CPT1: metabolism Flashcards
What is metabolism?
Enzymatic conversion of one chemical compound to another
Where does metabolism occur?
- Mostly the liver
- some in the gut wall, lungs and blood
What happens to a drug when it is metabolised? why is this required?
It can make it more water soluble which is essential from drugs being excreted in bodily fluids e.g. urine, bile
It usually results in dimished therapuetic effect
What are factors effecting metabolism?
- Aging - decline in hepatocyte number and activity as age increases. Babies have poorly developed metabolising enzyme
- Disease - reduced hepatic blood flow - heart failure/ shock - (tissues/ organs less perfused so hepatic cells die and less metabolising enzymes)
- Genetic - drugs, diet, enviro factors - grape fruit juice and st johns worts. Cigretter smoke and brussle sprouts
What do drugs which display ‘zero order’ or ‘non-linear’ kinetics do to eliminating enzyems?
They saturate elimination enxymes at therapeyutic concentrations. A small increase in dose leads to a disproportionaly large increase in plasma concentration.
What are example of compounds which dispaly zero order kinetics?
- Salicylates
- Phenytoin
- ethanol
Where are the enzymes essential for drug metabolism stored?
- Liver hepatocytes
To what group do the maintain metabolising enzymes belong and where are these found?
CYP450s - held in the smooth endoplasmic recticulm of the cells
What stages of metabolism occur and in what order?
- Phase 1 and 2
- Some drugs under go just 1 or just 2 but the majority under go 1 then 2
What does phase 1 involve?
- Involves hydrolysis, but most commonly oxidation
- Oxidation catalysed by CYP450s (mainly CYP450 monoxygenase) (results in loss of electrons)
- Drug metabolite may still be active
- What does phase 2 metabolism involve?
- Where does this normally occur?
- involves conjugation - the addition of an ionised group to the drug e.g. glutathione, methyl or acetyl group
- generally occur in hepatocyte cytoplasm
What does phase 2 do to the drug
Makes it more water soluble which facilitates excretion and decreases pharmacological action
- What is the first pass effect?
- What routes avoid this?
- When the concentration of a drug is greatly reduced before reaching the systemic circulation.
- Buccal and rectal
Which blood vessel takes the drug to the liver when absorbed orally?
Hepatic portal vein
What is the hepatic extraction ratio?
How is this calculated?
The fraction of the drug metabolised (and eliminated) by a single passage through the liver (E)
E= Cin - Cout / Cin
What enzyme metabolizes drugs in the GUT wall?
CYP 3A4
Discuss metabolism of paracetomal and how problems can be reversed
Paracetomal when metabolised produces a toxic metabolite. It can be detoxicifed with a phase 2 conjugation reaction with glutathione. However in over doses there is not enough glutathione to detoxify the metabolites. A compound which increases glutathione levels mjst be adminitstered to prevent hepatocytisis
Describe induction
When one drug A increases the rate of metabolism of the drug B. Drug Bs concentration is reduced to below therapeutic levels and becomes ineffective
Describe inhibition
When Drug A reduces the rate of metabolism of drug B and leads the concentration of drug B increasing above therapeutic levels to toxc levels
What is onset?
An accumulation of inducing agemts and increase in enzyme production
What is offset?
Elimination of inducing agents and decrease in efficacy of enzymes
Describe the withdrawl of an inducer referring to specific examples
- PAteint takes warfarin and barbituates
- Barbituate causes induction so warfarin clearance is increased. To prevent this the dose is increased of warfarin.
- If barbituate is withdrawn them the levels of warfarin will increase above to toxic levels
What are beneficail uses of inducers?
New borns have poorly developed metabolising enzymes.
If babies don’t conjugate bilirubin efficently iy will result in juandice. so small levels of barbituates can help induce liver enzymes to clear bilirubin
What is induction and inhibitation in relation to CYP450s?
induction - increase in no. of enzymes in liver
Inhibitation - decrease in efficacy of enzymes
Is alcohol a inhibitor or inducer?
Why?
It is normally an inducer however in acute intoxicatin it may not give enough time to synthesis new enzymes therefore leading to an inhibitory effect
What is st johns wort
- Herbel remedy used to treat mental health problems
- Its an inducer
- may significantly reduce the effectvieness of the following by induction of hepatic CYP450s and intestinal p-GP:
- Anticonvulsants
- Cyclosporin
- Digoxin
- Protease inhibitors
- Oral contraceptives
- Theophylline
- Warfarin
What effect do fruit juices have?
- Grape fruit juice contains antioxidants which inhibit CYP3A4 in the intestinal and GUT wall - leads to increased Ca2+ channel blockers
- Cranberry juice contains antioxidants which inhibit CYP450s - leads to rising levels of warfairn
