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Chapter 4 Pcol

Drug metabolism refers to the process by which the body breaks down and eliminates drugs. There are two phases: Phase I involves reactions that make the drug more polar through oxidation, reduction, or hydrolysis. Phase II involves conjugating the drug with endogenous compounds like glucuronic acid to make it more water soluble for excretion. The liver is the primary site of drug metabolism through enzymes in the smooth endoplasmic reticulum. The rate of biotransformation can be affected by genetic factors, other drugs through induction or inhibition of drug-metabolizing enzymes, and environmental factors like diet. Drug interactions occur when one drug alters the metabolism or effects of another drug through various mechanisms.

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0% found this document useful (0 votes)
192 views4 pages

Chapter 4 Pcol

Drug metabolism refers to the process by which the body breaks down and eliminates drugs. There are two phases: Phase I involves reactions that make the drug more polar through oxidation, reduction, or hydrolysis. Phase II involves conjugating the drug with endogenous compounds like glucuronic acid to make it more water soluble for excretion. The liver is the primary site of drug metabolism through enzymes in the smooth endoplasmic reticulum. The rate of biotransformation can be affected by genetic factors, other drugs through induction or inhibition of drug-metabolizing enzymes, and environmental factors like diet. Drug interactions occur when one drug alters the metabolism or effects of another drug through various mechanisms.

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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

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