General Pharmacology

Vijay Elipay
Asst. Professor
Malla Reddy College of Pharmacy
Topics
▪ Pharmacokinetics:
• The dynamics of drug absorption, distribution,
biotransformation and elimination.
• Significance of Protein binding.
• Concepts of linear and non-linear compartment models.
▪ Pharmacodynamics:
• Mechanism of drug action and the relationship between
drug concentration and effect.
• Receptors, structural and functional families of
receptors, quantitation of drug receptors interaction and
elicited effects.
Drug Metabolism/
Biotransformation
▪ Drug elimination is the irreversible loss of drug
from the body. It occurs by two processes:
metabolism and excretion.
• Metabolism consists of anabolism (build-up) and
catabolism (breakdown) of substances by enzymic
conversion of one chemical entity to another entity
within the body.
• Excretion consists of elimination from the body of drug
or drug metabolites.
▪ Animals have evolved complex systems that
detoxify foreign chemicals (xenobiotics).
• Drugs are a special case of xenobiotics.
▪ Like plant alkaloids, xenobiotics often exhibit
chirality (i.e. >1 stereoisomer), which affects their
overall metabolism.
▪ Drug metabolism involves 2 kinds of reaction,
which frequently occur sequentially, phase 1 and
phase 2.
▪ Both phases decrease lipid solubility, thus
increasing renal elimination.
Phase 1 Reactions
▪ Phase 1 reactions (e.g., oxidation, reduction or
hydrolysis) are catabolic.
▪ The products are often more chemically reactive and
hence, sometimes more toxic or carcinogenic than the
parent drug.
▪ Phase 1 reactions often introduce a reactive group,
such as hydroxyl, into the molecule, a process known as
functionalization.
• The reactive group then serves as the point of attack for the
conjugating system to attach a substituent such as
glucuronide.
• So, phase 1 reactions often precede phase 2 reactions.
The Two Phases of Drug Metabolism
▪ Many hepatic drug-metabolizing enzymes,
including CYP enzymes, are embedded in the
smooth endoplasmic reticulum.
▪ They are often called ‘microsomal’ enzymes.
▪ To reach these metabolizing enzymes, a drug must
cross the plasma membrane.
▪ Polar molecules do this less readily than non-polar
molecules except where there are specific
transport mechanisms.
• So, intracellular metabolism is important for lipid-soluble
drugs. Polar drugs are, at least partly, excreted
unchanged in the urine.
▪ P450 Monooxygenase System:
• Cytochrome P450 enzymes are haem proteins,
containing a large superfamily of related but distinct
enzymes, each referred to as CYP followed by a defining
set of numbers and a letter.
• P450 enzymes differ from one another in amino acid
sequence, in sensitivity to inhibitors and inducing
agents, and in the specificity of the reactions that they
catalyze.
• Different members of the family have distinct, but often
overlapping, substrate specificities.
• Not all 57 human CYPs are involved in drug metabolism.
Examples of
drugs that are
substrates of
P450
isoenzymes
• CYPs 1A2, 3A4, 2D6, 2C9 and 2C19 were responsible for
approximately 60% of drug metabolism.
• It has been estimated that CYP enzymes in families 1–3
mediate 70%–80% of all phase 1-dependent metabolism
of clinically used small molecule drugs.
• Drug oxidation by the monooxygenase P450 system
requires drug (substrate, ‘DH’), P450 enzyme, molecular
oxygen, NADPH and NADPH–P450 reductase (a
flavoprotein).
• The mechanism involves the addition of 1 atom of
oxygen (from molecular oxygen) to the drug to form a
hydroxylated product (DOH), the other atom of oxygen
being converted to water.
 Monooxygenase
P450 Cycle
Each of the pink or blue rectangles represents
one single molecule of cytochrome P450
(P450) undergoing a catalytic cycle.

Iron in P450 is in either the ferric (pink

rectangles) or ferrous (blue rectangles) state.

P450 containing ferric iron (Fe3+) combines

with a molecule of drug (‘DH’), and receives an
electron from NADPH–P450 reductase, which
reduces the iron to Fe2+.

This combines with molecular oxygen, a proton

and a second electron (either from NADPH–
P450 reductase or from cytochrome b5) to
form an Fe2+OOH–DH complex.

This combines with another proton to yield

water and a ferric oxene (FeO)3+–DH complex.

(FeO)3+ extracts a hydrogen atom from DH,

with the formation of a pair of short-lived free
radicals, liberation from the complex of
oxidized drug (‘DOH’), and regeneration of
P450 enzyme.
• In humans, there are major sources of inter-individual
variation in P450 enzymes that are important.
o These include genetic polymorphisms (alleles – that

persist in a population through several generations).

• Environmental factors are also important, since enzyme
inhibitors and inducers are present in the diet and
environment.
o Grapefruit juice inhibits drug metabolism (leading to

disastrous consequences, including cardiac

dysrhythmias).
o Brussels sprouts and cigarette smoke induce P450

enzymes.
o The herbal medicine St John’s wort induce CYP450

isoenzymes as well as P-glycoprotein (P-gp).

• Drug interactions based on one drug altering the
metabolism of another are common and clinically
important.
• Not all drug oxidation reactions involve the P450 system.
o Some drugs are metabolised in:

• plasma (e.g., hydrolysis of suxamethonium by

plasma cholinesterase)
• lung (e.g., various prostanoids)
• gut (e.g., tyramine, salbutamol)
o Ethanol is metabolised by a soluble cytoplasmic

enzyme, alcohol dehydrogenase, in addition to

CYP2E1.
 o Xanthine oxidase inactivates 6-mercaptopurine
o Monoamine oxidase (MAO) inactivates many
biologically active amines, e.g., noradrenaline,
tyramine, 5-hydroxytryptamine.
▪ Hydrolytic Reactions
• Hydrolysis (e.g., of aspirin) occurs in plasma
and in many tissues.
• Both ester and (less readily) amide bonds are
susceptible to hydrolytic cleavage.
• Reduction is less common in phase 1 metabolism than
oxidation.
o Warfarin is inactivated by reduction of a ketone to a

hydroxyl group by CYP2A6.

Phase 2 Reactions
▪ Phase 2 reactions are synthetic (anabolic) and
involve conjugation (attachment of a substituent
group).
• It usually results in inactive products.
o Exceptions: E.g., active sulphate metabolite of

minoxidil, a potassium channel activator used to

treat severe hypertension and to promote hair
growth (as a cream).
▪ Phase 2 reactions take place mainly in the liver.
▪ If a drug molecule or phase 1 product has a suitable
‘handle’ (e.g., a hydroxyl, thiol or amino group), it is
subject to conjugation.
▪ The chemical group inserted may be glucuronyl,
sulphate, methyl or acetyl.
▪ In glucuronide conjugation reaction, a glucuronyl
group is transferred from uridine diphosphate
glucuronic acid (UDPGA) to a drug molecule.
• Glucuronidation involves the formation of a high-energy
phosphate (donor) compound, uridine diphosphate
glucuronic acid (UDPGA).
• From UDPGA, glucuronic acid is transferred to an
electron-rich atom (N, O or S) on the substrate, forming
an amide, ester or thiol bond.
• UDP-glucuronyl transferase catalyzes these reactions.
o It has very broad substrate specificity embracing

many drugs and foreign molecules.

• Several important endogenous substances, including
bilirubin and adrenal corticosteroids, are conjugated by
the same pathway.
▪ Acetylation and methylation reactions occur with
acetyl-CoA and S-adenosyl methionine, respectively,
acting as the donor groups.
▪ Besides liver, other tissues, such as lung and
kidney, are less involved in conjugation reactions.
▪ The tripeptide glutathione conjugates drugs or
their phase 1 metabolites via its sulfhydryl group,
as in the detoxification of paracetamol.
Potential
mechanisms of
liver cell death
resulting from
the metabolism
of paracetamol
to N-acetyl-p-
benzoquinone
imine (NAPBQI)
In paracetamol
overdose,
glutathione
depletion may lead
to oxidative stress
and hepatic cell
necrosis.
GSH,
glutathione
Inhibition of P450
▪ Inhibitors of P450 differ in their selectivity towards
different isoforms of the enzyme and are classified
by their mechanism of action.
▪ Competitive inhibitors:
• E.g., quinidine is a potent competitive inhibitor for the
active site of CYP2D6 but is not a substrate for it.
▪ Non-competitive inhibitors:
• E.g., ketoconazole forms a tight complex with Fe3+ form
of the haem iron of CYP3A4, causing reversible
noncompetitive inhibition.
▪ Mechanism-based inhibitors: They require
oxidation by a P450 enzyme. Examples:
• oral contraceptive gestodene for CYP3A4
• the anthelmintic drug diethylcarbamazine for CYP2E1
▪ Suicide inhibition: An oxidation product (e.g., a
postulated epoxide intermediate of gestodene)
binds covalently to the enzyme, which then
destroys itself.
Induction of Microsomal Enzymes
▪ It is the result of increased synthesis and/or
reduced breakdown of microsomal enzymes.
▪ Several drugs, such as rifampicin, ethanol and
carbamazepine, increase the activity of microsomal
oxidase and conjugating systems when
administered repeatedly.
▪ Many carcinogenic chemicals (e.g., 3-MC,
benzopyrene) also have this effect, which can be
significant.
▪ Enzyme induction can increase drug toxicity and
carcinogenicity, because several phase 1
metabolites are toxic or carcinogenic.
• E.g., paracetamol is an important example with a highly
toxic metabolite.
▪ Enzyme induction is used therapeutically.
• E.g., administering phenobarbital to premature babies
induces glucuronyltransferase, thereby increasing
bilirubin conjugation and reducing the risk of kernicterus
(neurological damage of the basal ganglia by bilirubin).
Presystemic (First-pass) Metabolism
▪ The term, presystemic (first-pass) metabolism, is
used for drugs which are extracted (removed)
effectively by the liver or gut wall.
• So, the amount reaching the systemic circulation is
considerably less than the amount absorbed.
• It reduces bioavailability, even when a drug is well
absorbed.
▪ Presystemic metabolism is important for many
drugs. It is a problem because:
• A much larger dose is needed when the drug is taken by
mouth than when it is given parenterally.
• Marked individual variations occur in the extent of first-
pass metabolism:
o in the activities of drug-metabolizing enzymes

o as a result of differences in hepatic or intestinal

blood flow
• Hepatic blood flow can be reduced in disease
(e.g., heart failure) or by drugs (e.g., β-
adrenoceptor antagonists). This impairs the
clearance of drugs like lidocaine (that are subject
to presystemic metabolism due to a high hepatic
extraction (removal) ratio).
• Intestinal blood flow is strongly influenced by
eating and pharmacokinetic effects of food for
orally administered drugs.
Some drugs that undergo substantial Pre-systemic
(First-pass) elimination
Pharmacologically Active Drug
Metabolites
▪ Prodrug: The parent compound lacks activity of its
own and becomes pharmacologically active only
after it has been metabolized. Examples:
• Azathioprine, an immunosuppressant drug, is
metabolized to mercaptopurine
• Enalapril, an ACE inhibitor, is hydrolyzed to its active
form enalaprilat
▪ Prodrugs are sometimes designed intentionally to
overcome problems of drug delivery.
▪ Metabolism can change the pharmacological
actions.
• Aspirin inhibits platelet function and has anti-
inflammatory activity.
• It is hydrolyzed to salicylic acid, which has anti-
inflammatory but not antiplatelet activity.
▪ Metabolites with pharmacological actions like
those of the parent compound.
• E.g., benzodiazepines, many of which form long-lived
active metabolites that cause sedation to persist after
the parent drug has disappeared.
▪ Metabolites responsible for toxicity.
• Bladder toxicity of cyclophosphamide caused by its toxic
metabolite acrolein.
• Methanol and ethylene glycol both exert their toxic
effects via metabolites formed by alcohol
dehydrogenase.
o Poisoning with these agents is treated with ethanol

(or a more potent inhibitor), which competes for the

active site of the enzyme.
Some drugs that produce Active or Toxic Metabolites
Drug Interactions due to Enzyme
Induction
▪ Enzyme induction refers to the increase in the
biosynthesis of enzyme following exposure of the
organism to certain drugs.
• The slow onset of induction and slow recovery after
withdrawal of the inducing agent, together with the
potential for selective induction of one or more CYP
isoenzymes, contribute to the tricky nature of the clinical
problems that induction presents.
• More than 200 drugs cause enzyme induction.
• They decrease the pharmacological activity of a range of
other drugs.
▪ Adverse clinical outcomes from such interactions
are diverse:
• graft rejection as a result of loss of effectiveness of
immunosuppressive treatment
• seizures due to loss of anticonvulsant effectiveness
• unwanted pregnancy from loss of oral contraceptive
action and thrombosis (from loss of effectiveness of
warfarin)
• bleeding (from failure to recognize the need to reduce
warfarin dose when induction decreases after an
inducing agent is discontinued)
Some Drugs that Induce Drug-metabolising Enzymes
▪ E.g., rifampicin (given for few days) reduces the
effectiveness of warfarin as an anticoagulant.
▪ Enzyme induction can result in slowly developing
tolerance because the inducing agent is often itself
a substrate for the induced enzymes.
• This pharmacokinetic kind of tolerance is generally less
marked than pharmacodynamic tolerance, e.g., to
opioids.
• However, it is clinically important when starting
treatment with the antiepileptic, carbamazepine.
o Treatment starts at a low dose to avoid toxicity

(because liver enzymes are not induced initially) and

is gradually increased over a period of a few weeks.
▪ Enzyme induction can increase toxicity if the toxic
effects are mediated via an active metabolite.
• E.g., paracetamol (acetaminophen) toxicity caused by
its CYP metabolite N-acetyl-p-benzoquinone imine
(NAPQI).
• Thus, the risk of serious hepatic injury following
paracetamol overdose is increased in whom CYP has
been induced, for e.g., by chronic alcohol consumption.
Drug Interactions due to Enzyme
Inhibition
▪ Enzyme inhibition (particularly of CYP enzymes)
slows the metabolism and hence increases the
action of other drugs inactivated by the enzyme.
▪ Such effects can be clinically important.
▪ They are major considerations in the treatment of
patients with HIV infection with combination
therapy, because several protease inhibitors are
potent CYP inhibitors.
Some Drugs that Inhibit Drug-metabolising Enzymes
▪ Several inhibitors of drug metabolism influence the
metabolism of different stereoisomers selectively.
• Drugs that inhibit the metabolism of active (S) and less
active (R) isomers of warfarin are given below:
▪ The therapeutic effects of some drugs are a direct
consequence of enzyme inhibition.
• E.g., xanthine oxidase inhibitor allopurinol, to prevent
gout.
▪ Xanthine oxidase metabolizes several cytotoxic and
immunosuppressant drugs. E.g., mercaptopurine
(active metabolite of azathioprine).
• So, the action of mercaptopurine is potentiated and
prolonged by allopurinol.
▪ Disulfiram (used to produce aversion to ethanol) is
an inhibitor of aldehyde dehydrogenase.
• It inhibits metabolism of other drugs, e.g., warfarin
(potentiating warfarin effect).
▪ Metronidazole (an antimicrobial used to treat
anaerobic bacterial infections and several protozoal
diseases) also inhibits aldehyde dehydrogenase.
• Thus, patients prescribed metronidazole are advised to
avoid alcohol.
▪ There are also drugs that inhibit the metabolism of
other drugs, even though enzyme inhibition is not
the main mechanism of action.
• Glucocorticosteroids and cimetidine potentiate a range
of drugs, including some antidepressant and cytotoxic
drugs.
▪ Inhibition of the conversion of a prodrug to its
active metabolite can result in loss of activity.
• Proton pump inhibitors (e.g., omeprazole) and the
antiplatelet drug clopidogrel have been widely co-
prescribed.
o This is because clopidogrel is often used with other

antithrombotic drugs which may cause bleeding

from the stomach.
o Omeprazole reduces gastric acid secretion and the

risk of gastric hemorrhage.

• However, clopidogrel works through an active
metabolite formed by CYP2C19 which is inhibited by
omeprazole.
o This may reduce the antiplatelet effect.
o Hence, FDA continues to warn against concomitant
use of clopidogrel and omeprazole.
Drug Excretion
▪ Excretion consists of elimination from the body of
drug or drug metabolites.
▪ The main excretory routes are:
• kidneys
• hepatobiliary system
• lungs (important for volatile/gaseous anesthetics)
▪ Most drugs leave the body through urine via
kidneys, either unchanged or as polar metabolites.
▪ Some drugs are secreted into bile via liver, but most
of these are then reabsorbed from intestine.
▪ Exceptions:
• Fecal route accounts for elimination of a significant
fraction of unchanged drug in healthy individuals, e.g.,
rifampicin.
• Drugs that are usually excreted in urine are gradually
eliminated more through fecal route in patients with
advancing renal impairment, e.g., digoxin.
Biliary Excretion and Enterohepatic
Circulation
▪ Liver transfers various substances, including drugs,
from plasma to bile by transport systems (organic
cation transporters (OCTs), organic anion
transporters (OATs) and P-glycoproteins (P-gps)) like
those of the renal tubule.
• Various hydrophilic drug conjugates (particularly
glucuronides) are concentrated in bile and delivered to
the intestine.
• In the intestine, the glucuronide can be hydrolysed,
regenerating active drug.
• Free drug can then be reabsorbed, and the cycle
repeated.
• The whole process is called enterohepatic circulation.
• The drug reservoir from enterohepatic circulation can
amount to 20% of total drug in the body, prolonging
drug action.
• Examples:
o Morphine and ethinylestradiol.

o Vecuronium (a non-depolarizing muscle relaxant) is

excreted mainly unchanged in bile.

o Rifampicin is absorbed from gut and slowly
deacetylated, retaining its biological activity.
• Both forms are secreted in the bile, but the
deacetylated form is not reabsorbed.
• So, gradually most of the drug leaves the body in
deacetylated form.
Renal Excretion of Drugs and
Metabolites
▪ Renal Clearance:
• Renal clearance (CLren) is defined as the volume of
plasma containing the amount of substance that is
removed from the body by the kidneys in unit time.
• It is calculated from plasma concentration (Cp), urinary
concentration (Cu) and rate of flow of urine (Vu) as,
C ×V
CLren = u u
Cp
• CLren varies greatly for different substances from ˂1
mL/min to ~700 mL/min (theoretical maximum).
o Theoretical maximum is obtained for p-

aminohippuric acid (PAH) clearance (renal extraction

of PAH is ~100%).
o Penicillin (like PAH) is cleared from the blood almost

completely on a single transit through the kidney.

o Amiodarone and risedronate are cleared extremely

slowly.
o Most drugs fall between these extremes.
3 fundamental
processes account
for renal drug
excretion:
1. Glomerular
filtration
2. Active tubular
secretion (carrier-
mediated)
3. Passive
reabsorption
(diffusion across
the renal tubule)
▪ Glomerular Filtration:
• Glomerular capillaries allow drug molecules of
molecular weight <20 kDa to pass into the glomerular
filtrate.
• Plasma albumin (molecular weight ~68 kDa) is almost
impermeant.
• Most drugs (except macromolecules such as heparin or
biopharmaceuticals) cross freely.
• If a drug binds to plasma albumin, only free drug is
filtered.
o E.g., warfarin is ~98% bound to albumin. So, the

concentration in the filtrate is only 2% of that in

plasma.
▪ Tubular Secretion:
• Up to 20% of renal plasma flow is filtered through the
glomerulus.
• Remaining >80% of delivered drug passes on to the
peritubular capillaries of the proximal tubule.
o Thus, tubular secretion is potentially the most

effective mechanism of renal drug elimination.

• Drug molecules are transferred to the tubular lumen by
2 relatively non-selective carrier systems.
1. OAT (organic anion transporter) transports acidic
drugs in their negatively charged form (as well as
endogenous acids, such as uric acid)
2. OCT (organic cation transporter) transports
organic bases in their protonated cationic form.
Important Drugs and Substances Secreted into the
Proximal Renal Tubule by OAT or OCT Transporters
• OAT can transport drug molecules against an
electrochemical gradient.
o Therefore, OAT can reduce the plasma concentration ≈0.
• However, OCT facilitates transport down an
electrochemical gradient.
• Unlike glomerular filtration, carrier-mediated transport
can achieve maximal drug clearance even when most of
the drug is bound to plasma protein. Example:
o Penicillin (~80% protein-bound and therefore slowly

cleared by filtration) is almost completely removed

by proximal tubular secretion and is therefore
rapidly eliminated.
 o Many drugs compete for the same transport
systems, leading to drug interactions. Example:
• Probenecid was developed originally to
potentiate penicillin by delaying its tubular
secretion.
▪ Diffusion Across the Renal Tubule:
• Diffusion across the renal tubule is passive reabsorption
from the concentrated tubular fluid back across the
tubular epithelium.
• If the tubule is freely permeable to drug molecules (like
water), ~99% of filtered drug will be reabsorbed
passively.
• Lipid-soluble drugs are passively reabsorbed.
• Polar drugs of low tubular permeability remain in the
lumen and become gradually concentrated as water is
reabsorbed. E.g., Digoxin and aminoglycoside
antibiotics.
o A relatively small but important group of drugs are

drugs that are not inactivated by metabolism and

the rate of renal elimination determines their
duration of action.
Drug Interactions due to Altered
Drug Excretion
▪ The main mechanisms by which one drug can affect
the rate of renal excretion of another:
• altering protein binding, and hence filtration
• inhibiting tubular secretion
• altering urine flow and/or urine pH
▪ Inhibition of Tubular Secretion:
• Probenecid was developed to inhibit secretion of
penicillin and thus prolong its action.
• Probenecid also inhibits excretion of other drugs like
zidovudine.
• Other drugs have an incidental probenecid-like effect
and can increase the actions of substances that depend
on tubular secretion for their elimination.
• Diuretics (like furosemide) act from within the tubular
lumen.
o So, drugs that inhibit their tubular secretion (like

non-steroidal anti-inflammatory drugs) reduce their

effect.
Examples of Drugs that Inhibit Renal Tubular Secretion
▪ Alteration of Urine Flow and pH:
• Diuretics tend to increase the urinary excretion of other
drugs and their metabolites.
o This is rarely directly clinically important.

• On the contrary, loop and thiazide diuretics indirectly

decrease the excretion of lithium.
+
o These diuretics cause Na depletion.

o The kidney responds by increased proximal tubular

reabsorption of Na+ and Li+ (which is handled in a

similar way to Na+).
o This can cause lithium toxicity in patients treated

with lithium carbonate for mood disorders.

• The effect of urinary pH on the excretion of weak acids
and bases is used in the treatment of poisoning with
salicylate but is not a cause of accidental interactions.
Thank You!