Metabolism- Pharmocokinetics Flashcards
Phase I drug metabolism
This is when enzymes introduce reactive and polar groups into the drug substrate
Metabolism by P450 cytochrome
- Hydroxylation
This involves:
- Reduction
- Hydrolysis
Phase II drug metabolism
Drug is made soluble by conjugating with charged species.
Includes these processes:
- Glucuronidation
- Acetylation
- Sulfation
- Methylation
Pro-drug
- Examples
A drug or compound that is metabolised to become pharmacologically active.
Examples:
- Enalapriat from enalapril
- Morphine from codeine
- Dopamine from levodopa
Cytochrome P450 inhibitors
- Examples
Inhibits Phase I metabolism of certain drugs and compounds.
- Very rapid process
Examples:
- Amiodarone
- Ciprofloxacin
- Erythro/Clarithromycin
- Metronidazole
- Fluconazole
- Isoniazid
- Acute Alcohol
- Grapefruit juice
Amiodarone
Cytochrome P450 inhibitor
- arrhythmic drug
Ciprofloxacin
Cytochrome P450 inhibitor
Fluoroquinolone antibiotic
Erythromycin
Macrolide antibiotic
- Cytochrome P450 inhibitor
Metronidazole
Antibiotic
- Cytochrome P450 inhibitor
Fluconazole
Antifungal
- Cytochrome P450 inhibitor
Isoniazid
Antibiotic, used to treat TB
- Cytochrome P450 inhibitor
Cytochrome P450 inducer
- Significance
- Examples
Increases metabolism of drugs metabolised by cytochrome P450 and increases effect of drug metabolised.
- Slow process
Examples: Carbamazepine Phenytoin Rifampicin Chronic alcohol
Carbamazepine
Na+ channel blocker used to treat epilepsy and neuropathic pain.
Induces cytochrome P450.
Phenytoin
Anti-seizure drug
Inducer of cytochrome P450.
Rifampicin
Antibiotic used to treat TB.
Inducer of cytochrome P450.
Drugs metabolised by Cytochrome P450 with narrow therapeutic index
When these drugs interact with CYP450 inhibitors, this can have potentially adverse effects
- Increases drug toxicity rapidly.
Examples:
- Warfarin
- Aminophylline
Genetics and drug metabolism
Genetic polymorphism of drug metabolising enzymes can affect drug handling.
Extensive metaboliser- Two normal, active alleles
Intermediate- One normal, one abnormal
Poor- Two abnormal
Ultrarapid- Duplication of normal alleles
Codeine phosphate and CYP2D6 (Cytochrome P450 2D6)
Ultrarapid metabolisers of codeine can get opiate toxicity at low doses.
Whereas poor metabolisers do not get adequate pain relief at higher doses.
N-acetyltransferase
Enzyme used in phase II reaction- acetylation.
Its activity is genetically determines.
Fast enzyme= increased risk of isoniazid hepatotoxicity
Slow= Increased risk of isoniazid neuropathy
- Also increased risk of drug-induced lupus with hydralazine.
Saturable metabolism
- Zero order kinetics
When drug concentrations rise disproportionately to the dose
Seen in:
- Phenytoin
- Alcohol
- Aspirin
- Verapamil
- Methotrexate
- Fluoxetine
