Pharmacology General Principles Flashcards (Drug Metabolism II): Set 9 (20 questions)

Press "Next" button to begin flashcard set and press "Next" again to show the other side of the card.

A number of cytochrome P450 enzyme isoforms have been identified. This isoform is responsible for metabolized in over 50% of prescription drugs which are metabolized by the liver.CYP3A4; this isoform accounts for about 30% of total human liver P450 content.
Effect of repeating doses of drugs which are substrates for the cytochrome P450 enzyme system:Dosing in this manner may induce (increase) cytochrome P450 expression. Increasing the amount of P450 increases the rate of drug metabolism which reduces the drug pharmacological action. This effect may also change the pharmacokinetics of co-administered agents. Sometimes enzyme induction may cause increased metabolite-mediated toxicity when the parent drug is transformed to a reactive, toxic metabolite.
Mechanisms associated with increased P450 expression:Increase synthesis rate or decreased degradation rate of the P450 isoform.
Requirements for increased P450 synthesis:Increased gene transcription and translation along with increased heme synthesis (heme: cofactor)
Cytoplasmic receptor for polycyclic aromatic hydrocarbons such as benzo[a] pyrene:AhR
P450 enzyme induction by substrate stabilization:In this process there is reduced P450 degradation. An example in which this process leads to P450 conduction is troleandomycin--mediated CYP3A4 enzyme induction. Another example is the ethanol-mediated induction of CYP2E1.
Examples of drugs inhibiting cytochrome P450 enzyme activity:Cimetidine and ketoconozole, by binding to the P450 heme iron, reduces metabolism of endogenous substances, e.g., testosterone or other coadminister drugs. The latter mechanism is by competitive inhibition, i.e. several drugs competing for the reduced cytochrome P450 capacity.
Metabolic products of drugs which then inactivate cytochrome P450 enzymes:Certain antibiotics including erythromycin and erythromycin derivatives along with troleandomycin metabolized probably by CYP3A4 to metabolites that, by complexing with cytochrome P450 heme iron, result in catalytic inactivity.
Individuals may metabolize a certain drug at different rates. Discussion points: Within a given population, steady-state drug levels for one agent may vary within the population by a factor of 30 times. Also, the metabolism of another drug may reflect a more limited, 2-fold variation metabolism. Some of these differences may be explained by genetic factors affecting metabolic enzyme levels.
Differing metabolic enzyme levels and population variances in drug metabolism:This effect may be due to genetic polymorphisms in drug metabolism. Genetic polymorphism in this context refers to a variation in either gene expression or activity of the gene product-both possibilities are possible concurrently.
Genetic polymorphisms influence in drug metabolism:Genetic polymorphisms have been noted for both phase I and phase II drug-metabolizing enzyme systems. Results of this effect include variation in drug efficacy as well as adverse drug effects. Such adverse drug effects may be mitigated by drug dose adjustments. Among the first examples of drugs affected by genetic polymorphisms include succinylcholine, a muscle relaxant, isoniazid, an anti-tuberculosis medication, and warfarin, an anticoagulant drug.
An example of a drug affected by phase II enzyme polymorphism:Succinylcholine administration causes a 50% reduction in metabolism in those individuals exhibiting a genetically-associated deficiency in pseudocholinesterase (a.k.a. butyrylcholineesterase), as compared to individuals with normal functioning enzyme. One consequence in this case is that when succinylcholine is used as a surgical muscle relaxant, the patient with enzyme deficiency may experience a prolonged respiratory paralysis as a result of the slowed succinylcholine inactivation.
Factors that can lead to increased susceptibility to toxic or pharmacological drug activities:Age: very young or elderly patients may be more sensitive to both pharmacological and toxicological drug effects. These population groups compared to young adults may exhibit not only differences in drug metabolism but also differences in pharmacokinetic factors such as drug absorption, distribution, and elimination. Sex:  sex-dependent differences in drug metabolism may occur for propranolol, ethanol, some benzodiazepines, salicylates and estrogen. Animal models suggest that differences may be associated with androgenic hormones.
Examples of enzyme-inducing drugs:Sedative-hypnotic agents, anticonvulsants, antipsychotics, rifampin (an anti-tuberculosis drug). For example, patients who commonly take barbiturates, other sedative-hypnotic drugs, or certain antipsychotic agents may require higher doses of warfarin to maintain warfarin therapeutic effects. Discontinuation of a sedative inducer, on the other hand, could then result in decreased metabolism of the anti-coagulant and consequent bleeding susceptibility.
Effects of an inducer drug on drug metabolism:The inducer drug may increase the metabolism not only of other drugs but also of itself. A pharmacokinetic tolerance occurs when progressively decrease therapeutic effectiveness of a drug results from the drug enhancing its own metabolism.
Diseases affecting drug metabolism:Some diseases that affect the liver also affect drug metabolism in the liver. Such diseases include alcoholic hepatitis, alcoholic cirrhosis, active hepatitis (chronic), hemochromatosis, biliary cirrhosis, as well as acute viral or drug-induced hepatitis. Significant increases, for example, in the half-lives of the sedative hypnotic benzodiazepines chlordiazepoxide and diazepam are noted in patients with liver cirrhosis or acute viral hepatitis.
Drug metabolism and cardiac disease:For drugs very readily metabolized by the liver, the limiting factor may be blood flow to the liver. For these drugs, cardiac disease which reduces liver blood flow may reduce drug clearance.
Drug metabolism and pulmonary disease:In patients with chronic respiratory insufficiency, impaired hydrolysis of procaine and procainamide may be noted.
Localization of cellular enzymes involved in drug biotransformation:Endoplasmic reticulum, lysosomes, cytosol, mitochondria, nuclear envelope, plasma membrane.
Comparative speed of phase II reactions compared to phase I reactions:Generally, phase II reactions are faster than P450-catalyzed reactions.