JNTU B.Pharmacy II PHARMACOLOGY-I Previous Question Paper (August-2021 - R17)

Elimination kinetics describes the rate at which a drug is removed from the body. Most drugs follow first-order kinetics, where the rate of elimination is directly proportional to the plasma drug concentration. In this process, a constant fraction of the drug is eliminated per unit time, resulting in a constant half-life regardless of the dose.

Conversely, zero-order kinetics (capacity-limited elimination) occurs when the elimination mechanisms, such as enzymes or transport proteins, become saturated. In this case, a constant amount of drug is eliminated per unit time, independent of the plasma concentration. This leads to non-linear pharmacokinetics, where the half-life is not constant and plasma levels can rise disproportionately with dose increases. Common examples of drugs exhibiting zero-order kinetics at therapeutic doses include ethanol, phenytoin, and high-dose aspirin.

Enzyme induction is the process by which a drug or chemical increases the rate of synthesis or decreases the rate of degradation of hepatic microsomal enzymes (primarily the Cytochrome P450 system). This acceleration of enzyme activity leads to an increased rate of metabolism for the inducer itself or for other co-administered drugs, often resulting in decreased therapeutic efficacy or therapeutic failure.

The mechanism typically involves the induction of gene transcription, where the inducing agent binds to nuclear receptors (such as PXR, CAR, or AhR), which then dimerize and bind to response elements in the DNA, promoting the synthesis of new enzyme proteins. This process is time-dependent, often requiring several days to reach maximal effect.

Examples include:

• Rifampicin: A potent inducer of CYP3A4, which can significantly reduce the plasma concentrations of oral contraceptives, leading to potential contraceptive failure.
• Phenobarbitone: Induces various CYP isoforms, increasing the metabolism of drugs like warfarin, thereby reducing its anticoagulant effect.
• Chronic alcohol consumption: Induces CYP2E1, which can enhance the conversion of paracetamol into its toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI), increasing the risk of hepatotoxicity.