drug metabolism

Question 1

define drug metabolism

Answer 1

biochemical modification of pharmaceutical substances by living organisms usually through specialised enzymatic activity

Question 2

which substances undergo excretion

Answer 2

only water soluble ones

lipid soluble are passively reabsorbed from renal or extra renal accessory sites back into the blood

Question 3

important sites of metabolism

Answer 3

liver
gut lining
kidneys
lungs

Question 4

what is the purpose of metabolism

Answer 4

increase water solubility and so aid excretion
deactivate compounds
- some drugs are activated (prodrugs)

Question 5

what is a prodrug

Answer 5

inactive until they are metabolised in the liver e.g. codeine

Question 6

effects of metabolism

Answer 6

loss of pharmacological activity
decrease in activity
increase in activity - prodrugs
production of toxic metabolites

Question 7

production of toxic metabolites can cause …

Answer 7

direct toxicity
carcinogenesis
teratogenesis

Question 8

terfenadine

Answer 8

inactive terfenadine is converted to its active metabolite fexofenadine

Question 9

enzymes

Answer 9

there are numerous metabolising enzymes
they often have wide substrate specificity
enzyme control is regulated at several levels
some enzymes are expressed constitutively
others are expressed or induced in the presence of . particular substrate

Question 10

phase 1 reactions

Answer 10

convert the drug into a more reactive species which can then be conjugated in phase 2

Question 11

what are the 3 processes in phase 1 reactions

Answer 11

oxidation
reduction
hydrolysis

Question 12

phase 1 reactions - exposing or introducing polar groups onto molecules

Answer 12

involves hydrolysis, oxidation or reduction
increases polarity of the compound, provides active site for phase 2 metabolism
cytochrome P450 enzymes are the most important family

Question 13

drug specificity is determined by …

Answer 13

isoform of cytochrome P450

specificity tends to be relative rather than absolute

Question 14

phase 2 metabolism - conjugation

Answer 14

involves conjugation
increases water solubility and enhances excretion of the metabolised compound
attachemnet of glucuronic acid, glutathione, sulphate, acetate to the metabolite
usually results in inactivation

Question 15

factors the affect drug metabolism (8)

Answer 15

other drugs/herbal substances
genetics
hepatic blood flow 
liver disease
age 
sex
ethnicity 
pregnancy

Question 16

enzyme induction

Answer 16

many enzymes involved in drug metabolism can be induced by other compounds
- increased drug metabolism
- decreased drug effect
most common enzyme inducers are alcohol and smoking
also includes drugs and herbals (phenytoin, carbazepine, rifampicin, St Johns wort)

Question 17

enzyme inhibition

Answer 17

includes commonly used drugs, herbal medicines and foods
can be reversible or irreversible
- cimetidine, valproate, erythromycin, clarithromysin, ketoconazole, CCBs, grapefruit juice

Question 18

grapefruit juice

Answer 18

increase felodipine oral availability in humans by decreasing intestinal CYP3A protein expression

Question 19

genetic variation pharmacogenetics

Answer 19

• Wide variability in the response to drugs between individuals
• Consequences of such variation may be therapeutic failure or an adverse drug reaction
• Genetic diversity is the rule rather than the exception with all proteins, including drug metabolizing enzymes
• Drug metabolising enzymes are often expressed in multiple forms (with different levels of activity)
• Therefore inter-individual differences in gene expression are common.
  Gene mutations can also occur resulting in deficiencies or absence of a particular metabolising enzyme.

Question 20

genetic polymorphisms

Answer 20

• 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 (suxamethoneum).

Question 21

CYP2D6 polymorphisms

Answer 21

• Approximately 70 nucleotide polymorphisms are known
• Four phenotype subpopulations of metabolizers
  • Poor metabolizers (PM): 6-10% of caucasians
  • Intermediate metabolizers (IM)
  • Extensive metabolizers (EM): majority of the rest of the pop
  • Ultrarapid metabolizers (UM) - may not respond in the expected way to normal doses, 20-30% of S aisian/ethiopian

More than 65 commonly used drugs are substrates
- Metabolizes some 16 commonly used drugs e.g. warfarin and phenytoin

• Two allelic variants are known: metabolizes substrates 5% to 12% of the wild type enzyme
• Warfarin clearance is greatly reduced in individuals possessing the allelic variants
  Dose adjustments are required for drugs in individuals who have the mutant enzymes

Question 22

CYP2C19

Answer 22

• Eight allelic variants identified
• All are nonfunctional proteins
  Dose adjustments must be made for poor metabolizers of S-mephenytoin and for other drugs that are substrates for this enzyme

Question 23

Enzymes that exhibit genetic variation

Answer 23

Pseudocholinesterase
N-Acetyltransferase (isoniazid is a substrate)
• Cytochrome P450 2D6
• Cytochrome P450 2C19
• TMPT -Thiomethylpurinetransferase
• Dihydropyrimidine Dehydrogenase
Patients with low activity (6-10%) or absent activity (0.3%) are at risk of drug-induced bone marrow toxicity

Question 24

children

Answer 24

• Drug metabolising enzymes are often deficient or reduced particularly in the foetus 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. Rate falls as they become adults.

Question 25

gender

Answer 25

• 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 26

elderly

Answer 26

• 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 27

ethnicity

Answer 27

• Race may also affect drug metabolism.
• There are many incidences of racial differences in the genetic expression of cytochrome P-450 isoforms
Results from drug studies in one area may not be generalisable worldwide to other ethnicities