Finals Reviewer – LE 4 PHYSIOLOGY

April 15, 2018 LE 4

OUTLINE 2. Submucosa
o Consists mainly of loose connective tissues
o Larger nerve trunks, blood vessels, and lymph vessels
4.01 Upper GI Physiology are present.
4.02 Lower GIT o Contains the submucosal or Meissner’s plexus
4.03 Accessory Organs
4.04 Absorption, Digestion, Nutrition 3. Muscular layers/ Muscularis externa/ Muscularis Propria
4.05 Renal Physiology I • Composed of two layers *ICOL*
4.06 Renal Physiology II
• Inner: circular smooth muscle layer
4.07 Water, Electrolytes
• Outer: longitudinal smooth muscle layer
4.08 Acid-Base Balance
• Myenteric / Auberbach plexus is present in between
the two muscle layers

4.01 Upper GI Physiology 4. Serosa/Adventitia

o Serosa
UPPER GI FUNCTIONS § Outermost layer of GIT
§ Thin layer of connective tissue with blood lymphatics
• Mechanical breakdown § Mesothelium (simple squamous epithelium) for
• Chewing: mouth covering
• Churning: stomach § Present in organs suspended in the body wall by
• Segmentation: small intestine mesentery
• Digestion: physical and chemical modification of food for o Adventitia
absorption § Lacks mesothelium
• Absorption: happens after digestion, mainly in the small § Present in organs that are adjacent to other organs
intestine (e.g. Esophagus)
o Lymph and blood vessels direct the absorbed nutrients to
the body NEUROCRINE CONTROL OF GIT
• Motility the muscular GIT wall aids in digestion mixed with
glandular secretion Autonomic Nervous System
o Swallowing: mouth to esophagus • Predominant since 90% of GIT is composed of smooth
o Peristalsis: esophagus to intestines muscle
• Storage: stomach and colon stores food temporarily • Parasympathetic Nervous System
• Excretion of wastes: anus o Cranio-sacral
• Immunity: the gut is considered as the largest immune organ. o Controls feeding, breathing, rest and digestion
• Esophagus o Control secretions and motility
o Upper 1/3: composed of skeletal muscles o Preganglionic nerves have nicotinic synapse with
o Middle 1/3: mix of skeletal and smooth muscles postganglionic neurons of ENS involving Acetylcholine
o Lower 1/3: composed of smooth muscles • Cranial Division
o Governed by the autonomic nervous system (ANS) o Almost entirely in the Vagus nerve except in mouth and
• Sphincters pharyngeal regions
o Increased presence of circular muscles to open and o Controls
close them § Esophagus
o Provide selective retention of contents or prevent § Stomach
backflow § Pancreas
o Six sphincters in the GIT: o Salivation is stimulated by CN VII and IX
§ Upper & Lower esophageal sphincter • Sacral Division: S2 – S4
§ Pyloric sphincter o Involves the pelvic nerves to the distal half of the large
§ Ileocecal Sphincter intestine and all the way to the anus
§ Internal & External anal sphincter o The sigmoidal, anal, and rectal regions are better
supplied with parasympathetic fibers than the other
GIT WALL LAYERS intestinal areas
• Sympathetic Nervous System
1. Mucosa / Mucous Membrane – has 3 distinct layers o Thoracolumbar
1) The outer layer/epithelium contains glands § Mainly inhibitory and is composed of spinal
§ Enterocytes: most abundant type of cells afferents, splanchnic nerves from T5 – L2
§ Tight junctions link the columnar epithelial cells o Composed of four ganglia:
together. 1) Cervical Ganglia
2) Inner layer is called the lamina propria 2) Celiac Ganglia
§ Composed of loose connective tissue 3) Superior mesenteric Ganglia
§ Rich in lymph vessels and nodules, capillaries and 4) Inferior mesenteric Ganglia
nerve fibers o Innervates all the GIT, in contrast to parasympathetic that
3) Muscularis mucosae is a thin innermost muscle layer of are more focused on the oral cavity and anus
the intestinal smooth intestine. o Neurotransmitter is mainly norepinephrine and some
epinephrine

1 of 24
Enteric Nervous System 4. Spike potential – true action potential directly causing
• “Little brain of the gut” that functions independently but close stronger and phasic contractions. Occur when the
association with ANS membrane potential of the GI smooth muscle becomes
• Local functions: Digestion, secretion, and motility more positive than -40mV
• Wholly contained within the Submucosal/Meissner’s and
Myenteric/Auerbach’s plexuses in GIT wall Figure below: membrane potentials in intestinal smooth
• Communicates intensively with the parasympathetic and
muscle (Guyton, 13th Ed. Pg 798)
sympathetic nervous systems
• Quasi-autonomous part of the nervous system and includes
neural circuits that control motor functions, local blood flow,
mucosal transport and secretions, and modulates immune
and endocrine functions

1. Submucosal/Meissner’s Plexus
o Contained in submucosal layer
o Control local intestinal secretion and absorption
o Contraction of submucosal muscle causes the in-foldings
of GI mucosa

2. Myenteric/Auerbach’s Plexus
o Found between the longitudinal and circular muscle
layers
o Controls mucosa where most glands are present
o Linear chain of interconnecting neurons
o Mainly controls muscle activity
o When stimulated, increases the following:
§ Tonic contraction of the gut ENDOCRINE
§ Intensity of contraction
§ Rate and rapidness of contraction • Hormones travel to their cells through the bloodstream
o Also secretes inhibitory neurotransmitters that inhibit • Endocrine regulation happens when a regulatory peptide or
intestinal sphincter muscles
hormone is released by an enteroendocrine cell (EEC) in
Somatic Nervous System response to a stimulus
• Voluntary control; Innervates parts with skeletal muscle • Secretin: promotes pancreatic secretion
• Mouth, upper ⅓ of pharynx, and external anal sphincter • Gastrin: released from the “G” cells of the stomach antrum;
• Start of swallowing requires voluntary muscle control to start stimulates gastric acid secretion and growth of the gastric
the process mucosa
• There is a pacemaker group called the intermuscular cells • Cholecystokinin (CCK) is secreted by the “I” cells of the
of Cajal mucosa of duodenum and jejunum
• GIT Stimulation
o Stimulates gallbladder contraction
o Stretch receptors of the stomach send the signals once
the stomach lining is stretched because of food content o ¯ stomach contraction
o Parasympathetic nervous system stimulates the o ¯ appetite
sphincters to relax o Motilin is secreted by the stomach and upper duodenum
and stimulates the ­ gastrointestinal motility
NEUROTRANSMITTERS
PARACRINE
• Excitatory
o GABA – Induces smooth muscle contraction
o Acetylcholine – excitatory effect on GI activity • Chemical messenger from adjacent cell is released from EEC
• Inhibitory and acts on a nearby target cell by diffusion through the
o Norepinephrine – ¯ GI activity interstitial space
o Epinephrine – ¯ GI activity • Histamine is stored and released by enterochromaffin-like
o Somatostatin – muscle relaxant cells and stimulates production of acid
o Neuropeptide Y – inhibitory effect for smooth muscles • Serotonin regulates smooth muscle function and water
o Substance P, CGRP (calcitonin gene related peptide),
absorption across intestinal wall
Acetylcholine - for pain pathways and modulate
inflammation o Open type EEC
o Serotonin – immune response and gut inflammation § Most common EEC
§ Apical membrane in contact with the lumen of the GI
BASIC ELECTRICAL RHYTHM tract
o Closed type EEC
• Continuous slow intrinsic electrical activity causing excitation § No contact with the luminal surface of the gut
• Facilitated by Ca2+ / Na+ channels § EEC-like cell in the gastric epithelium which
1. Pacemaker cells – interstitial cells of Cajal secretes histamine
2. Slow waves - rhythmic gastrointestinal contractions § Ghrelin is secreted by closed type EECs. Also
o cause depolarization which may or may not reach known as the hunger hormone
threshold, cause contraction in the stomach
o In other parts of the GIT, slow waves promote production
of spike potentials
3. Threshold – opening of voltage gated Ca2+ and Na+ channels
2 of 24
 REFLEXES • Preserves teeth due to the presence of mucin
(inhibition of demineralization)
Table below: summary of reflex pathways • Lubrication helps retain the moisture in the mouth
Short Reflex Pathway Long Reflex Pathway (easier swallow of food)
Functions
Integration center in the Integration center in the • Buffering capacity against very strong acids
ENS CNS • Digestion of food (amylase/ptyalin)
Direct action on smooth Indirect action, acts • Maintenance of taste buds (zinc)
muscles through Autonomic • Antibacterial, antifungal, antiviral
(motor arm of the brain)

Figure below: Illustration of the GI reflexes (adapted from lecture ppt.) SWALLOWING

• Swallowing Reflex
• Inhibits respiration during wallowing
• Receptors: tactile receptors in the pharynx
• Afferent Nerves: CN V, IX
• Integration center: swallowing center in medulla & lower pons
• Efferent Nerves: CN V, IX, X, XII
• Effectors: muscles of the pharynx and cricopharyngeus
• Has 3 phases: oral, pharyngeal, esohageal

1. Oral Phase
• Involves 2 phases: (1) voluntary and (2) involuntary
• Voluntary phase: initiated when:
o The tip of the tongue and more posterior portions of the
tongue press against the hard palate to separate bolus
from the mass of food
• Gut Brain Axis (GBA) • Touch receptors near the pharyngeal opening, transmits
o Gut microbiota influence interaction in the central and sensory impulses to the swallowing center in the medulla &
enteric nervous system, linking emotional and cognitive lower pons
centers of the brain with peripheral intestinal functions o stimulates vagal motor neurons for the involuntary phase
o Bidirectional, describe as signaling from gut microbiota to to commence.
brain and from brain to gut microbiota by means of
neural, endocrine, immune, and humoral links 2. Pharyngeal phase
• Salivary Reflex Arc
• Soft palate moves upward covering nasopharyngeal opening
o Parasympathetic control for salivation when food is
• Palatopharyngeal folds move downward and medially forming
absent in the oral cavity
a passage that directs bolus to pharynx
o Stimuli: sight, thought, and smell of food initiate salivation
• Vocal cords are pulled together, larynx moving forward and
Table below: Summary of Information about Saliva upward to align with epiglottis
SALIVA • Bolus is pushed to esophagus by contraction of pharyngeal
muscles and UES
• Large volume relative to mass of salivary glands
• High K+ Concentration
3. Esophageal Phase
• Low osmolarity
Major • Primary Peristalsis – initiated from a swallow
• Major digestive functions carried out by salivary
Character amylase (breakdown of starch → oligosaccharide • Secondary Peristalsis – occurs to clear esophagus of bolus
istics molecules) • Tertiary Peristalsis – simultaneous, isolated, and dysfunctional
• Produced form filtrate of ECF esophageal contractions (elderly)
• Excess production may lead to: hypokalemia,
Figure below: Time of motor events during swallowing
dehydration, ↓ blood volume
(Berne & Levy, 6th Ed. Pg 501)
• Produced by salivary glands
• filters blood, cellular components, and platelets
• ↑ blood flow to a certain gland = ↑ amount of blood
Formation that the gland can filter to produce secretion
• Extracellular fluid
• used as a base for secretion while
adding/subtracting component
• Primary secretion: filtered blood - cellular
components + components produced in acini
(amylase, mucus, ECF)
• Primary isotonic secretion:
o produced by acinar cells
Secretion
o modified by duct cells
o Na+ and Cl- are extracted, adding K+ and HCO3-
are added to the saliva
• Final salivary secretion: Hypotonic & Slightly
Alkaline

3 of 24
 LOWER ESOPHAGEAL SPHINCTER (LES) • Constrictor waves progress from body to antrum, becoming
more intense then provides peristaltic action potential-
• Prevents reflux of acid gastric contents into esophagus driven constrictor rings forcing the antral contents in higher
• Exhibits “receptive relaxation” mediated by Vagus Nerve (NO pressure towards pylorus
and VIP) when food is brought by peristalsis into esophagus • Peristalsis and retropulsion – an upstream squeezing
o Nitric Oxide – main neurotransmitter at LES, inhibiting action; important mixing mechanism of the stomach
smooth muscles → relaxation of sphincter • Chyme- chewed bolus round up to < 2 mm per size of
• ↓ LES Pressure = LES is more open and prone to acid reflux particulate

Table below: substances altering LES pressure 3. Emptying

↑ LES Proteins, Carbohydrates, Non-fat Milk, Low-dose • promoted by intense peristaltic contractions in the stomach
pressure Ethanol antrum
Fat, Whole milk, Orange Juice, Tomatoes, Anti- • Mixing waves can increase intensity and cause very strong
↓ LES
flatulent, Chocolates, High-dose ethanol, Smoking, contractions resulting in the production of tight ring-like
pressure
Lying on either side, Sitting constrictions that facilitate emptying
• Pyloric pump: pumping action caused by peristaltic waves
• LES Abnormalities • Slow delivery of chyme through the pyloric sphincter at a rate
a) Achalasia not to exceed the digestive and absorptive capacity of the SI
§ neuromuscular disorder of lower 2/3 of esophagus and • Slower and larger particles repulses back for more grinding
failure of LES to relax
§ Tx: Botulinum toxin inj. Table below: Events that take place at different meal times
b) Gastroesophageal Reflux Disease GASTRIC MOTILITY
§ Sclerodoma – causes GERD, muscle replaced by CT RIGHT AFTER OR IN-BETWEEN MEALS
§ Tx: H2 receptor antagonist or Proton Pump Inhibitors DURING A MEAL
Contractions • Fundus- quiescent. • synchronous
STOMACH PHYSIOLOGY of the parts Food is stored contractions of
of the • Midbody and fundus, body and
Table below: 3 Functional regions of the Stomach stomach antrum- crush food antrum
REGIONS DESCRIPTIONS LUMINAL MOTILITY to <1 mm
SECRETIONS Mechanical • Peristalsis- • Migrating
Lower LES: still part of Mucus • prevention and electric increases intensity myoelectric cycle
Esophageal the esophagus HCO3- of reflux events from midbody to (MMC)
Sphincter • entry of antrum
(LES) and food
Cardia • Retropulsion- food
• regulation
of belching particles impact on
H+ pyloric sphincter
Fundus and Upper 1/3: quiet • a reservoir/
Body Intrinsic Factor when it closes
storage
Lower 2/3: very Mucus • tonic force
active; where HCO3- Table below: Summary of the functional motility controlled by
during
rugae are mostly Pepsinogen neurohormonal mechanism
emptying
prominent; where Lipase ACTIONS THAT TAKES STIMULATED
several PLACE
contractions Proximal Gastric Basal Vagus nerve (CN X)
occur Tone Sympathetic Inhibition
Antrum and Near the Mucus • mixing Proximal Gastric Motilin
Pylorus antrum: where HCO3- • grinding Contraction
vigorous • sieving Proximal Gastric Receptive GRP VIP
contraction
• regulation Relaxation Gastrin Somatostatin
happens due to
of emptying CCK Glucagon
mixing and
grinding
Secretin Bombesin
Duodenal Distension Acid, protein, and fat content
GASTRIC MOTILITY
GASTRIC EMPTYING
1. Storage
• Liquids have faster emptying time than solids
• Fundus enlarges as food enters the stomach ® relaxation
• Local reflexes dictate the rate by which the stomach empties
• Concentric circles of food are formed as it enters the stomach
• Receptive relaxation: a wave of relaxation transmitted Table below: summary of excitatory and inhibitory effects on gastric
through myenteric inhibitory neurons, precedes peristalsis emptying in relation to sense of hunger
when esophageal peristaltic wave approaches the stomach EXCITATORY INHIBITORY
• Vagovagal reflex- from stomach ® brain stem ® stomach; • makes stomach empty • makes you feel full longer
reduces the tone off the muscular wall of the body of the faster into the duodenum = • volume of the chyme in the
stomach. This bulges the wall outward hungry faster duodenum becomes too
• storage capacity of stomach (relaxed state): 0.8 - 1.5 L • stretching of antrum and much = ↓ enterogastric
increase in volume of liquid reflexes, gastric emptying
2. Mixing in the stomach (e.g. eat a and acid secretion
• Food in the body and antrum results in increased contraction lot)
• Gastric glands secrete digestive juices.
• Mixing waves is present as long as the food is in stomach
• Occurs every 15-20 seconds
• Initiated by Basic Electrical Rhythm (small waves)

4 of 24
• Moods and hormonal levels also affect the gastric emptying Mucus and Bicarbonate (HCO3-)
a. Depression inhibits gastric emptying • Mucus: gel-forming glycoproteins (mucins); 80% CHO
b. Anger stimulates gastric emptying • Secretions that contain mucins
o Secreted by mucous neck cells that protects the stomach
Table below: Important hormones in response to a meal mucosa from acidic secretions
• secreted in response to stimuli associated with • Sodium Bicarbonate
ingestion of a meal o ↑ in mucosal irritation, parasympathetic stimulation,
Gastrin • Stimulates gastric acid secretion and growth of prostaglandins, empty stomach
the gastric mucosa
o ↓ in stress (NE, Epi), aspirin, NSAIDs, smoking
• ­ stomach contraction and emptying = ­ hunger
• Released by I cells from the mucosa of the GASTRIC DIFFUSION BARRIER
jejunum in response to fatty and caloric
Cholecystokinin • Relatively impermeable to acid of the apical membrane
substances in the chyme
• Mucous gel layer varying in thickness between 50 - 200 µm
• inhibits gastric emptying overlying epithelial cell surface
• Released from the duodenal mucosa in • HCO3- is present adjacent to the surface epithelial cells to
response to gastric acid that passed from maintain relatively high pH
Secretin the stomach to pylorus
• stimulates pancreatic bicarbonate Enzymes: Pepsins
secretion
• Secreted as inactive pepsinogens- I and II
• Foods that make you feel longer • Activated by ↓ pH (HCl)
o Hypertonic: e.g. blenderized, thickened food o Endoproteases: digest aromatic amines
o High caloric content: e.g. fatty and oily food • Secreted stimulated by PNS (Ach)
o Acidity: e.g. drinking lemonade or eating green mangoes o Major hormones: gastrin, CCK, secretin
• Other enzymes: gastric lipase- triglycerides, cathepsin,
Table below: Factors that affect gastric emptying gelatinase
FACTOR CHANGE EFFECT ON GE • ¯ pH ® more acidic ® faster breakdown
RATE
Volume of meal ↑ ↓ Hydrochloric Acid (HCl)
• Provides optimal pH for pepsins
Viscosity of meal ↑ ↓
• Kills ingested bacteria
Composition of Fatty or high ↓ • Converts ferric (Fe3+) ® ferrous (Fe2+) ions
meal electrolytes • ­ Ca2+ absorption of calcium and other minerals
Disease states Diabetes and • Stimuli for secretion: Histamine, Acetylcholine, Gastrin
duodenal/ pyloric ↓
ulcers Intrinsic Factor (IF)
Temperature of Hot contents ↑
• Binds Vitamin B12 and aids in absorption in the ileum
contents
• Secreted by the parietal cell as the same rate as the HCl
Effect of body Lying on LHS ↓
position • The only gastric secretion required is intrinsic factor
Emotional/ Aggression ↑
Mechanisms that Inhibit Gastric Secretion
Physical state Depression, ↓
exercise or • Low pH ® stimulation of somatostatin
physical stress • Reverse enterogastric reflex activated when there’s food in
Drugs Anticholinergics, ↓ small intestine
administered narcotic analgesic, • Presence of acid, fat, protein breakdown products or any
ethanol ↑ irritating factor
metoclopramide • Inhibitory hormones: GIP, VIP, somatostatin (paracrine
inhibitor)
GASTRIC SECRETION
3 PHASES OF GASTRIC SECRETION
Table below: Cells found in the glands of the stomach, their secretions
and functions Phase 1: Celiac Phase
CELL TYPES SUBSTANCE FUNCTION • Stimuli: sight, smell, taste, or thoughts of food
SECRETED • Duration: few minutes
Mucous neck cell Mucus protects lining of • Prepares the stomach for digestion of food
stomach from acid
• Inhibited by depression
Bicarbonates pH buffer
• Mechanism: neural via preganglionic fibers in vagus nerves +
Parietal Cells Gastric Acid (HCl) activates pepsinogen to synapses in submucosal plexus
pepsin
• Actions: ­ acid + pepsinogen; ­ gastric motility
kills microorganisms
Intrinsic Factor binds Vitamin B12 and Phase 2: Gastric Phase
(Ca2+) absorption aids absorption in the
ileum • Stimulus: entry of food into the stomach
Enterochromaffin- Histamine stimulates acid • Duration: 3 – 4 hours
like cell secretion • ­ HCl, pepsinogen secretion, motility, and mixing waves in
Chief cells Pepsin digests proteins motion
Gastric Lipase breaks down lipids • Mechanisms:
D cells Somatostatin inhibits HCl secretion o Neural: via short reflexes triggered by stretch receptors
and chemoreceptors as pH increases
G cells Gastrin stimulates acid o Hormonal: via gastrin release through parasympathetic
secretion activity and presence of peptides + chyme
o Local: via histamine release

5 of 24
Phase 3: Intestinal Phase ILEOCECAL JUNCTION
• Stimulus: Presence of food in duodenum
• Duration: hours • Functional valve – close link between terminal ileum and
• Function: control rate of chyme entry into the duodenum cecum by ileocecal ligaments
• Little amount of gastric secretion due to feedback inhibition o Sphincter closes in the presence of pressure/chemical
• Mechanisms: irritation and prevents backflow of cecal contents back to
o Neural: via short reflexes triggered by duodenal the ileum
distention o Keeps small intestinal bacterial concentrations at usual
o Hormonal: low levels
o Ileum is attached to the side of the ascending colon (vs
§ Primary: ­ CCK, GIP, secretin by presence of carbs
GIT – attached from end to end)
and lipids
§ Secondary: gastrin release stimulated by presence
Table below: Summary of stimuli and their effects
of undigested proteins and peptides
Stimulus Effect
• Actions:
Fluidity of contents (terminal Emptying
o Feedback inhibition of gastric acid + pepsinogen
ileum)
o ¯ gastric motility
Pressure/Chemical Irritation Excites peristalsis; Relaxes
(terminal ileum) sphincter
4.02 Lower GIT Pressure/Chemical Irritation Excites Sphincter
(cecum)
INTESTINAL SEGMENTS
INTESTINAL REFLEXES
• Duodenum
o Further food breakdown Intestinointestinal Reflex
o Regulates stomach emptying • Distention of the intestine at any area will lead to inhibition of
o Thick mucosa intestinal motility
o Shortest + widest part of small intestine
• Jejunum Gastroileal reflex
o Has specialized lining for absorption • A full stomach stimulates the ileum to increase motility
• Ileum • If ileum or anus is full of contents, stomach will stop moving
o Absorption of vitamin B12 and bile salts o When proximal is full, distal will move
o Longest part of small intestine o When distal is full proximal will stop moving
o Ileocecal sphincter: contains the most bacteria
Ileogastric reflex
SMALL INTESTINE MOTILITY • A full ileum inhibits gastric motility
• Functions of small intestine as a whole Anointestinal reflex
o Mix the chyme
o Propels the chyme in aboral direction • A full anus inhibits intestinal motility
• Transit time in small intestine: 2 – 4 hours
Peristaltic reflex
• Digestion in the SI
o Limited mechanical digestion • A contraction above the area of bolus and relaxation after the
o Enzymatic digestion predominates area of bolus; mediated by ENS
• Small Intestine and Stomach • Goal of the peristaltic reflex is to remove area of distention to
o Exhibits different kinds of motility pattern depending on avoid obstruction that may stop reflexes and intestinal
whether it is filled or not movement
o Two types: Immediately after a meal vs. In-between
meals Gastro-enteric reflex
• Initiated by distention of stomach and conducted principally
Table below: Summary of temporal-based Small Intestine Motility through the myenteric plexus from the stomach down along
Immediately After a Meal In-between meals the wall of the small intestine
• SI is filled • food is totally
• Segmentation: non-adjacent processed LARGE INTESTINE MOTILITY
segments of alimentary tract • Migrating • Enhances efficiency of water and electrolyte absorption
alternately contract and relax, Myoelectric • Promotes excretion of fecal material
moving food forward and Complex/ Cycle • No distinction between fed and fasting state (unlike the
backwards (MMC) stomach and small intestine)
• Peristalsis: propulsive, forward • Cycles occur 60-90 • Displays nocturnal suppressions
contractions, occurs intermittently minutes. o Can be stimulated by a meal, mass peristalsis/
• mixing contractions: chyme is movement, haustrations & rectal motor complex
mixed, along with bile secretion o Short-duration contractions: ~ 8 seconds
o Long-duration contractions: 20 - 60 seconds
MIGRATING MYOELECTRIC CYCLE • Mass Movement
o Also known as High Amplitude Peristaltic
1. Phase I – quiescent phase (30 – 60 mins) Contractions (HAPCS)
2. Phase II – intermittent, irregular, low amplitude contractions, o Propulsion in the cecum and the ascending colon is the
result of slow and persistent haustral contractions
with increasing frequency (20 – 40 mins)
o Occurs in 10 - 30 minutes
3. Phase III – short bursts of regular, high amplitude o The urge to defecate will be stimulated by the rectum
contractions with maximum frequency, and ­ secretions (10 – being stretched by enough fecal material
20 mins). Influenced by motilin. o Estimated transit time: Approx. 2-3 days prior to
4. Phase IV – transition back to phase I excretion

6 of 24
 From the cecum ® sigmoid colon, mass movements may
o
take over the propulsive role
4.03 Accessory Organs
§ A “constrictive ring” occurs in response to either a
distended or irritated area in the colon SALIVARY GLANDS
§ The haustrations contract as a unit, propelling the
fecal material in a single mass down the colon • 3 Main Classes + additional class:
o Sublingual Gland
• Non-propulsive “segmentation” o Submandibular Gland
o Mixing movement of large intestine ® high absorption o Parotid Gland
o Buccal Glands
and ­ exposure to the surface area of the colon
o 2 - 4 cycles per minute • Functions: initiate starch digestion, lubrication and protection
o Colonic contents move slowly toward the anus during • Acinus: produces primary secretion; responsible for starch
contraction and are gradually exposed to the mucosal digestion
surface of the colon to allow further absorption • Ductular Cells: causes ­ pH
o Short-duration contractions ® circular muscle o Primary secretion from acinar cells – isotonic ® as it
o Long-duration contractions ® taenia coli pass through the ducts ® ­ [K+]
o movements may be oral or aboral o As salivary secretion increases ® ¯ ability of ductular
cells to secrete K+ ® salivary composition almost similar
RECTAL MOTOR COMPLEX to plasma (increased flow, less effective duct processes)

• Refers to bursts of sigmoid colon and rectum contractions PANCREAS

• Enhanced during sleep
o However, does not stimulate immediate defecation • Endocrine: ductless gland, secretions directly into
o During sleep, the sigmoid colon and rectum undergo bloodstream
minimal tonic contractions in order to prevent • Exocrine: (predominant) secretions directed into a duct
defecation o Acinar Cells - produces the primary components of
pancreatic juices and acinar fluids that are isotonic
GASTROCOLIC REFLEX § Have profuse RER for protein synthesis
§ Granules are also present for storage
• Serotonin & Acetylcholine – important mediators o Ductular Cells –produce HCO3- for dilution and
o Works to clear the colon and prepare it to receive the alkalization of pancreatic juices while reabsorbing Cl-
residues of new meal § Water passes through ductular lumen through
• Mechanism: paracellular route (in between cells) ® more basic
o Stretching → Mass peristalsis → Fecal materials stuffed fluid due to mixing of HCO3- and ­ dilution
in rectum → Rectum is distended → Start of defecation • Acinar cells deal with proteases and can be susceptible to
reflex autodigestion. Some protective factors of pancreatic acinar
cells include:
DEFECATION REFLEX § Packaging of digestive proteins as zymogens
§ Presence of nondigestive proteases (e.g. trypsin
• Stimulus: Distension or Filling of rectum and sigmoid colon inhibitors) to degrade such active proteases
• Mediated by local ENS § Low pH initially in the acinar cells for proper
• Responses: enzymatic functions of its secretions
o Contraction of rectum & sigmoid colon
o Relaxation of internal anal sphincter Pathway of pancreatic acinus to the duodenum
o Contraction or relaxation of external anal sphincter acinus ® intercalated duct ® interlobular duct ® main pancreatic
• Parasympathetic Nervous System Control (Defecate) duct ® mixes with bile coming from common bile duct ® sphincter
o Controls the internal anal sphincter of Oddi ® duodenum
o Relaxes the external anal sphincter
o Defecation aided by Valsalva Maneuver (­ abdominal Products of the pancreatic acinar cells released as zymogen
pressure) • Trypsinogen
• Defecation/Rectosphincteric Reflex: • Chymotrypsinogen
o Mass peristalsis → Parasympathetic & Enteric Nervous • Proelastase
System → Reflex peristalsis waves (through Myenteric • Procarboxypeptidase A & B
Plexus) → Relaxation of Internal Anal Sphincter
(involuntary) & External Anal Sphincter → Valsalva REGULATION OF PANCREATIC SECRETION
Maneuver → Fecal evacuation
• Puborectalis Muscle Cholecystokinin (CCK)
o Maintains fecal continence
• most important regulator of pancreatic secretion
o Contraction → forming anorectal angle → delays
• Functions: contracts gallbladder, reduce gastric emptying,
defecation
enzymatic secretion of the pancreas
o Initiate defecation:
§ Relaxation of Puborectalis • I-cells – found in the small intestine; stimulated by CCKRP
§ Descent of pelvic floor and GRP; secrete CCK
§ Straightening of anorectal angle (squatting/sitting) • CCK release – inhibited by ­ pancreatic secretion
§ Relaxation of Internal Anal Sphincter • Cholecystokinin releasing peptide (CCK-RP) – secreted
§ Valsalva Maneuver (­ anorectal angle) when FAs and AAs are sensed by intestinal epithelium
• Monitor Peptides (MP) – secreted by pancreas when
stimulated by Ach or GRP

7 of 24
Secretin o Stellate cells are found in the Space of Disse
• primary regulator of pancreatic duct secretion § Serving as storage sites for retinoids
• produced by S cells in duodenum when there is ¯ pH § Source of key growth factors for hepatocytes
• function: promotes bicarbonate secretion of the pancreas ® § Normally activated in order to synthesize collagen
­ pH in duodenum • Bile canaliculus: passageway between the hepatocytes
• Bicarbonate release into the duct lumen where bile is drained into the biliary ductules
o Secretin opens CFTR, promoting Cl- efflux from the
ductular cell to the lumen BILE
o Cl- is transported back through Cl- / HCO3- Exchanger
that pumps a HCO3- into the lumen for every Cl- taken • Synthesized by hepatocytes, bile is secreted into the bile
back. canaliculi across their apical membranes
o HCO3- is produced by the duct cell by the enzyme • Stored and concentrated in the gallbladder
carbonic anhydrase • Bile is a micellar solution consisting of in 10:3:1 ratio in the
following order:
LIVER o Bile acid
o Phosphatidylcholine
Liver Zones in the Portal Acinus o cholesterol
• Portal acinus emphasizes on the O2 supply to hepatocytes • Primary function: Lipid digestion and absorption
• Zone I (periportal zone): most oxygenated; closest to portal • Bile flow: driven by active secretion of bile acid via an
tract ATPase known as bile salt export pump (BSEP)
• Zone II: moderately oxygenated; between zones I & III • Bile pathway to storage in the gallbladder:
• Zone III (pericentral zone): least oxygenated; surrounds o Synthesized by hepatocytes ® bile canaliculi ® bile
central vein ductules ® bile ducts ® hepatic ducts ® cystic duct ®
gallbladder
Table below: comparison between zone I and zone III
Zone I Zone III Steps in bile release to storage in gallbladder
• Bile acid-dependent • Bile acid – independent 1. Starts with hepatocytes, which will actively (uses ATP)
canalicular bile flow canalicular bile flow secrete the following substances: Bile acids,
• Cholesterol synthesis • Glycogenesis phosphatidylcholine, bilirubin, and drugs (xenobiotics)
• Gluconeogenesis • Lipogenesis 2. The other components of bile will pass through tight junctions
• Amino acid catabolism • Ketogenesis 3. Once the bile is formed in the canaliculus, it will drain into the
bile ductules.
• ureagenesis • Biotransformation of drugs
4. The ductules will drain into the bile ducts and hepatic ducts.
5. The left + right hepatic ducts will ultimately drain into the
Hepatic Circulation
cystic duct.
• Portal Vein 6. The cystic duct is where the bile will move to and from the
o Where majority of blood that goes into the liver comes gallbladder
from
o 1300mL/min Primary Bile Acids
o Deoxygenated blood from spleen, stomach, pancreas,
small intestine, and colon. • Synthesized by the hepatocytes
o During a meal, blood flow may increase up to 90% • Created as end-product of cholesterol metabolism:
o Due to the opening of liver sinusoids (discussed further o Cholic acid
in the next page) after a meal o Chenodeoxycholic acid
• Hepatic artery • 0.3 – 0.5 grams / day produced
o 500mL/min of oxygenated blood • Hydrophobic
o supplies nutrients to the hepatocytes • Needs to be conjugated with glycine or taurine before it can
• Portal triad: Contained in liver lobules which consists of be secreted into intestinal lumen.
branches of the bile duct, hepatic artery, and the portal vein
• Sinusoids: cavities supplied by portal veins & hepatic arteries Secondary Bile Acids
o Has low resistance to blood flow – therefore blood flow • Produced when colonic bacterial enzymes metabolized the
can increase without increased pressure primary bile acids into the following:
• Central vein: drain the blood from sinusoids to the hepatic o Deoxycholic acid – from cholic acid
vein for pulmonary circulation o Ursodeoxycholic acid - from Chenodeoxycholic acid
o Lithocholic acid - cytotoxic; from Chenodeoxycholic acid
First Pass Effect • Need to be conjugated with glycine or taurine as well
• Nutrients & compounds absorbed by the GIT go through
hepatic portal circulation for processing by the liver. Conjugated Bile Acids
• This processing (e.g. absorption, modification to be substrates • Purpose: to make bile acids more polar or hydrophilic by
for metabolic process, elimination of toxic compounds) often attaching these molecules to glycine or taurine.
times lead to the inactivation of drugs before reaching the • Glycine becomes glycocholic, and taurine becomes
circulation taurocholic.
• Cannot passively cross the cell membranes
Hepatic Parenchyma • These are retained in the intestinal lumen until they are
• Composed of hepatocyte plates supplied by a series of actively absorbed in the terminal ileum via the apical sodium-
sinusoids dependent bile salt transporter (asbt)
• These sinusoids contain Kupffer cells – liver macrophages • Conjugated bile acids that escape this uptake step are
• Space of Disse / Perisinusoidal Space deconjugated by bacterial enzymes in the colon ® passively
o Located inferior to sinusoidal epithelium reabsorbed across the epithelium because they are no longer
o Thin layer of loose CT separating endothelium from polar
hepatocytes

8 of 24
Role of Bile Acids in Lipid Digestion and Micelle Formation o Stones in the gall bladder may pass through the cystic
• Bile acids emulsify lipids ® ­ surface area for increased duct. This may result in the obstruction in the sphincter of
interaction with digestive enzymes (lipases) for hydrolysis Oddi
• Becomes a concentrated solution of biological detergents that o This results in the back flow of pancreatic contents to
aids in solubilization of the products of lipid digestion in the return to the pancreas resulting in the destruction of the
aqueous environment of the intestinal lumen pancreas: Pancreatitis.
o This enhances the rate of lipid transfer to the absorptive
epithelial surface Bile Acid (from the gallbladder)
• Primary products of the degradation: • Bile Acid Composition:
o 2-monoacylglycerol o Water – 97%
o unesterified cholesterol o Bile salts – 0.7%
o free fatty acids o Bilirubin – 0.2%
• Micelles (triacylglycerol, 2-monoacylglycerol, free fatty acids o Cholesterol – 0.06%
and bile salts) o Other lipids – 0.4%
o Hydrophobic tails are directed inside and polar head o Inorganic salts – 0.7
outside forming a single surface layer on emulsion • Concentration of bile components in gallbladder is higher than
particles directed to the aqueous environment. the bile from the liver – the hepatic bile.
o Higher Na+ in the gallbladder bile vs hepatic bile
Enterohepatic Circulation of Bile Salts o HCO3 and Cl- in the gallbladder bile vs hepatic bile
• Enterohepatic circulation of bile acids is a loop consisting of: o However, bile acid ions increase in the gallbladder vs
o Secretion by the liver liver
o Reabsorption by the intestine
o Return to the liver in portal blood for repeat secretion into BILIRUBIN
bile
• Bile salt pool of 2 – 4 grams: circulates 6 – 10 times / day • Metabolite of heme that is potentially toxic to the body
• Bile formed from the liver and stored in the gall bladder → • Acts as antioxidant and serves to eliminate the excess heme
released in common bile duct → serves its function → goes to released from the hemoglobin of senescent RBCs
terminal ileum and absorbed by apical sodium-dependent • Provides color to bile, feces, and to a lesser extent, urine
bile transporter → bile acid is transported back to the portal • Responsible for yellowing or jaundice of the skin and
circulation → goes to the liver to be recycled conjunctiva when there is accumulation in the circulation
• Pathway of some bile salts that are not reabsorbed in the • Nonpolar: can easily pass through the blood-brain barrier and
ileum: can get deposited in tissues and cause injuries
o Modification by the colonic bacteria → formation of
secondary bile acids → can either: (1) move back to liver Reticuloendothelial system and Bilirubin Reabsorption
for recycling or (2) excreted with feces (approx. 0.6 g / • Bilirubin synthesis occurs in the phagocytic cells of the
day) reticuloendothelial system, including Kupffer cells, and cells in
the spleen.
4 ways in which bile salts are recycled out of the intestine: • Heme oxygenase liberates iron from the heme molecule and
1) Passive diffusion along the small intestine produces the green pigment biliverdin ® this will be acted by
2) Carrier-mediated active absorption in the terminal ileum (most biliverdin reductase to form yellow bilirubin ® Bilirubin will
important absorption route) bind to albumin
3) Deconjugation to primary bile acids before being absorbed
either passively or actively Hematoma Stages
4) Conversion of primary bile acids to secondary bile acids with • Stage 1: Reddish - Breakdown of heme
subsequent absorption of deoxycholic acids • Stage 2: Purple - Degradation of hemoglobin to biliverdin
• Stage 3: Blue - Biliverdin to bilirubin
GALLBLADDER
• Stage 4: Yellow - Bilirubin to hemosiderin
• Distensible, pear-shaped structure that has a capacity of 30 – Glucuronic Acid Conjugation
50 mL in adults
• Bilirubin is conjugated with glucuronic acid to enhance its
• Stores, modifies, and concentrates bile acids during
aqueous solubility ® becomes bilirubin diglucuronide ®
interdigestive periods
o Concentrated by isosmotically removing salt and water goes through enterohepatic circulation or gets excreted with
feces
• Regulated by cholecystokinin (CCK), acetylcholine, and CN X
o Bilirubin diglucoronide reaches the terminal ileum and the
(parasympathetic)
large intestine where the diglucuronides are removed
o Activation of cholinergic receptors and CCK receptors will
by specific bacterial enzymes (β-glucuronidases), and
cause smooth muscle contraction of the gall bladder →
the pigment is subsequently reduced by the fecal flora to
release of bile acid → travels to the cystic duct → goes to
a group of colorless tetrapyrrolic compounds called
the sphincter of Oddi → duodenum
urobilinogen, which is reabsorbed
• Effects of CCK on gallbladder:
o Oxidation of urobilinogen yields urobilin (gives urine its
o Gallbladder contraction – along with acetylcholine
yellow color) + stercobilin (contributes to the color of
o Sphincter of Oddi relaxation via release of VIP + NO
feces)
o Bile secretion from gallbladder
• Absorbed urobilinogen can be taken up by hepatocytes and
reconjugated.
Mechanism of Sphincter of Oddi
• Under abnormal conditions, particularly when excessive bile
• Sphincter of Oddi is constricted in between meals, directing pigment is formed, or liver disease interferes with this
the bile produced from the liver ® gallbladder intrahepatic cycle, urobilinogen may also be excreted in the
• CCK secretion stimulates the enteric nervous system ® urine.
release of nitric oxide → relaxation of Sphincter of Oddi →
passage of bile into the duodenum
• Clinical Correlation: Gallstones

9 of 24
Figure below: Schematic diagram of bilirubin metabolism and excretion
(Source: doctorlib.info/physiology/illustrated/26.html) 4.04 Absorption, Digestion, Nutrition
ABSORPTIVE SURFACES

• Plicae Circulares
o only in the small intestine (except the bulb of duodenum)
o ­ surface area for absorption by 3x
• Villi
o ­ surface area for absorption by 10-20x
o each containing numerous enterocytes
• Enterocytes
o cells lining each villus
o each containing numerous microvilli
• Microvilli
o ­ surface area for absorption by 200x
o where digestive enzymes are found

INPUT vs OUTPUT OF WATER

Table below: summary of the amount of input and output of water

Input Output
• 2,000 mL = food + drink Absorption
• 7,000 mL = secretions • 7,000 mL – small intestine
o 1,500 mL – saliva • 1,900 mL – proximal large
o 2,500 mL – gastric intestine
Types of Bilirubin o 500 mL – Bile ------------------------------------------
• Unconjugated bilirubin o 1,500 mL – pancreatic -
o Nonpolar o 1,00 mL - intestinal total: 8.9 L / day
o Free bilirubin ------------------------------------------
o Fully albumin bound and cannot be excreted in urine total: 9 L / day Output
• Conjugated bilirubin 100 mL = excreted
o Polar or more soluble
o suitable for excretion into bile, but cannot be reabsorbed CARBOHYDRATES
by the biliary or intestinal epithelia
o Characterized by the presence of bilirubin in urine, to • Starch and Glycogen
which it imparts a dark coloration. o composed of amylose and amylopectin with a,1-4
linkage
Reabsorption of Bile in the Liver o examples: potatoes, grains, bread
• Bilirubin bound with albumin reaches the liver and enters • Cellulose
the space of Disse, where bilirubin is selectively taken up o cannot be digested due to ß,1-4 linkage (no enzyme
across the basolateral membrane of hepatocytes via an present in humans)
OATP transporter o ­ bulk, softens stools, shortens transit time in GIT
o Bilirubin is then conjugated with 1 or 2 molecules of o being undigested, it stays in the lumen to collect water
glucuronic acid to enhance its aqueous solubility. and other indigestible substances
o The reaction is catalyzed by UDP glucuronyl o lowers blood cholesterol
transferase (UGT) • Dietary fiber
o The bilirubin conjugates are then secreted into bile by a o cellulose, pectins, lignins, gums
multidrug-related protein (MRP2) located in the o benefits:
canalicular membrane. § hunger satisfaction from fullness of stomach
o Notably, the conjugated forms of bilirubin cannot be § antioxidants
reabsorbed from the intestine § for constipation
o However, transport of bilirubin across the hepatocyte,
and indeed its initial uptake from the bloodstream, is CARBOHYDRATE DIGESTION
relatively inefficient, so some conjugated and
unconjugated bilirubin is present in plasma even under Figure below: Schematic diagram of carbohydrate digestion
normal conditions. (source: Dr. Tan’s PPT)
malotriose,
amylose
Clinical Correlation Starch
amylopectin maltose, a-
1) Jaundice limit dextrins
o Yellowish discoloration of the skin due to
hyperbilirubinemia
o Primary cause: having abnormally high levels of bilirubin
in the blood, regardless if it’s conjugated, unconjugated, Glucose,
Sucrose,
portal blood galacose,
or both Lactose
fructose
2) Hyperbilirubinemia
o Production of more bilirubin than the normal liver can
excrete, or it may result from the failure of a damaged Luminal Digestion
liver to excrete bilirubin produced in normal amounts. • Responsible for hydrolysis of 5% of total starches in GIT
lumen

10 of 24
 o Dietary (50%): essential AAs, plants, animals
• salivary amylase (ptyalin) • Endogenous (50%): enzymes, hormones, immunoglobulins,
o secreted by parotid gland GIT secretions, enterocytes, desquamated epithelial cells
o starch ® maltose, maltotriose, a-limit dextrins
o hydrolyzes 30 – 40% of starches Figure below: Overview of Protein Digestion + Absorption, based on
• Pancreatic amylase Dr. Tan’s ppt.
o 94% identical to salivary amylase, secreted by pancreas
o present in small intestine
o starch ® maltose, maltotriose, a-limit dextrins
o cleaves internal a,1-4 linkage but not terminal a,1-4
linkage, a,1-6 linkage, and a,1-6 linkage beside the
branching

Brush Border Digestion

Figure below: Schematic diagram of further carbohydrate digestion
(source: Dr. Tan’s ppt)

Substrates
Sucrose Products
lactose Enzymes glucose (80%)
maltose sucrase galactose (5%)
Maltotriose lactase fructose (15%) PROTEIN ABSORPTION
a-limit dextrins glucoamylase
• Divided into 3 phases: (1) Stomach, (2) small intestine, (3)
isomaltase
brush borders
• digestion takes place in the brush borders of enterocytes
Phase 1: Stomach
• all enzymes in the figure above cleave a,1-4 linkages of
maltotriose and maltose • protein digestion begins in the stomach, not oral cavity
• isomaltase: only enzyme that hydrolyzes the a,1-6 linkages • pepsinogen is released from chief cells ® pepsin when
exposed to acidic pH in the stomach lumen
of a-limit dextrins
o digests collagen, major meat component
• all hydrolases are abundant except lactase
• yields intact protein, large polypeptides, and limited free AAs
CARBOHYDRATE ABSORPTION
Phase 2: Small Intestine
• Only monosaccharides are reabsorbed in the small intestine • pancreatic juices: secreted as inactivated form to avoid
• absorption requires transporters / channels; they are not autodigestion
regulated • these are activated at brush border in presence of
enterokinase
Figure below: Absorption of Monosaccharides (Boron, 2nd Ed. pg 952) • endopeptidases
o trypsin – cleaves basic amino acids
o chymotrypsin – cleaves neutral amino acids
o elastase
• Ectopeptidases – both hydrolyze from carboxyl end
o carboxypeptidase A – cleaves neutral amino acids
o carboxypeptidase B – cleaves basic amino acids
o yields dipeptides, tripeptides (70%) and free AAs (30%)

Phase 3: Brush Border

• various peptidases
• most dipeptides and tripeptides are absorbed and digested
Uptake at Apical Membrane | lumen ® enterocyte into free amino acids in cytosol
• need lipoproteins for digestion of AAs to proceed to
• SGLT1 (Na+ / Glucose co-transporter 1)
absorption
o secondary active transport that allows Na+ to enter in
response to the efflux via Na+/K+ ATPase
PROTEIN ABSORPTION
o Na+/K+ ATPase (primary active transport)
o depletes intracellular Na+ by moving it out across the
Amino Acid Transporters (75%)
basolateral membrane into the interstitial space
• GLUT5 • some are co-transport with Na+
o fructose transporter via facilitated diffusion • less efficient vs peptide transporter 1

Exit across the basolateral membrane | enterocyte ® bloodstream Peptide Transporter 1 (25%)
• all monosaccharides leave via GLUT2 into the interstitial • cotransport with peptides and H+
space ® bloodstream • responsible for intestinal reuptake of certain dipeptides (e.g.
antibiotics)
PROTEIN • only prefers peptides and tripeptides
• peptides absorbed ® cytoplasmic peptidases
• 20 amino acids; 9 of them being essential (PVT TIM HALL) • kinetic advantage: fast movement of AAs across the apical
o Phe, Val, Thr, Trp, Ile, Met, His, Arg, Leu, Lys membrane
• proteins rich in proline, hydroxyproline, and glycine are less • has less osmotic drive than amino acid transporters
digested – plants contain more proline
• Sources of proteins:

11 of 24
Figure below: Schematic diagram summarizing protein absorption table below: lists the enzymes in the small intestine
(Boron, 2nd Ed. 955) Enzyme Description End Product
Pancreatic • hydrolyze both 1 and 3 • 2 free FAs
Lipase 1 positions of TAGs • 2-monoacylglyceride
colipase
• inhibited by bile acids
• activated by colipase
Phospholipase • synthesized in active • free FA
A2 form, requiring bile • lysophospholipid
acids to be active
Cholesterol • hydrolyze esters of • free FAs
Esterase cholesterol, fat-soluble • cholesterol
vitamins, phospholipid,
TAGs
• activated by bile acids

LIPID ABSORPTION

• micelle formation: a ferrying process for fat absorption

• Inside epithelial cells:
o FAs diffuse out of micelle ® taken up by smooth ER ®
re-esterified ® form TAGs, cholesterol ester, and
phospholipids ® released in the form of chylomicrons ®
Clinical Correlation lymph vessels ® stored in peripheral tissues
• Pancreatic Insufficiency Absorption of short and medium chain FAs
o in absence of pancreatic proteases ® insufficient protein
• directly into the portal blood without converted to TAGs
digestion ® malnutrition
• direct diffusion to capillary blood vessels
• Cysteinuria
o mutation in amino acid transporters of cysteine
2 important channels involved in lipid absorption
o manifests with insoluble kidney stones
• Hartnup’s Disease • Microvillus Membrane Fatty Acid-Binding Protein (MVM-
o mutation in SCLA6A19 – transporter of neutral AA, FABP)
particularly tryptophan o provides uptake of long-chain fatty acids across brush
border
LIPIDS • Niemann-Pick C1-like1 (NPC1L1)
o uptake pathway for cholesterol
Dietary lipids o blocked by ezetimibe, medication for
hypercholesterolemia
• triglycerides
• cholesterol ester
Table below: Summary of digestion + absorption of macronutrients
• phospholipids Description Carbohydrates Proteins Lipids
• fat-soluble vitamins (A, D, E, K) Salivary lipase
Mouth Salivary amylase None
LIPID DIGESTION
Stomach Gastric lipase
NONE Pepsin
Digestion in the Oral Cavity and Stomach
Small Pancreatic Pancreatic Pancreatic lipase
• Lingual Lipase: secreted by Von Ebner’s gland
intestine amylase protease
o hydrolyzes dietary TAGs
Brush Micelle formation
• Gastric Lipase: secreted in the stomach Disaccharidases Peptidases
border
o hydrolyzes TAGs ® free FAs + diacylglycerols Tripeptides, Micelle SCFA,
Absorption Monosaccharide Dipeptides, MCFA
Digestion in the small intestine AA
• Emulsification Cytoplasmic Re-esterified to
Enterocyte NONE
o breakdown of fat globules into small sizes of fine oil peptidases chylomicrons
droplets to ­ surface area for enzymatic lipid digestion Na-AA Micelle, MVM-
SGLT1
o occurs due to bile salt, mixing, and peristalsis cotransport, FABP, NPC1L1
Channels GLUT2
PepT1,
• Major lipid digestion is due to pancreatic enzymes: GLUT5
Endocytosis
o pancreatic lipase
o cholesterol esterase
SODIUM ABSORPTION
o Phospholipase A2
• Cholecystokinin (CCK) helps with lipid digestion by causing Small Intestine
gallbladder contraction ® bile secretion and secretion of
pancreatic enzymes • Electric potential gradient is established by Na+/K+ ATPase
(primary active transport) in the basolateral walls of
enterocytes
• Secondary active transporters in the apical membranes allow
Na+ to be absorbed:
o SGLT
o Na+-AA cotransporter
o Na+-H+ exchanger
o Na+/Cl- cotransporter

12 of 24
• Osmotic gradient in the paracellular space is followed by Na+ NUTRITION
and other ions (“water follows sodium”)
Dietary Reference Intake (DRI)
Large Intestine • Quantitative estimates of nutrient intakes with 4 types:
• No cotransporters due to trace amounts of glucose and
amino acids 1) Estimated Average Requirement (EAR): amount of nutrient
• Epithelial Na+ Channel (ENaC) absorbs Na+ in the apical to be adequate for 50% of healthy individuals of particular sex
surface via passive diffusion and age
o aldosterone has a stimulatory effect 2) Recommended Dietary Allowances (RDA): avg. daily
dietary intake level that meets the nutrient requirements of
CHLORIDE nearly all healthy people
3) Adequate Intake (AI): based on observed approximations of
Absorption nutrient intakes in healthy people; good for neonates
• Paracellular route vis tight junction following an electrical 4) Tolerable Upper Level (UL): Highest level of chronic nutrient
potential gradient intake that is unlikely to pose adverse effects of toxicity
• Na+/Cl- cotransport
Dietary Assessment
• Cl-/HCO3- exchanger - Cl- enters in exchange for HCO3-
1. Screening for malnutrition or obesity
Secretion 2. Assessing the diet and other data (e.g. history physical
examination, BMI, waist circumference)
chloride channels in the basolateral membrane
3. Planning and implementing appropriate nutritional therapy
4. Reassessing intakes to make sure that they have been
BICARBONATE
consumed or diet is followed
Absorbed through “active absorption”
VITAMINS
• CO2 can freely cross the cell membrane to the blood stream • cannot be synthesized by the body thus obtained through diet
• CO2 + H2 O ⇌ H2CO3 ⇌ H+ + HCO3- takes place in the only
cytoplasm in presence of intracellular carbonic anhydrase • water-soluble vitamins: Na+ dependent cotransport via
• H+ leaves to the lumen via apical Na+/H+ exchanger passive diffusion
• HCO3- crosses the basolateral membrane via transporter • fat-soluble vitamins: incorporated with micelles
• H2CO3 is formed again via extracellular carbonic anhydrase
from the H+ and HCO3- in the bloodstream FAT-SOLUBLE VITAMINS

Secretion Vitamin A
• Occurs in the ileum and large intestine • retinol as principal form; retinal (w/ aldehyde); retinoic acid
• Cl-HCO3 exchanger • Sources: ß-carotene from carrots and other vegetables
• Neutralizes acid products formed by bacteria in colon • important for production and regeneration of rhodopsin of
retina (retinal)
CALCIUM ABSORPTION • retinoic acid is needed for normal growth of epithelial cells
• stored in the liver with retinol-binding protein
• In duodenum: Active transport regulated by PTH + Vitamin D • Deficiency:
• the rest of small intestine: passive paracellular diffusion o night blindness as first symptom
• ­ absorption: ¯ Ca2+, pregnancy, lactation, bile salts o damaged epithelial structures
• ¯ absorption: ­ Ca2+, FAs o eyes with Bitot’s spots or white spots
• Inside the intestinal epithelial cell: calbindin binds with Ca2+ to • Toxicity: Hypervitaminosis A with ­ intracranial pressure
keep intracellular Ca2+ levels low
o note that vitamin D increases calbindin synthesis Vitamin D
• Unbinding occurs in order for Ca2+ to be pumped out across • Synthesized in the body as Calciferol
the basolateral membrane via Ca2+ ATPase pump and
• Vitamin D3 (calcitriol) – active form with sunlight stimulation
Na+/Ca2+ exchanger
• Functions:
o ­ Ca2+ absorption from GIT and kidneys
IRON ABSORPTION
o ­ calbindin synthesis and Ca2+ channels
Non-Heme Moiety • Toxicity: most toxic of all vitamins
o hypercalcemia and renal stones
• Can be ferrous (Fe2+) or ferric (Fe3+) forms
• Deficiency: Rickets (children) and Osteomalacia (adults)
• must be in ferrous state to be absorbed
• Vitamin C aids in iron absorption that is restricted in Vitamin E
duodenum by reducing ferric to ferrous iron
• a-tocopherol from diet
• Ferric reductase Cyctb also reduces ferric to ferrous iron
• sources: vegetables, nuts, grains, oil
• Divalent metal transporter (DMT1): cotransports Fe2+ & H+
• Functions:
• Ferroportin Transporter (FP1): transports iron to the
o potent antioxidant and prevents lipid peroxidation
bloodstream
o inhibits prostaglandin synthesis
• in the bloodstream, ferroxidase hephaestin oxidizes ferrous
into ferric iron where it can bind to transferrin (must be in
Vitamin K
ferric state)
• Vitamin K1: Phylloquinones (green leafy veggies)
Heme Moiety o energy-dependent process
• Vitamin K2: Menaquinones (GIT flora)
• derived from myoglobin and hemoglobin
o passive diffusion via micelles
• enters via endocytosis
• Vitamin K3: Menadione (synthetic)
• hepcidin inhibits FP1 and ferroxidase hephaestin
• essential in activating clotting factors and protein C and S

13 of 24
• Causes of deficiencies:
o overuse of antibiotics resulting in GIT flora destruction Vitamin C (Ascorbic Acid)
o warfarin intake • Important in many oxidative processes as cofactor or
o malabsorption coenzyme
• Newborns have no Vitamin K2 due to sterile GIT • Antioxidant that promotes iron absorption
• Involved in Dopamine ® norepinephrine, carnitine synthesis,
WATER-SOLUBLE VITAMINS bile acid synthesis
• B1, B2, B3, B5, B6, B9, B12, C, Biotin • Involved in hydroxylation of proline ® tensile strength of
• less stored (except B12) ® more deficits than fat-soluble vit. collagen
• can be easily excreted through kidney ® less toxicities • Deficiency:
o Scurvy – impaired collagen synthesis
Vitamin B1 (Thiamine) o Anemia – impaired iron absorption
• CHO metabolism: pyruvate dehydrogenase and a-

•
ketoglutarate dehydrogenase
AA metabolism: branched-chain amino acid dehydrogenase
4.05 Renal Physiology I
• Deficiency:
FUNCTIONS OF RENAL SYSTEM
o Beri-beri (diet)
o Wernicke-Korsakoff Syndrome (alcoholism)
o memory loss, hallucination, dementia • Excretion of metabolic waste, metabolites, and foreign
chemicals;
Vitamin B2 (Riboflavin) • Regulation of body osmolality + fluid volume, electrolyte
balance, acid-base balance the composition and mean arterial
• important in metabolism of macronutrients: FAD and FMN
pressure
• needed for electron transport chain: succinate dehydrogenase
• Hormone secretion (erythropoietin, renin, and calcitriol)
• Deficiency:
• ­ Gluconeogenesis
o cracked lips (cheilosis) and skin
• Renal blood flow is 20-25% of the cardiac output.
o tongue desquamation (glossitis)
o anemia • Outline of Renal Tubular Fluid Flow:
o Cortex ® Medulla ® Renal Pyramid ® Renal Papilla ®
Vitamin B3 (Niacin) Minor Calyx ® Major Calyx ® Renal Pelvis ® Ureter ®
Bladder ® Urethra
• component of oxidation-reduction agents: NADH and NADPH
• associated with tryptophan
NEPHRON
• used to treat hypercholesterolemia - ¯ LDL but ­ HDL
• Deficiency: Pellagra
• Functional unit with no regeneration capacity
o 3Ds: dementia + diarrhea + dermatitis ® death
• Vascular Component: 2 arterioles (providing resistance
• Toxicities: controls), Vasa Recta, Glomerulus, Peritubular capillaries
o elevated uric acid
• Tubular Component: Proximal Convoluted Tubule, Loop of
o flushing & muscle pain
Henle, Distal Convoluted Tubule, and Collecting Duct.
• Juxtaglomerular Apparatus: Regulates renal blood flow and
Vitamin B6 (Pyridoxine)
glomerular filtration rate (GFR)
• Involved in AA and CHO metabolisms • There are two types of nephrons: cortical nephrons and
• Coenzyme in heme synthesis, Cori cycle, deamination, and juxtamedullary nephrons
glycogenolysis
• Deficiency: from isoniazid (TB medication) Table below: Difference between the Cortical an Juxtamedullary nephrons
o microcytic anemia, peripheral neuropathy, glossitis CORTICAL PARAMETER JUXTAMEDULLARY
70-80% QUANTITY 20-30%
Vitamin B9 (Folic Acid) Cortex LOCATION Border of Cortex
• Found in the diet as polyglutamyl conjugates Long, extending deep
Short LOOP OF HENLE
to medulla
• important in formation of nucleic acids and RBC maturation
Peritubular Capillaries VESSEL Vasa Recta
• absorption: polyglutamyl conjugates are degraded by brush
border enzyme ® absorbed via facilitated transport RENAL CORPUSCLE
• Deficiency:
o megaloblastic anemia
• Glomerulus: with fenestrated glomerular capillaries,
o spina bifida podocytes, & mesangial cells which are important for the
o folic acid inhibitors from chemotherapy barrier and filter for the plasma.
• Bowman’s Capsule: simple squamous epithelium
Vitamin B12 (Cobalamin)
• Bowman’s Space: between Glomerulus & Bowman’s
• Only vitamin that can be stored for a long time in the liver for Capsule
about 3 – 4 years
• Source: dairy products, meat, fish TUBULAR COMPONENTS
• Important in RBC maturation with folic acid
• Neural membrane maturation • Proximal Convoluted Tubule (PCT): main site of
• Absorption reabsorption. Abundant mitochondria for active transport
o passive absorption (< 1% absorbed) • Loop of Henle: Concentrating and diluting the urine at the
o active absorption – ileum via receptor-mediated process ascending limb and descending limbs.
§ Intrinsic Factor complex • Distal Convoluted Tubule (DCT): contains NaCl channel.
• Transported via transcobalamin • Collecting Duct:
• Deficiency: o Cortical Part: with principal cells (Na+ reabsorption, K+
o Pernicious anemia due to lack of Intrinsic Factor secretion), intercalated cells (for K+ reabsorption, H+
o Malabsorption disorder secretion), and aquaporin channels
o Demyelination of nerve fibers

14 of 24
 o Medullary Part: final site for urine dilution/concentration; • Inulin: Best exogenous substance to use for GFR
with aquaporin channels • Creatinine: also used to approximate GFR

RENAL PROCESSES RS CWX − YZ[ (\[YO]) ^ _[TZ`a(bZ)

NONP Q V=
RTU gRhP
Glomerular Filtration / Ultrafiltration: Filters & removes X. cCd ^ ][OeR fO[YaTUTU[ ( )
o S
toxic material carried by blood, at the glomerulus
§ When it CANNOT be filtered it returns to the efferent FILTRATION FRACTION
arteriole.
§ When it CAN be filtered it proceeds to the Bowman’s • Represents the portion of the fluid reaching the kidneys that
Space & Capsule goes through the renal tubules. A percent of RPF that is
o Reabsorption: For those that your body needs. filtered or simply a percent of your GFR
o Secretion: For those that your body doesn’t need or is ji#
ii = k 100
toxic to the body. None in the Loop of Henle. #=i
o Excretion: waste removal • Normal value = 10-20% the plasma that enters the
glomerulus is actually filtered and the remaining percent
Figure below: Pathways of substances in the renal system. Substance A = continues through the glomerular capillaries into the efferent
Inulin & Creatinine. Substance B = Sodium. Substance C = Glucose, Amino arterioles
Acids. Substance D = Para-aminohippuric Acid • ­ FF = ­ oncotic pressure in peritubular capillaries = ­
reabsorption

Table below: Impact of the dilation and constriction of arterioles

Condition Subsequent events
AFFERENT ­ diameter ® ¯ resistance ® ­
ARTERIOLE IS RBF ® ­ capillary hydrostatic pressure ®
DILATED ­ GFR
AFFERENT ¯ diameter ® ­ resistance ® ¯ blood flow
ARTERIOLE IS ® ¯ capillary hydrostatic pressure ®
CONSTRICTED ¯ GFR
¯ diameter ® ­ resistance at the exit point
EFFERENT ® ¯ outflow of blood ® blood “pools” in the
ARTERIOLE IS glomerulus within Bowman’s space ®
CONSTRICTED increased hydrostatic pressure ® ­ GFR

EFFERENT ­ diameter ® ¯ resistance ® ¯ capillary

ARTERIOLE IS hydrostatic pressure ® ¯ GFR
DILATED

STARLING FORCES

• Hydrostatic pressure: “Push away”

o (PGC) = Hydrostatic pressure in the glomerular capillary;
RENAL CLEARANCE Principle force that favors filtration
o (PBC) = Hydrostatic pressure in the Bowman’s capsule;
• Rate at which the substance in plasma is being cleared Opposes filtration
filtered to estimate the renal blood flow (RBF) and glomerular • Oncotic pressure: “Pull towards”
filtration rate (GFR) o (πGC) = Oncotic pressure in the glomerular capillary;
12 13 Opposes filtration
,)-%$(.%*. 0 4 ∗ ,)-%$6.'71$ ( )
#$%&' ('$&)&%*$ = 13 min o (πBS) - Oncotic pressure in Bowman’s space; Favors
12
='&>1&(.%*. ( ) filtration
13

RENAL BLOOD FLOW (RBF) GLOMERULAR FILTRATION

• Volume of blood delivered into the kidney per unit of time (20- • The first step: Ultrafiltration
25% of cardiac output) • End product: Ultrafiltrate of plasma, devoid of cells & protein
?BA • Normal GFR: 90-140 mg/mL | 80 – 125 mg/mL
?@A = • Starling forces drive ultrafiltration
(C − EFGHIJKLMI)
• Autoregulation: GFR & RPF are maintained in narrow range
RENAL PLASMA FLOW (RPF) • Importance of high GFR:
o To allow rapid removal of waste & toxins
• Volume of plasma that passes through kidneys per unit time. o To allow filtration and processing of bodily fluids
o Derived from the Renal Blood Flow equation
o Directly proportional to GFR Glomerular Filtration Barrier
o Indirectly proportional to the filtration fraction. • Determines the content of ultrafiltrate
o Can be measured by using para-aminohippuric acid (PAH) • Endothelial Cells of Glomerular Capillaries
o Fenestrations present
GLOMERULAR FILTRATION RATE • Basement Membrane
o A charge-selective filter due to proteoglycans (negatively
• Functional capacity of the kidneys by summing up all filtration charged)
rates of all nephrons o Positives & neutral substances may pass
• To determine GFR: substances should be cleared by the • Foot Processes of Podocytes
glomerulus and not reabsorbed or secreted by tubules o A size-selective filter due to slit-pores (< 60KD)

15 of 24
 AUTOREGULATION TUBULAR PROCESS

• Self-sustaining property of the kidney; intrinsic control • Begins after ultrafiltration

• Mainly contributes to the regulation of GFR & RBF, as a • Ultra-filtrate: 180- 200 L/day filtered by the glomeruli
means to prevent hyper/hypofusion • Excreted as urine: 1.5-2 L/day (only less than 1% of ultra-
• Maintains GFR, despite the varying mean arterial pressure filtrate)
(80-180 mmHg) • Most are reabsorbed: 99% of ultrafiltrate
o Beyond the range, other mechanisms of regulation take • Mechanisms of Reabsorption & Secretion
place o Active Transport
o Mainly involves the vascular components (efferent § Primary: Directly couple with an energy source (Na-
arteriole) K-ATPase)
§ Secondary: Indirectly coupled to an energy source
Myogenic Mechanism (uses ion gradients, co-transporters, Na-Glucose
• Based on pressure sensitivity (arterial pressure) transporters)
• Increased BP: § Pinocytosis
o ­ blood flow to afferent arteriole → arteriole stretched → o Passive Transport
contraction & increased resistance in arteriole → GFR § Diffusion, Facilitated Diffusion, Osmosis
remains constant
• Decreased BP: Transport Maximum
o Efferent arteriole tendency to dilate → ­ blood flow → o Transport rate at which the transporters are already
arteriole stretched → contraction → constant GFR saturated with solutes
o When your solutes exceed the transport maximum, they
TUBULOGLOMERULAR FEEDBACK will appear in the urine

• NaCl dependent (NaCl in tubular fluid) PROXIMAL CONVOLUTED TUBULE

• Juxtaglomerular Apparatus is involved
• Afferent arm - Tubules (Macula Densa of distal thick • Brush Border: For high surface area at the luminal and
ascending limb) basolateral sides of the epithelium
o Senses NaCl concentration changes • Epithelium cells are abundant in mitochondria
o May release both vasoconstrictors or vasodilators • Reabsorption of Na (65%), Organic Molecules, HCO3, H2O, Cl
• Juxtaglomerular cells of afferent arteriole – secrete • Secretion of Hydrogen organic acids and base
hormones/metabolites which affects the afferent arteriole • Osmolality: Isotonic
• Increased GFR:
o ­ NaCl concentration ® JG cell stimulation ® afferent Reabsorption of Sodium and Organic Solutes
arteriole constricts ® ¯ GFR • Early portion of PCT
• Decreased GFR: o Reabsorbed: Mainly Na+ with HCO3-, glucose, amino
o ¯ NaCl concentration ® JG cell stimulation ® Dilate acids, phosphate, lactate.
afferent arteriole ® ­ reabsorption ® ­ GFR o All the reabsorption processes are linked to the function
of basolateral Na+/K+ Pump, thus, the transport
SYMPATHETIC CONTROL PROCESS mechanisms are almost all secondary transport
o Transporters:
• Sympathetic fibers from the celiac plexus § Basolateral side: Na+-K+-ATPase
• Adrenergic fibers: release norepinephrine & epinephrine § Apical/Luminal side: Na+-H+ antiporter, SGLT2, Na+-
o Innervates afferent & efferent arterioles Amino acid, Na+-Pi, Na+-Lactate
• Sympathetic responses o Solute reabsorption establishes an osmotic gradient in
o vasoconstriction and lower RBF the tubule and the tubular cells, driving water
o Stimulates renin secretion (afferent arteriole) reabsorption in PCT.
o Enhances Na+ and water reabsorption • Late portion of PCT
o Reabsorbed: Mainly Na+ with Cl-
HORMONAL SYSTEM o Transcellular pathway: Na+-H+ antiporter & Cl—anion
antiporter
Table below: Hormones and substances that increase or decrease GFR o Paracellular pathway: Cl- diffuses across the tight
and RBF, through the contraction or dilation of arterioles junctions, and Na+ follows in order to maintain electrical
Nitric oxide neutrality
Natriuretic peptides:
ANP & BNP Water Reabsorption
Afferent Arteriole Dilation
Prostaglandin
­ GFR
Bradykinin • 67% of water is reabsorbed passively
Dopamine • PCT is highly permeable to water
Efferent Arteriole Low dose angiotensin II • Contributes to the nearly isosmotic volume reabsorption
Constriction Natriuretic peptides • Apical & basolateral channels: Aquaporin-1
High dose Angiotensin II • Water movement can be paracellular
Epinephrine & • solvent drag: solutes are carried with water as it flows
Norepinephrine passively through the tight junctions
Afferent Arteriole ADH
Constriction Endothelin Glucose Reabsorption
¯ GFR
Adenosine
Prostaglandin blockers • Glucose is 100% reabsorbed – absent in normal urine
(NSAID) • SGLT2 (90%), early PCT: Low affinity, high capacity
Angiotensin blockers • SGLT1 (10%), Late PCT: High affinity, low capacity
Efferent Arteriole Dilation • It exhibits Transport Maximum (Tm)
(medication)
o Appearance threshold: 200 mg/min –some nephrons are
saturated

16 of 24
 o Actual Saturated threshold: 375 mg/min – All nephrons LOOP OF HENLE
are saturated with glucose
• Similar to DCT and Cortical CT
PCT Secretion of Organic Acids & Bases • Presence of ENaC at apical side
• Function: to limit exposure to toxic compounds from • Hypotonic or hypertonic, depending on ADH
endogenous and exogenous sources
• Appearance threshold: 200 mg/min – Actually only some of Table below: Reabsorption and secretion across the renal tubular system,
the nephrons are saturated with notes on osmolality
reabsorbed /
Site Transporter(s) Osmolality
Secreted
Figure below: Concentration of solutes in PCT’s tubule fluid. Concentration
SGLT1 & SGLT2 All reabsorbed:
going below 100 suggests reabsorption. ­ concentration indicates secretion
Na+-AA Na+, glucose
(Berne & Levy, 7th Ed. pg 607) Na+-Lactate Na+-AA
Na+-Pi Na+-Lactate
PCT isotonic
Na+-H exchanger Na+-Pi
NaCl +
Na Cl -

H+ - secreted
Descending
Aquaporin water hypertonic
Limb LoH
Ascending Na+/K+/2Cl- reabsorbed:
hypotonic
Limb LoH cotransport Na+, K+, Cl-
NaCl symport Reabsorbed:
Early DCT hypotonic
Na+ Cl-
principal cells: Reabsorbed:
Late DCT ENaC Na+, K+
hypo /
Collecting Intercalated cells: Secreted:
hypertonic
Duct K+-H+ pump K+, H+
Aquaporin water

VII. REGULATION OF TUBULAR PROCESSES

LOOP OF HENLE Starling Forces

• Reabsorption back to capillaries: oncotic pressure in the
Thin Descending Limb – Concentrating Segment capillaries & hydrostatic pressure in the interstitial space
• Exclusively for water reabsorption via aquaporin-1 • Secretion to tubular lumen: oncotic pressure in the interstitial
• impermeable to solutes space & hydrostatic pressure in the capillaries
• Hypertonic due to increasing solute concentration
Glomerotubular Balance
Ascending Limb – Diluting Segment • changes in GFR (in glomerulus) will result in a response by
• Permeable to solutes for reabsorption (does 25% of Na the tubules ® tubular reabsorption is altered
reabsorption) • Action / Response: Tubules will increase/decrease their
o Na+, K+, & Cl- via the Na-K-2Cl channel reabsorption of Na and Water
o Ca2+, Mg2+, other Na+ and K+ via passive diffusion o If Na+ is filtered and not reabsorbed ® fluctuation in BP,
paracellularly ECF volume, and homeostasis will occur
o HCO3- - is also reabsorbed via the Na+-H+ antiporter • Tubuloglomerular feedback – changes in salt and fluid
(apical membrane) delivery to distal tubule will result in adjustments in the GFR
• Impermeable to water in the glomerulus
• Hypotonic due to water in the lumen & reabsorption of
solutes; tubular fluid is being diluted Sympathetic & Hormonal Influence
• ­ reabsorption: Angiotensin II, Aldosterone, Catecholamines,
DISTAL CONVOLUTED TUBULE and ADH (for water)
• ¯ reabsorption: ANP, BNP, Dopamine, and Uroguanylin
• Roughly 5% of the Na+ reabsorbed occurs here (PCT – 65%, • Sympathetic pathway: ­ reabsorption of H2O & Na+
10-15% - Loop of Henle) o Constriction of arterioles, increasing GFR, and leading to
Early DCT Tubuloglomerular feedback
• Acts like an extension of ascending limb o RAAS signaling for Aldosterone & Angiotensin II
• Reabsorption of Na+, Cl-, and Ca2+, via the Na-Cl symporter o Catecholamine stimulation
• Impermeable to water, thus a diluting segment (hypotonic)
MICTURITION
Late DCT & Collecting Tubes
• Principal Cells – Absorption of Na+, Cl-, & water, K+ secretion Innervations to the urinary bladder
• Na+ reabsorption via ENaC followed by Cl via paracellular • Parasympathetic activity
pathway (passive diffusion) o Contracts detrusor muscle & relax trigone + internal
• Water reabsorption via aquaporin channels sphincter ® micturition/urination
o Apical membrane: AQP2 • Pudendal nerve – somatic nerve fibers provides voluntary
o Basolateral membrane: AQP3 & AQP4 control of external sphincter
• Hypotonic without ADH; hypertonic with ADH o Inhibition of pudendal nerve ® opens sphincter
• K+ secretion via passive diffusion
• HCO3- - is also reabsorbed via the Na+-H+ antiporter Micturition Process
• Intercalated Cells – Secretion of H+ or HCO3- • Process by which bladder empties when it becomes
o H+ Secretion via H+/K+-ATPase filled/stretched; emptying occurs when tensions go above
o Secretes H+, reabsorbs K+, for acid-case Balance threshold levels

17 of 24
Micturition reflex
Bladder fills up → Sensory stretch receptor stimulated → Pelvic • Urea perfectly illustrates the relationship between solute osmotic
Nerves → Sacral Segments (Spinal Cord) → Parasympathetic efficacy and membrane permeability, diffusion surface area, and
Nerve fibers of Pelvic Nerve → Detrusor Muscle Contraction → kinetics of solute generation or loss as an effective osmole.
Increased pressure in bladder → Pudendal Nerve is inhibited → • Effective Osmole - has capacity to attract solvent with water
External Urethral Sphincter relaxes → Micturition • In cases of diarrhea
o Isosmotic volume contraction
o The ECF volume decreases, but no change occurs in the
Single complete cycle
osmolarity of ECF or ICF.
• Progressive and rapid increase in pressure • In cases of infusion of isotonic NaCl
• Period of sustained pressure o Isosmotic volume expansion
• Return to basal tone of bladder o The ECF volume increased but did not affect the osmolarity
of the compartments
Figure below: Relationship between the intravesicular pressure and the • In cases of getting lost in the desert
volume of urine stored in the bladder o Hyperosmotic volume contraction
o The ECF volume decreases because of the loss of volume in
the sweat. Water shifts out of ICF; as a result of the shift, ICF
osmolarity increases.
• In cases of excessive NaCl intake
o Hyperosmotic volume expansion
o The osmolarity of ECF increases because NaCl has been
added to the ECF. Because of this, water shifts from the ICF
to the ECF, causing an increase in ICF osmolarity until it
equals that of ECF. As a result, the ECF volume increases
and ICF volume decreases.

TUBULAR REABSORPTION AND SECRETION

Tubular Secretion
• Higher centers (brain) act as the final control of micturition • Movement of material form peritubular capillaries to interstitial
o Inhibit the reflex unless desired (hold the pee) space then to nephron tubules.
o By tonic contraction of external urethral sphincter
o With the desire to urinate ® micturition center is Proximal Convoluted Tubule
activated ® reflex occurs • 65% reabsorption of water and solutes.
• 100% reabsorption of glucose and amino acid.
• Tubular fluid: Isosmotic
4.06 Renal Physiology II
Loop of Henle (LoH)
BODY FLUID COMPARTMENTS • Also known as “countercurrent multiplier” with high medullary
osmolarity
Total Body Water (TBW) • Reabsorbs 25% NaCl and 15% Water.
• TBW = BW x Factor • Side by side with Vasa Recta.
• 45-55% of the total body weight in an obese adult • 3 functional distinct segments:
• 50-55% of the total body weight in a normal female adult and in a 1. Thin Descending Limb
thin adult 2. Thin Ascending Limb
• 60% of the total body weight in a normal male adult 3. Thick Ascending Limb
• 80% of the total body weight in an infant
Table below: Summary of the characteristics of the segments of Loop
Table below: Visual representation of the total body water relative to of Henle (adapted from lecture ppt)
body compartments. Thin Thin Thick
Descending Ascending Ascending
Total Body Mass
water
permeable impermeable impermeable
60% Fluids 40% Solids permeability
less
ECF = 1/3 reabsorption of
Moderately reabsorptive
electrolytes Na+, K+, Cl-,
ICF = 2/3 Interstitial Plasma = permeable to capacity
absorbed Ca2+, Mg2+,
Fluid = 20% Na+ and urea compared to
HCO3-
80% ECF ECF thick ascending
Permeability
permeable impermeable impermeable
Movement of Water to urea
Active
• Osmosis: movement of water across a semipermeable transport –
membrane Transport simple diffusion Na+/H+
thick epithelial
• Tonicity: effect of solutes on the cell cells
o Isotonic: no change
Tubular Na+/K+/2Cl-
o Hypotonic: swelling hypertonic hypotonic
Fluid cotransport
o Hypertonic: crenation/shrinking
• high amounts • little solute • concentrates
of aquaporins reabsorption urine
Changes in Volume and Osmolarity of Body Fluids
• most of water occurs here • most of the
Other notes
reabsorption water
280 mOsm/kg glucose in LoH occurs remained in
No change
the tubules
Swell
280 mOsm/kg urea
Normal plasma osmolality = 275-285 mOsm

18 of 24
Countercurrent Multiplier
• Generates the hyperosmotic medullary Interstitium Osmotic Control of ADH Secretion
• Due to NaCl reabsorption in Thick Ascending Limb and • Receptor: Osmoreceptors in the posterior hypothalamus
continued inflow of new NaCl from PCT. o Respond to effective osmoles (e.g. Urea)
• Builds up gradient by 2-step processes: o Incomplete in osmolality of plasma ® Stimulation
o Ave range= 280-295 mOsm/kg
• First step: “Single Effect”
o Refers to the function of thick ascending limb where NaCl
Hemodynamic Control of ADH Secretion by Receptors
is reabsorbed ® ­ osmolality in the interstitial fluid
1. Left Atrium and Large Pulmonary Vessels
• Second Step: “Flow of Tubular Fluid” o Low pressure areas
o New fluid enters the descending limb ® equal volume of o Responds to overall vascular volume
fluid is displaced from ascending limb ® “fluid shift” with 2. Aortic Arch and Carotids
the high osmolarity fluid in descending limb getting o High pressure areas
pushed down toward the bent of the Loop of Henle o Responds to arterial pressure
• A decrease of 5-10% blood volume is required before ADH is
Figure below: Diagram Illustrating the Counter Current Multiplier stimulated
System o Compared to 1% change in osmolality that stimulates ADH

Action of ADH in Kidneys

• Primary action: ­ water permeability of the collecting duct
• Medullary portion of the collecting duct to urea
• ADH stimulates the reabsorption of NaCl by the thick
ascending limp of Henle’s loop, distal tubule, and
collecting duct
• ADH binds to a receptor (V2 receptor) on the basolateral
membrane.
• coupled with adenylyl cyclase via a stimulatory G protein
increase intracellular levels of cAMP
• ­ cAMP activates protein kinase A ® insertion of vesicles
containing Aquaporin 2 (AQP2) water channels into the
apical membrane in the cell along with synthesis of this
channel
• Once ADH is removed, the water channels are reinternalized
in the cells and the apical membrane is impermeable again.

THIRST
Distal Convoluted Tubule • Thirst perception is altered by the changes in plasma
• First portion forms a part of the Juxtaglomerular complex osmolality and blood volume
• Provides feedback control for GFR and blood flow • Relief of thirst can be:
• 5% of filtered load of Na is reabsorbed. 1. Short lived: Oropharyngeal and upper GI receptors
• Na-Cl co-transporter moves sodium inside the cell and the 2. Fully Relieved: Correct of plasma osmolality / blood
Na-K ATPase from the basolateral fluid moves Na to the volume
interstitial space. • Thirst: ­ Blood osmolality, ↓BP & BV
• Strong desire to drink:
Late DCT and Cortical Collecting Tubule o ­ Plasma osmolality (2-3%)
• Composed of 2 types of cells: ↓ BP &BV (10-15%)
1) Principal Cells: reabsorbs Na+ and Cl-, secretes K+ • ADH threshold secretion: 285mOsm/kgH2O
2) Intercalated cells: Reabsorbs water in presence of • thirst threshold: 295mOsm/kgH2O
ADH, HCO3- and K+ and secretes H+
COUNTER EXCHANGE MECHANISM
Medullary Collecting Duct
• Reabsorbs less than 10% of filtered water and Na+. • Occurs in the vasa recta leading to preservation of
• Final site of processing hyperosmolarity
• Permeability to water is controlled by the ADH • Plasma flowing down the descending limb of vasa recta
• Permeable to urea unlike the cortical collecting tubule becomes more hyperosmotic because of diffusion of water out
• Capable of secreting hydrogen ions against a large of blood and diffusion of solutes from renal interstitial fluid into
concentration gradient (acid-base regulation) the blood
• In the ascending limb of vasa recta, solutes diffuse back
ANTIDIURETIC HORMONE (ADH) into interstitial fluid and water diffuses back into the vasa recta

• Acts on kidneys to regulate volume and osmolality of urine CONTROL OF EXTRACELLULAR FLUID VOLUME
o ¯ ADH=Diuresis | ­ ADH= Anti-diuresis
• Synthesized in neuroendocrine cells located within the • Kidneys keep ECF volume constant by adjusting the excretion
supraoptic and paraventricular nuclei of the hypothalamus of NaCl to match the ingested in the diet
• Secretion by the posterior pituitary gland is influenced by • Volume-sensing systems exert control in the ECF volume
the following:
o Osmolality of the body fluids (Osmotic) Vascular Sensors
o Volume and pressure of the vascular system • Low-Pressure Volume Sensors
(Hemodynamic) o Respond to distention of cardiac atria, right ventricle,
o Others: Nausea (stimulation) ANP (inhibitor), Angiotensin and large pulmonary vessels
II (stimulation)

19 of 24
 o ¯ in filling of pulmonary vessels and cardiac atria → ­ RENIN-ANGIOGTENSIN-ALDOSTERONE SYSTEM (RAAS)
sympathetic activity and stimulates ADH secretion
o Natriuretic peptides reduce blood pressure and • Cells in afferent arterioles: Synthesis, storage, and release
increases the excretion of NaCl and water of renin
• High-Pressure Volume Sensors • Intravascular volume or ­ osmolality ® secretion of renin
o Baroreceptors - in the walls of the aortic arch, carotid • Important factors that stimulate the release of renin:
sinus, and afferent arterioles of the kidneys 1. Perfusion pressure
o Alter sympathetic outflow and ADH secretion 2. Sympathetic nerve activity
o Example: ¯ in blood pressure → ­ Sympathetic nerve 3. Delivery to NaCl to the macula densa
activity and ADH secretion
o Juxtaglomerular Apparatus (afferent arteriole) Angiotensin II:
§ Reduced perfusion pressure → release of renin • Stimulates aldosterone secretion by adrenal cortex
• Arteriolar vasoconstriction → ­ blood pressure
Hepatic Sensors • Stimulation of ADH secretion and thirst
• ­ pressure within hepatic vasculature or ­ in portal blood • Enhancement of NaCl reabsorption by the PT, TAL of Henle’s
[Na+] → ¯ efferent sympathetic nerve activity → ­ renal NaCl loop, DT and CD
excretion
Figure below: Essential components of the renin-angiotensin-
aldosterone system. Activation of this system results in a decrease
Sensors in Central Nervous system in the excretion of Na+ and water by the kidneys.
• ­ [Na+] in the carotid and CSF → ¯ renal sympathetic nerve
activity → ­ renal NaCl excretion

Volume Sensor Signals

• Send signals to kidneys when vascular volume sensors detect
change in ECF volume
• Expanded ECF volume → ­ renal NaCl and water excretion
• Contacted ECF volume → ¯ renal NaCl and water excretion

Table below: Summary of the signals and their effects on renal NaCl
and water excretion (Berne & Levy, 6th Ed. pg 610)

NATRIURETIC PEPTIDES: URODILANTIN

• Produced by the kidneys (ANP) and brain (BNP)

• Promotes NaCl and water excretion by the kidneys
• Antagonizes the actions of the renin-angiotensin-aldosterone
system

OTHER HORMONES INFLUENCING KIDNEY FUNCTION

• Estrogen
o ¯ Na+ excretion by direct stimulation of tubular Na+
reabsorption
o Water retention during pregnancy
• Glucocorticoids (cortisol)
o ­ tubular reabsorption but also ­ GFR which masks the
effect
RENAL SYMPATHETIC NERVES
4.07 Water & Electrolytes
• ECF volume contraction activates low and high pressure
vascular baroreceptors ® stimulation of sympathetic nerves SODIUM CHLORIDE EXCRETION
• Effects of renal sympathetic nerves:
1. Vasoconstriction of arterioles ® ¯ Hydrostatic pressure Control of NaCl Excretion during Euvolemia
within glomerular capillary lumen ® ¯ GFR ® ¯ filtered • During euvolemia, distal tubule + collecting tubule are the
load of Na+ to the nephrons main nephron segments where Na+ reabsorption is
2. Secretion of renin by the cells of afferent arterioles readjusted.
3. Stimulation of NaCl reabsorption • Constant amount of Na+ is reabsorbed on proximal tubule
• ­ renal sympathetic nerve activity ® ¯ excretion of NaCl in and thick ascending loop of Henle
order to restore ECF volume to normal (euvolemia) • Two general processes:
1. Na+ absorption by proximal tubule and loop of Henle is
regulated so that constant portion of filtered Na+ is
delivered to distal tubule (DT)

20 of 24
 2. Reabsorption in remains portion of filtered Na+ is • Plasma Osmolality
regulated = Na+ excretion matches the ingested Na+ o ­ plasma osmolality of ECF enhances release of K+ by
cells as water leaves the cell until ECF and ICF water
Mechanisms for maintaining constant NaCl to distal Tube concentration reach equilibrium
1. Autoregulation of Glomerular Filtration Rate (GFR) o High K+ in diabetic patients is because of high plasma
o Maintains relatively constant filtration rate osmolality and decrease in insulin secretion/sensitivity
2. Glomerotubular balance o Loss of water shrinks cells and causes K+ in cells to rise
o Occurs when there is failure of GFR autoregulation o Rise in intracellular K+ provide a driving force to exit K+
o If ­ GFR ® ­ Na+ reabsorption by proximal tubule from cells
3. Response of Loop of Henle • Cell Lysis
o Final mechanism maintaining constant Na+ reabsorption o Causes hyperkalemia as a result of ­ K+ in ECF
o Example: Severe trauma, tumor lysis syndrome, addition
Regulation of NaCl by DT and Collecting Duct of intracellular K+ to ECF
• Aldosterone: primary regulator of Na+ reabsorption by DT • Exercise
and collecting tubule (CT) ® ­ Na+ reabsorption o More K+ is released from skeletal muscle cells during
• Other factors: Natriuretic peptides, prostaglandins, exercise than during rest
uroguanylin, adrenomedullin, and sympathetic nerves
POTASSIUM EXCRETION BY KIDNEYS
RENAL SYMPATHETIC NERVES
• PCT reabsorbs 67% of filtered K+
• Stimulate a-adrenergic receptors ® constriction of afferent • 20% reabsorbed by Loop of Henle
and efferent arterioles ® ¯ hydrostatic pressure, ¯ GFR, ¯ • In contrast to: Distal tubule and collecting tubule can reabsorb
filtered Na+ and secrete K+
• Stimulate ß-adrenergic receptors lead to renin secretion by • ­ K+ ingested ® ­ K+ secretion
the cells of afferent arterioles • In low K+ intake: Kidneys cannot reduce K+ excretion to the
o ­ Angiotensin II and aldosterone which stimulate Na+ same low levels of Na+
reabsorption by nephron
• NaCl reabsorption along the nephron is directly stimulated Cellular Mechanism of K+ Secretion by Principal Cells
(mediated by a-receptor)
• Two-step process:
NATRIURETIC PEPTIDES 1) Uptake of K+ via Na+-K+-ATPase
2) Diffusion of K+ from cell to tubular fluid via K+ channels
• Atrial Natriuretic Peptide (ANP) – from the atria • K-Cl symport:
o Released when atria are distended → ¯ blood pressure o Downhill movement
o ­ NaCl excretion and water by the kidneys o Greater permeability of apical membrane
• Brain Natriuretic Peptide (BNP) – from cardiac ventricles
o Action is similar to ANP Factors affecting the rate of K secretion at DT and CD:
1. The activity of Na+-K+-ATPase
POTASSIUM 2. The driving force for movement across the apical membrane
3. Permeability of apical membrane K+ channels
• Most abundant cation intracellularly
• Critical for cell function: Cellular Mechanism of K+ Secretion by Intercalated Cells
o Regulation of cell volume and intracellular pH • Reabsorb K+ by a H+-K+-ATPase
o Synthesis of DNA and proteins • Stimulated by K+ depletion
o Growth and enzyme function • K+ exit the cell through a K+ channel
o Resting membrane potential
o Cardiac and neuromuscular activity Regulation of K+ Secretion by DT and Collecting Duct
• Normal plasma K+ = 3.5 - 5.0 mEq/L • Regulation of K secretion mainly by alteration in K+ secretion
• Total Body [K+] = 50 mEq/kg of BW by principal cells in DT and CD
• Na+-K+-ATPase maintains high intracellular [K+] • Major physiologic regulators: Plasma [K+] and Aldosterone
• Two mechanisms of K+ homeostasis • ADH also stimulates secretion but lesser degree
o Regulation of [K+] in ECF • Other factors:
o Renal adjustment of K+ excretion o Flow rate of tubular fluid
o Acid-base balance
REGULATION AND ALTERATIONS OF PLASMA [K+]
ADH EFFECT ON PLASMA [K+]
• Acute Stimulation: ­ in activity transporters
• Chronic Increase: ­ in quantity transporters • Affects urinary K+ secretion but not urinary K+ excretion
• Hormonal Regulation: all cause ¯ in Plasma [K+] • K+ secretion is stimulated by:
1. Epinephrine o ­ urinary flow rate
o Stimulation of a-receptors → release K+ from cells o ­ ADH levels ® ­ water reabsorption ® ¯ tubular flow
o Stimulation of ß2 receptors → ­ K+ uptake of cells ® ¯ K+ secretion
2. Insulin • K+ secretion is reduced by:
o stimulates uptake of K+ into cells in response to o ¯ urinary flow rate
elevated plasma [K+] o ¯ ADH levels
3. Aldosterone • ¯ Secretion of K+: due to ­electrochemical driving force
o ­ K+ uptake through ­ Na+ reuptake
• Acid-Base Balance • Effect countered by decreased flow of tubular fluid through
o Metabolic Acidosis: ­ plasma [K+] water reabsorption
o Metabolic alkalosis + respiratory alkalosis: ¯ plasma [K+]
o Respiratory acidosis: little or no effect on plasma [K+]

21 of 24
 Figure below: Opposing effects of ADH and urine flow rate on K+ PHOSPHATE
secretion (Berne & Levy, 7th Ed. pg655)
• Important in organic molecules and as intermediates of
metabolic pathways
• major constituent in the bone urinary phosphate important
buffer in acid-base balance
• 1% located in the ECF
1) 45% ionized
2) 30% complexed
3) 25% protein bound
• Phosphate is mostly reabsorbed in the PCT
o None in the thick ascending loop, distal tubule, and the
medullary collecting duct

MAGNESIUM

• important cofactor of enzymes

• controlled by intestinal uptake and urinary excretion
FACTORS THAT PERTURB K+ SECRETION • plasma range 1.3 to 2.1 mEq/L
• Three forms in the plasma:
Flow of tubular fluid 1) 60% free ionized Calcium
• ­ flow ® ­ Na+ entry ® cilia bending ® this bending causes 2) 25% bound to plasma proteins
3) 15% complexed with LMW anions
activation of PKD1 / PKD2 and Ca2+ entry ® ­ intracellular
• 25% reabsorbed in PCT
Ca2+ causes ­ K+ excretion
• 65% in Thick Ascending Loop of Henle
Acid-Base Balance • 1-5% Distal Sites of regulation: Thick Ascending Loop of
Henle and DCT
Acidosis Alkalosis
• ¯ K+ secretion due to • ­ K+ secretion caused by: 4.08 Acid-Base Balance
inhibition of Na+/K+ ATPase o stimulation of Na+/K+ ATPase
o ¯ intracellular K+ o ­ permeability of apical ACIDS AND BASES
o ¯ electrochemical driving membrane
force • Acids add H+ to body fluids; alkali (bases) remove H+
• Regulate concentration of free protons in the ECF = 40nM
Glucocorticorticosteroids (pH 7.4)
• ­ K+ secretion via ­ GFR ® ­ tubular flow rate • Range of plasma pH compatible with life is 6.8 – 7.8 while the
• Potent stimulus for K+ secretion normal pH of ECF ranges from 7.35 – 7.45
o Acidosis = pH < 7.35 (when addition of acids exceeds
CALCIUM excretion)
o Alkalosis = pH > 7.45 (when excretion of acids exceeds
• Important in bone formation, cell division, growth, blood addition)
coagulation, hormone response, and electrical stimulus FIRST SUBTOPIC
response VOLATILE AND NON-VOLATILE ACIDS
• 99% bone/teeth; 1% ICF; 0.1% ECF
• Three forms in the plasma: • Volatile acids come from cellular metabolism
o 45% free ionized Calcium o Ex: H2CO3 (from CO2; end product of oxidative
o 45% bound to plasma proteins metabolism)
o 10% complexed with LMW anions • Non-volatile acids come from the processing of proteins and
lipids from meat, and even from fruits/vegetables
Reabsorption in the Kidneys o Not derived from CO2
• PCT: 70% of filtered Ca2+ is reabsorbed via paracellular o Net daily production: 40-60 mmol
pathway o Do not circulate in the body but are neutralized by HCO3-
• Loop of Henle: 20% of filtered Ca2+ is reabsorbed via
paracellular pathway Table below: list of non-volatile acids and origin
• Driven by solvent drag Non-volatile Acid Origin
• Distal Tubule: ~ 9% of filtered Ca2+ is reabsorbed via sulfuric acid cystine + methionine residues
transcellular route phosphoric acid catabolism of phospholipids
• Driven by transepithelial electrochemical gradient ß-hydroxybutyric acid + keto-acids that build up in
• Ca2+ enters apical membrane via TRPV5 and TRPV6 ® binds acetoacetic acid people with Diabetes Mellitus
to calbindin ® Ca2+:calbindin complex diffuse across the cell Lactic acid from extraneous exercise
to exit in the basolateral membrane via Ca2+ ATPase Salicylic acid aspirin overdose
Formic Acid methanol ingestion
Glycolic and oxalic acids ethylene glycol ingestion

BUFFER SYSTEM

• Prevents large changes in pH when transient accumulations

or acid-base imbalance occur
• Does not eliminate added acid or base but only ameliorate the
effect on blood pH

22 of 24
• Can only exert delaying action to reduce magnitude of pH TITRATABLE ACID
changes
• Measured from the amount of strong base (NaOH) needed to
Buffer System In the Body bring the urine pH back to the pH of the blood
• Extracellular Fluid • Titratable acid is formed when secreted H+ combines with a
o Phosphate and albumin in the plasma non-buffer base in the tubular urine
o Hemoglobin in red blood cells • Represents the amount of H+ excreted, combined with urinary
o HCO3- buffer system – most common; principal ECF buffers e.g. phosphate, creatinine
buffer regulated by both the lungs and kidneys • Phosphate – largest component of titratable acid
• Intracellular Fluid
o The cytosol of the various cells in the body HOMEOSTATIC CONTROL OF PROCESSES THAT
o Phosphate Buffer System- major intracellular buffer DETERMINE RENAL COMPENSATION OF ACID-BASE
• Matrix of Bone DISTRUBANCES
o additional source of extracellular buffering
• ­ Glutamine metabolism and ­ NH4 excretion during
acidosis; opposite occurs during alkalosis
RESPONSES TO ACID-BASE DISORDERS • During respiratory acidosis (­ pCO2) - ­ tubular H+; opposite
during respiratory alkalosis (¯ pCO2)
1st Line of Defense: Fast Physiochemical Buffering • ­ tubular H+ secretion is independent from the changes in
• Innate and act directly on the acid to buffer it pCO2 by local effects of ¯ extracellular pH on tubules
• Chemical buffers in extracellular and intracellular fluids and in
bone are the first line of defense of blood pH imbalance ACID-BASE DISORDERS
• Most common buffer system in the ECF: HCO3- / CO2
Respiratory Acidosis
Chemical response to pH • Problem: hypercapnia (­ paCO2)
• Buffering in ECF occurs rapidly in minutes • Causes:
• Minimizes a change in pH without removing the acid or base o Respiratory depression by drugs
responsible o Inhibition of medullary respiratory center
o Neuromuscular disease
Strong acid + buffer salt ↔ Neutral salt + weak acid o Disorders of respiratory muscles (Guillain-Barre
HCl + NaHCO3 ↔ NaCl + H2 CO3 Syndrome, ALS, multiple sclerosis)
o Disorders of gas exchange (COPD, pneumonia,
Henderson-Hasselbalch Equation pulmonary edema)
• The equation is used to quantitate the changes in CO2 and o Airway obstruction
HCO3- affecting pH • Clinical Manifestations:
o Hypercapnia
pH= pK1 + log HCO3 o Hypoventilation
H2CO3 o Blunted sensation
o Pain
2nd Line of Defense: Fast Respiratory Component • Renal compensation: ­ H+ secretion and ­ NH4+ secretion
• ¯ blood pH stimulates ventilation via the central (medulla • Acute Respiratory Acidosis: insufficient renal compensatory
oblongata) & the peripheral (carotid & aortic bodies) response and body relies on ICF buffering to minimize pH
chemoreceptors changes
• ­ Ventilation = ¯ pCO2 ; ¯ ventilation = ­ pCO2 • Chronic Breathing Acidosis: renal compensation occurs
• Respiratory responses to changes in blood pH begin within
minutes & are at maximum between 12-24 hours Respiratory Alkalosis
• Elevated arterial blood pCO2 ® ­ ventilation • Problem: Hypocapnia (¯ paCO2)
o Acts on both peripheral and central chemoreceptors • Causes:
• ­ blood pH ® ¯ ventilation o Asthma
o Pneumonia
3rd Line of Defense: Slow Renal Component o Pulmonary edema
• Last line of defense; can eliminate large amounts of acid o Fever
• Most effective regulator of pH but requires several days to o Pregnancy
reach completion o Anxiety
• Role of kidneys: excrete H+ and replenish HCO3- stores o Stimulation of medullary respiratory center (salicylate
intoxication, gram [-] sepsis, hysterical hyperventilation)
• Although the chemical buffers in the body can bind H+, the
burden of removing excess H+ falls directly on the kidneys o Hypoxemia due to high altitude and severe anemia
o H+ are excreted including urinary buffers • Clinical Manifestations:
o Add new HCO3- to ECF to replace HCO3- used to buffer o Hyperventilation
strong acids o Numbness and lightheadedness
o Paresthesia
• Renal excretion of acid and bases
o When base has been added to the body fluids, the effect • Renal compensation: ¯ H+ secretion and ­ HCO3- excretion
is to ­ plasma HCO3- due to ¯ H+ and ¯ HCO3- conserved
o Kidneys do this by (1) allowing some filtered HCO3- to
pass through the urine or (2) secrete HCO3- via Type B Metabolic Acidosis
intercalated cells • Problem: ¯ plasma concentration of HCO3- and/or ­ HCl
• Causes:
o Uremia
o Excessive production or ingestion of fixed H+ (all with ­
anion gap)
§ Diabetic ketoacidosis

23 of 24
 § Salicylate intoxication • Two types based on pH:
§ Lactic acidosis o Acidosis: ¯ pH | Alkalosis: ­ pH
§ Formaldehyde poisoning o There is indirect relationship of H+ and pH:
o Loss of HCO3- from diarrhea or type 2 renal tubular § ­ H+ = ¯ pH | ¯ H+ = ­ pH
acidosis • Two types based on whether CO2 or HCO3-
o inability to excrete H+ o Respiratory: CO2
§ chronic renal failure o Metabolic: HCO3-
§ Type 1 renal tubular acidosis
§ Type 4 renal tubular acidosis (hyperaldosteronism, ¯ STEPS ON ANALYZING ACID-BASE DISORDERS
NH4+ excretion)
• Clinical Manifestations: 1. Check the pH:
o Fatigue o ¯ H+ = ¯ pH (<7.35) = acidosis
o Abdominal pain o ¯ H+ = ¯ pH (>7.45) = alkalosis
o Vomiting
o Kussmaul Breathing 2. Determine whether respiratory of metabolic disorder:
o Hypotension o pCO2 = respiratory
o Tachycardia § ¯ pH, ­ pCO2 = respiratory acidosis
o Cherry red lips § ­ pH, ¯ pCO2 = respiratory alkalosis
• Respiratory compensation: Hyperventilation o HCO3- = metabolic
• Renal compensation: ­ H+ secretion § ¯ pH, ¯ HCO3- = metabolic acidosis
§ ­ pH, ­ HCO3- = metabolic alkalosis
Metabolic Alkalosis
• Problem: 3. Determine whether or not there is a compensatory
o ­ plasma concentration of HCO3- response:
o Loss of non-volatile acids (HCl) o For respiratory disorders: RENAL compensation
o Addition of non-volatile base o For metabolic disorders: RESPIRATORY compensation
• Causes: o Note: compensatory responses counteract the disorder
o Volume contraction alkalosis – loop or thiazide diuretics to put the pH back to normal (refer to the table on the
o Vomiting previous page for compensatory response)
o Primary hyperaldosteronism (­ H+ secretion)
o Gain of HCO3- (ingestion of NaHCO3, Milk-Alkali
Syndrome) - THE END –
• Clinical Manifestations:
o Non-specific but may present as apathy, stupor,
confusion
• Respiratory compensation: Hypoventilation
• Renal compensation: ¯ H+ secretion

Table below: Summary of Acid-Base Disorders

Disorder Disturbance Compensatory Response
response
¯ 1 mEq/L in
Metabolic
¯ [ HCO3-] ¯ pCO2 HCO3- ® ¯ 1.3
Acidosis
mmHg in pCO2
­ 1 mEq/L in
Metabolic
­ [HCO3-] ­ pCO2 HCO3- ® ­ 0.7
Alkalosis
mmHg in pCO2
Acute ­ 1 mmHg in
Respiratory ­ pCO2 ­ [HCO3-] pCO2 ® ­ 0.1
Acidosis mEq/L in HCO3-
Chronic ­ 1 mmHg in
Respiratory ­ pCO2 ­ [HCO3-] pCO2 ® ­ 0.4
Acidosis mEq/L in HCO3-
Acute ¯ 1 mmHg in
Respiratory ¯ pCO2 ¯ [ HCO3-] pCO2 ® ¯ 0.2
Alkalosis mEq/L in HCO3- 2021C [PHY] LE 4 Finals Reviewer Groups
Chronic ¯ 1 mmHg in Trans Group - Salapare, Kristia
Respiratory ¯ pCO2 ¯ [ HCO3-] pCO2 ® ¯ 0.4 12 - Salvador, Alyanna
Alkalosis mEq/L in HCO3- - Salvador, Elaine
- Salvador, JIannelette
Table below: Normal Values *memorize* Trans Group - Samonte, Sharina
pH 7.35 – 7.45 13 - San Felipe, Pia
paCO2 35 – 45 mmHg - Sanchez, Jose
HCO3- 22 – 28 mEq/L - Sandiko, Justin
paO2 80 – 100 mmHg Trans Group - Tagaza, Mariel
Anion Gap 8 – 16 mEq/L 20 - Tagle, Catrize
- Tagorda, Zeke
- Tagra, Kaidee
Trans groups assigned for 4.06 – 4.08
Editor - Perez, John

24 of 24