Hepatic Drug Metabolism Flashcards
What are the effects the liver can have on drugs in metabolism?
- Conversion to drugs to inactive compounds (most common fate of active drugs) - this can promote excretion by the kidneys
- Inactive prodrugs converted to active drugs with altered absorption kinetics, preventing adverse effects and improving distribution E.G. codeine -> morphine
What is first pass metabolism?
Where a drug is taken in via the GI tract wall, into the blood and metabolised in the liver BEFORE it reaches the systemic circulation and therefore, its targets (reduces bioavailability) E.G. oral drugs
How can you avoid first pass metabolism?
By giving a drug IV as it goes straight into the systemic circulation (will still go through liver at some point still)
Do drugs only pass through the liver once?
No, this can happen continually if they are in the circulation, metabolising the drug each time to an extent
Provide an overview of drug metabolism in the liver.
Phase 1: Adds a functional group to increase polarity of drug, less pharmacologically active and make it more susceptible to phase 2 reactions
Phase 2: Conjugation reaction which add a group that makes the drug less pharmacologically active, more soluble and thus, more easily excretable (some drugs can go straight to phase 2 if they have a group already suitable for conjugation)
Phase 3: Conjugated metabolite gets out of hepatocyte and into excretion system e.g. kidneys(urine) or biliary system (faeces)
What reactions are involved in Phase I metabolism?
Oxidation
Reduction
Hydrolysis
- provide OH or NH2 group for e.g.
What is the relevance of cytochrome P450 enzymes having various isoforms?
A whole variety of drugs can be metabolised by the isoforms that have low specificity
What are cytochrome P450 enzymes and what do they do?
Haem proteins
Require presence of oxygen, NADPH and NADPH cytochrome P450 reductase to function = mixed function oxidase system
They catalyse the transfer of 1 oxygen atom to the drug whilst the other oxygen atom is reduced to water
What is the oxidation reaction involving cytochrome P450s?
DH + O2 + NADPH + H+ DOH + H2O + NADP+
What is the most abundant cytochrome P450 isoform?
CYP3A
What are examples of other Phase I reactions?
Reductions
Oxidations
Hydrolytic reactions
Example of oxidations NOT involving the P450 system?
Ethanol being metabolized by alcohol dehydrogenase which is a cytosolic enzyme
What does Phase 2 conjugation reactions involve?
Mainly in liver but also lung and kidney
Chemical groups involved include glucuronyl, acetyl, methyl, sulphate and glutathione
Conjugating enzyme UDP-glucuronyl transferase exist in many isoforms
What happens in Phase 3 transport?
Removed from hepatocyte by a multi-purpose membrane-bound transport carrier system into circulation then either: Renal elimination (most common) Into bile for elimination in faeces (principal route for larger molecules)
Where in the liver to drugs go to be excreted?
EITHER
the sinusoid so they can flow into the central vein, leave the liver and be emptied into the systemic circulation
OR
across canaliculi membrane to be emptied into the bile system
What types of transporters are on the hepatocyte relevant to this process?
Uptake transporters on the sinusoid take the drug up before metabolism
Efflux transporters either take them into vascular space or the bile canaliculi after metabolism
What is the problem with phase I metabolism and paracetamol?
Toxic metabolite that is more chemically reactive is produced
What are the effects of age on drug metabolism?
Neonates (1st 30 days of life) - hepatic drug metabolizing enzymes e.g. conjugating enzymes are absent or present in low amounts
Children (1-12yrs) - metabolic clearance can be quicker after 30 days of life so metabolic clearance can be greater than adults - obtain dosage from paediatric dosage handbook using age and body surface area
Elderly - hepatic drug metabolism, particularly phase I reduced and simultaneous use of several drugs is common so usually start drug treatment with lowest dose
Why is drug interaction a problem for hepatic metabolism?
Drugs compete for same metabolising enzyme and thus, the effect they have on the metabolism of others e.g. cytochrome P450s
What are examples of CYP3A inhibitors and what do they do?
Azole antifungal drugs Macrolife antibiotics H2 receptor antagonist Grapefruit juice -> reduced clearance and higher blood levels of primary drug (potentially toxic levels and adverse effects)
What are CYP3A inducers and what do they do?
Anti-convulsant Antibacterial Antiviral St Johns Wort -> increased clearance and lower blood levels of primary drug = lack of therapeutic efficacy
What is St. Johns Wort?
Herbal OTC remedy for depression that induces activity of many P450 enzymes increasing metabolism and reducing concentration of drugs such as warfarin, antiepileptics and oral contraceptives
How can we avoid drug interactions?
Full medication history
Remember high risk patients (4 or > medications & medications like warfarin, anticonvulsant and antibiotics et.)
Understanding of P450 metabolism
Consult BNF
What is the effect of genetic polymorphisms on drug metabolism?
Mutations in CYPP540 enzymes means variation in expression and activity of that particular type meaning drugs are metabolized at different rates
If a genetic polymorphism means a CYP is a poor metaboliser, what does this mean?
If the active drug is inactivated usually by CYP metabolism, the active drug may accumulate to toxic levels so may require decrease in dose e.g. CYP2C19 mutation and omeprazole (usually converted from active proton pump inhibitor to inactive form)
If the pro-drug is activated by CYP metabolism, there is decreased efficacy as pro-drug may accumulate to toxic levels so may require alternative drug
If a CYP has a mutation that makes it a rapid metaboliser, what does this mean?
If the pro-drug is normally activated by the CYP, there is increased efficacy, rapid onset of effect so may need decrease in dose to prevent accumulation of active metabolite e.g. CYP2D6 converting the weak analgesic codeine to the strong analgesic morphine
If the active drug is inactivated by CYP, there is decreased efficacy as active drug rapidly inactivated so may need increase in dose
How to poor metabolisers and ultra-rapid metabolisers respond to codeine?
Not well
Poor metabolizers cannot convert codeine to morphine so no pain relief but codeine side effects
Ultra-rapid metabolisers rapidly convert codeine to morphine so toxic levels of morphine causes opioid toxicity symptoms
What are codeine’s side effects?
Nausea/vomiting Light-headedness Dizziness Sweating Constipation
Symptoms of opioid toxicity:
Respiratory depression, skeletal muscle flaccidity, cold/clammy skin, bradycardia, hypotension and constipation
What is the effect of liver disease on drug action?
In cirrhosis, there is impaired liver function including decreased drug-metabolising capacity and porto-systemic shunting directs drug away from liver
How can liver disease influence drug action?
Increased bioavailability due to decreased 1st pass metabolism e.g. nicardipine, propranolol and verapamil (1st pass activation of pro-drugs decreased too e.g. ACE inhibitors)
Decreased protein binding because liver disease causes hypoproteinaemia leading to reduced drug-binding capacity = more unbound pharmacologically active drug to circulate -> enhanced response
What are the precautions that should be taken when prescribing in liver disease?
Carry out with care
Drugs extensively metabolised by liver should be given in smaller doses
Patients more susceptible to hepatotoxic effects of ANY drug
