drug metabolism Flashcards
pH equation
-log10[H+]
physiological pH
7.4
what happens to amino acids at physiological pH?
protonated at the amine group
what proteins can the kidney filter out?
xenobiotics
xenobiotics definition
proteins found in plants that the kidney can filter out
metabolism function
inactive and excrete xenobiotics
go from non polar molecules to polar ones
tag molecules so that the body can recognise them
what occurs in phase 1?
introduce or reveal a functional group by hydroxylation, oxidation, reduction or hydrolysis
what occurs in phase 2?
conjugate to a polar molecule such as glucuronate, sulfate, glycine and glutathione
allows a point of attack for conjugating systems
where does phase 2 take place?
liver primarily
GI, kidney and lungs
why are nonpolar drugs not excreted?
able to diffuse across the bilayer of the nephron epithelia, so they become reabsorbed easily
problem with phase 1 reactions?
products are often more chemically active and thus are more toxic
oxidation reaction definition
adding oxygen which results in a change within the chemical substance
reduction reaction definition
removal of oxygen
what may the activation of xenobiotics result in?
formation of carcinogens
prodrug definition
medication that becomes active once metabolised
important enzymes in phase 1
cytochrome P450 and monoamine oxidase
explain cytochrome P450 action
aliphatic hydroxylation, replacing CH with CO
oxidises hydrocarbons to form an alcohol and water
mixed function oxidase, will oxidise any tagged molecule
explain monoamine oxidase action
oxidise nitrogen on the monoamines to form aldehyde intermediates and ammonia
oxidative deamination
phase II general product properties
increased molecular weight
less active than substrates
polar metabolites- water soluble
where is alcohol metabolised in the body? + why
liver
has a high concentration of enzymes
brief stages of alcohol breakdown
ethanol–> acetaldehyde –> acetic acid and acetyl- CoA
phase I in alcohol metabolism
ethanol is oxidised to acetaldehyde using NAD+ and alcohol dehydrogenase
how is alcohol metabolised in a fetus + why?
alcohol dehydrogenase is not yet fully developed
alcohol metabolism depends on cytochrome P450
phase II in alcohol metabolism
acetaldehyde dehydrogenase catalyses the oxidation of acetaldehyde to acetic acid
why is phase II important?
aldehydes are highly unstable compounds that form free radical structures which are highly toxic
lead to the damage of neural crest cells and can cause severe birth defects
can cause severe liver and kidney disease
alcohol side effects
hypoglycaemia, lactic acidosis, hyperuricaemia
hypoglycaemia explained
alcohol contains sugars, leading to an increase in insulin secretion, which leads to low blood glucose
also impairs gluconeogenesis
lactic acidosis explained
ethanol is metabolised using NAD to form NADH
high levels of NADH inhibit the glycolysis pathway, to prevent too much glucose being broken down
this diverts the pyruvate metabolism towards lactate
hyperuricaemia definition
excess uric acid in the blood
what does the amount of urate depend upon?
balance between the amount of purines eaten in food, and urate synthesised by the body and the amount of urate excreted in urine or through the GI tract
explain alcoholic hyperuricaemia
ethanol increases uric acid by increasing lactic acid production
how may alcohol cause paracetamol toxicity?
- alcohol presence induces transcription of more cytochrome P450
- more cytochrome P450 will oxidise paracetamol
- 10% of the products are quinoneimine which is a hot electrophile which can cause cell death and organ failure
explain metabolism of paracetamol
- paracetamol does not undergo phase I, as it already has a polar hydroxyl group
- tagged with glucuronate or sulfate which is then urinated out
- 10% is oxidised by CYP2E1 to form an electrophile
why is paracetamol overdose dangerous?
large quantity of quinoneimine in the liver
will link sulfhydryls, crosslinking proteins resulting in coagulation
