Hepatic Drug Metabolism Flashcards
What are the 4 phases of pharmacokinetics?
ADME:
A: Absorption
D: Distribution
M: Metabolism
E: Excretion
What does drug metabolism do to:
Drug activity
Pro-drugs
Active metabolites
Conversion of active drugs to inactive compounds:
- Most common fate of active drugs
Pro-drugs: activated by metabolism in liver
Inactive metabolites: converted to active metabolites.
What can conversion of a drug to an inactive metabolite in the liver promote in the kidneys?
Excretion of the inactive metabolite
What is first pass metabolism?
What effect does this have on bioavailability?
= the extent of drug metabolism occuring before the drug has reached the systemic circulation.
Drugs administed orally are absorbed through the wall of the GI tract and carried via the hepatic portal system and undergo first pass metabolism by enzymes in the liver.
Reduces bioavailability as levels reaching the systemic circulation are reduced.
Where does the majority of drug metabolism take place?
In the hepatocytes of the liver
What is phase 1 metabolism?
Adds a functional group to the drug (e.g. hydroxyl group) to increase the polarity of the drug molecule and makes it a site for phase II conjugation reactions.
Does this by either:
- Oxidation (most common)
- Reduction
- Hydrolysis
Often makes drugs less pharmacologically active
What is phase II metabolism?
What types of drug can undergo this reaction?
Conjugation reaction that adds a large chemical group to a functional group on a drug, making the drug more soluble (hydrophilic) to make it more easily excreted. Forms a conjugated metabolite which is usually pharmacologically inactive.
Drugs that are susceptible to this reaction are those that have undergone phase I metabolism or those that already contain a functional group which makes them suitable for conjugation.
What is phase III transport?
The conjugated metabolite is transported out of the hepatocyte either into the systemic circulation for renal excretion or across the canalicula membrane into the bile for excretion via the faeces.
What are cytochrome P450 enzymes?
What are their roles?
What do they require?
What is the mixed function oxidase system?
Haem proteins that catalyse many of the phase I metabolism reactions.
Require the presence of molecular oxygen, cofactor NADPH and NADPH cytochrome P450 reductase to function. This together is the mixed function oxidase system.
How do cytochrome P450 enzymes oxidise drugs?
Catalyses the transfer of one oxygen atom to the substrate (drug) while the other atom is reduced to water
DH + O2 + NADPH + H+ → DOH + H2O + NADP+
Which is the most abundant cytochrome P450 enzyme in the liver?
CYP3A
Responsible for the greatest number of drug metabolism reactions.
What other phase I reactions exist other than oxidation?
Reduction:
Oxidations that do not involve cytochrome P450 enzymes:
- e.g. Monoamine oxidase inactivates biologically active amines e.g. NA and 5-HT.
- Ethanol is oxidised by alcoholic dehydrogenase
Hydrolytic reactions
- Occur in plasma and other tissues
- E.g. aspirin is hydrolysed to salicylic acid.
Where do phase II reactions commonly occur?
What groups are often added to the drugs?
Occurs mainly in the liver, can also occur in the lungs and kidneys.
Most common groups involved are glucuronyl, acetyl, methyl, sulphate and glutathione.
How are hydrophilic metabolites moved from the hepatocytes into the circulation/bile?
Multi-purpose membrane bound transport carrier systems (efflux transporters) on the lateral membrane and bile canalicula membrane.
Give an example of a pro-drug that is activated by phase I metabolism
ACE-inhibitors
Give examples of drugs that are not inactivated by metabolism and renal excretion is the main factor determining their duration of action
Digoxin
Atenolol
Give an example of a drug that yields a toxic metabolite when undergoing phase I metabolism
Paracetamol
How must dosage be adjusted for a neonate?
Why is this?
Dosage of all drugs must be reduced because:
- Hepatic drug-metabolising enzyme systems are immature
- Renal clearance is also inefficient
How must drug dosage be adjusted in children?
(1-9 years)
Metabolic clearance in children can be higher than in adults because cytochrome p450 enzymes are mature and relative hepatic blood flow and liver mass are higher.
Dose should be prescribed considering age and body surface area (should be obtained from paediatric dosing handbook)
How does hepatic drug metabolism vary with older adults?
Why is this?
How should dose be adjusted?
Older adults may have reduced hepatic drug metabolism capacity (all of ADME reduced), particularly phase I reactions as relative liver mass and blood flow are lower.
Dose should be started at lowest possible therapeutic dose and number of different drugs used should be minimised.
Where do drug interactions often occur?
How do some drug reactions occur?
In phase I reactions, drugs may compete for the same metabolising enzyme, affecting the metabolism of the other.
Some drug reactions occur as they inhibit the metabolising enzyme (e.g. CYP3A is inhibited by fluconazole), therefore its ability to metabolise other drugs is reduced, so metabolism and clearance is reduced and effects are increased.
Some drugs may induce the gene expression of metabolising enzymes (CYP3A increased by carbamazepine) which leads to increased clearance of the drug and a subtherapeutic dose.
Name some drugs that CYP3A is responsible for metabolising
Calcium channel blockers
Benzodiazepines
HMG-CoA reductase inhibitors
Cyclosporine
Oral contraceptives
Non-sedating antihistamines
What are the effects of genetic polymorphisms on drug metabolism?
Within the population, inter-individual variations in the activity of cytochrome P450 enzymes exist.
Mutations in the genes encoding P450 enzymes also alters their expression and therefore the activity of the enzymes.
Poor metabolism (low P450) will cause increased drug efficacy of drugs inactivated by P450 and decreased efficacy of drugs activated by P450. (& vice versa)
Give an example of a drug inactivated by cytochrome P450 metabolism.
Which P450 enzyme is responsible?
Omeprazole
CYP2C19
Give an example of a pro-drug activated by cytochrome P450 metabolism.
Which P450 enzyme is responsible?
Codeine is converted to morphine by CYP2D6
What is the effect of codeine in people with high metabolism and those with low metabolism of the drug?
- Low metabolisers: cannot convert codeine to morphine:
- No/poor therapeutic effect (no pain relief)
- Exaggerated side effects
- High metabolisers: Opioid toxicity
What are the effects of liver cirrhosis on drug metabolism?
Impaired liver function = decreased drug metabolising capacity
Porto-systemic shunting directs drugs away from the liver
In what ways can impaired drug metabolising capacity of the liver influence response to treatment?
Increased bioavailability from decreased first-pass metabolism:
- Hepatocyte injury or reduced number
- Hepatocytes may be bypassed by porto-systemic shunting directing drugs away from the liver.
- = increased quantity of drug = increased effect (or decreased effect for drugs that need to be activated in the liver)
Decreased protein binding
- Liver disease may result in decreased plasma protein synthesis = hypoproteinaemia
- Less protein to carry drugs in the circulation.
- = more pharmacologically active unbound drugs to bind to receptors (protein bound drugs inactive whilst bound) = increased effect.
