Drug Metabolism

Question 0

What are some examples of drugs where the metabolites are more pharmocologically active than the drug?

Answer 0

Primidine -> Phenobarbitone (anti-epileptic)
Codeine -> Morphine (analgesia)

Pro-drugs = undergo metabolism before becoming active.

note: Pethidine -> Norpethidine (metabolite is toxic)

Question 1

Define pharmacology and explain how it can be further sub-divided.

Answer 1

Pharmacology = study of how chemical agents affect the function of living systems

Pharmacodynamics = what the drug does to the body
Pharmacokinetics = what the body does to the drug
(ADME: absorption, distribution, metabolism, elimination)

Pharmacoepidemiology = study of drug effects in a large population

Pharmacovigilance = reporting of adverse drug reactions post-marketing

Question 2

What are the two phases of drug metabolism characterised by?

Answer 2

Phase 1 = oxidation, reduction, hydrolysis + (adds or exposes reactive group)

Sites: microsomes on ER of liver cells (+ GI, kidney, lung, cholinesterase enzymes in plasma)

Enzymes: CYP450 (cofactor = NADPH)

Phase 2 = conjugation (drug combined with water soluble group so it can be excreted by the kidney)

Site: liver (cytosolic enzymes)

Reactions: e.g. glucuronidation, sulfate conjugation, glutathione conjugation

Question 3

What factors affect drug metabolism?

Answer 3

GENETIC:
Polymorphisms = individual variation in population e.g. affects timescale of drug metabolism
Gene deletions -> enzyme deficiencies

ENVIRONMENTAL:
Enzyme inhibition = cimetidine inhibits metabolism of other drugs
(grapefruit & cranberry juice)

Enzyme induction = metabolism of one agent increases metabolism of other drugs
e.g. alcohol, nicotine, barbituates

Question 4

How is paracetamol metabolised?

Answer 4

Therapeutic dose -> glucuronidation/sulfation

Toxic dose -> glucuronidation/sulfation pathway saturated. Paracetamol converted to NAPQI (toxic) which can be conjugated to glutathione.
When glutathione runs out, liver failure due to oxidation results.

Treatment: N-acetyl cysteine

Question 5

How is alcohol metabolised? How much is one unit, and what is the recommended limit for men and women per week/day?

Answer 5

1 unit = 8g
Men: 21 units/wk or 4 units/day Women: 14 units/wk or 3 units/day

		  (CYP 2E1)               (aldehyde dehydrogenase) Alcohol ---------> Acetaldehyde ----------------------> Acetic acid 
          NAD+                      

Increased NADH -> increased fatty acid synthesis

Question 6

Describe the mechanism of chronic alcohol toxicity.

Answer 6

Excess NADH -> stimulates fatty acid synthesis & inhibits export of TAGs from liver

Production of acetaldehyde

Fatty liver -> Alcoholic hepatitis (inflammation) -> Alcoholic cirrhosis

Question 7

What is the pharmacological treatment of alcoholism?

Answer 7

Disulfiram inhibits aldehyde dehydrogenase -> increases [acetylaldehyde] -> hangover side-effects all week

Conditions patient not to drink alcohol