pharmacokinetics Flashcards
distribution: identify the factors that affect the passage of drugs across membranes and thus determine drug distribution
two methods of drug molecule movement in body
bulk flow transfer i.e. bloodstream, gut; diffusional transfer over short distances
what two environments do drugs have to traverse, with examples
aqueous (compartments i.e. blood, lymph, ECF, ICF) and lipid (barriers i.e. cel membranes in epithelium/endothelium)
4 methods of drugs crossing lipid bilayer
simple diffusion, diffusion across aquous pores (if water-soluble), carrier mediated transport (usually active), pinocytosis
which route is least relevant to pharmacokinetics
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
where does bulk flow occur in enteral drug routes
ingestion to stomach; liver to blood and lymph
where does diffusion occur in enteral drug routes
blood and lymph to ECF; ECF to orgnas
where are the barriers in enteral drug routes
GIT to liver; blood and lymph to ECF; ECF to organs
oral route of drug administration including membranes
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
what do most drugs exist as, and what does this ratio depend on
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
at physiological pH (7.4), what is aspirin more likely to do concerning protons
donate as weakly acidic (H+ donated from COOH group)
at physiological pH (7.4), what is morphine more likely to do concerning protons
accept as weakly alkali (H+ accepted onto NCH3 group)
solubility of unionized forms of aspirin and morphine
more lipid soluble
pH as determinant of drug absorption across lipid membranes (weak acids vs weak bases)
weak acids more unionized in acidic environments (at eqm), weak bases more unionizes in alkaline environments (eqm)
weak base Henderson-Hasselbalch equation
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
weak acid Henderson-Hasselbalch equation
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
does pKa of drug or pH of different bodily comparments change
pH of different bodily comparments
when does AH or A- predominate in stomach (pH 3), blood (pH 7.4) and urine (pH 8) when aspirin (pKa 3.5) administered
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)
when does B or BH+ predominate in stomach (pH 3), blood (pH 7.4) and urine (pH 8) when morphine (pKa 8) administered
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
ion-trapping definition
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
treatment with IV Na2CO3 and effect on aspirin excretion
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
4 factors influencing drug distribution
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
regional blood flow: liver, heart, brain, kidneys and muscle
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)
EC binding: plasma protein binding
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)
capillary permeability: continuous vs BBB vs fenestrated vs discontinous
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
capillary permeability: lipid-soluble drugs vs water-soluble drugs
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
localisation in tissues: blood flow to fat
blood flow to fat is 2% (very low), so only small amounts of non-ionised drug is being delivered to body fat
localisation in tissues: oil/water partition coefficients
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
