Pharmacokinetics 3 Flashcards
Define drug metabolism
Occurs in 2 phases
Phase 1 - breaking down, enzymatic process, Oxidation (P450 cytochrome), reduction and hydrolysis. Broken into active (pro-drug), inactive or toxic product. Depends on the drug
Phase 2 - Drug solubilisation by conjunction, elimination in urine or bile. (Glucuronidation, acetylation, sulfation, methylation)
What is a prodrug?
A Prodrug is a drug or compound that is metabolised into a pharmacologically active drug.
Give the importance of the order of phase reactions
Can occur in either order
Give some examples of prodrugs
- Enalapril to Enalaprilat
- Codeine into Morphine
- Levodopa to Dopamine
Give some examples of cytochrome p450 inhibitors
Amiodarone
Ciprofloxacin
Erythromycin/Clarithromycin
Metronidazole
Fluconazole
Isoniazid
Alcohol (acute)
Grapefruit juice
What do cytochrome P450 inhibitors do to the drug?
Reduce the metabolism of the drug so increases the amount of drug available
Rapid process
What do cytochrome P450 inhibitors do to the drug?
Increase the metabolism of the drug. Less drug in plasma so more active form produced.
Slower process
Give some examples of P450 inducers
Carbamazepine
Phenytoin
Rifampicin
Alcohol (Chronic)
What is the difference between the effect of consumption of alcohol on cytochrome P450
Alcohol (Acute)- INHIBITOR
Alcohol (Chronic)- INDUCER
What may drugs Drug metabolised by CYP450 with narrow therapeutic index/window
Eg. warfarin, aminophylline
combined with cytochrome P450 inhibitor lead to?
Adverse side effects
What is the therapeutic index?
Ratio of concentration associated with toxicity (MTC) vs concentration associated with efficacy (MEC).
How do genetics affect drug metabolism?
Genetic Polymorphisms are multiple genetic variants (allele combinations) which result in different phenotypes.
Polymorphisms of drug metabolising enzymes can affect drug handling.
Define extensive metaboliser
Two active ‘normal’ alleles
Define intermediate metaboliser
One normal and one abnormal allele
Define poor metaboliser
Two abnormal alleles
Define ultrarapid metaboliser
Duplication of normal alleles
Describe the effect of the CYP2D6 polymorphisms in ultrarapid metaboliser
CYP2D6 polymorphism with ultrarapid metaboliser effect causes opiate toxicity in some individuals even at low dose. This causes an exaggerated response to codeine.
Describe the effect of the CYP2D6 polymorphisms in poor metaboliser
CYP2D6 polymorphism with poor metaboliser effect causes inadequate pain relief by codeine in some individuals.
What are Fast acetylators at increased risk of?
Fast acetylators at increased risk of isoniazid hepatotoxicity
What are Slow acetylators at increased risk of?
Slow acetylators at increased risk of isoniazid neuropathy
Slow acetylators at increased risk of drug-induced lupus with hydralazine
What phase is the N-acetyltransferase involved in?
Phase 2
Genetically determined
Describe the relationship between the drug concentration and dose for most drugs
Linear relationship
First order kinetics
Higher the dose of drug the higher the concentration
Describe the relationship between the dose and drug concentration for saturable metabolism
Not a linear relationship
Drug concentrations rise disportionately compared with the dose
Zero order kinetics
Give some examples of drugs that have saturable metabolism
Phenytoin Alcohol Aspirin Methotrexate Fluoxetine Verapamil
