drug metabolism Flashcards
where does metabolism happen (biotransformation)
gut lumen and wall plasma lungs kidneys nerves liver
what is phase one metabolism
usually oxidation, reduction or hydrolysis
introduce/reveal a chemical group
‘functionalisation’
products are usually more reactive
prepares for phase 2
e.g. adds OH, NH2, -SH, -COOH
what is phase 2 metabolism
synthetic or conjugative
usually hydrophilic or inactive compounds
adding something on!
e.g. sulfation acetylation amino acid conjugation fatty acid conjugation condensation
requires something to conjugate with
can then be excreted in bile or urine
what are the possible results of metabolism
deactivation/ activation
type of pharmacological response
drug uptake/ distribution
hydrophilicity
what enzymes are responsible for oxidation
mixed functional oxidases- cytochrome P450
alcohol dehydrogenase
xanthine oxidase
name some reduction reactions
ketone reduction
anaerobic cytochrome P450 metabolism
name some hydrolysis reaction
ester hydrolysis
amide hydrolysis
what does cytochrome p450 require
oxygen
NADPH
what are the problems with drug metabolism
overlapping substrate specificities drugs for same enzyme different enzymes for same substrate enzyme can be saturated conjugate can be depleted variation between people
what are the sources of excretion
breath urine saliva perspiration faeces milk bile hair
remember that drug or metabolite could be excreted
how are substances transfered from plasma to bile
organic cation transporters
organic anion transporters
p glycoproteins
describe entero hepatic recirculation
hydrophilic conjugates e.g. glucuronides are delivered to intestine
hydrolysis can occur in intestine by gut microbiota (depends on person) - will affect half life and efficacy - think of antibiotics and oral synthetic oestrogens
what drugs can be filtered
below 20 kDa
not if bound to plasma albumin
describe tubular secretion of drugs
OATs and OCTs
OATs transport against a chemical gradient
cleared even if bound to albumin
how do you change urine pH in order to favour excretion of weak acids
make urine more alkaline
what is zero order kinetics
straight line
constant rate of drug removal
eg alcohol - 1 unit per hour approx
few drugs
does not vary with amount of drug present
enzyme saturation
what is first order kinetics
curvey graph
able to calculate a half life
most drugs
constant fraction metabolised per unit time
increases proportionately to drug
more drug, faster metabolism
eg aspirin
how do you calculate the apparent volume of distribution of a drug
total amount of drug in the body /
blood plasma concentration of the drug
what is the sum of all routes of elimination equal to (l/h)
clearance
what is the half life dependent on
ln2 x Vd/
Cl
what factors affect drug metabolism
age genetic variation race disease other medications
where are microsomal CYP450s found
in endoplasmic reticulum, mostlly in kidney but also lung, liver and intestine
describe the metabolism of aspirin
first undergoes hydrolysis to produce salicylic acid
some salicylic acid is excreted in urine
the rest is conjugated to from glucoronide
what is ion trapping
more ionised drug
is less able to be reabsorbed from the nephron so is eliminated
