DRUG METABOLISM

- Mechanism by which the body terminates the action of some drugs

- In some cases, it serves to activate prodrugs
1. Active ----- inactive (readily excreted by the kidneys)
2. Active ----- active metabolites
3. Inactive --- active
(Prodrug)

TYPES OF METABOLIC REACTIONS

PHASE I
- Non-synthetic reactions
- Converts the parent drug to a more polar conjugate (water soluble) or more
reactive product
- Introducing/inserting/unmasking a polar functional group
- OH, SH, NH2

PHASE I

1.Oxidation

2.Reduction

3.Deamination

4.Hydrolysis

PHASE II

- Synthetic reactions
- Endogenous substrate is conjugated to the parent drug to make it more polar

PHASE II

1. Glucoronidation-glucoronic acid

2. Acetylation-acetyl CoA

3. Sulfation 4. Methylation

5. Glycine conjugation-glycine

6. Glutathione conjugation

7. H20 conjugation

PHASE I ------- PHASE II (most drugs)

PHASE II ------- PHASE I (other drugs)

- Isoniazid Acetylation ------- hydrolysis

PENICILLIN

- Maybe metabolized by gastric fluid

- Must be given 2 hours before meals if given through the oral route

OTHER DRUGS METABOLIZED

- Gastric acid
*Penicillin

- Gastric and digestive enzymes

*Insulin

- Intestinal wall enzymes

*Epinephrine

LIVER

- Most important organ for drug metabolism

- Smooth endoplasmic reticulum (SER) contains high concentration of PHASE I
enzymes
- Mixed function oxidases
- Activity of these enzymes require: NADPH (reducing agent) and Molecular
form of oxygen

DETERMINANTS OF BIOTRANSFORMATION RATE

A. GENETIC FACTORS

1. HYDROLYSIS OF ESTERS

- Succinylcholine

- Ester that is metabolized by plasma choline esterase

- In most individuals, the process occurs rapidly

2. ACETYLATION OF AMINES

- Isoniazid (INH)

- Amines such as hydralazine, and procainamide

- Individuals deficient in acetylating capacity

- Prolonged or toxic responses to normal doses of this drug

3. OXIDATION
- Dextrometorphan, metoprolol and some tricyclic antidepressants

- Oxidation by P450 isoenzymes are genetically predetermined

Individual differences

A. Diet and environmental factors

- Charcoal inhibits the effect of the drug
- Grapefruit juice increases the amount of drug in the body
B. Age and sex
- Drug metabolites differ in young and old
- Males metabolize drugs faster than females
C. Hyperthyroidism

B. OTHER DRUGS

1. ENZYME INDUCTION

- Increase rate of synthesis of the enzyme

- Reduce the rate of degradation of the enzyme

- May also induce self-metabolism of the drug

- May also induce metabolism of other drugs and reduce its effects

- Enzyme inducers: Phenobarbital

Carbamazepine + drug = decreased effects

Phenytoin Rifampicin

2. ENZYME INHIBITION

- Inhibit CP450

-Metabolism of the drug is diminished

- Increase effect of the drug

- Enzyme inhibitors: Amiodarone and Cimetidine

Ketoconazole + drug = increased effect

Ritonavir and Furanocoumarin

TYPES OF DRUG INTERACTION MECHANISM

1. Altered absorption
- Cholestyramine inhibits the effect of digoxin when combined with it
2. Altered metabolism
- Affects drug action
3. Altered plasma binding protein
4. Altered excretion
- Probenecid inhibits the secretion of acids
- Penicillin inhibits the excretion of probenecid

DRUG INTERACTION
1. ADDITIVE *1 + 1 = 2
- Response elicited by combined drugs is equal to the combined response of
the individual drugs
- Sedative + ethanol
2. SYNERGISTIC *1 + 1 = 3
- response elicited by combined drugs is greater than the combined responses
of each individual
- Penicillin G removes the cell wall Gentamicin inhibits production of protein
3. POTENTIATION *0 + 1 = 2
- Drug which has no effect enhances the effect of the second drug
- Cimetidine + anticoagulant (enhances the anticoagulation)
4. ANTAGONISM * 1 + 1 = 0
- Drug inhibits the effect of another drug
- Heparin + protamine