Drug metabolism IA % +

Question 1

Drug metabolism

Answer 1

• Drug metabolism is biochemical modification of pharmaceutical substances by living organisms usually through specialized enzymatic activity.
• It converts lipid soluble and non-polar compounds to water soluble and polar compounds so that they can be excreted.
• Only water-soluble substances undergo excretion, whereas lipid soluble substances are passively reabsorbed from renal (kidney) or extra renal excretory sites back into the blood.

Question 2

Effects of metabolism

Answer 2

• Loss of pharmacological activity.
• Decrease in activity, with metabolites that show some activity.
• Increase in activity, more active metabolites.
• Activation of a prodrug (biologically inactive compound which can be metabolized in the body to produce a drug)
• Production of toxic metabolites.
• Direct toxicity
• Carcinogenesis. (the initiation of cancer formation.)
• Teratogenesis (defects in embryo/fetus)

Question 3

Enzymes

Answer 3

• Drug-metabolising Enzymes often have a wide substrate specificity, and individual drugs can be metabolised by more than one.
• Enzyme activity control is regulated at several levels.
• Some enzymes are expressed constitutively (regardless)
• Others are expressed or induced in the presence of a particular substrate.

Question 4

Factors that afffect metabolism

Answer 4

• Other drugs/herbals/natural substances
• Genetics
• Hepatic blood flow
• Liver disease
• Age
• Sex
• Ethnicity
• Pregnancy

Question 5

Enzyme induction

Answer 5

• Many of the important drug-metabolising enzymes can be induced by other compounds
• Increased metabolism of drugs metabolised by that enzyme
• Resulting in decreased drug effect
• Induction of an enzyme involves increased synthesis and therefore increased activity.
• The most common enzyme inducers include alcohol and smoking.
• Many drugs and herbals such as phenytoin, carbamazepine, rifampicin and St John’s Wort can also induce metabolising enzymes.
• Process may take weeks

Question 6

Enzyme inhibition

Answer 6

• Many commonly used drugs herbal medicines and food stuffs may conversely inhibit drug metabolising enzymes.
• Less metabolism occurs
• May be reversible or irreversible binding to the enzyme.
• Common culprits include: cimetidine, erythromycin, clarithromycin and ketoconazole, CCBs, grapefruit.

Question 7

Genetic variation- Pharmacogenomics

Answer 7

• Wide variability in the response to drugs between individuals
• Consequences of such variation may be therapeutic failure or an adverse drug reaction
• Drug-metabolising enzymes are often expressed in multiple forms.
• Therefore inter-individual differences in gene expression are common.
• Gene mutations can also occur resulting in deficiencies or absence of a particular metabolising enzyme.
• Genetic Polymorphisms
• Lack or decreased activity of an enzyme often results in increased drug toxicity.
• Less commonly there may be multiple expressions of a particular metabolising enzyme, which may result in enhanced metabolism and reduced drug effect or drug resistance.
• Eg – fast/slow acetylators; cholinesterase (suxamethonium).

Question 8

Age- children

Answer 8

• Drug-metabolising enzymes are often deficient or reduced in the fetus or premature infant.
• Renal function is also deficient so drug and metabolites rapidly build up to toxic levels.
• By the age of two years children can metabolise many drugs more rapidly than adults.
• By puberty the rate of metabolism is greater than that of adults.

Question 9

Gender

Answer 9

• Sex-based differences have been found in all four pharmacokinetic areas: Absorption, Distribution, Metabolism, and Elimination.
• Responsiveness to certain drugs is different for men and women
• Pregnancy – induction of certain drug-metabolizing enzymes occurs in second and third trimester
• Hormonal changes during development have a profound effect on drug metabolism

Question 10

Age (ederly)

Answer 10

• In the elderly parameters such as plasma protein, lean body mass and liver weight decrease significantly and so alter drug metabolism.
• Chronic disease is also more common and so the elderly are likely to be on multiple drug therapy.

Question 11

Ethnicity

Answer 11

• Race may also affect drug metabolism.
• There are many incidences of racial differences in the genetic expression of cytochrome P-450 isoforms.

Question 12

Drug metabolism phases

Answer 12

Phase 1:

• oxidation
• reduction
• hydrolysis

Phase 2:

• glucuronidation (xenobiotic metabolism) which leads to conjugation products.

Note:The cytochrome P-450 enzymes are the most important super family of metabolising enzymes.