulmonary capillaries
adequately removed from blood iii. It takes only 0.17 (1/4 PCBTT) sec for CO2 to diffuse into the alveoli.
B- Compared to O2, CO2 is more diffusible because of a higher molecular weight iv. Thus blood stays in the pulmonary capillaries for more than enough
C- During exercise the pulmonary capillary blood transit time is prolonged to promote time to have adequate gas exchange.
optimal gas exchange v. Even during exercise or other conditions with short transit time
D- During the tachycardia the pulmonary capillary transit time is shortened and therefore (tachycardia), normal respiratory units can still adequately fully
promotes hypoxemia saturate deoxygenated blood.
e. VQ relationship
8. Process of Gas Exchange across the Alveolo Capillary Membrane
a. Compartments Involved QUESTION
Compartment Abbreviations O2 Which of the following best describe the respiratory units affected by pulmonary
Alveoli PAO2 40-150 Varies with the amount delivered to the embolism?
(Mean alveoli by inspiration and amount of O2 A- The VQ relationship is zero
104) that diffuses along the AC membrane B- The Alveolar O2 tension is less than 104
End Capillary PcO2 104 Blood at venous end of the capillary (after C- The Alveolar CO2 tension is less than 40
complete gas exchange with alveolar gas) D- The respiratory units contribute to alveolar shunt effect
Venous PvO2 40 Arterial blood after O2 and CO2 are
extracted and added respectively by the 9. VENTILATION AND PERFUSION RELATIONSHIP
cells. a. Definition: V/Q matching is the relationship of the respiratory unit's
ventilation (V) with its perfusion or blood flow (Q).
b. Direction of Gas Exchange: Pressure gradient favors the following direction b. Types of VQ relationship
of diffusion
i. O2: from alveoli into capillaries
ii. CO2: from capillaries to the alveolar space Types Example Relative O2 & CO2 Physiologic
c. Factors that Determine Diffusion of Gases along the AC Membrane Ventilation Tension Effect
i. Fick’s law of Diffusion 0 VQ 0/3 Pneumonia Hypoventilation  Low O2 True Alveolar
A X S X (P1-P2)  High shunt
V gas dot = -------------------------- CO2
T X MW Low VQ 2/3 Asthma Hypoventilation  Low O2 Alveolar shunt
1. Surface Area (A)  High effect
2. Pressure Difference across AC membrane (P1-P2) CO2
TIM S. TRINIDAD, MD
VQ of 1 3/3 1. True alveolar shunt (V/Q = 0): A respiratory unit with a V/Q
High VQ 3/2 Hypotensive Hyperventilation  High O2 Alveolar dead of 0, the blood flowing into the RU is not allowed to undergo
state  Low CO2 space gas exchange because simply there is no gas in the alveolar
Infinity 3/0 Pulmonary Hyperventilation  Low O2 Alveolar dead space to have gas exchange with.
VQ Embolism  Low CO2 space 2. Alveolar shunt effect (V/Q <1): A respiratory unit with a V/Q
with < 1, not all blood perfussing the unit is allowed to have gas
complete exchange with gas in the alveoli. The volume of alveolar gas
obstruction is inadequate or inappropriately low for the volume of blood.
iii. Total Shunt
QUESTION 1. Total shunt is the sum of shunts due to the anatomic and
Which of the following occurs in the lower lung zone’s respiratory units of an upright alveolar shunt. Alveolar shunt (effect) exists in the
lung? lower lung zone of a normal lung.
A- High VQ relationship
B- Alveolar shunt effect c. Normally, the total shunt averages around 4% of the L cardiac output.
C- O2 tension greater than 104 i. This means 4% of the Left C.O. is not exposed to alveolar gas to
D- Shunt VQ have gas exchange with.
ii. This is the reason why the arterial O2 tension (PaO2) is less than the
10. VQ Relationship of a Normal Upright Lung end capillary O2 tension (PcO2).
a. The lower lung zones are 3X better ventilated than the upper. d. Pathological shunt
b. The lower lung zones are 8X better perfused than the upper. i. Disease affecting the lungs may create low V/Q or a V/Q of zero
c. Due to difference in the quantitative effect of gravity on ventilation and which will give rise to more alveolar shunt effect or true alveolar
perfusion, there is regional difference in the VQ relationship of a normal shunt respectively.
lung. ii. Heart problems (which can give rise to passage of blood from the
right heart chamber into the left heart chamber) can increase the
Zones VQ relationship PAO2 PACO2 Significance degree of anatomic shunts.
Upper High >104 <40 Alveolar Dead Space 12. Concept of VQ Mismatching
Mid Almost Ideal 104 40 a. Lungs are composed of millions of respiratory units, which are
Lower Low <104 >40 Alveolar Shunt Effect interconnected to each other.
b. Disease of the respiratory system gives rise to a primary VQ abnormality,
which causes a secondary (consequential) VQ abnormality.
c. Compensatory mechanisms are in place to lessen the impact of primary VQ
11. Shunt abnormality.
a. Definition: A shunt is a condition wherein blood was not allowed to have gas d. VQ mismatching gives rise to alveolar dead space and therefore increases
exchange with alveolar gas. the physiologic dead space ventilation (VD dot).
b. Types of Shunt
i. Anatomic shunt Primary Abnormality Consequential Compensatory
1. Bronchial vein - pulmonary vein anastomoses Abnormality Mechanism
2. Thebesian vein - left ventricle drainage Zero or Low VQ High VQ (dead space) Hypoxic vasoconstriction
ii. Alveolar High VQ or VQ of infinity (dead Low VQ Hypoxic

TIM S. TRINIDAD, MD
space) Bronchoconstriction 2. However the relationship is SIGMOIDAL. It has a steep
portion (PaO2 0-60) and a flat portion (61-100).
QUESTION v. Concept of P50
Which of the following is the correct Fick’s Equation? 1. P50 is the O2 tension wherein the Hgb is 50% saturated.
A- VO2 = CO X CaO2 2. Under normal conditions the P50 of arterial blood is 27.
B- VO2 = CO X CvO2 b. O2 Transport under Normal Condition
C- VO2 = CO X (CaO2 – CvO2) i. O2 Content
D- VO2 = CO X (CaO2 + CvO2) 1. Arterial Blood (CaO2)
a. (0.003 X PO2) + (Hgb X 1.34 X 02 Saturation)
13. Gas Transport b. (0.003 X 95) + (15 X 1.34 X 97)
a. O2 Transport c. 0.28 + 19.50 = 19.78 ml/100 ml of blood (20
i. Mode of O2 transport: O2 is transported in 2 forms namely: ml/100 ml)
1. Physical Solution 2. Mixed Venous Blood (CvO2)
a. This form accounts for the O2 tension a. (0.003 X PO2) + (Hgb X 1.34 X 02 Saturation)
2. Bound to Hemoglobin b. (0.003 X 40) + (15 X 1.34 X 75)
a. This is major mode of transport c. 0.12 + 15.08 = 15.19/ 100 ml of blood (15
b. The O2 bound to hemoglobin does not contribute to ml/100ml)
the O2 tension ii. Difference between Arterial and Mixed Venous Blood O2 Content
1. Ca-CvO2 = 20-15 = 5 ml/100 ml
ii. O2 Content 2. This means that the tissue extract 5 ml of O2 from arterial
1. The amount of O2 transported can be quantified using the blood for its metabolism.
following formula iii. O2 Delivery
a. Physical solution = 0.003 ml/1 mm Hg of PO2. 1. Oxygen Delivery (DO2) = Cardiac Output X O2 content
b. Bound to hemoglobin = Hgb grams/dl x 1.34 2. DO2 = 5000 ml/m X 20 ml/100 ml = 1000 ml/min
ml/gram x O2 sat 3. The pulmonary and cardiovascular systems deliver 1000 ml
iii. Concept of O2 Saturation of blood to the tissues
1. One molecule of hemoglobin is capable of binding to 4 iv. Concept of Fick’s Equation: VO2= CO X (Ca-CvO2)
molecules of oxygen. 1. VO2 = CO x (CaO2- CvO2)
2. Simplistically, assuming that there are just 25 molecules of 2. VO2 = Oxygen consumption
hemoglobin, then there are 100 possible binding sites for O2 3. VO2 = 5000ml/min x 5 ml/100
3. O2 saturation refers to the % of the possible binding sites 4. VO2 = 250 ml/min
occupied by O2 5. Out of the 1000 ml of O2 delivered to the tissues, the tissues
extract only 250 ml. for its metabolism.
Binding Sites Occupied by O2

Hg O2 saturation = -------------------------------------------
Total Binding Sites for O2 QUESTION
iv. Hgb O2 Dissociation Curve Which of the following is correct with regards a right shift of the hemoglobin O2
1. The higher is the PaO2 the higher is the Hgb O2 saturation. dissociation curve?

TIM S. TRINIDAD, MD
A- Hemoglobin affinity to O2 increases a. CaO2 is 20 mg/dl while CvO2 is 15 mg/dl. Therefore under normal
B- P50 rises conditions, the tissues extract 5 mg/dl for metabolism.
C- Hemoglobin rejects CO2 b. O2 is used in the Kreb’s cycle and electron transport chain to manufacture
D- Associated with low hydrogen ion concentration ATP. Other products of these processes are CO2, water and heat.
c. In the electron transport chain the enzyme Cytochrome oxidase plays a
c. Factors that affect O2 transport pivotal role in the use of O2.
i. Position of the Hgb O2 dissociation Curve d. Lack of adequate O2 supply to tissues will shift metabolism to anaerobic
1. Increase or RISE in 2-3 DPG, H+, CO2 and Temperature glycolysis, which will lead to LACTIC ACIDOSIS.
(23HCOT) e. Normally the O2 consumption (VO2 dot) for this metabolism is 200
a. will make hemoglobin REJECT or RELEASE Oxygen. ml/Kg/min. The CO2 produced (VCO2 dot) is 250 ml/Kg/min.
b. These conditions cause a shift of the curve to the f. Respiratory Quotient (RQ) is the ratio of the VO2 dot over VCO2 dot. It
RIGHT. depends on what particular substance the cells are using. The following are
c. This is manifested as a RISE in P50. the RQ of the different substances
2. LOW 23HCOT will make hemoglobin LOVE oxygen. These 1. Carbohydrate = 1
will cause the shift of the curve to the LEFT. This is 2. Proteins = 0.8
manifested by a LOW P50. 3. Fats = 0.7
ii. Anemia 15. Hypoxemia VS Hypoxia
1. Most forms do not affect the O2-Hgb dissociation curve i. Hypoxemia
2. It is the amount of Hgb, the oxygen-carrying capacity and 1. Definition: Low O2 tension in arterial blood
the arterial oxygen content that will be reduced, and not the 2. Causes:
percent saturation or the arterial PO2 a. Low PIO2 (high altitude, enclosed space)
iii. Carbon monoxide poisoning b. Hypoventilation (Thoracic Pump Problems)
1. Compared to the O2, CO has greater affinity to Hemoglobin. c. AC Membrane Diffusion Problems
It competitively binds with the O2 binding sites on the Hgb d. Circulatory Shunts
molecules. e. VQ mismatching
2. CO shifts the O2-Hgb dissociation curve to the left, thus CO ii. Hypoxia
interferes with the unloading of O2 to the tissues. 1. Definition: Inadequate O2 for cellular metabolism
2. Causes
d. Unloading of O2 in the systemic capillaries a. Causes of Hypoxemia
i. Oxygen diffuses from the capillary blood into the mitochondria while b. Low Cardiac Output
CO2 diffuses from the mitochondria into the capillary blood, because c. Low Normal Hemoglobin Level
of the relative gas tension (capillaries, interstitum, cytoplasm and d. Low Hemoglobin Level
mitochondria) e. Methemoglibinemia
ii. Bohr’s effect - due to accumulation of CO2 in tissue, this favors f. Cellular Enzyme Dysfunction
hemoglobin rejecting or release of oxygen (shift of Hgb O2 g. Cyanide Poisoning
dissociation curve to the right). b. CO2 Transport
i. Modes of CO2 Transport
14. Internal Respiration at a Glance 1. Physical solution
2. HCO3 -- predominant form of transport

TIM S. TRINIDAD, MD
3. Bound to Hemoglobin iii. The activity of the CPG is influenced by several inputs.
a. Uses carbonic anhydrase for CO2 to be converted to 1. Chemoreceptors- This connection is the basis of how the
HCO3 ventilatory system can adjust to the metabolic demands
b. Chloride shift causes the venous Hematocrit to be 2. Mechanoreceptors and Irritant Receptors- This connection is
higher than arterial hematocrit. the basis of how the ventilatory system can adjust to change
c. Competes with O2 for the hemoglobin binding sites in mechanical condition of the lungs (change in posture,
(Haldane Effect) lung volume) or presence of foreign bodies in the respiratory
i. OXYHEMOGLOBIN OBJECTS CO2 system.
ii. DEOXYHEMOGLOBIN DESIRES O2 3. Higher Centers – This connection is the basis of why the
c. Factors favoring unloading of CO2 in the pulmonary capillaries ventilatory system can accommodate such activities as
i. Pressure gradient speaking, playing musical instruments, swallowing and
ii. Haldane effect – binding of oxygen with hemoglobin tends to vomiting.
displace carbon dioxide in the blood; this results from the fact that
the O2-Hgb binding causes the Hgb to become a stronger acid c. The CPG is composed of the following RRNs
QUESTION Property DRG VRG

Which of the following is the central chemoreceptor most sensitive with? Rostral Intermediate Caudal
A- PaO2 Dominant Inspiratory Expiratory Inspiratory Expiratory
B- PaCO2 Activity
C- CSF CO2 tension Major Sensory via CN IX - - Rostral VRG
D- CSF pH Input &X
Major Pre motor Interneurons Motor (via CN 9 & Premotor 
16. Control of Breathing Output neurons spinal DRG and caudal 10)  accessory spinal cord 
a. Task cord primary VRG muscle of accessory
i. Establish an automatic rhythm for contraction of the respiratory muscles of inspiration muscle of
muscles inspiration expiration
ii. Adjust the rhythm according to the following Interneurons  Premotor  spinal
1. Metabolic demands (O2 consumption and CO2 production) VRG cord  primary
2. Varying mechanical conditions (changing posture) and accessory
3. Non ventilatory events (speaking, swallowing) muscle of
b. Overview of Control of Ventilation inspiration
i. Respiratory Related Neurons (RRNs) are found in the brain. These
RRNs can be classified as d. The following are the respiratory related receptors which send input to the
1. Interneurons: makes interconnections to other RRN CPG
2. Premotor Neurons: innervates the motor neurons
3. Motor Neuron: innervates the ventilatory muscles. Receptor Location Stimulus Response
ii. Automatic rhythmic output of ventilation is controlled by a group of 1. Stretch  Airway smooth  Inflation  Shortening of insp. Time
neurons located primarily in the medulla. These groups of neurons muscles   Duration of expiration
are collective called respiratory Central Pattern Generator (CPG).
 HERING-BREUR INFLATION
TIM S. TRINIDAD, MD
REFLEX i. Hypoxemia will stimulate the peripheral chemoreceptors, which will
2. Stretch  Airway smooth    Duration of expiration then influence the CPG to increase ventilation.
muscle Deflation  HERING BREUR DEFLATION ii. Hypercapnia will primarily stimulate the central chemoreceptors via
REFLEX change in CSF pH and peripheral chemoreceptors. This will send a
command to the CPG to increase ventilation.
3. Irritant  Airway epithelial  Noxious  Stimulates rapid, shallow
cells gases, breathing; coughing,
 I will appreciate if very much if you can inform me personally or via email
allergens, bronchoconstriction,
([email protected]) with regards physiologic misconceptions, typographical
lung hypersecretion
or grammatical errors in this document. Good Luck! 
inflammati
on
4. Juxtacapillary  Interstitum near   Rapid, shallow respiration
(J afferents) pulmonary Engorgem
capillaries ent of
pulmonary
capillaries,
edema
5. Chest Wall  Intrafusal fibers  Stretch  Maintenance of tidal volume
Receptors of the intercostal
muscles
6. Central  Ventrolateral  Sensitive to H+ concentration in CSF &
chemoreceptors surface of medulla brain interstitial fluid induced by changes in
near roots of CN arterial PCO2.
IX & X
7. Peripheral
Chemoreceptors
Carotid  In crotch of  Mainly sensitive to  PaO2 and slightly to

Bodies carotid bifurcation  PCO2 and  pH
to brain via the CN
Aortic IX  Mainly sensitive to  PaO2 and slightly to
Bodies  Scattered over  PCO2 and  pH
the surface of the
aorta to brain via
the
CN X
e. Interaction of the Chemoreceptors and CPG

REVIEW TEST
TIM S. TRINIDAD, MD

______8. Which of the following is accurate with
______1. Which of the following occurs to regards small airway resistance?
atmospheric air during ascent to high altitude? A. Contributes highest to the total
A. Atmospheric pressure increase airway resistance
B. FIO2 remains constant B. Highest at TLC
C. Nitrogen concentration remains C. Not dependent on bronchial
constant smooth muscle contraction
D. PIO2 increases D. Inversely related with lung
elastance
______2. Which of the following explains why
the PaO2 is much lower than PAO2? ______9. Which of the following most accurately
A. Upper airway humidification of air described inhalation from RV to TLC?
B. Low atmospheric pressure A. The bases are ventilated from RV
C. VQ relationship in the normal lung to FRC
D. Left to right shunt due to B. The apices are ventilated from
bronchial circulation FRC to TLC
C. AT RV, the lower lung zones are
______3. Which the following is equal to more compliant upper lung zone
function residual capacity? D. AT FRC, the lower lung zones are
A. IRV + TV more compliant upper lung zone
B. ERV + RV
C. TLC – VC ______10. Which work of breathing component
D. VC- IC increases in a patient with hyaline membrane
disease?
______4. Which of the following is equal to the A. Elastic
difference between alveolar and atmospheric B. Non-elastics
pressure? C. Airway resistance
A. Trans pulmonary pressure D. Viscous tissue resistance
B. Trans airway pressure
C. Trans chest wall pressure ______11. Which of the following constricts the
D. Trans respiratory pressure pulmonary arterioles?
A. Oxygen
______5. Which of the following statements B. Nitric oxide
best describe the elastic property of the C. Prostaglandin
respiratory system? At FRC D. Thromboxane A2
A. The lungs have a natural ______12. Which following best describe the
tendency to expand pulmonary vascular resistance (PVR)?
B. The chest wall has a natural A. PVR due to extra alveolar vessels
tendency to contract is highest at TLC
C. The respiratory system is most B. PVR due to alveolar vessels is
compliant highest at RV
D. The respiratory system is most C. Total PVR is higher in RV than
elastic FRC
D. Total PVR is higher in FRC than
______6. The alveolar pressure is most negative TLC
at which part of the tidal breathing?
A. Start of inspiration ______13. The respiratory zone starts at which
B. Mid inspiration anatomic structure?
C. End of inspiration A. Part of the airway wherein the
D. Mid expiration cartilage disappears
B. 10th generation of the lower
______7. Which of the following causes a airway
turbulent airflow pattern? C. 17th generation of the lower
A. Low gas density airway
B. Slow airflow velocity D. 20th generation of the lower
C. A low Reynold’s number airway
D. A large luminal airway diameter
______14. Which of the following is both seen in
the alveolar ventilation and alveolar gas
equation?
A. PACO2
B. PAO2
C. VCO2 dot
D. RQ
REVIEW TEST
TIM S. TRINIDAD, MD
______15. Which of the following is accurate

with regards the gas exchanges along the
alveolo capillary membrane? Under normal
conditions,
A. Blood stays in the pulmonary
capillary 4 X longer than necessary
for CO2 to be adequately removed
from blood
B. Compared to O2, CO2 is more
diffusible because of a higher
molecular weight
C. During exercise the pulmonary
capillary blood transit time is
prolonged to promote optimal gas
exchange
D. During the tachycardia the
pulmonary capillary transit time is
shortened and therefore promote
hypoxemia
______16. Which of the following best describe

the respiratory units affected by pulmonary
embolism?
A. The VQ relationship is zero
B. The Alveolar O2 tension is less
than 104
C. The Alveolar CO2 tension is less
than 40
D. The respiratory units contribute to
alveolar shunt effect
______17. Which of the following occurs in the

lower lung zone’s respiratory units of an upright
lung?
A. High VQ relationship
B. Alveolar shunt effect
C. O2 tension greater than 104
D. Shunt VQ
______18. Which of the following is the correct

Fick’s Equation?
A. VO2 = CO X CaO2
B. VO2 = CO X CvO2
C. VO2 = CO X (CaO2 – CvO2)
D. VO2 = CO X (CaO2 + CvO2)
______19. Which of the following is correct with

regards a right shift of the hemoglobin O2
dissociation curve?
A. Hemoglobin affinity to O2
increases
B. P50 rises
C. Hemoglobin rejects CO2
D. Associated with low hydrogen ion
concentration
______20. Which of the following is the central

chemoreceptor most sensitive with?
A. PaO2
B. PaCO2
C. CSF CO2 tension
D. CSF pH

NEUROPHYSIOLOGY SIGNAL TRANSDUCTION
AUTONOMIC NERVOUS SYSTEM
REMEDIOS DEE-CHAN, M.D.
NEUROPHYSIOLOGY
I. Principles of Diffusion and Electricity

A. Ions with the same charge repel each
other; while unlike charge ions attract
each other.
B. Ions with different charges are capable
of moving toward each other and
III. The equilibrium potential can be
capable (or has the potential) of doing
work. The difference in charge between computed based on the Nernst Equation.
Nernst Equation – the electrical potential that will
2 points is known as potential difference
or potential. balance a given ionic concentration gradient across a
C. The movement of an electric charge membrane so that the net flux of ion is zero.
(ions) is known as current. Current is
generated because there is a difference
in charge between two points (a
potential). The greater the potential
(difference), the greater will be the
current (flow of ions).
II. Ionic Equilibrium: The direction of net

movement of an ion depends on whether A. Based on the Nernst Equation the
the effect of the concentration difference equilibrium potential is primarily
or the effect of the electrical potential influenced by the concentration
difference is larger. When the two effects gradient. The greater the
are equal and opposite in direction, no net concentration gradient the greater
movement of the ion occurs, and the ion is is the equilibration potential.
said to be in electrochemical 1. When using this formula, it is
equilibrium. assumed that the potential in
the extracellular fluid remains
A. When placed on one side of a semi at zero potential, and the
permeable membrane, ions will move Nernst potential is the potential
across the membrane based on 2 inside the membrane.
factors 2. The sign of the potential is
1. Concentration gradient: Ions positive (+) if the ion diffusing
move from greater from inside to outside is a
concentration to lesser negative ion, and it is negative
concentration (-) if the ion is positive.
Q1: Negativity of the resting membrane potential

(RMP) is primarily determined by:
A. Na-K ATPase
B. Ratio of Na ions inside to outside of the cell
C. K permeability
D. Cl conductance
Resting Membrane Potential (RMP):

2. Electrical Gradient: As discussed
ions will moved towards an area I. All the cells in the human body have a resting
that is opposite its charge. membrane potential wherein the inside of the
cell is relatively negative to the outside. In
neurons it is in the range of -40 to -90 mV.
II. Results from the unequal distribution of
charged particles.
A. Na & Cl are the predominant ions in the
extracellular fluid. They play the most
important role in generating RMP.
B. Intracellular fluid contains K and non-
diffusible proteins which acts as anions.
III. When a membrane is permeable to several
different ions (i.e. Na, K, Cl), membrane
potential (Vm) can be calculated using the
Goldman equation that considers

A. polarity of the electrical charge of each ion therefore Na is the second most important
contributor to the RMP.
B. permeability of the membrane (P) to each - Opening of Na channel favors Na influx.
ion RMP will be less negative more excitable
- Opening of K channel favors K efflux. RMP
C. concentration (C) of the respective ions on will be more negative (losing positive
the inside (i) and outside (o) of the charges)  less excitable
membrane - Opening of Cl channel favors Cl influx. RMP
will be more negative  less excitable
Goldman equation is an expanded version of Nernst
Q2: Sodium conductance is greatest during this
equation that takes account of ion permeabilities.
phase of the action potential of a neuron
A. depolarization
B. overshoot
C. repolarization
Origin of the Normal Resting Membrane Potential (- D. after depolarization
90mv)
Types of Changes in Membrane Potential (MP)
I. Contribution of the potassium diffusion
I. Graded Potential (GP)
through the membrane
A. It is known as graded potential because
A. The ratio of potassium ions inside to
the greater intensity of the stimulus,
outside is 35: 1.
the greater is the change in the MP.
B. Permeability of membrane to potassium
B. The change in MP decreases as the
is 100x as great as its permeability to
distance from the site of origin
sodium. Thus, using the Goldman
increases. This is known as
equation, the calculated potential inside
decremental conduction of current.
the membrane is -86mv, which is near
the potassium potential.
II. Action Potential (AP)
II. Contribution of sodium diffusion through the A. results when depolarizing GP reaches a
membrane certain threshold potential
The ratio of sodium ions from inside to which stimulates all the Na-
outside of the membrane is 1:10. and K-gated channels.
III. Contribution of the Na-K ATPase pump B. Phases of Action Potential (D-O-R-A)
(Electrogenic pump)
Depolarization - membrane potential is less
A. By pumping Na out to the ECF and
negative to RMP
simultaneously pumping K into the cell,
Overshoot - reversal of polarity (inside
the Na/K ATPase pump creates the
positive relative to outside)
uneven distribution (concentration
Repolarization - membrane potential is
gradient) for the Na and K that is
returning to the RMP coming from a
needed for the genesis of the RMP.
depolarization state.
B. By promoting uneven transport of positive After depolarization or hyperpolarization -
ions across plasma membrane (3Na+ membrane potential is more negative than
out vs 2K+ in), it creates an electrical the RMP.
gradient - deficit of positive ion inside
the cell and therefore contribute to
RMP. This creates an additional
degree of negativity of about -4mv.
III. The net membrane potential with all these

factors is about -90mv.
Note:
- K has the greatest concentration gradient

and permeability, it contributes most to the
RMP.
- Na has a lower concentration gradient than
Cl, however it is more permeable than Cl

Summary of Ionic Event in Nerve Depolarization: Note:
- Changes in the membrane potential with

increasing strength of excitatory stimuli.
- When the membrane potential reaches
threshold, action potentials are generated.
Increasing the stimulus strength above
threshold level does not cause larger action
potentials.
AP is usually triggered in response to a stimulus. Type of Response Elicited by the Different Types
There is an all or none relationship between the of Stimuli
intensity of stimulus and generation of AP. AP can
either occur maximally or they do not occur at all. I. Subthreshold response- is elicited by
stimulus of subthreshold intensity on the
Q3: One of the following statements regarding membrane ion channels enough to
cause a change in membrane potential
stimulus applied and response is correct.
but not adequate to reach threshold
potential.
A. Threshold stimulus will result to no visible
II. Threshold response- is elicited by a
response.
stimulus strong enough for a
B. Subthreshold stimulus will result to the
depolarizing graded potential to reach
smallest visible response
threshold potential resulting to an action
C. Maximal stimulus gives rise to a maximal
potential triggering muscle contraction.
response
III. Maximal response- is elicited by maximal
D. Supramaximal stimulus gives rise to
stimulus in which all motor units are
supramaximal response.
recruited producing the greatest force of
contraction.
IV. Submaximal response- is seen when
Q4: Use of a maximal stimulus is likely to generate a
intensity increases from threshold to
second action potential if it is applied during this maximal recruiting more & more motor
phase of the first action potential units resulting to an escalation in the
force of contraction.
A. depolarization V. Supramaximal response- is elicited by
B. overshoot an intensity above the maximal wherein
C. first half of repolarization no further increase in the force of
D. hyperpolarization contraction occurs because all motor
units have been recruited.
Types of Stimulus: Difference Between Graded Potential and Action

Potential
I. Threshold stimulus: the lowest intensity of a
stimulus that will trigger an action potential.
Usually 15 mV less negative than RMP.
II. Sub-threshold stimulus: intensity of a stimulus
that will not trigger an action potential.
III. Maximal stimulus- is the least intensity that
will elicit the highest visible response.
IV. Submaximal stimulus- is any intensity of
stimulus between the threshold & maximal.
V. Supramaximal stimulus- is any intensity of
stimulus above the maximal.
Refractory Periods of a Neuron: A neuron may not

respond to a stimulus depending on which phase of
the action potential it is currently in.
Types of Refractory Period:
I. Absolute refractory period – neuron is unable

to fire a second AP no matter how strong it is
stimulated

- depolarization phase till repolarization phase

above threshold; Na channels inactivated
II. Relative refractory period – neuron is able to
fire a second AP but a stronger than normal
stimulus is required.
- repolarization below threshold till period of
hyperpolarization
- Above threshold stimulus triggers response
- Critical Na channels in resting state
- Some K channels still open
II. Local current flows from the site of 2nd

AP. This current flows in both direction.
One current flows to the site of the 1st
AP while the other current flows to the
site which is still in RMP.
III. The current that flows to the site of the

1st AP cannot trigger a new AP because
that site is still in the refractory period.
The other current can trigger a new AP
(3rd AP) because the site is at RMP and
therefore not in the refractory period.
Therefore, the presence of a refractory
period promotes only unidirectional
conduction of an AP.
Significance of the Refractory Period:
- Refractory period limits the number of

action potentials an excitable membrane can
produce for in a given period of time.
- It is the key in determining the direction of
action potential propagation
Q5: The direction of impulse conduction if a stimulus is

applied at the middle of the axon is IV. Since the 1st, 2nd and 3rd APs generated
are of the same form, AP conduction
A. towards the axon terminal unlike GP conduction is non-
B. towards the neuronal body decremental.
C. bidirectional
D. stationary (not propagated) Velocity of Action Potential Propagation depends on:
Action Potential Propagation - Diameter of the Nerve Fiber: Larger fiber

offers less resistance to local current and
I. APs are usually propagated along the axons.
therefore the larger the fiber the greater is
A local current flows to the adjacent area
from the original site of the AP (1st AP). the velocity of conduction.
Usually in the axons there are fast Na - Presence of Myelin Sheet: AP is usually
channels. The local current that flows from conducted faster when the nerve fibers are
the original site, opens this fast Na channels myelinated.
and trigger new AP (2nd AP).
Q6: If - 1 is binding of neurotransmitter (NT) to 3.Metabotropic: It requires

postsynaptic nicotinic receptor generation of a second messenger
to open the ion channels
2 is expulsion of NT to synaptic cleft IV. Activation of the ion channels along the post
synaptic membrane induces MP changes.
3 is rise in intracytoplasmic calcium resulting to V. Fate of unbound NT in the synaptic cleft:
movement of vesicles containing NT A. NT reuptaken by the axon terminal
B. NT diffusing out of the synaptic cleft
4 is opening of voltage-gated calcium C. NT enzymatically transformed to
channel then, the correct sequence of inactive form
events in neuromuscular transmission is
Summation of Postsynaptic Potentials
A. 1,2,3,4
I. Excitatory Post Synaptic Potential (EPSP)
B. 2,3,4,1
- brings the postsynaptic neuron „s MP closer
C. 3,2,1,4
to the threshold potential
D. 4,3,2,1
- opens mainly Na channels
- increases the probability of firing an AP.
Synaptic Transmission
II. Inhibitory Post Synaptic Potential (IPSP) -

brings the postsynaptic neuron „s MP farther
I. AP coming from the initial segment of away from the threshold potential - opens
presynaptic neuron reaches the axon up either Cl or K channels which favor
terminal chloride influx or K efflux respectively. Both
II. Axon terminal‟s voltage-gated calcium of these are negative generating event. Na
channels open up allowing calcium influx permeability is not affected.
(due to concentration gradient) - decrease the probability of firing an AP
III. Vesicle exocytosis (Neurotransmitter
release): Vesicle containing Q7: In an experiment, two subthreshold stimuli
neurotransmitter (NT) docks at the active applied at the same time resulted to a visible
site via the SNARE proteins  Ca binds to response. The property of synapse exhibited is
synaptotagmin, a Ca sensor 
conformational change in synaptotagmin  A. facilitation
trigger fusion of docked vesicle with the B. temporal summation
plasma membrane  NT release into the C. post-tetanic facilitation
synaptic cleft. D. spatial summation
Postsynaptic Summation
I. Temporal Summation: This is made

possible if the input signals from the same
presynaptic cell arrive at different
times but a very short interval. The
potentials summate because there are
IV. Activation/Deactivation of the Post Synaptic greater number of open ion channels and
Cells greater flow of positive ion into the cell.
A. NT diffuses across the synaptic cleft.
B. NT binds with a ligand gated receptor
which maybe of two types
2. Ionotropic: It contains the ion
channel itself

II. Biogenic amines: Small charged molecules

that are synthesized from amino acids and
contain an amino group (R-NH2)
A. Catecholamine
B. Serotonin
C. Histamine
III. Amino acids: The most prevalent

neurotransmitter in the central nervous
system.
A. Excitatory amino acids
1. Glutamate – most common
2. Aspartate
II. Spatial Summation: This is made possible a. Inhibitory amino acids
if the input signals from the different
1. GABA: The major inhibitory
presynaptic cell arrive at same location neurotransmitter in the brain
simultaneously. Greater number of ions
which operates via opening of
channels is stimulated to open and
the chloride channels
therefore the change in membrane 2. Glycine: The major inhibitory
potential will be greater.
neurotransmitter release by the
inhibitory interneuron in the
spinal cord. It causes opening of
the chloride channel
IV. Neuropeptides
V. Miscellaneous
A. Gases: Nitric Oxide
B. Purines: ATP & Adenosine
SIGNAL TRANSDUCTION
I. Modes of Intercellular Communication:

Synapse
A. Autocrine - release of molecules that
- is a junction between two cells, at which the affect the same cell.
electrical activity in one cell (presynaptic) B. Paracrine – signals from one cell
influences the electrical or metabolic activity diffuses a short distance to act upon by
of a second cell (post-synaptic). another type of cell nearby
C. Endocrine – release of hormone into
Differences between Two Types of Synapse: bloodstream and the binding of
hormone to specific target cell receptors
Electrical Chemical D. Synaptic - release of neurotransmitters
Anatomy Plasma Plasma at a synapse
membrane membrane E. Cell-to-cell - via gap junction or
of pre and of pre and chemical messengers
post post
synaptic synaptic II. Signal Transduction
cells are cells are A. A common way wherein cells
joined by separated by communicate with each other via
gap junction synaptic chemical messengers or ligands.
clefts B. Defined as the sequence of events
Speed of rapid Slow between receptor activation by a
communicati messenger and cellular response.
on
Density in rare Common III. Steps in Signal Transduction Pathway
human brain A. Receptor activation - binding of chemical
messengers (first messengers) like
hormones and neurotransmitters to
Classes of Neurotransmitter or Neuromodulators receptor protein causes a conformational
change.
I. Acetylcholine – major NT in peripheral B. Transduction- the conformational change
nervous system at the neuromuscular in receptor protein is transmitted to the
junction and in the brain cytoplasmic domain or part of the
receptor molecule. The transformed
molecule interacts with the information-
relaying molecules in the cytoplasm. Q10: GABA release results in sedation and muscle
These molecules are small molecules relaxation. The correct cAMP signal transduction
present in the cytoplasm known as sequence if
secondary messengers which stimulates 1- GABA binds to GPCR
downstream events. 2- less activation of adenylyl cyclase
C. Transmission – the sending of the second 3- G-protein (I-type) dissociates
messenger‟s signal to appropriate 4- less activation of protein kinase
effector. 5- decreased cAMP
D. Modulation of the effector – second
messenger can modulate expression or A. 3,1,5,4,2
activity of effectors (ie enzymes, ion B. 1,3,2,5,4
channels, cytoskeletal components and C. 2,1,3,4,5
transcription factors). D. 5,1,4,2,3
E. Cellular response – outcome of signal
transduction cascade is a physiological IV. Signal transduction using Receptors that
response ex: contraction, secretion, activate G Proteins or the G- Protein
metabolism, proliferation, division or Coupled Receptors (GPCR)
death. A. GPCR can be classified according to the
F. Termination of response – brought about type of second messengers it produces.
by feedback mechanisms at any or all These second messengers are
levels of the signaling pathway. 1. cAMP
2. cGMP
Q8: Glucocorticoid, a lipophilic hormone, interacts 3. IP3 & DAG
with a receptor resulting in the modulation of 4. Arachidonic Acid
transcription factors and gene activation that leads
to increased cellular metabolism. The type of
receptor is most likely: B. The components of the signal
A. Enzyme-linked transduction pathway that are initiated by
B. G protein-coupled GPCR stimulation
C. Intracellular 1. Ligand or the 1st Messenger
D. Ligand-gated 2. Receptor
3. G-Protein
Classification of receptors Based on Location and 4. Effector Protein
Signal Transduction Pathway 5. Second Messenger
6. Protein Kinase
7. Downstream Proteins
GPCR activation that produce cAMP second

messenger
I. Ligand (1st messenger) binds to its specific

receptor
II. Receptor activation leads to G-protein (S-
type) to dissociate
III. Alpha subunit activates the adenyl cyclase (1 st
effector protein)
IV. Adenylyl cyclase converts ATP to cAMP (2nd
messenger)
V. cAMP activates protein kinase A (PKA - 2nd
effector protein)
VI. PKA stimulates other downstream proteins
ultimately leading to a cellular response
VII. cAMP is terminated by several mechanism:
1. The ligand dissociates with the receptor

 GDP replacing GTP  rebinding of
the Alpha with the Beta Gamma subunit
 cessation of adenyl cyclase activation.
Q9: This is an activated G-protein:
A. GDP attached to alpha subunit 2. The cAMP is broken down by the enzyme
B. alpha, beta and gamma subunits are attached phosphodiesterase
to each other
C. attached GDP is replaced by GTP
D. cAMP activates protein kinase

B. Steps after DAG formation are the

following:
1. DAG stimulates a protein kinase C

2. Protein kinase C simulates
downstream proteins leading to a
cellular response
Ex: Thyroid stimulating hormone,
Vasopressin, GABA
GPCR Activation That Produces cGMP Second
Messenger

receptor
II. Receptor activation leads to G protein (T-type)
dissociation
III. Alpha subunit activates cGMP phosphodiesterase
(1st effector protein).
IV. Phosphodiesterase breaks down CGMP
(2nd messenger) to GMP
Q11: A boxer was prescribed an inhibitor of
I. Decrease in cGMP leads to closure of prostaglandin to decrease muscle
cGMP-dependent cation channels. pain and inflammation. The
signaling pathway being inhibited
II. Ensuing changes in cation channel activity
is:
alters membrane voltage.
A. cyclooxygenase
Ex: light rays acting of photoreceptor protein
B. epoxygenase
C. lipoxygenase
of the eyes
D. hemeoxygase
GPCR Activation That Produces IP3 and DAG
GPCR Activation That Produces Arachidonic Acid
receptor
receptor
II. Receptor activation leads to G-protein
II. Receptor activation leads to G-protein
(Q-type) dissociation
dissociation
III. Alpha sub-unit activates phospholipase C
III. Alpha sub-unit activates phospholipase A2
(1st effector protein)
(1st effector protein)
IV. Phospholipase C breaks down the PIP2
IV. Phospholipase A2 breaks down
(phosphatidylinositol diphosphate) to
phospholipid to form arachidonic acid.
produce 2 second messengers namely IP3
Depending on the enzymes present in the
(Inositol triphosphate) and DAG
cell, the arachidonic acid is further
(Diacylglycerol)
converted using 3 different pathways to
produce several types of second
A. Steps after IP3 formation are the
messengers known as eicosanoids. These
following pathways are
A. Cyclooxygenase pathway which leads to
1. IP3 stimulates a ligand gated the formation of thromboxanes,
calcium channel on the prostacyclin and prostaglandin.
endoplasmic reticulum to open up B. Lipooxygenase pathway which leads to
2. Calcium moves out form the the formation of 5 HETE and
endoplasmic reticulum into the leukotrienes
cytoplasm C. Epoxygenase which leads to the
3. Calcium binds to calmodulin formation of other HETEs and EETs.
4. Calcium-calmodulin stimulates
protein kinase C
5. Protein kinase C stimulates
downstream proteins leading to a
cellular response.

II. Epinephrine and norepinephrine receptors are

known as adrenergic receptors. It is further
sub-classified as alpha and beta receptors.
Each has a specific sub-types which is
summarized by the table below:
Summary of Signal Transduction Mechanism of the

Different GPCR:
Q14: One of the following organs is SINGLY

innervated by the sympathetic nervous system.
A. salivary glands
Q12: A drug acting on the muscarinic (M2) B. piloerector muscle
cholinergic receptor results in bradycardia. Its signal C. lacrimal glands
transduction mechanism involves: D. bronchial smooth muscles
A. IP3-DAG formation Q15: One of the following is an adrenergic fiber

B. activation of K channels
C. stimulation of cAMP
A. preganglionic sympathetic fiber
D. cGMP to GMP
B. preganglionic parasympathetic fiber
C. postganglionic sympathetic fiber
Q13: Type of G-protein involved in the signal
D. postganglionic parasympathetic fiber
transduction of adrenergic receptors B1, B2 and B3:
A. Gs Functional Anatomy:
B. Gi
C. Gt
D. Gq
Ligand-Receptor Binding and Signal Transduction

Mechanism:
I. Acetylcholine receptors are known as the

cholinergic receptors. It is further sub-
classified as nicotinic and muscarinic. Each
has a specific sub-type which is summarized
by the table below:

Chemical Transmission: A. Constipation

B. Tachycardia
General Principles: C. Mydriasis
D. Bronchoconstriction
I. Fibers that secrete acetylcholine (Ach) are
cholinergic; those that secrete norepinephrine Q17: This effect can be attributed to the beta-
(NE) are adrenergic. blocker prescribed to a patient for control of
II. All preganglionic neurons are cholinergic; both blood pressure
sympathetic and parasympathetic NS
III. Either all or almost all of postganglionic A. Decreased sweating
neurons of the parasympathetic system are B. Difficulty of breathing
also cholinergic C. Urinary retention
IV. Most of the postganglionic sympathetic D. Pupillary dilatation
neurons are adrenergic except to sweat
glands, piloerector muscles of the hair and to Q18: Micturition results from
some peripheral blood vessels which are
cholinergic. A. Acetylcholine binding to M3 receptors
that contracts detrusor muscle
B. Norepinephrine binding to B2 receptors
that contracts the bladder muscle
C. Acetylcholine binding to M3 receptors
that contracts the trigone and internal
sphincter
D. Norepinephrine binding to B2 receptors
that relaxes the trigone and internal
sphincter
Responses of Effector Organs to Autonomic Nerve

Impulses (See table last page)
I. Cholinergic system:
Ach does not circulate in blood; effects
localized and of short duration due to
acetylcholinesterase at cholinergic nerve
endings Ex: parasympathetic cardiovascular
reflexes – confined only to the heart
Promotes the vegetative aspects of day-to-
day living ex: cholinergic action favors
digestion and food absorption
II. Adrenergic system:

NE, epinephrine and dopamine effects
spreads farther and more prolonged. Almost
all portions of the sympathetic NS discharge
simultaneously – “fight or flight responses”
Q19: One of the following is a correct adrenergic

receptor-response pair
A. alpha-1 : vasoconstriction
B. Muscarinic-3 : miosis
C. beta-1: bronchoconstriction
D. Nicotinic (Nm) : muscle contraction
Q20: This effect can be attributed to an alpha

1 blocker given to a 65-year-old male for
benign prostatic hypertrophy
A. Difficulty of breathing
B. Decrease in blood pressure
C. Diarrhea
Q16: Which of the following findings would point out D. Urinary retention
to an overdose of a cholinomimetic agent


IMMUNOLOGY
MARIA RHONA G. BERGANTIN, MD, MSC
DAISY ILAGAN-TAGARDA, MD
IMMUNOLOGY - basophils: promotion of allergic responses

and augmentation of anti-parasitic
1. Definition of Terms: immunity
 Immunology: study of the immune system - mast cells: release of granules containing
and its responses to invading pathogens histamine and active agents
 Immune system: collection of cells, tissues, - natural killer cells: recognition of abnormal
and molecules that mediate resistance to
(i.e., tumor and viral-infected) cells
infection
- B cells (plasma cells): antibody production
 Immune response: coordinated reaction of
the immune system (cells and molecules) to - T cells:
infectious agents. o helper: activation through cytokine
 Immunity: state of relative resistance to production
disease o cytotoxic: killing of infected cells
 Antigen (Ag) (derived from antibody o regulatory: suppression of lymphocyte
generation): any molecule that can bind to activity and control of immune response
the components of the specific immune
response
 Antibody (Ab): family of defensive proteins
secreted by the plasma cells in response to
the presence of antigen, in the bound state,
referred to as immunoglobulin (Ig)
 Anamnestic response: pertains to the
immunologic memory, i.e. a rapid rise in the
immune reaction after re-exposure to an
antigen
 Cytokines: molecules secreted by cells
affecting the behavior of nearby cells (those 3.1. Lymphoid organs
with cytokine receptors), e.g. – chemokine
 2. Physiologic functions of the immune  Anatomically discrete tissues where
system: lymphocytes and accessory cells are
 immunological recognition: detection of the concentrated and interact to initiate the
presence of a foreign substance in the body immune response.
 immune effector functions: contain the  Pluripotent hematopoietic stem cells first
infection and if possible, eliminate it appear in the yolk sac at 2-3 weeks of
completely gestation, migrate to the fetal liver at 5
 immune regulation: immune response must weeks then stay in the bone marrow
be kept under control so that it does not throughout life.
itself do damage to the body
 B cells attain full maturity in the bone
 immunological memory: protects the
marrow while stem cells for the T lineage
individual against recurring disease due to
migrate and mature in the thymus
the same pathogen.
3.1.1. Primary (Central or Generative) Lymphoid
3. Cells of the Immune Response Organs
 From common myeloid progenitors:  Where lymphocytes first express antigen
macrophages, granulocytes (neutrophils, receptors and attain phenotypic and
eosinophils, basophils), mast cells, and functional maturity
dendritic cells
 From common lymphoid progenitors: 3.1.1.1. Bone marrow
lymphocytes (B and T cells) and natural-  site of generation of all circulating blood in
killer cells the adults
 Immune cell functions:  site of B cell maturation
- macrophage: phagocytosis and activation  also contains long-living antibody secreting
of bactericidal mechanisms; antigen- plasma cells which migrate to the marrow
presentation after being generated in peripheral lymphoid
- dendritic cells: antigen uptake in tissues
peripheral sites; antigen-presentation to T
cells 3.1.1.2. Thymus
- follicular dendritic cells: antigen  bi-lobed organ in the anterior mediastinum
and is the site of maturing T cells call
presentation to B cells
thymocytes
- neutrophils: phagocytosis and activation
 each lobe has multiple lobules separated by
of bactericidal mechanisms fibrous septa, each lobule with an outer
- eosinophils: killing of antibody-coated cortex densely populated with immature
parasites developing lymphocytes and an inner
medulla with sparse mature lymphocytes

IMMUNOLOGY
3.1.2. Secondary Lymphoid Organs because (1) antigenic challenge results in

 after maturation, naïve T and B cells leave stimulation and proliferation of lymphocytes
the marrow or thymus, enter the circulation and (2) lymphocytes enter the lymph node
and populate these organs where directly from the blood
lymphocyte responses to foreign antigens  Lymphocytes tend to recirculate to similar
are initiated and develop tissues, i.e., lymphocytes activated in
mucosal associated lymphoid tissue will
3.1.2.1 Lymph nodes return to MALT. The recirculation is ruled
 where adaptive immune responses to lymph by the expression of chemokines on both
borne-antigens are initiated the lymphocytes and the surface epithelium.
 encapsulated lymphoid tissues along the
Areas of endothelium through which
lymphatic channels of the body
lymphocytes migrate are known as high
 clustered in cervical, axillary, mediastinal,
periaortic and inguinal areas at junctions of endothelial venules (HEV)
lymphatic vessels forming a complete 4. Types of Immunity:
network, draining and filtering lymph A. Innate (natural or native) immunity is the early
derived from the tissue spaces. line of defense, with immediate onset and reacts
 lymph eventually drains into thoracic duct, against invasion through structures shared by a
the left subclavian vein and back into the wide-range of organisms (pathogen-associated
circulation molecular patterns) which are recognized by pattern
 surrounded by connective tissue capsule and recognition receptors (e.g. Toll-like receptors) on the
organized into: CORTEX (B cell area) –, surface or endosomes of phagocytes. Repeated
PARACORTEX (T cell area) and MEDULLA exposure induces a similar quality of reaction, with
(T and B cell area rich in plasma cells) no memory.
3.1.2.2. Spleen
 major site of response to blood-borne
antigens and phagocytosis of antibody-
coated microbes
 largest of the secondary lymphoid organs;
weighs about 150 g in the LUQ of the
abdomen
 asplenic patients are at increased risk for
infection especially with Neisseria
meningitidis, Streptococcus pneumoniae and
Haemophilusinfluenzae
3.1.2.3. Cutaneous Immune System  The pattern recognition receptors allow the
 skin is the largest organ and an important innate immune system to distinguish self
physical barrier to the environment (the body) from non-self (pathogen)
 epidermis contains APCs (keratinocytes,  Three of the most important transcription
melanocytes, epidermal Langerhans cells factors activated by TLR signals are
and intraepithelial T lymphocytes - NF-κB (nuclear factorκB), which promotes
 keratinocytes and melanocytes produce expression of various cytokines and
cytokines endothelial adhesion molecules
 Langerhans cells are immature dendritic - AP-1 induce production of pro-
cells that capture antigens and migrate to inflammatory cytokine and chemotactic
the dermis then lymph nodes factors
- IRF-3 (interferon response factor-3),
3.1.2.4. Mucosa Associated Lymphoid Tissue which stimulates production of type I
 aggregates of non-encapsulated lymphoid interferons, cytokines that block viral
tissue either diffusely aggregated or replication
organized into solitary or aggregated  The molecules recognized by pattern
nodules containing germinal centers recognition receptors are quite distinct from
(secondary follicles) in lamina propia and the individual pathogen-specific antigens
submucosal areas of GI, GU and respiratory recognized by lymphocytes.
tracts
 include: Waldeyer’s ring (LN, adenoids, A1. Components of Innate Immunity
tonsils); bronchus associated lymphoid  Epithelial barriers: skin, gastrointestinal tract
tissue; lamina propia of intestine; Peyer’s and respiratory tract – provide physical and
patches; urogenital lymphoid tissue chemical barriers against infection – mucus,
cilia
3.2. Lymphocyte Traffic  Peptide barriers: defensins, cathelicidins,
 Lymphocyte move continuously between histatins, lysozyme, secretory phosphor-
blood and lymph. Efferent lymph contains lipase A2 - kill bacteria
more lymphocytes than afferent lymphs
IMMUNOLOGY
 Phagocytes: neutrophils and  Increase in protein permeability of the

monocytes/macrophages – recruited to the capillaries and venules in the infected area,
site of infection for recognition and ingestion with diffusion of proteins and filtration of
of microbes fluid into the interstitial fluid
* macrophages produce cytokines for  Chemotaxis: movement of leukocytes from
initiation and regulation of inflammation; venules into the interstitial fluid of the
ingest and destroy microbes, clear dead infected area
tissue and initiate tissue repair  Destruction of bacteria in the tissue through
* macrophage activation maybe classical – phagocytosis or by other mechanisms
involved in microbe destruction and  Tissue repair
inflammation OR alternative – involved in
tissue repair and control of inflammation A3. Phagocytosis
 Dendritic cells: produce cytokines to initiate  allows cells to engulf foreign substances for
inflammation and stimulate adaptive processing and digestion
immune response  carried out by phagocytes: neutrophils,
 Mast cells: release vasoactive amines for macrophages and dendritic cells
inflammatory response  Degradation occurs along two pathways:
 Natural killer cells: destroys stressed and
infected cells and secrete interferon-γ A3.1. Oxygen-independent degradation
* Activation results from a balance between  Facilitated by primary and secondary
engagement of activating and inhibitory granules in neutrophils: lysozyme,
receptors, i.e., absence of MHC class I lactoferrin, reactive nitrogen intermediates,
molecules in virally infected cells results to proteolytic enzymes defensins, cathepsin G
non-engagement of inhibitory receptors and cationic proteins
A2. Receptors (for microbes and damaged cells) – A3.2. Oxygen-dependent Degradation:
maybe present on the cell surface, endoplasmic  Accompanied by respiratory burst mediated
reticulum, cytosol through: granule oxidases, NADPH and
 Cell-surface Toll-like receptors (TLR) – NADPH oxidase which reduce molecular
recognize products of extracellular microbes oxygen to superoxide radicals and
 Endosomal Toll-like receptors – intracellular hypochlorous acids and chloramines
microbe recognition
* Microbe-TLR engagement stimulates gene
expressions for cytokines, enzymes, proteins
used for antimicrobial functions (e.g. nuclear
factor κB [NF-κB] and interferon regulatory
factors [IRF])
 NOD-like receptors (NLRs) – cytosolic
receptors which sense PAMPs and DAMPS
 RIG-like receptor – cytosolic receptor for
viral RNA recognition
 Lectin receptors – for fungal glycans
 Mannose receptors – for phagocytosis of
bacteria and fungi
A3. Inflammation
 Body’s local response to infection or injury
 Manifested as warmth, swelling, erythema,
tenderness, loss of function
 Essential roles in combating infection.
- to deliver additional effector molecules A4. Complement System
and cells from the blood into sites of  a collection of plasma proteins produced
infection, and so increase the destruction mostly by the liver, which act as zymogens
of invading microorganisms.  the proteins are activated after proteolytic
- to induce local blood clotting, which cleavage leading to sequential activation of
provides a physical barrier to the spread the cascade of proteins with the goal of
of the infection in the bloodstream. eliminating pathogens
- to promote the repair of injured tissue.  Pathways of the complement cascade
activation:
A2.1. Sequence of events in a nonspecific
inflammatory response to bacteria A4.1. Alternative pathway:
 Entry of bacteria into tissue leads to tissue - initiated by spontaneous hydrolysis and
injury with release of chemical mediators activation of the complement component C3,
 Vasodilation of the microcirculation in the which can then bind directly to microbial
infected area leads to increased blood flow surfaces

IMMUNOLOGY
A4.2. classical pathway:

- initiated when the complement component
C1, which comprises a recognition protein (C1q)
associated with proteases (C1r and C1s), either
recognizes a microbial surface directly or binds
to antibodies already bound to a pathogen –
both part of innate and adaptive immune
response
A4.3. lectin pathway:

- initiated by soluble carbohydrate-binding
proteins-mannose-binding lectin and the
ficolins-which bind to terminal mannose
residues on the surface glycoproteins of
microbes
 The three pathways converge at the central

and most important step in complement
activation which is the cleavage of C3.
 Complement and pathogen surface
interaction generate C3 convertase which
cleaves C3 to generate large amounts of
C3b, the main effector molecule of the
complement system, and C3a, a peptide
that helps induce inflammation.  Regulatory proteins act as follows: to
 C3b binds covalently to the microbial surface stabilize the C3 convertase (e.g. properdin)
and acts as an opsonin. to amplify the complement reaction, prevent
 C3b can also bind to the C3 convertases the convertase from forming or promote its
formed by the classical and lectin pathways, rapid dissociation
forming another multisubunit enzyme, a C5  Function of complement
convertase which cleaves C5, liberating the - Opsonization
highly inflammatory peptide C5a and - Activation of inflammation
generating C5b. - Lysis of cells
 C5b initiates the 'late' events of complement - Solubilization of immune complexes
activation, in which a further set of
complement proteins interact with C5b to A5. Acute Phase Response
form a membrane-attack complex on the  Release of inflammatory cytokines (TNF-α,
pathogen surface, creating a pore in the cell IL-1β and IL-6) initiate a response known as
membrane that leads to cell lysis the acute- phase response
(membrane-attack complex)  The cytokines act on hepatocytes, which
 The three pathways of complement respond by changing the profile of proteins
activation differ in how they are initiated, that they synthesize and secrete into the
but they share the late steps and perform blood.
the same effector functions  In the acute-phase response, blood levels of
 The complement pathway is largely confined some proteins go down, whereas levels of
to the surface at which it is initiated, i.e. others increase markedly (acute phase
only on the surface of a pathogen or on proteins), which mimic the action of
damaged host cells antibodies, but unlike antibodies, they have
broad specificity for pathogen-associated
molecular patterns and depend only on the
presence of cytokines for their production
 Some examples of acute phase proteins: C-
reactive protein, mannose-binding lectin,
ceruloplasmin, haptoglobulin, ferritin,
complement proteins, albumin, antithrombin
A6. Antiviral Defense

 Involves interferons, NK cells
 Type I interferons produced by plasmacytoid
dendritic cells and virus-infected cells bind
to the IFN receptors on adjacent uninfected
cells and results to inhibition of viral
replication and destruction of viral genomes
* type 1 interferons enhance NK cell killing
of virus-infected cells

IMMUNOLOGY
A7. Properties of the Innate Immune System

 It recognizes structures that are shared by
various classes of microbes and are not
present on host cells.
- Structures shared by various classes of
microbes NOT present in host cells include
lipopolysaccharide (LPS/endotoxin), terminal
mannose residues on glycoprotein, double
stranded RNA in viruses, and unmethylated
CpG nucleotides in microbial DNA.
-recognition of the pathogen-associated
molecular patterns is thru pattern
recognition receptors
 It recognizes molecules that are released
from damaged or necrotic cells, i.e.
damage-associated molecular patterns
 The pattern associated receptors are
encoded in the germline and are not
produced by somatic gene combination
 It does not react against the host B1.2. Cell-mediated - provides defense for
- due to its inherent specificity for microbial intracellular microbes; mediated by T lymphocytes.
structures  Some T lymphocytes activate phagocytes to
- hosts express regulatory molecules that destroy microbes that have been ingested
inhibit innate immune reaction by the phagocytes into phagocytic vesicles
(T-helper cells).
A8. Regulation of Innate Immune Response  Other T lymphocytes kill any types of host
 Production of anti-inflammatory cytokines cells that are harboring infectious microbes
(e.g., IL-10) which inhibits microbicidal and in the cytoplasm (cytotoxic T cells)
inflammatory function of macrophages
 Induction of cytokine inhibitor signaling. B2. Phases of Adaptive Immune Response
B. Adaptive (specific or acquired) immunity has

specificity towards different pathogens; responds
more slowly but has memory which is potentiated by
successive exposure to a microbe
Mechanisms:
- block and eliminate extracellular pathogen: B
lymphocytes
- eradicate intracellular organism: T lymphocytes
Special characteristics:
- The lymphocytes express surface receptors which
recognize specific antigens produced by foreign (and
at times non-foreign) molecules
- The innate and adaptive immune responses are
bridged by dendritic cells which when immature
recognize foreign molecules (innate immune system)
and mature as they migrate to the secondary
lymphoid organs to present the antigens to the
lymphocytes, thus initiating the adaptive immune B2.1. Recognition of antigen
response B2.1.1 The Antigen Receptors: found on the surface
of the lymphocytes are responsible for antigen
B1. Types of adaptive immunity recognition
B2.1.1.1. Immunoglobulins or B-cell receptors (BcR)
B1.1. Humoral–provides defense for extracellular  glycoproteins on the surface of B cells
microbes; mediated byimmunoglobulins (or  identical to the antibodies secreted by the
antibodies as they are secreted by plasma cells) plasma cells but are technically NOT
 Antibodies are secreted into the circulation antibodies as only secreted immunoglobulins
and can neutralize and eliminate pathogens are called as such
at the site of infection  made up of four interlinked polypeptide
 Antibodies have no access to microbes that chains 2 heavy (long) and 2 light chains
live and divide inside infected cells. (short) linked by disulfide bonds
 Antibodies are able to recognize many  N terminal of antibody is composed of
different types of microbial molecules, variable regions or domains of both light
including proteins, carbohydrates, and lipids and heavy chains (VL and VH)

IMMUNOLOGY
 antibody binds to antigen in the variable - crosses the placenta conferring passive
domain – hypervariable region or immunity
complementarity-determining regions (CDR)  IgM
 Constant region is responsible for the signal - 10% of Ig pool, largely intravascular
transduction which leads to the effector - serum half-life: 5 days
activity of the receptors - fixes complement via C1q
 hinge region: found in the heavy chains
- predominant “early” antibody
between CH1 and CH2 which permits
- pentameric
flexibility to allow Ag binding sites to
operate independently  IgA
 Parts of antigen recognized by antibodies - 15 to 20% of Ig pool
are called epitopes - serum half-life: 6 days
 Affinity – strength with which one antigen-
binding surface of an antibody binds to one
epitope
 An immunoglobulin can bind different
epitopes (depending on the number of
antigen-binding sites) and the summation of
the strength of bindings is called avidity
 Antibodies in the primary immune response
have low affinity but with repeated
exposure, the affinity increases (affinity
maturation)
 Antibodies bound to an antigen may still
bind to a structurally similar antigen and the
process is called cross-linking
- production rate of 66 mg/kg/day
- predominant Ig in seromucous secretions
(saliva, colostrums, milk, tracheobronchial,
genitourinary secretions)
 IgE
- scarce in the serum
- found on basophils and mast cell surfaces
- serum half-life: 2 days
- sensitizes cells on mucosal surfaces like
conjunctival, nasal and bronchial mucosa
and has a role in immunity to helminthes,
asthma and hay fever
 IgD
- <1 % of total Ig pool
- present in large quantities on B cell
membrane
- precise role: UNKNOWN but may play a
role in triggered lymphocyte differentiation
B2.1.1.2.T-cell receptors
 transmembrane glycoproteins on the surface
B2.1.1.1.1. Five classes of immunoglobulins of T cells
 IgG  do not recognize and bind antigens directly
- major antibody in the serum and but recognize epitopes bound to major
histocompatibility (MHC) complex molecule
nonmucosal tissues
 also have variable and constant regions
- major antibody of the secondary immune
 have only one binding site
response  have no secreted forms
- monomeric  recognize peptide antigens that are bound
- production rate of 25 mg/kg/day to and displayed by major
- with 4 subtypes – IgG1, IgG2, IgG3, IgG4 histocompatibility complex (MHC)
(differ due to amino acid composition and molecules of antigen-presenting cells
degree of glycosylation) (APCs)
- serum half-life: 23 days
- mediates ADCC B.2.1.2. Major Histocompatibility Complex (MHC)
- fixes complement via C1q: mediated by  genetic regions of loci involved in rejection
IgG1 and IgG3 of foreign or non-self antigen
 encode for the cell surface proteins called
MHC antigens
IMMUNOLOGY
 in humans, called the human leukocyte

antigen (HLA) system
Difference between Class I and Class II

Major Histocompatibility Molecules
Class I Class II
Size of 8-9 amino 13-18 amino
bound acids acids (binding
peptide cleft more
open)
Peptide Cytosolic/nuc- Intravesicular/e
from leolar antigen xtracellular
antigen
Expres- All nucleated B cells, macro-
sed by cells (T cells, B phages, other
cells, mac- APCs, epithelial B2.1.4.1. Processing of vesicular antigens
rophages, cells of the  Antigens are ingested (thru phagocytosis,
other APCs, thymus, receptor-mediated endocytosis, pinocytosis)
neutrophils activated T by APCs, resulting to fusion of endocytic and
cells lysosomal vesicles with breakdown of
antigens to peptides (due to proteolytic
Recog- CD8 T cells CD4 T cells
enzymes)
nized by
 MHC Class II molecules are constantly
synthesized in the endoplasmic reticulum. A
B2.1.3. Antigens entering the body are captured
newly synthesized MHC Class II protein has
mainly by dendritic cells (DC).
an invariant chain (Ii) which contains class II
invariant chain peptide (CLIP) which makes
 Dendritic cells are divided into 2 major
the MHC Class II inaccessible.
population
 MHC class II fuses with endolysosome which
o Classical – found in tissues and
contain the peptide antigens; incidentally,
lymphoid organs, produce TNF,
DM, an MHC Class II-like protein exchanges
Interleukins 6,12 and 23; induction
CLIP in the MHC Class II with peptide
of T cell responses for most
antigen.
antigens
 The MHC Class II and the attached peptide
o Plasmacytoid (resemble plasma
are delivered to the surface of the APC
cells) – found in tissues and blood,
produce Type 1 interferons; antiviral
innate immunity and induction of T
cell responses against viruses
* as dendritic cells capture antigens,
inflammatory cytokines are produced due to
the stimulation of innate immune reaction
thru Toll-like receptor, dendritic cell,
macrophage binding of microbes
 Immature dendritic cells are incapable of
stimulating T lymphocytes.
 DC express membrane receptors that bind
microbes, enabling capture and endocytosis,
leading to production of inflammatory
cytokines
 Activation ensues with subsequent DC
migration to the lymph nodes – DC express
B2.1.4.2. Processing of cytosolic antigens
CCR7 which has strong affinity to the
 Cytoplasmic antigens from viruses, mutated
chemokines in the T cell zone of the lymph
host cells, or transported phagocytosed
nodes
microbes are unfolded and tagged with
 Maturation of DC occur with migration
ubiquitin and are degraded by enzymes in
accompanied by increased synthesis of MHC
the proteasome
molecules and co-stimulators.
 These peptide antigens meet with the MHC
Class I molecule in the endoplasmic
B2.1.4. Antigen Processing and Presentation:
reticulum with the aid of transporter
 Extracellular proteins internalized by
associated with antigen processing (TAP).
specialized APCs are processed in vesicles
 TAP binds the peptides from the cytoplasm
and displayed by class II MHC molecules;
and actively pumps them across the ER
proteins in the cytosol of any nucleated cell
membrane facilitating antigen capture by
are processed in the cytoplasm and
the MHC Class I molecule
displayed by class I MHC molecules

IMMUNOLOGY
B2.1.4.3. Antigen Presentation: and are therefore absent from the repertoire
 Once the fragmented peptide is coupled of mature lymphocytes
with the corresponding MHC molecule, class
I for cytoplasmic and class II for vesicular, B2.3. Effector Phase of Antigen Elimination
the antigen-MHC complex is transported to B2.3.1. Differentiation of T Lymphocytes to Effector
the cell surface to be recognized by the Cells
corresponding lymphocytes. For cytoplasmic  CD4+ helper T cells differentiate into effector
peptide, presentation is directed towards cells that respond to antigen by producing
cytotoxic T cells, while for vesicular peptide, surface molecules and cytokines that
presentation is directed towards helper T function to activate phagocytes and B
cells lymphocytes
- CD40L is transcribed in the CD4+ helper T
B2.2. Activation of Lymphocytes cell leading to its expression in response to
 initial activation of lymphocytes primarily activation. It binds with surface receptor
require the recognition of antigen and for CD40 in B cells, dendritic cells and
full activation of lymphocytes, co-stimulation macrophages.
in the antigen presenting cells must also - These cascades of events lead to co-
take place stimulation of the APCs and further
production of T-cell activating cytokines
B2.2.1. Lymphocyte activation - CD4+ helper T cells may differentiate into
 APCs express proteins aside from antigens. subsets of effector cells that produce distinct
These are co-stimulators. Best known are sets of cytokines and perform different
CD80 (B7-1) and CD86 (B7-2). These functions
proteins are recognized by receptors on the o TH1cells stimulate phagocyte
T cell surface CD28, leading to the activation mediated killing of microbes thru
of naïve T cells expression of interferon-γ, a potent
 CD40 on APCs pair with CD40 ligand activator of macrophages
(CD40L) on T cells to activate APCs to o TH2 cells stimulate phagocyte-
express more B7 co-stimulator to secrete IL- independent, eosinophil mediated
12 that enhances T cell differentiation immunity for helminthes. These
 The process of helper T cell mediated B cell subset of T cells produce IL-4 and
activation is similar to macrophage IL-5 which stimulates production of
activation IgE and activates eosinophils,
 In response to antigen and co-stimulators, T respectively
lymphocytes, especially CD4+ T cells secrete  IL-4 and IL-13 promote
cytokines expulsion of parasites from
- The first cytokine to be secreted by the mucosal organs and inhibit
antigen-stimulated T cell is IL-2 entry of microbes by
- IL-2 preferentially binds to and acts on the stimulating mucus secretion
same T cell  Macrophage activation also
- The principal action of IL-2: stimulate leads to synthesis of
survival and proliferation of T cells extracellular matrix proteins
for tissue repair
B2.2.1.1. Clonal Expansion:  IL-4, IL-13 and IL-10 inhibit
microbicidal activities of
 within 1 to 2 days after activation, T and B macrophages thus
lymphocytes begin to proliferate, thus the suppressing TH1 cell-
expansion of antigen-specific clones mediated immunity
o TH17 cells secrete IL-17 and IL-22
B2.2.1.1.1. Postulates of Clonal Selection Hypothesis and are the principal inflammatory
mediators in some immunologic
 Each lymphocyte bears a single type of reactions. They help protect against
receptor with a unique specificity extracellular bacteria and fungi by
 Interaction between a foreign molecule and stimulating the neutrophil response
a lymphocyte receptor capable of binding that helps to clear the pathogens
that molecule with high affinity leads to o Follicular helper T cells or TFH cells
lymphocyte activation provides help to B cells in the
 The differentiated effector cells derived from lymphoid follicles for high-affinity
an activated lymphocyte will bear receptors antibody production
of identical specificity to those of the o Regulatory T cells suppress T cell
parental cell from which that lymphocyte response and help prevent
was derived autoimmune responses.
 Lymphocytes bearing receptors specific for  natural regulatory T cells
ubiquitous self-molecules are deleted at an  induced regulatory T cells
early stage in lymphoid cell development (or adaptive regulatory T
cells)
IMMUNOLOGY
- Development of naïve T cells into these Antibody response leads to isotype

various subsets of cells are regulated by the switching, affinity maturation and
stimuli that the T cells receive when they production of memory B cells
encounter antigens - B cell activation elicited by polysaccharide,
 TH1 differentiation is driven by IL-12 lipids and other non-protein molecules are
and IFN-γ not mediated by T-cells, hence the term
 TH2 differentiation is driven by IL-4 T-cell independent (e.g. marginal zone B
 TH17 differentiation is driven by IL-6 cells and B-1 B cells)
and IL-1, IL-23 and TGF-β Antibody response creates only minimal
 Regulatory T cell differentiation is class switching, with little or no affinity
driven by TBF- β maturation and limited memory B cell
 TFH cell differentiation is? driven by production
IL-6  B cell effector functions
- CD8+ T lymphocytes activated by antigen - Opsonization
and co-stimulators differentiate into - Neutralization of microbes and toxins
cytotoxic T lymphocytes - Antibody-dependent cellular cytotoxicity -
 Perforins insert into the endosomal IgE and mast cell mediated reactions
membrane and facilitate movement - Complement activation via the classical
of granzymes pathway mediated by IgM and Ig
 Granzymes cleave and activate - Protection of the neonate
caspases in the cytoplasm of target
cells and induce apoptosis B2.4. Decline (return to homeostasis)
 CTLs also express Fas ligand which  once the immune response is over, the
binds to the Fas on target cells. The system has to return to the steady state or
binding leads to activation of homeostasis
caspases resulting to apoptosis - For B cells, as IgG circulates in the body,
the Ig binds to the antigen in the tissues
B2.3.2. Differentiation of B Lymphocytes to Effector and blood, leading to immune complex
Cells formation. The B cells may bind to the
antigen portion and the Fc portion of the
 Naïve B cells express 2 classes of Ig may be recognized by FcγRII receptors.
membrane-bound antibodies, IgM and IgD These receptors deliver inhibitory signals
 Upon activation, signal transduction brings which shut-off antigen receptor-induced
about transcription leading to clonal signals (antibody feedback)
expansion. The B cells differentiate to - For T lymphocytes, once the infection is
become plasma cells, the effector cells cleared, the stimuli which led to the
which secrete antibodies activation and proliferation decline, thus
 B lymphocytes express type 2 complement due to the absence of this signals (1 to 2
receptor (CR2) which binds C3d, a fragment weeks after eradication of pathogen), the
of complement protein C3; i.e. complement cells undergo apoptosis
activation leads to a production of a 2nd
signal for B lymphocytes B2.5. Maintenance of Memory
 Activation of the B cells lead to the  A fraction of the progeny of the activated T
production of antibodies of different heavy and B cells do not have effector functions
chain isotypes (class switching), which but become memory cells which circulate in
mediate varying effector functions the blood and reside in some tissues, ready
 B cells activation elicited by protein antigens to respond if the antigen is re-introduced
through the aid of T-cells are classified as T-  The response of the immune system to the
cell dependent (e.g. follicular B cells) initial and subsequent exposures to the
- Effector helper T cells interact with same antigen yield greater immunogenicity
antigen stimulated B cells at the edge of with each subsequent exposure
lymphoid follicles in the peripheral  Primary immune response is mediated
lymphoid organs by naive lymphocytes, that encounter the
- Antibody response leads to isotype antigen for the first time.
switching, affinity maturation and  Secondary immune responses are
production of memory B cells usually more rapid, larger, and better able
- B cell activation elicited by protein to eliminate the antigen compared to the
antigens through the aid of T-cells are primary immune response
classified as T-cell dependent (e.g.  Immunologic memory optimizes the ability
follicular B cells) of the immune system to combat persistent
Effector helper T cells interact with and recurrent infections, because each
antigen stimulated B cells at the edge of encounter with a microbe generates more
lymphoid follicles in the peripheral memory cells and activates previously
lymphoid organs generated memory cells.

IMMUNOLOGY
by autoantibodies and self-reactive T cells.

It is characterized by the breakdown of
immune tolerance
 Examples of autoimmune diseases are
- Multiple sclerosis: attack myelin
- Myasthenia gravis: attack on cholinergic
receptors on skeletal muscle
- Rheumatoid arthritis: attack on joints and
synovial membrane
- Type 1 Diabetes mellitus: attack on insulin
producing cells of the pancreas
- Systemic lupus erythematosus: attack on
various tissues and organs, including skin,
joints, kidneys
 The principal factors in the development of
autoimmunity are inheritance of
6. Immunological Tolerance and Autoimmunity susceptibility genes and environmental
A. Immunological tolerance triggers
 lack of response to antigens that is induced  Some infections produce peptide antigens
by exposure of lymphocytes to these that are similar to and cross-react with self-
antigens antigen (molecular mimicry)
- Immunogenic response – activation,  Proposed etiologies of autoimmunity
proliferation and differentiation of - Failure of clonal deletion in the thymus or
lymphocytes into effector cells clonal inactivation in the periphery
- Tolerogenic response – lymphocytes are - Alteration of normal body proteins by
either killed or inactivated combination with drugs or environmental
- Immunologic ignorance – antigen specific chemicals resulting to a “new” foreign
lymphocytes will not produce any reaction, antigen
i.e. lymphocytes ignore the presence of - Excessive and pathologic cell destruction
antigen during viral infection
 Tolerance maybe induced during encounter - Genetic mutations in body cells yielding
new proteins that serve as antigens
of self-antigen with developing lymphocytes
- Encountering microbes with antigens very
in the generative or the peripheral tissues
similar to self-antigens so that antibodies
- Central T cell tolerance – mechanisms to cytotoxic T cells produced also attack
include cell death (negative selection) and the “self”
generation of regulatory T cells - Exposure of proteins normally never
- Peripheral T cell tolerance – mechanisms encountered by lymphocytes as a result of
include functional inactivation of T cells some other disease
(anergy) or death (activation induced cell
death) or suppression by regulatory T cells 7. Hypersensitivity
- Central B cell tolerance - - mechanisms  Injurious or pathologic immune reactions
include changes in receptor specificity usually occurring due to (1) uncontrolled
(receptor editing) or killing (negative response to foreign antigens leading to
selection) tissue injury and (2) immune response
- Peripheral B cell tolerance – mechanisms directed to self-antigen
include anergy A. Types of Hypersensitivity Reactions
1. Immediate hypersensitivity -
 rapid, IgE antibody- and mast cell mediated
vascular and smooth muscle reaction
followed by inflammation on repeat
encounter with non-self antigens
A1.1. Sequence of events
 Production of IgE antibodies due to
strong TH2 cell response elicited by
allergens to produce IL-4 and IL-13
which stimulates class-switching
 IgE produced in response to an
allergen binds to high-affinity Fc
receptors specific for the ε heavy
Central and Peripheral Tolerance to Self-
chain expressed on mast cells
Antigen*
(sensitization)
 Cross-linking of the bound IgE by the
B. Autoimmunity –
antigens leading to (1) rapid release
 inappropriate immune attack against the
of granule contents of mast cells, (2)
body’s own proteins or antigens, mediated
synthesis and secretion of lipid
IMMUNOLOGY
mediators, (3) synthesis and secretion  Antigen sensitized cells release cytokines
of cytokines following a secondary contact with the same
 Release of mast cell mediators, which antigen
include vasoactive amines  Cytokines induce inflammatory reactions and
(histamines) and proteases, activate and attract macrophages
arachidonic acid metabolites and
cytokines A4.1. Example: Tuberculosis
 Anaphylaxis
- most severe form of immediate 8. Therapeutic Uses of Antibodies
hypersensitivity
- characterized by hypotension, tissue 8.1. Passive Immunization: is the administration of
edema and bronchiolar constriction and immunoglobulin prepared from individuals known to
cause death due to circulatory and have high levels of antibodies specific to an
infectious agent(s)
respiratory failure
 Late phase response:
8.1.1. Indications for passive immunization
- may follow immediate hypersensitivity in  In immunocompromised host if the ability to
the ensuing hours or days due to generate a sufficient immune response to
eosinophils that migrate in the inflamed vaccination is in doubt
areas due to chemoattractant cytokines  In patients who cannot make antibodies in
released by activated mast cells and TH sufficient time to protect against disease
cells.  Antivenin for snake bite
- eosinophils release mediators that prolong  Intravenous Immune Globulin
the inflammation and further sensitize the Replacement in some individuals who
tissues. Macrophages may infiltrate the innately do not have antibodies or have very
area causing tissue destruction low levels of antibodies
A1.2. Examples of Conditions resulting from 8.2. Monoclonal antibodies

Immediate Hypersensitivity
 Allergic rhinitis 8.2.1. Uses of Monoclonal antibodies
 Food allergies  graft rejections suppression
 Bronchial asthma  lymphomas and solid tumors
 Anaphylaxis (due to drug, food, bee sting) chemotherapeutic regimens
 interfere with the activity of
2. Antibody-mediated Cytotoxic Reaction proinflammatory mediators such as TNF-α
 IgG) directed towards self or nonself cells or  direct anti-infective agents (e.g. Palivizumab
tissues bind complement via the classical
pathway leading to cytotoxic actions or References:
complement mediated lysis 1. Abbas, AK, Lichtman, AH. Basic Immunology 4th
ed. 2014
A2.1. Examples of Conditions resulting from 2. Mandell G, Bennett, J, Dolin R. Principles and
Antibody-Mediated Cytotoxic Reaction Practice of Infectious Diseases 8th ed. 2014
 Good pasture’s syndrome with anti-GBM 3. Murphy, KM, Travers P, Walport M. Janeway’s
antibodies Immunobiology 8th ed. 2012
 Pemphigus vulgaris with antiepidermal
antibodies inducing skin blisters For any questions, clarifications: kindly send email to
 Transfusion reactions with red cell lysis [email protected] or
[email protected]
3. Immune Complex Disease –
 results when large amount of IgG or IgM *****G*O*D*B*L*E*S*S***Y*O*U* **********
combine with soluble antigens. These
immune complexes are deposited in tissues
leading to inflammation and tissue injury
 There is complement activation and Fc
receptor-mediated recruitment and
activation of leukocytes
A3.1. Examples:
 malaria
 infective endocarditis
 glomerulonephritis
4. Delayed Type Hypersensitivity

 the tissue injury is mediated by CD4+ T cells
or by killing of host cells by CD8+ cells
 Independent of antibodies
IMMUNOLOGY

_____9. Primary lymphoid organ
_____1. Cell specific for the innate immune A. bone marrow
response: B. lymph nodes
A. Dendritic cell C. peyer’s patches
B. Macrophage D. spleen
C. Natural killer cell
D. Plasma cell _____10. Type 1 hypersensitivity
A. Expressed within minutes
_____2. Characteristic of active immunity B. IgM and IgG mediated
A. Induced by immunoglobulin injection C. with direct tissue toxicity
B. Facilitated by maternal transfer of D. With immune complex binding
antibodies
C. Longer lasting protection _____11. Characteristic of MHC Class 2 molecule
D. D. Rapid onset of protection A. Binds more amino acids
B. Binds nucleolar antigen
_____3. Characteristic of secondary immune C. Expressed by all nucleated cells
response D. Recognized by cytotoxic T cells
A. Longer lag phase
B. Predominance of IgG _____12. Characteristic of B cell receptors
C. Predominance of IgM A. Binds peptide antigens coupled with
D. Low level affinity of antibodies MHC class 2 molecules only
B. Exists in both bound and secreted
_____4. Proper order of the phases of immune forms
response C. Has both Alpha and Beta chains
1. Decline of lymphocyte levels D. CD3 and zeta chain functions for
2. Identification of pathogen signal transduction
3. Elimination of pathogens
4. Lymphocyte differentiation _____13. Bestdescription of immunoglobulin class
A. 2,3,4,1 A. IgA: present in the cytoplasm
B. 2,1,4,3 B. IgD: abundant in naïve lymphocytes
C. 2,3,1,4 C. IgE: first antibody to appear in
D. 2,4,3,1 primary infection
D. IgG: mediates anaphylaxis
_____5. Appropriate complement pathway trigger
A. Alternative: ficolin _____14. Characteristic of vesicular antigen
B. Classical: antibody-mediated processing
C. Lectin: direct pathogen A. Antigen partners with MHC Class I
D. Alternative: antibody-mediated molecules
B. Epitopes are recognized by cytotoxic
_____6. B cell receptors T cells
A. recognize both lipopolysaccharides C. Epitopes undergo tagging with
and proteins ubiquitin
B. recognize proteins only D. Presence of DM protein facilitates
C. recognize polysaccharides bound to antigen and peptide binding
MHC Class 2 molecule
D. recognize polysaccharide bound to _____15. True of lymphocyte activation
MHC Class 1 molecule A. CD28 on antigen presenting cells
bind with B7-1 on the T cell surface
_____7. True of Immunoglobulins B. Initiated by antigen presentation to a
A. IgA: predominant in mother’s milk corresponding T cell
B. IgD: predominant in activated T C. Occurs only when T cells secrete
lymphocyte surface interleukin 2
C. IgE: predominant in primary immune D. Occurs in the absence of the B7-1
response and CD28 binding
D. IgM: predominant in secondary
immune response _____16. Characteristic of asthma
A. CD4 and CD8 mediated
_____8. True of T cell receptors B. IgM and IgE mediated
A. recognize both lipopolysaccharides C. Mast cells release vasoactive
and proteins peptides following Ig-antigen cross-
B. recognize proteins only linking
C. recognize polysaccharides bound to D. Mediated via the alternative pathway
MHC Class 2 molecule of complement
D. recognize polysaccharide bound to
MHC Class 1 molecule
IMMUNOLOGY
_____17. Immunologic mechanism in tuberculin skin

testing
A. Ensues for hours to days due to
eosinophil migration
B. Initiated by IgM and IgG through the
alternative pathway of complement
C. Mediated by macrophages that
migrate to the site of antigenic
stimulus
D. Results from immune complex
attachment to tissues
_____18. Characteristic of cell lysis during

transfusion reaction
A. IgM-IgG complement activation via
the classical pathway
B. Immune complex attachment to the
tissue
C. Initiated by mast cell degranulation
D. Occurs after 48-72 hours
_____19. Sequence of events in food allergy

1. Introduction of antigen
2. Attachment of antigen to the Fab
portion of IgE
3. IgE attaches to the mast cell surface via
the Fc portion
4. Release of vasoactive peptides
A. 1, 2,3,4
B. 1, 3,2,4
C. 1, 4, 2, 3
D. 1, 4, 3, 2
_____20. True of memory cells

A. Enhanced production upon encounter
with polysaccharide antigens
B. Have antigen receptors similar to the
parent cells
C. Increased production during T cell
independent B cell stimulation
D. Produces more IgM than IgG during
re-encounter with the stimulating
antigen

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BLOOD PHYSIOLOGY

MA. ROSARIO F. CABANSAG, MD

BLOOD PHYSIOLOGY Growth factors: Early acting: SF, FLK2/FLT3

a. -genes on chr 16 b. Non- genes - , ,

UST FMS MEDICAL BOARD REVIEW 2019 2 | PHYSIOLOGY

Disorders of Red Cell - more than 600 RBC antigens belonging to

Major Systems Minor Systems Platelet Plug Formation

Adhesion of platelets to the vascular

UST FMS MEDICAL BOARD REVIEW 2019 4 | PHYSIOLOGY

Depending on the vascular bed, available adhesive II. SECONDARY HEMOSTASIS

In each instance a prothrombin activator is

Most of the clotting factors are designated

Blood Coagulation Factors

Category and Hemostatic Plasma

HMW Kininogen surface 4 Interaction between the Extrinsic and

UST FMS MEDICAL BOARD REVIEW 2019 6 | PHYSIOLOGY

Role of platelets. Platelets play an

PATHWAYS FOR INITIATING BLOOD

CROSSOVER SCHEME OF COAGULATION

SCHEMA FOR CONVERSION OF

III. TERTIARY HEMOSTASIS

A. CONSOLIDATION AND GRADUAL

These fibrin molecules noncovalently interact with

B. ACTIVATION OF THE FIBRINOLYTIC

2. limited proteolysis of factors Va and VIIIa by

EFFECTS OF SOME DRUGS ON HEMOSTASIS

UST FMS MEDICAL BOARD REVIEW 2019 8 | PHYSIOLOGY

CHOOSE THE BEST ANSWER:

UST FMS MEDICAL BOARD REVIEW 2019 | PHYSIOLOGY

The gastrointestinal (GI) system includes the GI

UST FMS MEDICAL BOARD REVIEW 2019 1 | PHYSIOLOGY

2. Submucosa 2. Secretion - refers to the processes by which

UST FMS MEDICAL BOARD REVIEW 2019 2 | PHYSIOLOGY

Innervation of the GI Tract

1. Extrinsic Nervous System – nerves that innervate the

GASTROINTESTINAL MOTILITY Action Potentials

ELECTROPHYSIOLOGY OF THE GI SMOOTH

UST FMS MEDICAL BOARD REVIEW 2019 4 | PHYSIOLOGY

2. Lower Esophageal Sphincter (LES) Functions of Chewing

amylase Types of Peristalsis in Esophagus

UST FMS MEDICAL BOARD REVIEW 2019 6 | PHYSIOLOGY

which are stimulatory to gastric

1. Liquids flow around the mass of food 1. Extrinsic Neurons

UST FMS MEDICAL BOARD REVIEW 2019 7 | PHYSIOLOGY

UST FMS MEDICAL BOARD REVIEW 2019 8 | PHYSIOLOGY

Motilin - a 22-amino-acid peptide synthesized  In contrast, the longitudinal muscle of the

1. reabsorbs remaining fluid and electrolytes

UST FMS MEDICAL BOARD REVIEW 2019 9 | PHYSIOLOGY

a. Parasympathetic NS: small intestinal transit times are

GASTROINTESTINAL SECRETION Glandular Regions of the Stomach

1. Cardiac glandular region

UST FMS MEDICAL BOARD REVIEW 2019 11 | PHYSIOLOGY

 Cl- is major anion 2. Gastrin

Phases of Gastric Acid Secretion

 accounts for 30% of acid secreted 4. Intestinal Phase

UST FMS MEDICAL BOARD REVIEW 2019 13 | PHYSIOLOGY

INTRINSIC FACTOR 2. Exocrine pancreas

Gastric Mucosal Barrier

1. Endocrine pancreas – Islet of Langerhans. It