pharmacokinetics

Question 1

two methods of drug molecule movement in body

Answer 1

bulk flow transfer i.e. bloodstream, gut; diffusional transfer over short distances

Question 2

what two environments do drugs have to traverse, with examples

Answer 2

aqueous (compartments i.e. blood, lymph, ECF, ICF) and lipid (barriers i.e. cel membranes in epithelium/endothelium)

Question 3

4 methods of drugs crossing lipid bilayer

Answer 3

simple diffusion, diffusion across aquous pores (if water-soluble), carrier mediated transport (usually active), pinocytosis

Question 4

which route is least relevant to pharmacokinetics

Answer 4

diffusion across aqueous pores as <0.5nm wide (not many drugs are that small); if drug is lipid-soluble no problem crossing lipid bilayer; water-soluble must -pass via carrier mediated transport

Question 5

where does bulk flow occur in enteral drug routes

Answer 5

ingestion to stomach; liver to blood and lymph

Question 6

where does diffusion occur in enteral drug routes

Answer 6

blood and lymph to ECF; ECF to orgnas

Question 7

where are the barriers in enteral drug routes

Answer 7

GIT to liver; blood and lymph to ECF; ECF to organs

Question 8

oral route of drug administration including membranes

Answer 8

oesophagus to stomach by bulk flow; crosses membrane 1 (stomach) and 2 (intestinal capillary) into intestinal capillary before small intestine by diffusion; bulk flow via bloodstream to target tissue capillary; crosses membrane 3 (target tissue capillary) to target cell by diffusion

Question 9

what do most drugs exist as, and what does this ratio depend on

Answer 9

weak acids or weak bases, depending on pH as exist in ionised (polar; more water-soluble) and non-ionised (non-polar; more lipid-soluble) forms

Question 10

at physiological pH (7.4), what is aspirin more likely to do concerning protons

Answer 10

donate as weakly acidic (H+ donated from COOH group)

Question 11

at physiological pH (7.4), what is morphine more likely to do concerning protons

Answer 11

accept as weakly alkali (H+ accepted onto NCH3 group)

Question 12

solubility of unionized forms of aspirin and morphine

Answer 12

more lipid soluble

Question 13

pH as determinant of drug absorption across lipid membranes (weak acids vs weak bases)

Answer 13

weak acids more unionized in acidic environments (at eqm), weak bases more unionizes in alkaline environments (eqm)

Question 14

weak base Henderson-Hasselbalch equation

Answer 14

pKa (dissociation constant for loss of protons) = pH + log10 [BH+]/[B]; therefore, 10^[pKa-pH] = [BH+]/[B] so antilog pKa-pH gives proportion of ionised over unionised

Question 15

weak acid Henderson-Hasselbalch equation

Answer 15

pKa (dissociation constant for loss of protons) = pH + log10 [AH]/[A-], therefore, 10^[pKa-pH] = [AH]/[A-], so antilog pKa-pH gives proportion of unionised over ionised

Question 16

does pKa of drug or pH of different bodily comparments change

Answer 16

pH of different bodily comparments

Question 17

when does AH or A- predominate in stomach (pH 3), blood (pH 7.4) and urine (pH 8) when aspirin (pKa 3.5) administered

Answer 17

stomach: antilog(3.5-3)= antilog0.5, so AH; blood: antilog(3.5-7.4)= antilog-3.9, so A- (less), urine: antilog(3.5-8) = antilog-4.5, so A- (more)

Question 18

when does B or BH+ predominate in stomach (pH 3), blood (pH 7.4) and urine (pH 8) when morphine (pKa 8) administered

Answer 18

stomach: antilog(8-3) = antilog5, so BH+ (more), blood: antilog(8-7.4) = antilog0.6, so BH+ (less), urine: antilog(8-8) = antilog0, so same

Question 19

ion-trapping definition

Answer 19

drugs get very localised in certain body compartments: more unionised aspirin in stomach; more ionised aspirin in blood and lymph that doesn’t diffuse well across lipid membranes as ionised

Question 20

treatment with IV Na2CO3 and effect on aspirin excretion

Answer 20

increase as IV Na2CO3 increases urine pH (more alkali), so more ionised aspirin as pKa-pH has greater magnitude; therefore won’t diffuse back into bloodstream through kindey tubules

Question 21

4 factors influencing drug distribution

Answer 21

regional blood flow, EC binding (plasma-protein binding), capillary permeability (how easy it is to get out of blood to tissue; tissue alterations - renal, hepatic, brain/CNS, placental), localisation in tissues

Question 22

regional blood flow: liver, heart, brain, kidneys and muscle

Answer 22

liver > kidneys > muscle > brain > heart (cardiac output at rest, so more blood flow means more drug goes to that tissue); more highly metabolically active tissues have denser capillary networks (e.g. when eat meal, more blood, and therefore drug, diverts to gut; same with skeletal muscle at rest vs at exercise)

Question 23

EC binding: plasma protein binding

Answer 23

approx 50-80% of acidic drugs bound by plasma proteins, which cannot fit through H20-filled gap junction in capillary endothelium, so cannot leave bloodstream (e.g. warfarin is highly bound; acidic drugs are usually more highly bound; by taking multiple drugs, some can displace each other, increasing % free)

Question 24

capillary permeability: continuous vs BBB vs fenestrated vs discontinous

Answer 24

how easy is it for drug to leave blood and enter desired tissue (if lipid-soluble drug doesn’t matter too much, but significant for water-soluble drugs); most are continuous: H20-filled gap junction between cells; BBB: tight junction; fenestrated: small circular windows e.g. kidney glomerulus; discontinous: larger gaps e.g. liver

Question 25

capillary permeability: lipid-soluble drugs vs water-soluble drugs

Answer 25

lipid-soluble drugs: good access to all tissues incl. brain and well distributed across body tissues; water-soluble drugs: poor access to tissues and dependent on saturable carrier proteins, so less well-distributed across body tissues

Question 26

localisation in tissues: blood flow to fat

Answer 26

blood flow to fat is 2% (very low), so only small amounts of non-ionised drug is being delivered to body fat

Question 27

localisation in tissues: oil/water partition coefficients

Answer 27

if high, (really lipid-soluble drugs like general anaesthetics) more accumulate in body fat effectively, then slowly leak back into bloodstream (as poor blood flow to fat and preference to remain in fat; hence why 24hrs after general anaesthetic you feel drowsy again, as small bolus released from fat); as a result, very fat-soluble drugs have 75% partitioned in fat at eqm