General Pharmacology IV

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• Acidic drug in acidic medium

• Acidic drug in basic medium

• Basic drug in acidic medium

• Basic drug in basic medium

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 First-Pass Biotransformation
(Presystemic elimination)
• Drugs that are absorbed from gut reach the liver via portal vein
Antianginal agent, glyceryl nitrates, are extensively converted to
inactive metabolites during their first pass through gut wall and liver,
and have low bioavailability after oral administration

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• First-pass effect lowers their degree of bioavailability.

• Some drugs are extensively metabolized in intestine than liver,

eg, clonazepam, chlorpromazine, cyclosporin, midazolam

• sublingual or rectal route less first-pass metabolism and have a

higher degree of bioavailability than oral route

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 Eg of First-Pass Biotransformation

1. Analgesics: morphine, paracetamol,

2. CVS drugs: propranolol, verapamil

3. CNS drugs: chlorpromazine, imipramine, levodopa

4. Respiratory drugs: salbutamol, terbutaline.

5. Oral contraceptives

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 Bioavailability
fraction of unchanged drug reaching the systemic circulation
following administration by any route
The area under the blood concentration-time curve (AUC) is a
measure of bioavailability for drug given by particular route
IV dose of the drug -- bioavailability = 100% (F=1)

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• administered orally-- bioavailability may be less than 100% for
two main reasons—incomplete extent of absorption and first-pass
elimination

• Incomplete bioavailability after s.c. or i.m. injection is less

common, but may occur due to local binding of the drug

• The greater bioavailability of a drug produces a greater effect

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Factors influencing bioavailability
Pharmaceutical factors:
 formulations (different dosage form), eg, enteric coated tablet,
sustained release form, capsule, powder, etc
particle size (microfine tablets), eg, increases the rate of absorption
of aspirin, however, no need to reduce the particle size of freely
water soluble drugs, e.g. paracetamol
disintegration (break into individual particles of the active drug),
dissolution (dissolving)
used materials: diluents, stabilizing agents, binders, lubricants, etc;
the manufacture process, e.g. force used in compressing the tablet
chemically equivalent and bioequivalent (rate and extent of
bioavailability): may varied by different manufacturer or different
batch of same manufacturer

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Biologic factors:
the effects of food, which can sequester or inactivate a drug;
the effects of gastric acid, which can inactivate a drug; and
the effects of gut and liver enzymes, which can metabolize a drug
during its absorption and first pass through the liver.
• The CYP3A4 isozyme found in intestinal enterocytes and hepatic cells is
a particularly important catalyst of first-pass drug metabolism
• CYP3A4 works in conjunction with Pgp (p-glycoprotein) as the 3A4
isozyme located in enterocytes inactivates drugs transported into the
intestinal lumen by Pgp

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for those drugs with extensive first-pass metabolism: hepatic disease may
increase oral availability of these drugs because hepatic metabolic
capacity decreases because vascular shunts develop around the liver
There is Bioavailability variation assumes practical significance for drugs
with low safety margin (digoxin) or where dosage needs precise control
(oral hypoglycaemics, oral anticoagulants)
It may also be responsible for success or failure of an antimicrobial
regimen

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 DRUG DISTRIBUTION
• Following absorption or systemic administration into the
bloodstream ---- distributes into interstitial and intracellular fluids

• Most drugs are not uniformly distributed throughout TBW

• Some drugs are restricted to ECF or plasma compartment

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 DRUG DISTRIBUTION

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 1.Lipid solubility is a major factor affecting drug distribution

 - particularly to brain, where the blood-brain barrier restricts the

penetration of polar and ionized molecules
 2. Cardiac output,

 3. regional blood flow,

 4. capillary permeability,

 5. tissue volume

 6. tissue predilection determine the rate of drug distribution

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• Initially, liver, kidney, brain, and other well-perfused organs
receive most of the drug;

• delivery to muscle, most viscera, skin, and fat is slower,

• this 2nd distribution phase may require minutes to several

hours before concentration of drug in tissue is in equilibrium
with that in blood

7. PLASMA PROTEIN BINDING The drug binds with plasma

proteins and tissue macromolecules limit its distribution

8. Molecular size is a factor affecting the distribution of

extremely large molecules, such as anticoagulant heparin
which largely confined to the plasma compartment
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 Plasma Protein Binding
Almost all drugs are reversibly bound to plasma proteins (albumin,
lipoproteins, glycoproteins, and β globulins)
The extent of binding ranges from less than 10% to as high as 99%

acid drugs --- albumin

basic drugs -- alpha 1-acid glycoproteins & β globulins

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• As the free (unbound) drug diffuses into interstitial fluid and
cells, drug molecules dissociate from plasma proteins to maintain
the equilibrium between free drug and bound drug

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PPB is saturable,

A drug can be displaced from binding sites by other drugs that have
a high affinity for such sites
Many drugs displace other drugs from plasma proteins & thereby
increase the plasma concentration of the free (unbound) drug.

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Hypoalbuminemia secondary to severe liver disease or nephrotic
syndrome results in reduced binding and increase in free form.

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Acute-phase reaction response (e.g., cancer, arthritis,
myocardial infarction, Crohn's disease) lead to elevated levels of
alpha1-acid glycoprotein and enhanced binding of basic drugs

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Drug transport and glomerular filtration are limited by PPB.

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However, PPB generally does not limit renal tubular secretion or
biotransformation (d/t rapid dissociation of drug from the drug-
protein complex, thereby reestablishing equilibrium between bound
and free drug.)

(Note: A measure of plasma concentration of a drugs by most assay do not

distinguish
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free drug from bound drug.)
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 Redistribution
Redistribution of drug from its site of action into other tissues or sites

primarily when a highly lipid-soluble drug that acts on the brain or CVS
is administered rapidly by IV or by inhalation

• E.g. use of intravenous anesthetic thiopental, a highly lipid-soluble drug

• Because blood flow to the brain is so high, the drug reaches its maximal
concentration in brain within a minute of its IV injection

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After injection is concluded, the plasma concentration falls as
thiopental diffuses into other tissues, such as muscle

The concentration of the drug in brain follows that of the plasma

because there is little binding of the drug to brain constituents

Thus, in this eg, onset of anesthesia is rapid, but so is its termination

 Both are related directly to the concentration of drug in the brain

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 Placental Transfer of Drugs
critically important because drugs may cause anomalies in fetus

 Administered immediately before delivery (e.g. use of tocolytics for

preterm labor) → adverse effects on the neonate

Depend on Lipid solubility, PPB, degree of ionization

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• The fetal plasma is slightly more acidic than that of the mother (pH 7.0-
7.2 versus 7.4), so that ion trapping of basic drugs occurs

• P-gp in placenta → limit fetal exposure to potentially toxic agents

• Placenta is NOT an absolute barrier to drugs

because a number of influx transporters also (+)

• The fetus is to some extent exposed to all drugs taken by the mother

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 Volume of Distribution
(Vd is defined as the volume of fluid in which a drug would need to
be dissolved to have the same concentration as it does in plasma)
• not correspond to an actual body fluid compartment
• it is an apparent volume that represents the relationship between the
dose of a drug and the resulting plasma concentration of the drug

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• Vd of warfarin = 8 L
(high degree of PPB → less distribution to tissue compartment)

• A low Vd → drug is concentrated in ECF/plasma

low concentration in the ICF

• A large Vd → drug is concentrated ICF

low concentration in the ECF/plasma

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• After a weak base diffuses into a cell, a larger fraction is ionized in
the more acidic intracellular fluid

• This restricts its diffusion out of a cell and results in a large V d.

• Many weak bases (e.g. antidepressant fluoxetine (Prozac), have a

large Vd (40–55 L) because of intracellular ion trapping.

• Weak bases are less ionized in ECF than ICF (since pH of ICF < ECF)

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• A large Vd may also result from sequestration into fat tissue
(e.g. antimalarial agent chloroquine)
• Therefore, drug distribution (Vd) depends on
1. plasma protein binding
2. lipid solubility
3. ion trapping of drug
4. blood flow to tissue
5. membrane barriers
6. body weight

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 Drug Biotransformation

• enzyme-catalyzed conversion of drugs to metabolites

• Mostly in liver, also gut, kidneys, brain, lungs, skin

• cytochrome P450 is major catalyst

• Three CYP families (CYP1,2,3) Subfamily - A, B, C, D, E.

• CYP3A4; >50% , CYP2D6; 20%

• Role; inactivate and detoxify drugs and xenobiotics that can

harm the body

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 Products of biotransformation

• active drug to inactive metabolite (most drugs)

• active drug to active metabolite

(diazepam → oxazepam)

• prodrug to active metabolite

(cyclophosphamide → 4-hydroxycyclophosphamide)

• active/inactive drug to toxic metabolite/lethal synthesis

(phenacetin → 2-hydroxyphenacetin)

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 Phases
• Drug biotransformation reactions are classified as either
phase I functionalizations or
phase II biosynthetic (conjugation) reactions

• It is carried out by unique sets of metabolic enzymes

• Phase I(Functionalization) create/unmask chemical group

required for phase II

• Some drugs bypass phase 1 and enter directly into phase II

• Although some phase I drug metabolites are pharmacologically

active, most phase II drug metabolites are inactive.
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 Phase I Functionalization
• Oxidation (most common) by cytoplasmic enzymes

• Ethanol by alcohol dehydrogenase.

• Caffeine, theophylline by xanthine oxidase

• Hydrolysis (few)

• Ach, LA, esmolol by cholinesterase and plasma esterases

Reduction (less common)

• Chloramphenicol by nitro reductase

• Nitroglycerin by glutathione-organic nitrate

reductase
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 Phase II Conjugation
• attachment of polar groups (endogenous) for more rapid excretion

• Glucuronide formation (most common) by glucuronosyltransferase

• Acetylation by N-acetyltransferase

• Sulfation by sulfotransferases
Sulfate metabolites of minoxidil and triamterene are
pharmacologically active.

• Methylation,

• glycine conjugation,

• glutathione conjugation,

• water
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conjugation. KK 43
Drug conjugations were once believed to represent
“terminal inactivation” events or “true detoxification” reactions.
However, this concept must be modified, because

certain conjugation reactions

(acyl glucuronidation of NSIAD,
O-sulfation of N -hydroxyacetylaminofluorene, and
N -acetylation of isoniazid)
lead to formation of reactive species responsible for toxicity

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• Furthermore, sulfation is known to activate the orally active
prodrug minoxidil into a very efficacious vasodilator, and

• morphine-6-glucuronide is more potent than morphine itself.

Factors modifying drug metabolism:

1. genetics,
2. immaturity of drug metabolizing
enzyme system
(newborn, especially premature),
3. elderly,
4. diseases,
5. drug-drug interaction,
6. hepatic blood flow, etc.

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 Metabolic enzyme induction and inhibition

 Many drugs alter drug metabolism by inhibiting or inducing CYP enzymes

 drug interactions can occur when these drugs are administered concurrently with
other drugs that are metabolized by CYP.

 Drugs that induce CYP enzymes activate the binding of nuclear receptors to
enhancer domains of CYP genes, increasing the rate of gene transcription.
(increased mRNA and protein synthesis. )

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 Microsomal enzyme inhibition (Inhibition of drug metabolism)
some drugs inhibit the activity of drug metabolizing enzymes and
potentiate other drugs by decreasing their clearance.
It occurs when co-administered drugs have affinity for the same
isozyme, since the different drugs are substrates for different
CYP 450 isoenzymes.

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  Examples of metabolic enzyme inhibitors

 CVS: amiodarone, verapamil, diltiazem, quinidine, clopidogrel, ticlopidine

 Antimicrobials: erythromycin, clarithromycin, trolandomycin,

chloramphenicol, ciprofloxacin, isoniazid, itraconazole,
ketoconazole, metronidazole, ritonavir, sulfonamides
 GIT: cimetidine, omeprazole,

 CNS: sodium valproate, fluroxene, ethchlorvynol, selegiline;

phencyclidine, MAO inhibitors
 Hormonals: certain steroids (ethinyl estradiol, norethindrone, and
spironolactone), propylthiouracil, mifepristone, troglitazone, raloxifene,
tamoxifen
 Others: allopurinol, disulfiram, grapefruit furanocoumarins (a
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constituent of grape fruit juice)
enzyme inhibition occurs by direct effect on the enzyme, it has a
fast time course (within hours) compared to enzyme induction.

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 Microsomal enzyme induction

 many drugs, insecticides, and carcinogens, on repeated administration increase

the synthesis of microsomal enzyme (esp CYP P450 and glucuronyl transferase)

 Rate of metabolism of inducing drug itself or other drug increased

2-4 fold.

 induction takes 4-14 days to reach its peak and is maintained till inducing agent
is being given, then the enzyme return to their original value over 1-3 weeks

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rifampin induces many CYPs including two important isoform; CYP3A,
CYP2D6 (substrates: tricyclic antidepressant, selective serotonin
reuptake inhibitor, many neuroleptics, antiarrhythmics, β blockers,
antiHIV and opiates)

glucocorticoid induces CYP3A

cigarette smoke, charcoalbroiled meat, industrial pollutants

induce CYP1A2 (substrate: theophylline, warfarin, paracetamol &
only few drugs)

isoniazid and chronic alcohol consumption: CYP2E1 (substrate:

paracetamol, enflurane, halothane)

other important inducers: chloral hydrate, griseofulvin, DDT

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 Consequences of microsomal enzyme
induction:
• decreased intensity of effect

• decreased duration of action

• therapeutic failure

• toxicity

• tolerance

• faster metabolism of endogenous substances like steroids, bilirubin

• precipitate acute intermittent porphyria

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 Eg of clinically important drug interactions:
1. failure of oral contraceptives or loss of anticoagulant control

2. disease may result: antiepileptics increase breakdown of vitamin D

leading to osteomalacia. The accompanying hypocalcaemia increases
tendency to fits and convulsion may lead to # of demineralised
bones.

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3. tolerance to drug therapy may result if the drug induces its
own metabolism (autoinduction), e.g., carbamazepine,
rifampin

4. variability in response to drugs is increased in heavy alcohol

drinking or heavy smoking

5. drug toxicity more likely. e.g., paracetamol toxicity occurs

at lower doses in patient taking rifampicin or chronic alcohol.

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 Questions?

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