Drug Metabolism

Question 1

What makes a drug unsuitable for oral administration? Give example of functional groups that are unsuitable

Answer 1

Insulin/GH/oxytocin/antibodies (amide bond) will be broken down by peptidases in the stomach

siRNA/nucleotides (phosphodiester) will be broken down by bacteria and enzymes in gut

Penicillin can be actively transported into the PCT cells and be reabsorbed

Question 2

What effect does drug binding to plasma proteins like albumin have?

Answer 2

Reduces free in plasma drug concentration, reducing concentration that can diffuse into tissue fluid across capillaries

Reduces renal clearance as albumin does not get flushed into glomerular filtrate

Increases half life of drug as it remains in body for longer

Question 3

What is carrier-mediated transport?

Answer 3

Where drug uses an existing membrane carrier to be transported across a membrane, usually by mimicking the characteristics of the normal substrate

Question 4

What is the overarching goal in all drug metabolism?

Answer 4

To turn a drug from non-polar/hydrophobic to polar/hydrophilic

Question 5

What generally occurs in phase 1 and 2? Which phase is necessary?

Answer 5

Phase 1 = oxidation (to reveal or introduce functional group(s)) increasing polarity

— either inactivates drug, partially inactivates drug or activates (in which case original molecule was pro-drug)

Phase 2 = conjugation of polar molecule (e.g. glucuronate/sulphate/glutathione) to further increase polarity so that metabolite can be excreted in urine

— Phase 2 can happen independently of phase 1

Question 6

What are the most common reactions that occur in phase 1? Give examples

Answer 6

Hydrolysis (e.g. acetylsalicylic acid + water —> salicylic acid + acetic acid)

Oxidation

— oxidative deamination by monooxygenases
— mixed function oxidases such as Cytochrome P450 system (CYP450)

Question 7

What does ADME stand for?

Answer 7

Absorption

Distribution

Metabolism

Excretion

Question 8

Function of MAO?

Answer 8

Oxidises amines to aldehydes, thus degrading some NTs

Question 9

Function of CYP450s?

Answer 9

Big superfamily of mixed function oxidases

Mostly replace H with OH using NADPH (e.g. introducing alcohol functional group)

Question 10

Common inhibitors of MAO and CYP450, and their effects?

Answer 10

MAO-inhibitor = Iproniazid, causing sympathomimetic effect

CYP450-inhibitor = warfarin, preventing its metabolism of other drugs like Ibuprofen

Question 11

Explain the effects of a paracetamol overdose

Answer 11

Phase 2 mostly:

60% metabolised to UDP-GT adding glucuronate
30% metabolised by sulphotransferase adding sulphate

But:

10% oxidised by CYP2E1 to form N-acetyl-p-benzo-quinoneimine (NAPQI) which is very reactive, cross-linking with many proteins

— in low doses, glutathione S-transferase adds glutathione which is safe

— in high doses, first two pathways become saturated, so more goes through phase 1 pathway and hepatocellular glutathione is depleted, leading to greater production of NAPQI… this remains in liver where it damages proteins and membranes

Question 12

How do you prevent lidocaine toxicity when administering IV? Why is it toxic otherwise?

Answer 12

Co-injection of Noradrenaline, which constricts blood vessels by binding to A1-adrenoreceptors (Gq-PhospholipaseC-PIP2 cleaved to IP3 and DAG-IP3 induced calcium release-contraction)

Otherwise, lidocaine would be carried in blood around the whole body, inhibiting the ubiquitously expressed voltage gated Na-channels

Question 13

Genetic consideration with respect to suxamethonium

Answer 13

Suxamethonium/succinylcholine is a short acting muscle relaxant, depolarising nicotinic acetylcholine receptors so that depolarisation is sustained and repolarisation can not occur, inhibiting action potentials

Usually lasts <10mins

Pseudocholinesterase deficiency - suxamethonium hydrolysis takes longer due to enzyme deficiency

Hydrolysis lasts 6-8 hours