Hepatic Drug Metabolism Flashcards
What are the 4 phase of pharmacokinetics?
Absorption
Distribution
Metabolism
Excretion
What is first pass metabolism?
After absorption, orally administered drugs enter portal system
Drugs can be rapidly metabolised by enzymes in the liver, so their effect when reaching systemic circulation s greatly reduced
= major effect on bioavailability
What happens in phase 1 metabolism?
Oxidation
Reduction
Hydrolysis
Provides functional group (NH2 / OH) to increase polarity of the drug and provide a surface for phase II reactions
What are, and the role of, cytochrome P450 enzymes?
Haem proteins and many different isoforms
Drug oxidation to catalyse transfer of one O atom to the drug while the other O atom is reduced to H20
Requires molecular O2, NADPH and NADPH cytochrome P450 reductive = mixed function oxidase system
What are phase 2 reactions?
Involve conjugation of a large chemical group to the functional group (from phase 1) = pharmacologically inactive and more hydrophilic conjugate made so easily excreted from body
What’re the routes (including the most common) for drug excretion in phase 3 transport?
Into the circulation for renal elimination
Into bile for excretion in faeces (larger molecules)
What drug:
A) yields a toxic metabolite in phase 1 metabolism
B) administered as prodrug and becomes activated by phase 1 metabolism
C) aren’t inactivated by metabolism and rate of renal elimination is main factor to determine duration of action?
A) Paracetamol
B) ACE inhibitors
C) Digoxin, Atenolol
What are the effect of age on drug metabolism? (Neonates, children and elderly)
In neonates hepatic drug metabolising enzymes are immature = lower doses of all drugs used (get doses from paediatric dosage handbook)
Metabolic clearance in children is quicker due to higher relative liver mass and hepatic blood flow
Elderly: capacity for phase 1 reactions is reduced as lower relative liver mass and hepatic blood flow so start on lowest dose
Why are drug interactions most common in phase 1 reactions?
Cytochrome P450 enzymes
Increase exponentially with 4+ medications
CYP3A is the most common cytochrome P450 enzyme - what is it most responsible for metabolising?
Ca2+ channel blockers Benzodiazepines HIV protease inhibitors HMG-CoA reductase inhibitors Cyclosporine (immunosuppressant) Non sedating antihistamines Oral contraceptives
What’s a consequence of CYP3A inhibitors and name some drugs that could inhibit CYP3A
Inhibit drug metabolism leading to reduced clearance and higher blood levels of the primary drug = potentially toxic levels and adverse effects
Cimetidine (H2 antagonist)
Grapefruit juice
Fluconazole (antifungal)
Erythromycin (macrolide antibiotic)
What’s the effect of CYP3A inducers? Name some drugs
Increased clearance and lower blood levels of primary drug therefore leading to lack of therapeutic efficacy
Carbamazepine
Rifampicin and Rifabutin (antibacterial)
Ritonavir (antiviral)
St John’s Wort - reduces plasma concentration of warfarin, anti epileptics, oral contraceptives
How can you avoid drug interactions?
Full medication history, including herbal and OTC medicines
Beware of high risk patients (4+ medications)
Consult BNF
Understand P450 metabolism
What is genetic polymorphism?
What is its effect on drug metabolism?
If a mutation is relatively common (>1%)
Individuals expressing polymorphism metabolise drugs by CYP450 at a different rate
Poor metabolising phenotypes may cause drug to accumulate to toxic levels as have increased efficacy
Rapid metabolising phenotypes causes active drug to be rapidly inactivated - decreasing efficacy
What drug to poor metabolisers and rapid metabolisers not respond well to and why?
Codeine
Poor metabolisers: cannot convert codeine to morphine so reduced therapeutic effect
Rapid metabolisers: ultra rapid conversion of codeine to morphine leading to toxic levels
