Hepatic drug metabolism Flashcards
What are the four phases of pharmacokinetics?
Absorption
Distribution
Metabolism
Excretion
What is first pass metabolism?
The extent of metabolism occurring before the drug enters the systemic circulation
What is phase I of drug metabolism in the liver?
Oxidation
Reduction
Hydrolysis
[Addition of functional group e.g. OH or NH2 to increase polarity of drug and provide a site for phase 2 reactions]
What are cytochrome P450 enzymes?
Haem proteins that require presence of oxygen, NADPH and NADPH cytochrome P450 reductase in order to function (mixed function oxidase system)
What is the process of drug oxidation?
Cytochrome P450 catalyses the transfer of one oxygen atom to the drug (oxidation) and other oxygen atom reduced to water (reduction)
What other phase 1 reactions can occur?
Reduction
Oxidation not involving P450 system
Hydrolysis
What occurs during phase II of drug metabolism?
Drug must possess suitable site for phase II reaction (either present before or as a result of phase I reaction)
Conjugation reaction (attachment of large chemical group to functional group on drug molecule)
Almost always makes drug inactive and hydrophilic (and therefore more easily excreted)
What does phase III involve in drug metabolism?
Transport into circulation or bile
Excretion via kidneys or faeces
How does drug metabolism differ in neonates?
Immature metabolising enzymes
Inefficient renal clearance
= Lower drug doses required
How does drug metabolism differ in children?
Mature CYPs and relative liver mass/ hepatic blood flow higher = quicker metabolic clearance than in adults
Doses dependent on age and body surface area
How does drug metabolism differ in elderly patients?
Reduced capacity for drug metabolism (due to lower relative liver mass and hepatic blood flow)
Drug dose should be started with smallest effective dose
What drug metabolism reactions are characterised by CYP3A?
Calcium channel blockers Benzodiazepines HIV protease inhibitors HMG-CoA-reductase inhibitors Cyclosporine Non-sedating antihistamines Oral contraceptives
What are common examples of CYP3A inhibitors?
Antifungal drugs (-azole)
Macrolide antibiotics (.g. erythromycin)
Cimetidine (H2 receptor antagonist)
Grapefruit juice
What can the presence of CYP3A inhibitors result in?
Reduced drug clearance = higher blood levels of primary drug = potentially toxic levels/ adverse effects
What are common examples of CYP3A inducers result in?
Carbamazepine (anti-convulsant)
Rifampicin + Rifabutin (anti-bacterial)
Ritonavir (antiviral)
St. John’s Wort (herbal)
What can the presence of CYP3A inducers result in?
Increased drug clearance = lower blood levels of primary drug = lack of therapeutic
What effect does St. John’s Wort have on drug metabolism?
Induces activity of many P450 enzymes (e.g. CYP3A4, CYP2C9, CYP2E1, CYP1A2)
Increases metabolism and reduces plasma concentration of drugs such as warfarin, anti-epileptics and oral contraceptives
What steps should be taken to avoid drug interactions?
- Full medication history
- Awareness of high risk patients (e.g. those on multiple medications, warfarin etc.)
- Understanding of P450 enzymes
- Use BNF
How does codeine metabolism differ in poor metabolisers?
Cannot convert codeine to morphine = no pain relief + increased side effects (especially if dose is increased to relieve pain)
How does codeine metabolism differ in ultra-rapid metabolisers?
Rapid conversion of codeine to morphine = opioid toxicity
What are the common side effects of codeine?
Nausea/ vomiting
Light-headedness/ dizziness
Sweating
Constipation
What are the common side effects of opioid toxicity?
Respiratory depression Skeletal muscle flaccidity Cold/ clammy skin Bradycardia Hypotension Constipation
What are the effects of liver disease on drug action?
- Impaired drug-metabolising capacity (especially first pass metabolism)
- Porto-systemic shunting (directs drug away from liver)
- Increased bioavailability (due to decreased first-pass metabolism)
- Decreased protein binding
What is the definition of bioavailability?
The proportion of administered drug which reaches the systemic circulation unchanged and is thus available for distribution to the site of action
Where does first pass metabolism occur?
Liver (mainly)
Gut lumen (e.g. gastric acid and proteolytic enzymes)
Gut wall
What drugs commonly have increased bioavailability due to cirrhosis?
Nicardipine (calcium channel antagonist)
Propanolol (beta-adrenoceptor antagonist)
Verapamil (calcium channel antagonist)
