pharmacokinetics

Question 1

two major routes of drug excretion

Answer 1

kidney: most drugs by urine; liver: some drugs concentrated and secreted in bile (usually large molecular weight conjugates) and lost in faeces

Question 2

drug excretion in kidney

Answer 2

low MW drugs ultrafiltered at glomerulus (20%); of 80% plasma passing round (including all other drugs), massive amount of active secretion of basic/acidic drugs in proximal tubule (dependent on available transporters); passive reabsorption of lipid soluble drugs in distal tubule and collecting duct (dependent on urine pH, drug pKa and extent of drug metabolism)

Question 3

drug excretion in liver: biliary

Answer 3

large discontinuous capillary structure, so drugs can easily leave bloodstream into hepatocytes; concentrated larger molecular weight molecules, with active transport systems pumping into bile (bile acids and glucuronides) to be lost in faeces, as made more water-soluble in kidney for excretion

Question 4

drug excretion in liver: enterohepatic cycling as problem of bile excretion

Answer 4

drug/metabolite excreted into gut via bile then reabsorbed (gut bacteria break down conjugate, releasing free drug back to lipid-soluble form and diffuses back into bloodstream)

Question 5

drug excretion in liver: what does enterohepatic cycling lead to

Answer 5

drug persistence (once reabsorbed into bloodstream can re-enter hepatic circulation)

Question 6

other excretion routes

Answer 6

lungs, skin, GI secretions, sweat, saliva, milk, genital secretions

Question 7

reason why a drug should be lipophilic

Answer 7

so can access tissues (from blood and lymph) to have a therapeutic effect; all will eventually return to blood and lymph (down concentration gradient)

Question 8

reason why drug should be water-soluble

Answer 8

so it can be retained in the blood (and lymph) and delivered more easily to excretion sites

Question 9

why are drugs designed to be relatively lipid soluble

Answer 9

as body alters drug and converts it to metabolites (metabolism), to make it less lipid-soluble and easier to excrete

Question 10

phase 1 drug metabolism aim

Answer 10

introduce a reactive group to drug to increase polarity and activate drug

Question 11

phase 2 drug metabolism aim

Answer 11

add water soluble conjugate to reactive group (which serves as a point of attachment)

Question 12

what reactions create new functional groups, and what are these groups

Answer 12

oxidation to electrophiles, reduction to nucleophiles

Question 13

what reaction unmasks the new functional groups

Answer 13

hydrolysis to nucleophiles

Question 14

what is the most common phase 1 metabolism

Answer 14

oxidation, which often starts with hydroxylation

Question 15

where does phase 1 metabolism occur, and with what enymes; what is difficult to predict about this

Answer 15

liver; 57 subtypes of cytochrome P450 enzyme in smooth endoplasmic reticulum (different subtypes metabolise different drugs; proportion varies between people, so difficult to predict metabolism)

Question 16

where does oxidation occur with aspirin

Answer 16

on -OCOCH3 acetyl group; converted to -OH (salicylic acid by removing acetyl group)

Question 17

process of nicotine to cotinine

Answer 17

oxidation

Question 18

process of cocaine to ecgonine methyl ester and benzoic acid

Answer 18

hydrolysis

Question 19

process of chloral hydrate to trichloroethanol

Answer 19

reduction

Question 20

what can an active parent drug be converted into

Answer 20

inert metabolite (no effect on body; e.g. nicotine) or active metabolite (continues/increases effect on body, so prolongs effects; e.g. cannabis)

Question 21

what can an inactive parent drug be converted into

Answer 21

active metabolite (prodrug e.g. codeine)

Question 22

example of phase 2 metabolism reactions: electrophiles (from oxidation)

Answer 22

glutathione conjugation

Question 23

examples of phase 2 metabolism reactions: electrophiles: nucleophiles (from hydrolysis or reduction)

Answer 23

glucuronidation, acetylation, sulfation; conjugating agents are larger chemicals that donate side-chain onto drug

Question 24

what is the most common phase 2 metabolism reaction

Answer 24

glucuronidation

Question 25

what type of reaction is glucuronidation and drugs

Answer 25

low affinity/high capacity, so is more likely to occur at high drug dosages e.g. aspirin, paracetamol (20-30% metabolism but only when at high dose)

Question 26

in electrophile (oxidation) phase 2 metabolism, what are the conjugation agent and target functional group of electrophiles

Answer 26

glutathione; electrophiles

Question 27

in nucleophile (hydrolysis or reduction) phase 2 metabolism, what are the conjugation agent and target functional group in glucuronidation

Answer 27

UDP-glucuronic acid; -OH, -COOH, -NH2, -SH

Question 28

in nucleophile (hydrolysis or reduction) phase 2 metabolism, what are the conjugation agent and target functional group in acetylation

Answer 28

acetyl CoA; -OH, -NH2

Question 29

in nucleophile (hydrolysis or reduction) phase 2 metabolism, what are the conjugation agent and target functional group in sulfation

Answer 29

3’-phosphoadenosine-5’-phosphosulphate; -OH, -NH2

Question 30

what type of reaction is sulfation and drug

Answer 30

high affinity/low capacity, so is more likely to occur at low drug dosages e.g. paracetamol (100% at low dose but 40-60% metabolism at high dose)

Question 31

what must the other 10% of paracetamol (at high doses) be to undergo glutathione conjugation and drug

Answer 31

electrophilic or biotransformed to an electrophilic conjugate

Question 32

how is paracetamol converted to an electrophile and final product

Answer 32

lose H groups on -OH (forming =O), ring and NH (forming C=N) to generate NAPQI, before undergoing glutathione conjugation on ring C next to COH

Question 33

problem of electrophiles and impact of paracetamol overdose

Answer 33

NAPQI extremely reactive, so if paracetamol overdose the gluathione stores are overwhelmed so can’t conjugate, so left with very reactive NAPQI (reacts with proteins in liver, causing dysfunction); forms NAPQI glutathione conjugation if not overdose, otherwise remains as NAPQI

Question 34

less common phase 2 metabolic pathways

Answer 34

acetylation, methylation, amino acid conjugation

Question 35

in phase 2 acetylation, what is the usual R group and what enzyme is used; drug example

Answer 35

aromatic amine with acetyl group, N-acetyltransferase (NAT); isoniazid

Question 36

in phase 2 methylation, what is the R group and what enzyme is used; drug example

Answer 36

methyl group, methyltransferases (MT); levodopa

Question 37

in phase 2 amino acid conjugation, what are two possible reactions

Answer 37

with carboxylic acid group of amino acid, with amino group of amino acid

Question 38

5 purposes of drug metabolism: biological half-life, duration of exposure, accumulation of compound, potency/duration of biological activity; pharmacology/toxicology of drug

Answer 38

biological half-life is decreased, duration of exposure is reduced, accumulation of compound in body is avoided, potency/duration of biological activity can be altered; pharmacology/toxicology of drug can be governed by its metabolism