Week 2 Pharmacology - Biotransformation Flashcards
What is the purpose/goal of biotransformation reactions?
Transformation of lipid molecules into more readily excitable hydrophilic molecule - usually taking place in the liver (but also GIT, lungs, skin, kidneys)
What are phase I reactions?
Conversion of parent drug to a more polar metabolite, by introduction or unmasking of a ‘functional group’ –> OH, NH2, SH
Often these metabolites are highly polar and inactive, and can be readily excreted.
Mediated by cytochrome p450 system
What are examples of phase I reactions?
Oxidation: Propranolol, warfarin
Reduction: methadone, naloxone, clonazepam
Hydrolysis: Procaine, aspirin, lidocaine
Deamination: amphetamine, diazepam
What are phase II reactions?
‘Conjugation reactions’ - where new highly polar functional group interacts with endogenous substrate (glucaronic acid, sulphuric acid, acetic or amino acid) to form highly polar conjugate
What are examples of phase II reactions?
Conjugation: Morphine, Diazepam, Digoxin
Acetylation: Sulphonamides, ionoiazid, clonazepam
Sulfation: Methyldopa
Methylation: Dopamine, adrenaline, histamine
What are the mechanisms by which activity of p450 pathways can be increased?
Increased gene expression
Increased synthesis
Reduced degradation
What is the effect of an p450 inducer?
It increases the activity of the cytochrome p450 system, which potentiates increased drug metabolism (and therefore will reduce the pharmacological action of the inducer and of co-administered drugs)
What are examples of drugs that induce p450?
CRAP GPs
Carbemazepine
Rifampicin
Alcohol (chronic)
Phenytoin
Griseofulvin
Phenobarbitone
Sulphonylureas
What is the effect of inhibition of p450 system?
Reduced activity = a reduction in substrate metabolism and usually an increase in the pharmacological action of the inhibitor and co-ingested drugs
What are examples of p450 inhibitors?
CAFE KFC
Cimetidine
Amiodarone
Fluconazole
Erythromycin
Ketoconazole
Fluoxetine
Chloramphenicol
Also, Metronidazole, Na+ Valproate, Alcohol binge, sulphonamides
What is phase I clinical trial?
Studied in small group health volunteers
What is phase II clinical trial?
Studied small group with target disease
What is phase III clinical trial?
Tested in large cohort of disease
What is phase IV clinical trial?
Monitoring safety of a new drug in clinical conditions on the market
