Drug metabolism Flashcards
What is first pass metabolism?
breakdown of drug before reaching systemic circulation
a medication undergoes metabolism at a specific location in the body. The first-pass effect decreases the active drug’s concentration upon reaching systemic circulation or its site of action
What drugs have high first pass?
nitrates (but not isosorbide mononitrate)
opioid analgesics
beta-blockers
clomethiazole
chlorpromazine
What is a pro drug?
inactive precursors that are converted to active metabolites
Name some pro drugs
oral cyclophosphamide - doesn’t harm GI tract but active after liver metabolism
levodopa - crosses BBB using amino acid transport, converted to dopamine in brain
azathioprine - activated to mercaptopurine
How are most drugs eliminated?
by kidneys
water-soluble drugs easily eliminated
fat-soluble = difficult to remove in urine, must be converted to soluble product usually through liver metabolism
Describe how there may be variations in liver metabolism
genetic differences in enzyme activity
environmental influences on activity - drugs that induce/inhibit enzymes, alcohol, smoking
Give some examples of drugs that can reduce effect of COCP
carbamazepine
phenytoin
strong inducers of liver enzymes - enhanced enzyme activity breaks down oestrogen component of combined pill
Name some P450 inducers
phenytoin
carbamazepine
rifampicin
St John’s Wort
barbiturates
Name some P450 inhibitors
antibiotics:
- macrolides (clarithromycin, erythromycin)
- quinolones (ciprofloxacin)
antifungals - fluconazole, itraconazole
SSRIs - fluvoxamine, fluoxetine, paroxetine
If prodrug A is activated by an enzyme, and an inducer compound is given, what is the effect on the amount of drug A available?
increase amount of active drug A
more of prodrug A is metabolised into drug A
If drug B is broken down by an enzyme and an inducer compound is given, what is the effect on the amount of drug B available?
less drug B
more drug B is broken down
If prodrug A is activated by an enzyme, and an inhibitor compound is given, what is the effect on the amount of drug A available?
less amount of active drug A
less prodrug A metabolised to drug A
If drug B is broken down by an enzyme and an inhibitor compound is given, what is the effect on the amount of drug B available?
increased amount of drug B
less drug B is broken down
What foods should be avoided while on isoniazid?
tyramine-rich foods (mature cheeses, salami, pickled herring, bovril, oxo, marmite)
histamine-rich foods (very mature cheese, scromboid fish eg. tuna, mackerel, salmon)
What drug does azathioprine have a serious interaction with?
allopurinol
Allopurinol and azathioprine should not be co-prescribed unless the combination cannot be avoided. Allopurinol interferes with the metabolism of azathioprine, increasing plasma levels of 6-mercaptopurine which may result in potentially fatal blood dyscrasias
Which blood test predicts toxicity in patients on azathioprine?
TPMT activity
enzyme that breaks down azathioprine
low activity = toxicity
What drugs should you be careful prescribing in patients with liver disease?
have extensive 1st pass
pro-drugs
sedatives - benzos, opiates
affect electrolytes/kidneys
narrow therapeutic range + are metabolised in liver - warfarin, theophylline
What should you do before prescribing in renal disease?
check medication history
assess volume status (JVP, ankle oedema)
determine level of renal insufficiency
Problem drugs in renal disease
furosemide - bigger doses needed, potential toxicity worsened
NSAIDs - worsen renal failure
Metformin - lactic acidosis
Insulin - hypoglycaemia because kidneys not excreting injected insulin
Aminoglycosides - rapid rise in concentration with repeated dosing, monitoring needed
morphine
With which drugs are elderly patients at increased risk of ADRs?
CNS drugs:
- greater response than expected from plasma concentration - increased sedation
- respiratory depression with opioids + sedatives
Orthostatic hypotension with many drugs due to poor baroceptor response
