Drugs and Liver Disease Flashcards
What are the CYP450 enzymes for drug metabolism?
Liver hepatocytes contain P450 enzymes for drug metabolism
These P450 enzymes are in microsomes in the SER of the cell.
CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.
These enzymes may be induced or inhibited by other agents.
What are the 3 phases of drug metabolism?
Phase 1 occurs in sER, catalysed by CYP450 enzymes to make substrate polar
Phase 2 (conjugation) makes the drug more water soluble
(Phase 3): the conjugate substance is eliminated into blood or bile w ATPase pumps.
Not all drugs use both phases
What is a prodrug?
Some drugs are given in an inactive form called a prodrug.
Prodrugs require metabolic conversion to their active state.
Eg codeine is metabolised via CYP2D6 to its active by-product morphine.
Some metabolites can be toxic such as those produced from paracetamol; (usually detoxified by phase 2)
What is enzyme induction?
Enzyme induction may cause:
increased CYP enzyme synthesis, so faster drug metabolism. This means subtherapeutic drug concs and risk for ineffective drug therapy.
E.gs. drugs that cause enzyme induction are the barbiturates, some anticonvulsants and rifampicin.
What is enzyme inhibition?
Enzyme inhibition is non-competitive or competitive inhibition of CYP enzymes by a second drug.
E.g. cimetidine, erythromycin are hepatic enzyme inhibitors
In cases of drug toxicity due to CYP inhibition, presenting symptoms would display signs of overdose.
How do inhibitors and inducers work?
Inhibitors mainly work on the enzyme levels to block or compete at the site of metabolism.
Inducers act by increasing the gene transcription that result in higher enzyme content.
Some drugs can increase and stabilize the enzyme to be more active, increasing overall metabolic rate.
What are the potential effects from pharmacokinetic drug interactions?
What factors affect drug metabolising enzymes?
Age: infants have lower enzyme expression, decreasing drug metabolism.
Gender: Adverse reaction more common in women, perhaps due to sex hormones, body weight, fat composition.
Pregnancy: changes in body water, fat content, and hormones can alter drug metabolism.
Diabetes M: Drug-metabolizing enzymes are altered in diabetes.
Kidney and liver disease
How is polymorphism related to drug metabolism?
Between 6-10% of the UK population have a deficiency of CYP2D6 enzyme (called poor metabolizers),
while approximately 1% have more than two copies of the genes and are termed ultra-rapid metabolizers.
Relate liver disease to drug metabolism
Patients with liver disease have altered:
Hepatic blood flow, expression of drug-metabolizing enzymes, availability of co-substrates, binding of drugs to plasma proteins.
These affect metabolism of drugs and endogenous compounds
Drugs metabolized in the liver is decreased in cirrhosis.
