Metabolism/Pharmacogenetics Flashcards
Important sites for metabolsim
lining of gut, liver, kidneys and lungs
What are prodrugs
drugs activated following metabolism
Examples of prodrugs
codeine, enalapril, simvastatin, sacubitril
Effects of metabolism (4)
Loss of pharmacological activity
Decrease in activity
Increase in activity (prodrug)
Production of toxic metabolites
Individual drugs can be metabolised by more than one enzyme (T/F)
T
How many phases does drug metabolism have
2
Phase 1
Oxidation
Reduction
Hydrolysis
What is the purpose of phase 1 meatbolsim
Increases the polarity of the compound and provides an active site for phase 2
Cytochrome P450
Family of enzymes critical for the metabolism of drugs
Cytochrome P450
Family of enzymes critical for the metabolism of drugs
CYP3A4
Found in gut and responsible for the pre-systemic metabolism of several drugs- methadone,diazepam, Simvastatin, CCBs
CYP2D6
Responsible for the metabolism of anti-depressants, anti-psychotics and conversion of codeine to morphine
CYP1A2
Induced by cigarette smoke and is important in the metabolism ofntheophylline
Phase 2
Glucuronidation (glucuronide acts as a conjugation molecule and binds to a substrate) which increases water solubility and enhances excretion of metabolised compound
Factors that affect metabolism (8)
Herbal/natural drugs Genetics Hepatic blood flow Liver disease Age Sex Ethnicity Pregnancy
Grapefruit_____effects of____ by inhibiting CYP3A
increases and felodipine
CYP2D6 has ____ nucleotide pleomorphisms
70
CYP2C9 has_____ allelic variants known
2
CYP2C19 has _____ allelic variants known
8
Enzymes that exhibit genetic variations (6)
Pseudocholinesterase N-Acetyletransferase CYP2D6 CYP2C19 TMPT Dihydropyrimidine
Women don’t metabolise drugs faster than men (T/F)
F they do
Production of toxic metabolites can lead to___
Direct toxicity
Carcinogenesis
Teratogenesis
Example of activation of prodrug
Terfenadine ___> Fexofenadine
Drug substrate for CYP1A2
Theophylline
Drug substrate for CYP2D6
Coedine
Drug substrate for CYP3A4
Cyclosporine
CYP2D6 can be induced by
Cigarette smoke
Drugs and Food stuffs that inhibit drug metabolising enzymes
Cimetidine Erythromycin Clarithromycin Ketoconazole CCBs Grapefruit
CCBs
Calcium Channel Blockers- medications to decrease blood pressure in patients with hypertension
Grapefruit Juice_____ Felodipine Oral Availibility by ____
increases
decreasing intestinal CYP3A protein expression
Four phenotype subpopulations of metabolisers
Poor metabolisers
Intermediate metabolisers
Extensive metabolisers
Ultrarapid metabolisers
How many nucleotide polymorphisms are known
70
CYP2CP metabolises ___ commonly used drugs which include
Warfarin and Phenytoin
A poor metaboliser will need a ___ dose and an ultrarapid metaboliser will need a ____ dose
Lower and higher
