3. Metabolism or Biotransformation
Chemical alteration of the drug in the body.
Required to change nonpolar (lipid-soluble) compounds to polar
(lipid insoluble)
Prevent reabsorption in the renal tubules
The primary site for drug metabolism is liver; others are—kidney,
intestine, lungs and plasma.
4. Consequences of metabolism
Inactivation:
Most drugs and their active metabolites are rendered inactive or less
active
E.g- Ibuprofen, paracetamol, lidocaine, chloramphenicol.
Active metabolite from an active drug:
Many drugs are partially converted to one or more active metabolite,
the effects observed will be the sum of parent drug and its active
metabolite
E.g- Digitoxin — Digoxin, Codeine — Morphine
Activation of inactive drug:
Inactive or prodrug are converted to one or more active metabolites
E.g- Levodopa — Dopamine, Enalapril — Enalaprilat.
6. Nonsynthetic reactions
1. Oxidation:
Involves addition of oxygen/negatively charged radical or removal of
hydrogen/positively charged radical.
hydroxylation, oxygenation, dealkylation, oxidative deamination
Oxidative reactions are carried out by monooxygenases in the liver
2. Reduction:
Opposite of oxidation and involves cytochrome P-450 enzymes working
in the opposite direction.
Alcohols, aldehydes, quinones are reduced.
E.g- chloramphenicol, halothane, warfarin.
7. 3. Hydrolysis: cleavage of drug molecule by taking up a molecule of water.
• Hydrolysis occurs in liver, intestines, plasma and other tissues.
• Ester + H2O esterase acid + alcohol
• Amides by amidases and polypeptides by peptidases
e.g- lidocaine, aspirin, pethidine, oxytocin.
4. Cyclization: formation of ring structure from a straight chain
compound, e.g. proguanil.
5. Decyclization: Opening up of ring structure of the cyclic drug molecule,
a minor pathway.
e.g. barbiturates, phenytoin.
8. Synthetic reactions:
• Conjugation of the drug or its phase I metabolite with an
endogenous substrate
• Formation of a highly polar ionized organic acid, which is easily
excreted in urine or bile
• Conjugation reactions require energy
9. 1. Glucuronide conjugation:
Most important synthetic reaction carried out by a group of UDP-
glucuronosyl transferases (UGTs).
• Compounds having hydroxyl or carboxylic acid group are
conjugated with glucuronic acid
• Glucuronidation increases the molecular weight of the drug,
favouring its excretion in bile.
e.g- chloramphenicol, aspirin, paracetamol, diazepam,
lorazepam, morphine, metronidazole, endogenous substrates like
bilirubin, steroidal hormones and thyroxine.
10. 2. Acetylation:
• Compounds with amino or hydrazine residues are conjugated with the help
of acetyl coenzyme-A
• Multiple genes control the N-acetyl transferases (NATs), and rate of
acetylation shows genetic polymorphism (slow and fast acetylators)
e.g- sulfonamides, isoniazid, PAS, dapsone, hydralazine,
Procainamide.
3. Methylation:
• Amines and phenols are methylated by methyl transferases (MT)
• Methionine and cysteine are the methyl donors,
e.g - adrenaline, histamine, nicotinic acid, methyldopa, captopril,
mercaptopurine.
11. 4. Sulfate conjugation:
• Phenolic compounds and steroids are sulfated by sulfotransferases (SULTs),
e.g. chloramphenicol, methyldopa, adrenal and sex steroids.
5. Glycine conjugation:
• Drugs having carboxylic acid group are conjugated with glycine,
• Not a major pathway of metabolism.
e.g- Salicylates, nicotinic acid and other
6. Ribonucleoside/nucleotide synthesis:
• Important for the activation of purine and pyrimidine antimetabolites used
in cancer chemotherapy.
12. 7. Glutathione conjugation:
• Carried by glutathione-S-transferase (GST) forming a mercapturate, a minor
pathway.
• Inactivates highly reactive quinone or epoxide intermediates formed during
metabolism of certain drugs,.
• When large amount of such intermediates are formed glutathione supply
falls short—toxic adducts are formed with tissue constituents → tissue
damage.
e.g- Paracetamol
13. The drug metabolising enzymes are divided into
two types:
Microsomal enzymes:
• Located on smooth endoplasmic
reticulum, primarily in liver, Kidney,
intestinal mucosa and lungs.
• Function:- oxidations, reductions,
hydrolysis and glucuronide
conjugation.
• Inducible by drugs, diet and other
agencies.
e.g- monooxygenases, cytochrome
P450, ugts, epoxide hydrolases.
Nonmicrosomal enzymes:
• Cytoplasm and mitochondria of
hepatic cells other tissues including
plasma.
• Some oxidation, reductions, many
hydrolytic reactions and all
conjugations except glucuronidation.
• not inducible but show genetic
polymorphism
e.g-Esterases, amidases, some
flavoprotein oxidases, conjugases
14. Enzyme inhibition:
• One drug can competitively inhibit the metabolism of another if it
utilizes the same enzyme or cofactors.
• A drug may inhibit one isoenzyme while being itself a substrate of
another isoenzyme
e.g. quinidine is metabolized mainly by CYP3A4 but inhibits CYP2D6.
• enzyme inhibition has rapid onset (within hours)
Inhibitors of drug metabolizing enzymes
e.g- Omeprazole, Erythromycin, Isoniazid, Cimetidine, Ketoconazole,
Itraconazole, Ciprofloxacin MAO inhibitors, Sulfonamides, Ritonavir
15. Enzyme induction:
• Many drugs, insecticides and carcinogens increase the synthesis of
microsomal enzyme protein, especially cytochrome P-450 and UGTs
• Rate of metabolism of inducing drug itself and/or other drugs is
increased by 2–4 fold.
• Induction takes 4–14 days to reach its peak and is maintained till the
inducing agent is being given.
• Thereafter the enzymes return to their original value over 1–3 weeks.
16. Consequences of microsomal enzyme induction
• Decreased intensity and/or duration of action of drugs that are
inactivated by metabolism
e.g. failure of contraception with oral contraceptives.
• Increased intensity of action of drugs that are activated by
metabolism.
• Tolerance—if the drug induces its own metabolism (autoinduction),
e.g. carbamazepine, rifampin.
• Some endogenous substrates (steroids, bilirubin) are also metabolized
faster.
17. Possible uses of enzyme induction
1. Congenital nonhaemolytic jaundice: It is due to deficient
glucuronidation of bilirubin; phenobarbitone fastens clearance of
jaundice.
2. Cushing’s syndrome: phenytoin may reduce the manifestations by
enhancing degradation of adrenal steroids which are produced in
excess.
3. Chronic poisonings: by faster metabolism of the accumulated
poisonous
18. Excretion
Excretion of drug from the body after being converted to water-soluble
metabolites while some are directly eliminated without metabolism.
• Major organs of excretion are the kidneys, the intestine, the biliary
system and the lungs.
• Drugs are also excreted in small amounts in the saliva, sweat and milk.
19. Kidney:
• Kidney is responsible for excreting all water soluble substances
• 3 processes involved in the elimination of drugs through kidneys are
glomerular filtration,
active tubular secretion and
passive tubular reabsorption.
• Net renal excretion = (Glomerular filtration + tubular secretion) –
tubular reabsorption
20. 1. Glomerular filtration:
• Molecular size
• Plasma protein binding
• Renal blood flow
2. Tubular secretion:
• Energy dependent carrier mediated
transport
• 2 classes of nonspecific transporters
(OAT and OCT) which operate in the
proximal tubules
Organic acid transport (OATP)
operates for penicillin, probenecid,
uric acid, salicylates, indomethacin,
sulfinpyrazone, nitrofurantoin etc
21. Organic base transport (OCT)
operates for thiazides, amiloride, triamterene, furosemide, quinine,
procainamide, choline, cimetidine, etc.
3. Tubular reabsorption:
• Occurs by passive diffusion and depends on lipid solubility
• Ionization of the drug at the urinary pH
22. Fecal and biliary excretion:
• Unabsorbed orally Administered
drugs.
• Liver transfers acids, bases and
unionized molecules into bile by
specific transport processes.
• free drug in the gut, deconjugates of
glucuronides are reabsorbed
undergo (enterohepatic cycling) and
ultimately excreted in urine
23. Exhaled air:
• Gases and volatile liquids (general anaesthetics, alcohol) are eliminated by
lungs, independent of lipid solubility.
• Alveolar exchane of the gas/vapour depends on its partial pressure in the
blood.
Saliva and sweat:
• Minor route of drug excretion.
• Lithium, KI, rifampin and heavy metals
• Most of the saliva along with the drug in it, is swallowed and meets the
same fate as orally taken drug.
24. Milk:
• Most drugs enter breast milk by
passive diffusion.
• Lipid soluble and less protein
bound drugs cross better.
25. Plasma Half-life
• The Plasma half-life (t½) of a drug is
the time taken for its plasma
concentration to be reduced to half
of its original value.
• 4-5 half-lives are required for the
complete elimination of a drug
26. Drug Dosage:
Posology
• Therapeutic dose of a drug is the quantity of the drug needed to
produce the therapeutic effect
Minimum dose: smallest dose required to produce a desired therapeutic
effect of the drug.
Maximum dose: Largest dose of the drug that can be given safely to a
patient without producing harmful effects.
Toxic dose: Dose which produces undesirable effects in majority of the
patients.
Lethal dose: Dose of the drug which can cause death.
e.g- lethal dose of phenobarbitone is 6 to 10 grams.
27. Fixed dose: for safe drugs, a fixed dose of the drug is suitable for most
patients.
e.g- Paracetamol—500 mg to 1000 mg 6 hourly is the usual adult dose.
Individualizing dose: Drugs with low safety margin, the dose has to be
‘tailored’ to the needs of each patient
e.g. anticonvulsants, antiarrhythmic drugs.
28. Loading dose:
This is a single or few quickly
repeated doses given in the
beginning to attain target
concentration rapidly.
• loading dose is governed only by
V and not by CL or t½
Maintenance dose:
Dose that is to be repeated at
specified intervals after the
attainment of target plasma
concentration so as to maintain it
by balancing elimination
