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Pharmacokinetics
Chapter 1
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I. ABSORPTION OF DRUGS
Absorption: is the transfer of a drug from its site of
administration to the bloodstream via one of several
mechanisms. (except for drugs that are applied directly to the target
tissue)
• The rate and extent of absorption depend on:

1. the environment where the drug is absorbed
2. The chemical characteristics of the drug
3. Route of administration (bioavailability).
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Absorption: Rate & Extent
➢ Rate: how rapidly does the drug get from its site of
administration to the general circulation ?
➢ Extent: How much of the administered dose enters the

general circulation ? ( % bioavailability = F)
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Rate versus extent of absorption
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Rate versus extent of absorption
8
Mechanisms of absorption of drugs from the GI
tract
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Mechanisms of absorption of drugs from the GI
tract
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1. passive diffusion:
Movement of a solute
through a biological
barrier from the phase of
higher concentration to
phase of lower
concentration (No need of
energy and carrier)
e.g. highly lipid soluble drugs
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2. Facilitated diffusion: It means the passage of drug
across the biological membrane along the concentration
gradient by the protein carrier mediated system also
called as carrier mediated diffusion
3. Active transport: The process by which drugs pass
across the biological membrane most often against their
concentration gradient with the help of carriers along
with the expenditure of energy
4. Endocytosis: It is the process by which the large
molecules are engulfed by the cell membrane and
releases them intracellularly
13
Factors influencing absorption
1. Effect of pH on drug absorption
2. Blood flow to the absorption site
3. Total surface area available for absorption
4. Contact time at the absorption surface
5. Expression of P-glycoprotein
14
Bioavailability
• Bioavailability is the fraction of administered drug that

reaches the systemic circulation.
• Or, it is the rate and extent to which an administrated
drug reaches the systemic circulation
• For example
– if 100 mg of a drug are administered orally
– 70 mg of this drug are absorbed unchanged
– the bioavailability is 0.7, or 70 percent.
15
Determination of bioavailability
• Bioavailability is determined by
comparing plasma levels of a
drug after a particular route of
administration (for example, oral
administration) with plasma drug
levels achieved by IV injection
• Determining bioavailability is
important for calculating drug
dosages for non-intravenous
routes of administration
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Factors that influence bioavailability
1- First-pass hepatic metabolism
If the drug is rapidly metabolized by the liver, the amount of unchanged
drug that gains access to the systemic circulation is decreased
2- Solubility of the drug:

– Very hydrophilic drugs are poorly absorbed because of their
inability to cross the lipid-rich cell membranes
– Extremely lipophilic drugs are also poorly absorbed, because
they are totally insoluble in aqueous body fluids and, and cannot
gain access to the surface of cells
– drug to be readily absorbed, it must be largely lipophilic, and
have some solubility in aqueous solutions. This is one reason
why many drugs are weak acids or weak bases
18
Factors that influence bioavailability
3. Chemical instability
• Some drugs, such as penicillin G, are unstable in the pH of the gastric
contents
• Others, such as insulin, are destroyed in the GI tract by degradative
enzymes
4. Nature of the drug formulation

Drug absorption may be altered by factors unrelated to the chemistry of
the drug
For example, particle size, salt form, enteric coatings and the presence
of excipients can influence the ease of dissolution and, therefore, alter
the rate of absorption.
19
Factors influencing the oral bioavailability of drugs :
1. Decomposition in acidic gastric juices

2. Decomposition by hydrolytic gut enzymes (eg, proteases,
lipases)
3. Degradation by gut microorganisms
4. Food in the gut may alter absorption rate and amount (eg.
interact or form a complex)
5. Metabolism by gut wall enzymes
6. Metabolism by liver enzymes prior to reaching the systemic
circulation (first-pass metabolism)
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Bioequivalence
• Two related drug preparations are bioequivalent if:
1. They show comparable bioavailability
2. Similar times to achieve peak blood concentrations.
Bioequivalence or pharmaceutical equivalence: the
two drugs release the active ingredient into the
bloodstream at the same amount, the same rate,
and have the same quality.
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Therapeutic equivalence
• Two similar drug products are therapeutically equal if they are
pharmaceutically equivalent with similar clinical and safety
profiles.
Therapeutic Equivalents: Drug products are

considered to be therapeutic equivalents
only if they are pharmaceutical equivalents and if they
can be expected to have the same
clinical effect and safety profile when administered to
patients under the conditions specified in the labeling.
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II. DRUG DISTRIBUTION
• Distribution: is the process by which a drug reversibly
leaves the blood-stream and enters the interstitium
(extracellular fluid) and then the cells of the tissues.
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Factors affecting drug distribution
• The delivery of a drug from the plasma to the

interstitium primarily depends on:
A. Cardiac output and regional blood flow

B. Capillary permeability
C. The tissue volume
D. The degree of binding of the drug to plasma and
tissue proteins
E. lipophilicity of the drug
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Factors affecting Capillary permeability
1. Capillary structure
2. Drug structure
– Hydrophobic drugs are readily move across most biologic
membranes.
– hydrophilic drugs are not readily penetrate cell membranes, and must
go through the slit junctions.
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Binding of drugs to plasma proteins:
1. Binding to plasma proteins: Reversible binding to plasma
proteins (as albumin) sequesters drugs in a nondiffusible form and
slows their transfer out of the vascular compartment
2. Binding to tissue proteins: many drugs accumulate in
tissues (binding to lipids, proteins, or nucleic acids), leading to
higher concentration in tissues than in the extracellular fluid and
blood
– Prolong drug action
– Local drug toxicity
27
Volume of distribution:
• The volume of distribution (Vd), = apparent volume of

distribution is defined as
– The distribution of a medication between plasma and the rest of
the body
Or,
– Apparent or hypothetical volume of fluid into which a drug
is homogeneously distributed in the body
• Vd is a property of the drug and is determined by the drug’s

manufacturer
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Apparent volume of distribution:
• No exclusive distribution to water compartments.
– Majority of drugs distribute into several compartments, often
avidly binding cellular components, such as, lipids, proteins,
nucleic acids
• The volume into which drugs distribute is called the

apparent volume of distribution (Vd)
• If Vd is big the drug is more diluted than it should be

(in the blood plasma), meaning more of it is distributed in
tissue (i.e. not in plasma).
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Determination of Vd
• Vd is useful to compare the distribution of a drug with the

volumes of the water compartments in the body.
• Vd is useful for calculating loading dose of a drug
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log
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Distribution into the water compartments in the
body:
• Once a drug enters the body,
it has the potential to:
– distribute into any one of

the three functionally
distinct compartments of
the body water or
– become sequestered in a
cellular site.
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Effect of Vd on drug half-life:
• Vd has an important influence on the half-life of a drug

– As drug elimination depends on the amount of drug delivered to the organs of
metabolism per unit of time
• Larg Vd for a drug, most of the drug is in the extraplasmic space and
is unavailable to the excretory organs.
• Any factor that increases Vd can lead to:

– An increase in the half-life
– Extend the duration of action.
• Delivery of drug to the organs of elimination depends on:

– Blood flow
– The fraction of the drug in the plasma.
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III. DRUG CLEARANCE THROUGH
METABOLISM
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III. DRUG CLEARANCE THROUGH
METABOLISM
• The process of elimination begins as soon as the drug
enters the body.
• Three major routes of elimination:

1) hepatic metabolism
2) elimination in bile
3) elimination in urine.
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• Elimination causes the plasma
concentration of a drug to
decrease exponentially.
• A constant fraction of the drug

is eliminated in a unit of time.
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• Metabolism leads to products with increased polarity,
which will allow the drug to be eliminated.
• Clearance (CL) estimates the amount of drug cleared from

the body per unit of time
• Elimination could be through

1. first-order kinetics: most drugs
2. zero-order or non-linear kinetics: e.g. aspirin in high
doses
• . 39
1st order elimination vs. zero order elimination
Drug half-life is often used as a measurement of drug CL, as , Vd is a

constant for many drugs.
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log
41
Reactions of drug metabolism
• Lipophilic drugs are not efficiently eliminated by the kidney
• Lipophilic drugs must first be metabolized into more polar
(hydrophilic) substances in the liver
• Two general sets of reactions
– Phase I
– Phase II
(lipophilic) (hydrophilic)
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1. Phase I:
• Phase I reactions convert lipophilic molecules into more

polar molecules by:
introducing or unmasking a polar functional group
such as –OH or –NH2.
• Pharmacologic activity after phase I metabolism may:

– Increase
– Decrease
– Unchanged
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a. Phase I reactions utilizing the P450 system:
• Are catalyzed by the cytochrome P450 system (microsomal mixed-
function oxidases)
• The most common reaction catalyzed by cytochromes P450 is a
monooxygenase reaction
e.g., insertion of one atom of oxygen into an organic substrate (RH)
while the other oxygen atom is reduced to water:
45
Cytochrome P450 (CYP)
• The P450 system is important for the:
– metabolism of endogenous compounds (such as
steroids, lipids, etc.)
– the biotransformation of exogenous substances
(xenobiotics)
• Cytochrome P450 (CYP450) is :
• Superfamily of heme-containinig isoenzymes
• Located in most cells (primarily in the liver and GI tract)
• P: pigment as these enzymes are red because of their heme
group
• 450: wavelength of the absorption maximum of the enzyme
when it is in the reduced state and complexed with CO.
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1) Nomenclature:
• The enzymes themselves, are designated with the
abbreviation CYP
• Followed by a number indicating the family (3)
• A capital letter indicating the subfamily (A)
• Another numeral for the individual gene or specific
enzymes (4)
• Example: CYP3A4.
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2) Specificity:
• Many different P450 isoforms.
• They can modify a large number of structurally
diverse substrates.
• One drug may be a substrate for more than
one isozyme.
• Four isozymes are responsible for the vast
majority of P450-catalyzed reactions.
• CYP3A4/5
• CYP2D6
• CYP2C8/9
• CYP1A2
• Considerable amounts of CYP3A4 are found in
intestinal mucosa ( responsible for first-pass
metabolism)
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3) Genetic variability:
• P450 enzymes exhibit considerable genetic variability
among individuals and racial groups.
• Variations in P450 activity may alter a drug’s efficacy and
the risk of adverse events.
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Example 1:
• CYP2D6 exhibits genetic polymorphism.
• Patients lacking CYP2D6 can not benefit from codeine
analgesic effect
• Codeine is activated by O-demethylation by CYP2D6
enzyme
• This polymorphism is in part racially determined:
– 5 to 10 percent in European Caucasians
– 2 percent of Southeast Asians
Demethylation
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Example 2:
• CYP2C subfamily of isozymes.
• Clopidogrel is CYP2C19 substrate
• Poor CYP2C19 metabolizers have a higher incidence of
cardiovascular events (for example, stroke or myocardial infarction)
when taking clopidogrel.
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4) Inducers:
• Enzyme synthesis initiated within 24 h of exposure,
increasing over 3 –5 days
• Effect decreases over 1 –3 weeks after inducing agent is
discontinued
• Environmental Factors and xenobiotics:
– Cigarette smoking, high protein diet, ethanol, exposure to
insecticides (DDT, Lindane) & polychlorinated biphenyl (PCBs)
• Certain drugs:
– Barbiturates, phenytoin, carbamazepine, rifampicin&
dexamethasone
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Consequence of increasing drug metabolism
1. Decrease plasma drug concentrations

2. Decrease drug activity if the metabolite is inactive
3. Increase drug activity if the metabolite is active
4. Decrease therapeutic drug effect
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The effect of smoking on theophyline metabolism
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5) Inhibitors:
• Inhibition of CYP isoenzyme activity is an important source
of drug interactions
• Forms of inhibition:
– Through competition for the same isozyme.
– Inhibiting reactions for which they are not substrates
(e.g., ketoconazole)
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Important CYP inhibitors are:
• Drugs: Erythromycin, Ketoconazole, Ritonavir, Cimetidine
• Natural substances may also inhibit drug metabolism.

– grapefruit and its juice inhibits CYP3A4
• Examples on drugs that are substrate s for this enzyme
are:
– Nifedipine (CCBs)
– Clarithromycin (Macrolide antibiotic)
– Simvastatin (Lipid lowering agent)
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Example:
Warfarin biotransformation may be inhibited by omeprazole
• Omeprazole is a potent inhibitor of three of the CYP isozymes

responsible for warfarin metabolism
• If the two drugs are taken together, plasma concentrations of

warfarin increase, which leads to greater inhibition of
coagulation and risk of hemorrhage and other serious bleeding
reactions.
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Bioavailability of felodipine after an oral after dose in patients
receiving anticonvulsants (carbamazepine), and in healthy
volunteers taken with a glass of water (controls) or grapefruit juice
Inhibition
Induction
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Inhibition/induction of warfarin metabolism,
examples …
• The effect of co-administration

of the inhibitor cimetidine (A),
on steady-state plasma
warfarin concentration and its
anti-coagulant effect
• The inducer phenobarbitone

(B) on steady-state plasma
warfarin concentration and its
anti-coagulant effect
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b. Phase I reactions not involving the P450
system:
• These include:
– amine oxidation
• e.g., oxidation of catecholamines or histamine
– alcohol dehydrogenation
• e.g. ethanol oxidation
– esterases
• e.g., metabolism of pravastatin in liver
– hydrolysis
• e.g., of procaine
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2. Phase II (conjugation of endogenous molecule with drug)
1. If the metabolite from Phase I metabolism is sufficiently polar, it can be
excreted by the kidneys.
2. many Phase I metabolites are too lipophilic
conjugation with an endogenous substrate

glucuronic acid, sulfuric acid, acetic acid and an amino acid
polar, more water-soluble compounds

most often therapeutically inactive.
A notable exception is morphine-6-glucuronide , which is

more potent than morphine.
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Glucuronidation:
• Most common phase 2 reaction

• Most important conjugation reaction.
• Neonates are deficient in this conjugating
system
• Chloramphenicol
is inactivated by the addition of glucuronic
acid, resulting in gray baby syndrome.
• Billirubin
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• Drugs already possessing an –OH, –NH2, or –COOH group may
enter Phase II directly and become conjugated without prior
Phase I metabolism.
• The highly polar drug conjugates may then be excreted by the

kidney or in bile.
3. Reversal of order of the phases:

• Not all drugs undergo Phase I and II reactions in that order.
• For example, isoniazid is first acetylated (a Phase II reaction)

and then hydrolyzed to isonicotinic acid (a Phase I reaction).
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Site of Biotransformation
Tissue: Cellular
Liver Endoplasmic reticulum
Kidneys Cytosol
GI tract Mitochondria
Lungs Nuclear Envelope
Skin Plasma membrane
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Outcomes of metabolism:
1. Abolishes activity and terminates drug action
2. Can promote activity -prodrug–eg, acetylsalicylate
3. No change in activity –eg, diazepam ---> nordiazepam
4. Produce toxic metabolites – eg, paracetamol
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IV. DRUG CLEARANCE BY THE
KIDNEY
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Routes of excretion
• Main routes of excretion
1. Renal excretion
2. Biliary excretion
• Others routes of excretion
1. Exhaled air
2. Salivary
3. Sweat
4. Milk
5. Tears
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Renal excretion
70
Renal excretion
• The main organ for drug
excretion is the kidney
• The functional unit of the
kidney is the nephron
• There are three major
processes:
1. Glomerular filtration
2. Proximal tubular secretion
3. Distal tubular reabsorption
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Nephron structure
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Physiology of nephron
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A. Renal elimination of a drug
• Elimination of drugs via the kidneys into urine involves the three
processes:
1. Glomerular filtration:
• The normal glomerular filtration rate is125 mL/min
• Passage of drugs into the glomerular filtrate influenced by:
– Glomerular filtration rate
– Protein binding of the drugs
– No effect of lipophilicity and pH
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2. Proximal tubular secretion:
• Secretion in the proximal tubules occurs through
active transport:
– One for anions (e.g., deprotonated weak acids, A-)
– One for cations (e.g., protonated weak bases, BH+)
• They show low specificity
• Can transport many compounds
• Competition between drugs for these carriers can
occur within each transport system.
• Example: Penicillins and probenecid
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Note:
• Premature infants and neonates have an
incompletely developed tubular secretory
mechanism
• May retain certain drugs in the glomerular filtrate
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3. Distal tubular reabsorption:
• Passive reabsorption of lipid soluble and uncharged drugs
• Urine pH affect reabsorption of drugs
– Increasing the ionized form of the drug decrease its back-
diffusion and increase the clearance of an undesirable drug.
• Manipulating the pH of the urine “ion trapping.”

– Acidification of the urine increases elimination of weak bases
– Alkalinization of the urine increases elimination of weak acids
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Example:
a) An overdose of phenobarbital or acetylsalicylic acid(weak
acids) can be treated with bicarbonate , which alkalinizes
the urine and enhances the excretion of the ionized drug
b) An overdose of amphetamine (weak base) can be treated

with NH4Cl which acidifies the urine and increase the
protonated form of drug (BH+) and enhance its renal
excretion
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Role of drug metabolism:
• To minimize this reabsorption, drugs are modified primarily in

the liver into more polar substances using two types of
reactions:
– Phase I reactions which involve either:
• the addition of hydroxyl groups or
• the removal of blocking groups from hydroxyl, carboxyl, or
amino groups
– Phase II reactions that use conjugation with
• sulfate, glycine, or glucuronic acid to increase drug polarity.
• The polar, and the charged molecules cannot back-diffuse
out of the kidney lumen
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CLEARANCE BY OTHER ROUTES
• Other important routes of drug clearance

• Intestines
• Bile
• Lungs
• milk in nursing mothers
• The feces are primarily involved in elimination of:
– Unabsorbed orally ingested drugs
– Drugs that are secreted directly into the intestines or in bile.
• The lungs are primarily involved in the elimination of:
– anesthetic gases (for example, halothane and isofurane).
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• Elimination of drugs in breast milk:
– Considered as a potential source of undesirable side
effects to the infant.
• Excretion of most drugs into sweat, saliva,

tears, hair, and skin occurs only to a small
extent
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Total body clearance
• The total body clearance (CLtotal): is the sum of the
clearances from the various drug-metabolizing and
drug-eliminating organs
• CLtotal=CLhepatic+CLrenal+CLpulmonary+Clother
• CLtotal and t1/2 are important measures of drug

clearance that are used to:
– Optimize drug therapy
– Minimize toxicity
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Renal Clearance
Rate of urinary excretion

Clrenal =
Plasma concentration
Rate of renal excretion = urine flow x drug concentration in urine
*Example: Rate of urinary excretion of creatinine = 1.3 mg/min

Serum concentration of creatinine = 0.01 mg/ml
CLCr= 1.3 mg/0.01 mg/ml = 130 ml/min

Factors altering renal drug clearance
Renal drug clearance is lower therefore you must

reduce the dose in:
1. Elderly and newborn
2. Women (-20%) than men
3. Kidney and heart disease
4. Patients taking drugs which block secretion
(aspirin, probenecid, cimetidine)
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Drugs excreted mainly by the kidney include:
• Aminoglycosides antibiotics (Gentamycin)
• Penicillin
• Lithium
These drugs are contraindicated in:

• Elderly people
• Renal disease
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Clinical situations resulting in changes in
drug half-life
• Dose Adjustment is required

– When a patient has an abnormality that alters the half-life of a
drug
• It is important to be able to predict in which patients a drug

is likely to have a change in half-life.
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The half-life of a drug is increased by :
1) Diminished renal or hepatic blood flow as:
cardiogenic shock, heart failure, or hemorrhage
2) Decreased ability to extract drug from plasma as
seen in renal disease
3) Decreased metabolism
• Another drug inhibits the biotransformation
• In hepatic insufficiency, as cirrhosis
Lower doses or less frequent dosing

interval may require 89
The half-life of a drug may decrease by:
1) Increased hepatic blood flow

2) Decreased protein binding
3) Increased metabolism
Higher doses or more frequent dosing

interval may require
90
Dosage Regimens
91
• A dosage regimen:
is defined as the manner in which a drug is
taken
• An optimal dosage regimen is to:

– Maximize benefit of the drug
– Minimize adverse effects
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• To initiate drug therapy a dosage regimen is administrated
either by continuous infusion or in intervals of time and
dose
• The regimen depends on various patients and drug factors,
including the rapidly a steady state must be achieved
– Steady state: the state at which the rate of administration equals
the rate of elimination
• The regimen is refined to achieve the optimal dosage
regimen
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❖Drug administration
o Single dose
o Continuous administration
• IV infusion
• Fixed-dose/fixed-time interval regimens
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Dosage regimens
➢ IV infusion or oral fixed-dose/fixed-time interval
regimens
➢ The drug accumulates until a steady state occurs
➢ At steady state the amount of drug administered equals

the amount being eliminated
➢ At steady state:
➢ The plasma and tissue levels remain constant with IV
infusion and fluctuate around a mean in oral fixed dosage
95
Plasma concentration of a drug following IV
infusion
• Following initiation of IV infusion, the
plasma concentration of a drug rises
until the rate of drug eliminated from
the body balances the input rate
steady state is achieved
• The plasma concentration of the drug

remains constant (1st order elimination)
96
Influence of the rate of drug infusion on the
steady state
• The steady state plasma
concentration (Css) is directly
proportional to the infusion rate
• The Css is inversely proportional to

the clearance of the drug
– Hepatic or renal diseases can
increase Css
– Increased metabolism decreases Css
Effect of infusion rate on the steady-state
concentration of drug in the plasma. (Ro = rate of
infusion of a drug.)
97
Time required to reach Css
98
Fixed-dose/fixed-time-interval regimens
• Administration of a drug by fixed doses is more

convenient than continuous infusion
• Fixed doses administered fixed-time intervals result in
fluctuations in drug levels
• Fixed dose regimens
– Multiple IV injections
– Multiple oral administrations
99
Multiple IV injections
• When a drug is given

repeatedly at regular intervals,
the plasma concentration
increases until a steady state is
reached
• The Using smaller doses at

shorter intervals dose not
change the at which the steady-
state is approached
100
Multiple oral administrations
• Orally administered drugs

may be absorbed slowly
• Plasma concentration of
the drug is influenced by
– Rate of absorption
– Rate of drug elimination
101
Optimization of dose
• The goal of drug therapy is to:

• Achieve an maintain concentration within therapeutic window
• Minimize toxicity and/or side effects
• Drugs of small therapeutic window (e.g., digoxin, warfarin):
• Caution should be taken in selecting dosage regimen
• Monitoring of drug levels may be needed
• Drug regimens are administered as:
• Maintenance dose with/without loading dose
102
Maintenance dose/loading dose
• To maintain the plasma concentration within a specified
range over long periods of therapy (Css) maintenance
doses is used.
• If it is necessary to achieve the target plasma level rapidly,
a loading dose is used
• Loading dose: is a higher single dose or a series of doses
given to achieve the desired plasma level rapidly
• Loading dose may be associated with risk of drug toxicity
103
• Ideally, the dosing plan is based on knowledge of:
– Minimum therapeutic level
– Minimum toxic concentrations for the drug
– Clearance
– Vd
• Loading dose= (Vd)x (desired Css)/F
• For IV:
Loading dose= (Vd)x (desired Css)
• Loading dose is usefull for drugs relatively having long t1/2
104
105
Therapeutic Window
• The therapeutic window is the safe range between the

minimum therapeutic concentration and the minimum toxic
concentration of a drug.
• The concept is used to determine the acceptable range of

plasma levels when designing a dosing regimen.
106
A
107
Therapeutic Window
108
Introduction to Pharmacology
Pharmacodynamics§
By: Dr. Maisa NABULSI
Monday, October 1, 2018

Drugs:
• Chemical agents that interact with components of a
biological system to alter the organism’s function.
• Examples of such components (sites of drug action) are:

• Enzymes
• Ion channels
• Neurotransmitter transport systems
• Nucleic acids
• Receptors
• Many drugs act by mimicking or inhibiting the

interactions of endogenous mediators with their
receptors
2
Receptors:
• Regulatory proteins that interact with drugs or
hormones and initiate a cellular response
• 4 types of receptors:
1. Ion channels (Ligand-gated Ion Channels)
2. G-protein coupled receptors
3. Receptor-enzymes
4. Cytosolic-nuclear receptors
• Act as transducer proteins

• Receptor-effector signal transduction
• Post-receptor signal transduction provides for
amplification of the signal
3
1. Ligand-gated Ion Channels
4
2. G-protein
coupled receptors
5
6
3. Enzyme-linked receptors:
7
4. Intracellular
receptors
8
Properties of drugs
• Affinity: the chemical forces that cause the drug

to associate with the receptor.
• Efficacy: the ability of a drug to elicit a response

when it interacts with a receptor.
9
Graded dose–response Relations
• Potency: the amount of drug necessary to

produce an effect of a given magnitude.
• Dependent upon receptor density, efficiency of the

stimulus-response mechanism, affinity and efficacy.
• Efficacy (Magnitude of effect): maximal

response
• Solely dependent upon intrinsic efficacy.
10
11
12
13
• A drug with greater efficacy is more
therapeutically beneficial than one that is more
potent.
• Maximal efficacy of a drug assumes that all

receptors are occupied by the drug, and no
increase in response will be observed if more
drugs are added.
• This concept holds true only if there are no "spare

receptors" present. 14
Concepts to remember!
• Threshold: Dose that produces a just-noticeable
effect.
• ED50: Dose that produces a 50% of maximum

response.
• EC50: refers to the concentration of a drug which

induces a response halfway between the
baseline and maximum after a specified
exposure time.
• Ceiling: Lowest dose that produces a maximal
effect.
15
Dose-response curve
100
Ceiling
80
60
ED50
Response
40
20
Threshold
0
0.1 1 10 100 1000 10000
Dose
16
Important parameters:
• Onset: The time it takes for the drug to elicit a

therapeutic response.
• Peak: The time it takes for a drug to reach its

maximum therapeutic response.
• Duration: The time a drug concentration is

sufficient to elicit a therapeutic response
17
Spare receptors
• only a fraction of the total receptors for a specific ligand may
need to be occupied to elicit a maximal response from a cell.
• Systems that exhibit this behavior are said to have spare
receptors.
• Spare receptors are exhibited by:
• insulin receptors: 99 percent of the receptors are “spare.”
• β-adrenoceptors in the heart: 5 to 10 percent of the total β-
adrenoceptors are spare.
18
Desensitization and down-regulation of receptors:
• Repeated or continuous administration of an

agonist (or an antagonist) may lead to changes
in the responsiveness of the receptor.
• When repeated administration of a drug results
in a diminished effect, the phenomenon is called
tachyphylaxis.
• The receptor becomes desensitized to the action
of the drug.
• In this phenomenon, the receptors are still
present on the cell surface but are unresponsive
to the ligand.
19
• Receptors can also be down-regulated in the
presence of continual stimulation.
• Binding of the agonist results in molecular changes
in the membrane-bound receptors, such that the
receptor undergoes endocytosis and is sequestered
within the cell, unavailable for further agonist
interaction.
20
Classification of a drug based on
drug-receptor interactions
1. Agonist: If a drug binds to a receptor and
produces a maximal biologic response that mimics
the response to the endogenous ligand, it is known
as a full agonist.
e.g. phenylephrine is an agonist at α1-
adrenoceptors, because it produces effects that
resemble the action of the endogenous ligand,
norepinephrine.
• In general, a full agonist has a strong affinity for its

receptor and good efficacy
21
cont.
2. Partial agonists:
• Drug that, no matter how high the dose, cannot produce
a full response.
• Partial agonists have efficacies (intrinsic activities) greater
than zero but less than that of a full agonist.
• Affinity of a partial agonist may be greater than, less than,
or equivalent to that of a full agonist.
• Under appropriate conditions, a partial agonist may act as
an antagonist of a full agonist. (i.e. Partial agonists have
both agonist and antagonist properties)
• Example, aripiprazole, an atypical neuroleptic agent, is a 22

partial agonist at selected dopamine receptors.
23
24
3. Inverse agonist:
• Drug that binds to a receptor to produce an
effect opposite that of an agonist.
• Stabilizes receptors in the inactive state.
25
26
4. Antagonists
• Antagonist: drug that binds to receptors but cannot initiate
a cellular response, but prevent agonists from producing a
response; affinity, but no efficacy. Antagonists maintain the
active-inactive equilibrium. Antagonists mgit be competitive
or non-competitive;
1. Competitive Antagonists: Antagonist binds to same
site as agonist in a reversible manner.
2. Noncompetitive Antagonists: Antagonist binds to the
same site as agonist irreversibly.
• Physiologic Antagonists: Two drugs have opposite effects
through differing mechanisms
• Allosteric: Antagonist and agonist bind to different site on
same receptor
27
28
29
30
Allosteric Antagonism
31
32
33
34
35
Chemical Antagonism
• Simple chemical reaction.

• No receptor.
• Examples:
• Heparin & proteamine sulfate

• Iron & Deferoxamine.
36
Physiological Antagonism
• Physiological effect is antagonized.

• Drugs acting on different receptors:
• Examples:
üNorepinephrine → Vasoconstriction → ↑ BP.
üHistamine → Relax vascular smooth muscle→
↓BP
37
Desired vs undesired effects: therapeutic Index ,
index of drug safety… tolerability profile
• ED50 - Median Effective Dose 50 ; the dose at

which 50% of the population or sample
manifests a given effect.
• TD50 - Median Toxic Dose 50 - dose at which 50%

of the population manifests a given toxic effect
• LD50 - Median Toxic Dose 50 - dose which kills

50% of the subjects
Therapeutic Index = TD50 or LD50/ ED50
38
39
Unusual Responses:
Definitions:
1. Idiosyncratic response: unusual response

2. Hyporeactive: less than normal response
3. Hyperreactive: more than normal response
4. Hypersensitivity: allergic or other immunological
reaction.
5. Tolerance: decreased response with continued
administration
6. Tachyphylaxis: rapidly developing tolerance
40
Introduction to Autonomic
Nervous System
Wednesday, October 21, 2020

NS: CNS + PNS
PNS:Types of receptors
Ionotropic vs Metabotropic
• Miosis
• mydriasis
Cholinergic agonists

Cholinergic Synapse and Neurotransmission
• Myasthenia Gravis:
• Epilepsy
Cholinergic receptors
❖ Gq: Stimulatory: increase Ca

intake and so contraction,
secretion and neurotransmission
M1: Gastric glands ❖ Gi: Inhibitory: Hyperpolarization

M2: Cardiac cells
Reduction in heart rate
M3: numerous places
in SM of eye, bladder,
lungs and digestive
tract and exocrine
• Neuromuscular
junction: muscle CNS and autonomic
contraction ganglia: mainly in
transmission of
cholinergic signals
Cholinergic agonists
1. Direct acting
2. Indirect acting reversible
3. Indirect acting irreversible
1. Direct acting
1. Acetylcholine:
• non specific effects
• Rapidly degraded by cholinesterases
Clinical use is limited
IV:
Miosis in ophthalmic surgeries

1. Direct acting
2. Carbachol
• Structurally similar and mimics effects of Ach
• Limited therapeutic use
• BUT; not very sensitive to esterases (Duration of
action ????)
• Uses:
Intraocular pressure
1.Direct acting
3. Pilocarpine
Decrease Intraocular pressure

1. Direct acting
4. Bethanechol
• Selectively stimulates
urinary and GIT.
• Given orally or SC.
• Uses:
✔ urinary retention
✔ GIT lack of muscular
tone
2. Indirect acting agonists:
1. Edrophonium
• Short duration of action (10-20 min.)
• Use:
Neuromuscular disease
Result: rapid increase in muscular strentgh

2. Physostigmine:
• Stimulates both nicotinic and muscarinic
receptors.
• Increases intestinal and bladder motility ( organ
atony).
• Duration of action: 30 min. – 2 hrs
• Uses: to treat overdose of anticholinergics
Atropine
3. Neostigmine
• Intermediate acting agent
• Structure is more polar than Physostigmine; So…
• Not absorbed well in GIT and do not cross BBB
Reverse the effect of anesthesia from neuromuscular

blocking agents
4. Pyridostigmine: chronic management of myasthenia gravis.

• duration of action is intermediate (3 to 6 hours
Miscellaneous agents…..
Alzheimer’s disease
• Reduction in the activity of cholinergic neurons is a feature of

disease.
• Aim: improve cognitive functions
• BUT, nothing can stop the progression of the disease
3. Irreversible agents
• Most are extremely toxic
• Developed by military as nerve agents
Ecothiophate: only agent still encountered in medical practice

• Forms covalent bonds with Achase:::: strong cholinergic stimulatin
• Therapeutic use: LIMITED to open angle glaucoma
• RARELY used , side effect profile.

Cholinergic side effects
• Diarrhea
• Urination
• Miosis/Muscle weakness DUMBBELS
• Bronchorea and
Bronchospasm
• Bradycardia
• Emesis
• Lacrimation
• salivation/sweating
Anticholinergis

Anticholinergics
1. Antimuscarinic agents
2. Ganglionic blockers
3. Neuromuscular blockers
1. Antimuscarinic agents: Atropine
Longer duration
mydriasis
Cycloplegia
Unrespon
sive to
light DECREASE INCREASE Heart Dryness increases
Transient time beat by 30-40 body temperature
1. Antimuscarinic agents: Scopolamine
• More effect on CNS

• Longer duration of
action
• Very effective in
motion sickness and
post operative N&V.
Effects may last up to

• CTZ: Chemoreceptor three days
trigger zone
Ipratropium and Tiotropium
Ipratropium
Nasal spray for rhinorrhea
• Specific for certain M receptor subtypes

• Decrease contractility of SM in lungs = Bronchodilation and decrease
mucus secretion.
• Administered as INHALATIONS for maintenance tx in ptns with COPD
Others…
• Specificity for M3 receptors in the bladder.
• Overall efficacy is very similar.
• Uses: over reactive bladder

Suppress central cholinergic activity
Beneficial in Tx of Parkinson like disorders
TREMORS
Nervous excitation and anxiety
2. Ganglionic blockers
• Main component of cigarette smoke.
• It is a cholinergic agonist but also

considered as a functional antagonist,,,,
WHY????
• B/c: It has the ability to stimulate and

then block cholinergic function.
❑ Non-selective.
❑ It acts on nicotinic receptors in both
sympathetic and parasympathetic
system.
Nicotine
❑ Stimulates and then depresses autonomic
ganglia.
??????? Is it efficient to help

people quit smoking
3. Neuromuscular blockers
• Simply block neurotransmission between motor
nerve endings and nicotinic receptors on the
skeletal muscle.
Neuromuscular blockers
Non Depolarizing Depolarizing

Inhibit muscle contraction
• In clinical practice, these agents are used :

✔ to facilitate mechanical ventilation
✔ In muscle relaxation during surgery which leads to lower doses of anesthetics.
• Generally, these agents are • Paralysis of small fast contracting
NOT absorbed from GIT. muscles: Eyes, face , fingers, neck, trunk,
• SO, need to be injected limbs and lastly Diaphragm
usually IV. • Recovery : in the opposite
• Very rapid onset of action
( usually 2 min.)
• The choice of agent depends on:
✔ Desired Onset of muscle relaxation
✔ Desired Duration of muscle relaxation
Excreted unchanged in the urine.
Replaced by its • Metabolized by liver
somer • Prolonged action in liver
problems
• Generally safe with
minimal side effects
Causes histamine release
2. Depolarizing agents
• ACh receptor agonists but with

persistent depolarization.
In Clinical use only
Prolonged depolarization leading to transient

Phase I fasiculations and finally paralysis
Phase II
Eventually, Na channels closes and membrane repolarizes.

But, continuous stimulation leads to desensitization of
receptors and prevention of further action potential.
• Complete
muscle
relaxation
within 1
min.
Parkinson’s and Alzheimer’s
Diseases
Wednesday, April 17, 2024

• Cells in certain parts in the brain ( basal ganglia)
became damaged.
• We do not know why??
• Only up to 15% of cases is genetic, the rest is
idiopathic
Pakinson’s: Etiology
Drugs in Parkinson’s Dse
increase Dopamine signaling

Tx: 1. Levodopa & Carbidopa
N,V, and
hypotension
1. about 20% is adequate ( levodopa to dopamine).
2. therapeutic response to levodopa is consis tent, and the patient
rarely complains that the drug effects “wear off
3. With time, no. neurons decreases, and fewer cells are capable of
converting exogenously administered levodopa to dopamine.
Consequently, motor control fluctuation develops.
Unfortunately, with time, Relief provided by levodopa is only

symptomatic, and it lasts only while the drug is present in the body.
++ carbidopa lowers the dose of levodopa needed by four- to fivefold

decreases the severity of the side effects
✔ severity of symptoms for the first few years of

treatment.
✔ decline in response after 3-4 yrs .
✔ Withdrawal from the drug must be gradual.
PK: Levodopa
1. Absorption: rapidly from the small intestine (when

empty of food).
✔ short half-life (1 to 2 hours), which causes

fluctuations in plasma concentration.
✔ Ingestion of meals, particularly if high in protein,

interferes with the transport of levodopa into the CNS.
• Thus, levodopa should be taken on an empty stomach,

typically 30 minutes before a meal.
Adverse effects
Peripheral
effects
CNS effects
1.Visual and auditory hallucinations and

abnormal involuntary movements
(dyskinesias) may occur.
2.Mood changes, depression & anxiety.
Interactions:
1. pyridoxine (B6) = diminishes
effectiveness .
2. Concomitant administration of
levodopa and non-selective MAOIs can
produce a hypertensive crisis caused by
enhanced catecholamine production.
3. Cardiac patients should be carefully

monitored for the possible development
of arrhythmias.
.
Tx: 2 Amantadine
✔ less efficacious than levodopa, and tolerance develops more readily.

However, amantadine has fewer side effects.
Tx: 3. Dopamine agonists
✔ Dopamine agonists may delay the need to use
levodopa in early Parkinson’s disease and may
decrease the dose of levodopa in advanced
Parkinson’s disease.
✔ Hallucinations, insomnia, dizziness, constipation, and

orthostatic hypotension are among the more
distressing side effects of these drugs
Dopamine agonists: Adverse effects
Drugs in Parkinson’s Dse
Inhibit Dopamine degradation

Tx: 2. Selegiline
• Selective MAOI type B inhibit monoamine
oxidase (MAO) type B.
• NO MAOI type A (metabolizes

norepinephrine and serotonin) unless given
above recommended doses, where it loses
its selectivity.
• When selegiline is administered with

levodopa, it enhances the actions of
levodopa and substantially reduces the
required dose.
• Metabolites: methamphetamine &
amphetamine (CNS stimulants === produce
insomnia if the drug is administered later
than midafternoon.
Tx: 3. COMT inhibitors
Pharmacokinetics:
✔ Oral absorption occurs readily & not influenced by food.
✔ They are extensively bound to plasma albumin, with a limited volume of
distribution.
✔ Tolcapone has a relatively long duration of action (probably due to its
affinity for the enzyme) compared to entacapone, which requires more
frequent dosing.
✔ Both drugs are extensively metabolized and eliminated in feces and urine.
✔ Dose adjustments?/??.
✔ S/E: fulminating hepatic necrosis is associated with tolcapone use.
✔ Entacapone does not exhibit this toxicity and has largely replaced tolcapone
Miscellaneous……
Quick Recap….
Alzheimer’s Disease:
• Fragment is Not
soluble and creates
a monomer called
amyloid beta.
• Sticky and form
plaques either
between neurons
and may start
immune resposnse.
Areas of brain affected ……
Hippocampus is a cognitive map!!!!!!!!!!!
Learning and storing information referring to portions of
space, in the form of cognitive maps.
Alzheimer’s Disease: Symptoms
Is their a treatment??????
Numerous studies have linked
the progressive loss of
cholinergic neurons and,
presumably, cholinergic
transmission within the cortex
to the memory loss that is a
hallmark symptom of
Alzheimer’s disease.
❖ AChE inhibitors within the CNS

will improve cholinergic
transmission, at least at those
neurons that are still
functioning.
Aim of Treatment:
Provide a modest reduction in the Rate of

Loss of cognitive Functioning
Available Drugs:
✔ Reversible AChE inhibitors approved for the treatment
of mild to moderate Alzheimer’s disease include:
1. Donepezil
2. Galantamine
3. Rivastigmine
✔ All of them have some selectivity for AChE in the CNS,

as compared to the periphery.
✔ Galantamine may also augment the action of
acetylcholine at nicotinic receptors in the CNS.
Possible Side Effects
NMDA receptor antagonist
• Memantine is an NMDA receptor antagonist indicated for
moderate to severe Alzheimer’s disease.
• It acts by blocking the NMDA receptor and limiting Ca2+

influx into the neuron, such that toxic intracellular levels
are not achieved.
• Memantine is well tolerated, with few dose-dependent

adverse events.
• Expected side effects, such as confusion, agitation, and

restlessness.
• Is often given in combination with an AChE inhibitor.
Antidepressant Drugs
ffects of wearing a daily disposable lens on
tear film: a randomised controlled trial
Diagnosis
DSM5 Criteria :
Diagnostic and
Statistical manual 5)
Questions to help diagnosis
Questions to help diagnosis
Two more questions to be asked……
4=5 symptoms
Have these symptoms persisted at least two weeks?

Wait …….
• 2-3 symptoms means you have mild depression.

• No need for drugs
• Psychotherapy and life style changes may help.
Antidepressant Drugs
Classes of Antidepressants
SSRIs
S/E of abrupt
discontinuations:
Headache
N,V
Agitation and sleep
disturbances
And Erectile
dysfunction
SSRIs: Actions • SSRIs block the reuptake of
serotonin, leading to
increased concentrations of
the neurotransmitter in the
synaptic cleft.
• Typically take at least 2
weeks to produce
significant improvement in
mood, and maximum benefit
may require up to 12 weeks
or more.
• Patients who do not respond
to one antidepressant may
respond to another, and
approximately 80% or more
will respond to at least one
antidepressant drug
SSRIs: Therapeutic uses
1. Depression
2. Other psychiatric disorders including:

✔ Obssessive compulsive disorder (OCD)
✔ panic disorder,
✔ generalized anxiety disorder,
✔ posttraumatic stress disorder, social anxiety
disorder, premenstrual dysphoric disorder
✔ Bulimia nervosa (only fluoxetine is approved for
bulimia).
SSRIs: Pharmacokinetics
✔ All of the SSRIs are well absorbed after oral administration.
✔ Peak levels are seen in approximately 2 to 8 hours on average.
✔ Food has little effect on absorption (except with sertraline, for which
food increases its absorption).
✔ The majority of SSRIs have plasma half-lives that range between 16
and 36 hours.
✔ Metabolism by cytochrome P450 (CYP450)–dependent enzymes and
glucuronide or sulfate conjugation occur extensively.
✔ Fluoxetine differs from the other members of the class by having a

much longer half-life (50 hours), and the half- life of its active
metabolite S-norfluoxetine is quite long, averaging 10 days. It is
available as a sustained-release preparation allowing
once-weekly dosing. Fluoxetine and paroxetine are potent inhibitors
of a CYP450 isoenzyme (CYP2D6)
✔ Dose adjustments in patients with hepatic impairment.

SSRIs: S/E
SSRIs: Special concerns
1.Use in children and teenagers:
✔ Antidepressants should be used cautiously in children

and teenagers.
✔ Pediatric patients should be observed for worsening

depression and suicidal thinking with initiation or dosage
change of any antidepressant.
✔ Fluoxetine, sertraline, and fluvoxamine are approved

for use in children to treat obsessive–compulsive
disorder, and fluoxetine and escitalopram are approved
to treat childhood depression.
SSRIs: Overdose
1.Seizures: lowering of the seizure Threshold.
2.Serotonin syndrome:
✔ Hyperthermia,
✔ muscle rigidity,
✔ sweating,
✔ myoclonus (clonic muscle twitching)
✔ changes in mental status and vital signs.
3. Discontinuation Syndrome
✔ Headache
✔ malaise,
✔ flu-like symptoms,
✔ agitation and irritability, nervousness, and changes
in sleep pattern.
S/E:
• Very similar
to SSRis
• BP and HR
• Additional uses: Reduce pain

associated with Fibromyalgia and
neuropathic pain
SNRIs: Uses
1. Unresponsive depression to SSRIs.
2. Painful symptoms associated with Depression(

back ache and muscle aches).
3. Diabetic peripheral neuropathy.

Tricyclic antidepressants (TCA)
TCAs: MOA
1. Inhibition of neurotransmitter reuptake:
✔ Maprotiline and desipramine are relatively selective
inhibitors of norepinephrine reuptake.
2. Blocking of receptors:
✔ TCAs also block serotonergic,α-adrenergic, histaminic, and
muscarinic receptors.
✔ responsible for many of their adverse effects.
TCAs: Actions
1. elevate mood
2. improve mental alertness
3. increase physical activity
✔ The onset of the mood elevation is slow,

requiring 2 weeks or longer.
✔ Patient response can be used to adjust dosage.
✔ Physical and psychological dependence have
been rarely reported.
✔ Slow withdrawal to minimize discontinuation
syndromes and cholinergic rebound effects.
TCAs: Uses
• Moderate to severe depression.
• panic disorder.
• Imipramine used to control bed-wetting in
children older than 6 years of age…. BUT. now
largely been replaced by desmopressin and
nonpharmacologic treatments (enuresis alarms).
• TCAs, particularly amitriptyline, have been used
to help prevent migraine headache and treat
chronic pain syndromes (neuropathic pain) in a
number of conditions for which the cause of pain
is unclear.
• Low doses, especially doxepin can be used to
treat insomnia.
TCAs: PK
• Absorption: well absorbed upon oral
administration.
• Distribution: lipophilic, widely distributed and
readily penetrate into the CNS.
• Variable first-pass metabolism in the liver, TCAs
have low and inconsistent F.
• Metabolism: CYP450 isoenzymes involvement
???? and conjugated with glucuronic acid.
• Excretion: excreted as inactive metabolites via
the kidney.
TCAs: Side effects
MAO inhibitors:
MAOIs: Special Considerations
✔ Selegiline is also used for the treatment of Parkinson’s

disease. only antidepressant available in a transdermal
delivery system.
✔ LIMITED USE: due to the complicated dietary restrictions

required while taking these agents.
MAOIs: MOA
• Irreversible inactivation of enzyme.
• Inhibit MAO in the brain. Liver and Gut.
• MAOIs show a high incidence of drug–drug and
drug–food interactions.
• Selegiline as transdermal patch= produce less
inhibition of gut and hepatic MAO because it
avoids first-pass metabolism.
MAO: Uses
• Patients unresponsive or allergic to TCAs and
SSRIs.
• High risk for drug– drug and drug–food
interactions = last-line agents in many treatment
settings.
MAOIs: PK
• Absorption: well absorbed after oral administration.
• Enzyme regeneration varies, but it usually occurs several
weeks after termination of the drug.
switching antidepressant agents, a minimum of 2 weeks of

delay must be allowed after termination of MAOI therapy and the
initiation of another antidepressant from any other class.
• MAOIs are hepatically metabolized and excreted rapidly

in urine.
MAOIs: S/E
1. Severe, unpredictable side effects often due to
drug–food and drug–drug interactions.
2. Tyramine in foods is normally inactivated by
MAO in the gut.
• Individuals receiving a MAOI are unable to
degrade tyramine obtained from the diet.
• Tyramine causes the release of large amounts of
stored catecholamines from nerve terminals.
• resulting in a hypertensive crisis, with signs and
symptoms such as occipital headache, stiff neck,
tachycardia, nausea, hypertension, cardiac
arrhythmias, seizures
Atypical Atidepressants
Bupropion:
• Bupropion is a weak dopamine and norepinephrine reuptake
inhibitor.
• Is used to alleviate the symptoms of depression.
• Bupropion is also useful for decreasing cravings and attenuating
withdrawal symptoms of nicotine in patients trying to quit
smoking.
• Side effects may include dry mouth, sweating, nervousness,
tremor, and a dose- dependent increased risk for seizures.
• It has a very low incidence of sexual dysfunction.
• Bupropion is metabolized by the CYP2B6 pathway and has a
relatively low risk for drug–drug interactions, given the few
agents that inhibit/induce this enzyme.
• Limitations: at risk of seizures or those who have eating disorders
such as bulimia.
Bipolar Disorder: Lithium
Bipolar disorder: Lithium
✔ Lithium is effective in treating 60% to 80% of patients
exhibiting mania and hypomania.
✔ lithium salts can be toxic.
✔ Common adverse effects may include headache, dry mouth,

polydipsia, polyuria, polyphagia, GI distress (give lithium with
food), fine hand tremor, dizziness, fatigue, dermatologic
reactions, and sedation.
✔ Toxic effects: ataxia, slurred speech, coarse tremors,

confusion, and convulsions.
✔ Thyroid function may be decreased and should be monitored.
Antipsychotics and CNS
stimulants
Wednesday, April 17, 2024

• Schizophrenia
• Mania
• severe
depression
Dopamine pathways involved in Schizophrenia
• Unusual behaviors are
related to changes in
Dopamine functions in Dystonia
the brain. parkinsonism
Motor
• Low function and
motivation Hyperkinetic movement
and social movements
(ticks)
withdrawal
Delusions and
Dopamine: hallucinations
1.Prolactin secretion
2.Sexual desire
3. Regulation of immune system
Block D2
receptors in all the
brain ???????
CNS stimulants
Therapeutic uses
1.
Methylphenidate
Hallucinogens
LSD
Drugs of Abuse
• 1.2.5.6.8.10.11
Adrenergic receptors
Thursday, October 11, 2018
https://eclass.alquds.edu/pluginfile.php/1596199/mod_resource/content/1/Adrenergic%20receptors%20%5BAutosaved%5D%281%29.pptx 12/03/2024, 9 38 AM
Page 1 of 18
:
NS: CNS + PNS
Page 2 of 18
:
Page 3 of 18
:
Efferent Pathways of PNS Parasympathetic
AUTONOMIC PATHWAYS
Sympathetic Adrenal sympathetic
pathway pathways pathway
CNS CNS CNS
AC
Nicotinic h Adrenal
receptor cortex
Adrenal
Ganglia
medulla
AC
Nicotinic
h
Ganglion receptor
N
AC receptor E
h
Muscarini Autonomic Blood
c • Smooth
effectors:
and cardiac muscles 1 vessel
receptor • Some endocrine and receptor
exocrine E
glands
• Some adipose tissue 2
KEY
receptor
ACh= acetylcholine
E= epinephrine
NE=
norepinephrine
Figure 11-11 (2 of 5)
Page 4 of 18
:
Page 5 of 18
:
Page 6 of 18
:
Page 7 of 18
:
Page 8 of 18
:
Page 9 of 18
:
• Vascular SM
• Arteries of SKM
Page 10 of 18
:
Page 11 of 18
:
alpha1
• Mainly activates alpha • At normal doses activated
B1 dopamine receptors.
1 receptors at
B2 therapeutic doses. As doses increases, …..
• Almost no B2 activity
Activates all adrenergic • Uses: cardiac arrest and• Acute severe heart failure
hypotensive shock and hypotensive shock
receptors.
Uses: Anaphylactic shock,
respiratory conditions.
Page 12 of 18
:
Relieve acute
symptoms
• Detrusor muscle
• Relieve
Prevent symptoms of
asthma overreactive
attacks bladder
Page 13 of 18
:
• In the region of the brain that control reward system
• Highly addictive
• Also alpha 1 and B1 activation: sympathetic response =. B.P and Heart rate
Page 14 of 18
:
• Rarely used in clinical
practice due to side
effects and availability
• Decongestant
of better drugs
Page 15 of 18
:
Page 16 of 18
:
Alpha- Blockers
Page 17 of 18
:
• Effects HR, AV conduction
and contractility
• Uses: :HTN, Angina,
arrythmia
Page 18 of 18
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Pharmacokinetics

• The rate and extent of absorption depend on:

➢ Extent: How much of the administered dose enters the

• Bioavailability is the fraction of administered drug that

2- Solubility of the drug:

4. Nature of the drug formulation

1. Decomposition in acidic gastric juices

Therapeutic Equivalents: Drug products are

• The delivery of a drug from the plasma to the

A. Cardiac output and regional blood flow

• The volume of distribution (Vd), = apparent volume of

• Vd is a property of the drug and is determined by the drug’s

• The volume into which drugs distribute is called the

• If Vd is big the drug is more diluted than it should be

• Vd is useful to compare the distribution of a drug with the

– distribute into any one of

• Vd has an important influence on the half-life of a drug

• Any factor that increases Vd can lead to:

• Delivery of drug to the organs of elimination depends on:

• Three major routes of elimination:

• A constant fraction of the drug

• Clearance (CL) estimates the amount of drug cleared from

• Elimination could be through

Drug half-life is often used as a measurement of drug CL, as , Vd is a

• Phase I reactions convert lipophilic molecules into more

• Pharmacologic activity after phase I metabolism may:

1. Decrease plasma drug concentrations

• Drugs: Erythromycin, Ketoconazole, Ritonavir, Cimetidine

• Natural substances may also inhibit drug metabolism.

Warfarin biotransformation may be inhibited by omeprazole

• Omeprazole is a potent inhibitor of three of the CYP isozymes

• If the two drugs are taken together, plasma concentrations of

• The effect of co-administration

• The inducer phenobarbitone

conjugation with an endogenous substrate

polar, more water-soluble compounds

A notable exception is morphine-6-glucuronide , which is

• Most common phase 2 reaction

• The highly polar drug conjugates may then be excreted by the

3. Reversal of order of the phases:

• For example, isoniazid is first acetylated (a Phase II reaction)

• Manipulating the pH of the urine “ion trapping.”

b) An overdose of amphetamine (weak base) can be treated

• To minimize this reabsorption, drugs are modified primarily in

• Other important routes of drug clearance

• Excretion of most drugs into sweat, saliva,

• CLtotal and t1/2 are important measures of drug

Rate of urinary excretion

*Example: Rate of urinary excretion of creatinine = 1.3 mg/min

CLCr= 1.3 mg/0.01 mg/ml = 130 ml/min

Renal drug clearance is lower therefore you must

These drugs are contraindicated in:

• Dose Adjustment is required

• It is important to be able to predict in which patients a drug

Lower doses or less frequent dosing

1) Increased hepatic blood flow

Higher doses or more frequent dosing

• An optimal dosage regimen is to:

➢ The drug accumulates until a steady state occurs