Phenytoin and lithium are said to have narrow therapeutic indices. The term therapeutic index refers to:
A. Therapeutic index is a measure that relates the dose of a drug required to produce a desired effect to that which produces an undesired effect. In animal studies, the therapeutic index is usually defined as the ratio of the median toxic dose to the median effective dose for some therapeutically relevant effect. The therapeutic index of a drug in humans cannot be measured directly and the value itself does not have much clinical use; instead, drug trials often reveal a range of usually effective doses and a range of possibly toxic doses, from which a safe therapeutic range is determined, for example 1.0 to 1.2 for lithium which when exceeded results in toxic effects.
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The lower incidence of extrapyramidal side-effects due to clozapine compared to haloperidol is possibly related to:
A. Clozapine has a hit-and-run profile at D2 receptors. The occupancy is around 40% and the time course of occupancy is comparatively shorter than typical antipsychotics. Quetiapine has a similar mode of action to that of clozapine. Clozapine and quetiapine bind more loosely to D2 receptors than dopamine itself whereas haloperidol and risperidone bind to these receptors more tightly. It is suggested that antipsychotics with low binding affinity and fast dissociation rates, such as clozapine and quetiapine, are more responsive to endogenous changes in dopamine than those that bind more tightly and dissociate from the receptor more slowly. This is because baseline dopamine levels are interspersed with task- or stress-induced, several-fold increases in dopamine from normal physiological level.
The volume of distribution of a drug depends on all of the following except:
D. Volume of distribution is a measure of the apparent space in the body available to contain an administered drug. It can be calculated as a ratio of the administered dose (intravenous) and plasma (or blood) concentration at time = 0, that is when administration occurred. Hence, the higher the plasma concentration, the lower the volume of distribution and vice versa. Volume of distribution can vastly exceed any physical volume in the body because it is an apparent, not an actual, volume necessary to contain a drug homogeneously at the concentration found in the plasma. Drugs with very high volumes of distribution have higher concentrations in extravascular tissue than in the vascular compartment, while those that are contained fully in the vascular compartment have a smaller volume of distribution limited by the volume of plasma component. The apparent volume of distribution depends on properties of the drug molecule, such as lipid solubility and protein binding. Tissue binding decreases the plasma concentration and makes the apparent volume larger. Plasma protein binding increases plasma concentration and makes the apparent volume smaller. Half-life is a secondary measurement calculated from the volume of distribution and clearance rates, but volume of distribution itself does not depend on half-life of a drug. If the rate of clearance is slower or the volume of distribution is more extensive, the half-life will be longer.
Drug A is an anticonvulsant, metabolized to inactive metabolites by the CYP450 system. Drug B, which induces CYP450, is expected to produce which one of the following if coadministered with drug A?
B. The cytochrome P450 (CYP450) enzyme system is responsible for much of the phase 1 metabolism of drugs. Phase 1 metabolism includes oxidation, reduction, and hydrolysis, as a result of which a molecule (active or inactive) suitable for conjugation is produced. The phase 2 metabolism involves conjugation reactions such as glucuronidation, as a result of which polar compounds (mostly inactive), which are excretable in bile or urine, are formed. Induction and inhibition of the activity of the CYP450 system can result in various potential drug interactions. The most important enzymes in the CYP family involved in the metabolism of psychotropic drugs are CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. CYP3A4 is responsible for the metabolism of more than 90% of psychotropic drugs that undergo hepatic biotransformation. In this question, if the CYP system is induced then the metabolic breakdown of drug A will be increased, producing more inactive metabolites. This will reduce the efficacy of drug A.
Glucuronyl transferase acts on an antidepressant drug A and converts it into a more water-soluble component with less potency but a higher concentration in bile. This process is called:
A. Conjugation refers to phase 2 metabolism of administered drugs. These take place after oxidation-type reactions in phase 1. Enzymes such as transferases carry out conjugation, which usually results in inactive metabolites (or, rarely, active compounds, e.g. morphine). It is not essential that a drug must undergo phase 1 metabolism in order to undergo phase 2 metabolism, for example oxazepam undergoes direct phase 2 reactions.
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