Which of the following is not an example of nonlinear kinetics -
Ans. is 'd' i.e., Metabolism of diazepam Pharmacological basis of zero order kinetics o At higher concentration, the kinetics of some drugs changes from linear (first order) to non-linear (zero-order). o This is because, metabolic or other elimination pathway become saturated, so the drug can not be eliminated at the same rate as in lower concentrations. How does it occur? o Elimination of a drug is dependent on metabolism or other pathway of elimination (for example renal excretion). o At higher concentration these elimination pathways (metabolsim and renal excretion) becomes saturated. o Taking an example of a drug that is metabolized : - a Suppose, 1000 molecules of an enzyme are available to metabolize a drug and the usual concentration of drug is 100 molecules. Then only 100 out of 1000 molecules of the enzyme are required to metabolize the drug and they metabolize the 50% of drug in 5 hours (t% 5 hours). Now, we give double dose of drug, 200 out of 1000 molecules will be required and they will metabolize the 50% of drug in same t1/2 (as all enzyme molecules have same metabolizing propeies). That means at lower Concentrations:-0 P/2 remains constant ii) Rate of elimination is propoional to plasma concentration (In this example), when the concentration was 100 molecules, 50 molecules (50% of 100 molecules) were metabolized in one 0/2; and when the concentration was 200 molecules, 100 molecules (50% of 200 molecules) were metabolized in one t1/2 --> Constant fraction of drug is eliminated per unit time. iii) Clearance remains constant becuase, as the plasma concentration increases, rate of elimination increases propoionaly. iv) This is first order kinetic So drug will follow first order kinetic up to the dose of 1000 molecules. However, if we give sufficiently high dose, e.g., 1500 molecules, 1500 molecules of enzyme will be required to metabolize the drug. But we have only 1000 molecules of enzyme. Therefore all enzyme molecules will act only on 1000 molecules of drugs and remaining 500 will he metabolize latter when the enzyme molecules become free from the already existing metabolic reaction (metabolism of first 1000 molecules of drug). Therefore, at higher concentration. -0 t% increases with increasing concentration as the enzyme molecules can metabolize 1000 molecules of drug and above this concentration t1/2 will increase with increasing concentration. ii) Constant amount of drug is eliminated per unit time (In this example 1000 molecules). iii) Clearance is more at lower concentration and less at higher concentration (CL = rate of elimination/ Plasma conc.). In sho o At lower concentration ofdrug, elimination pathways (metabolism or excretion) are present in sufficient amount and are not a limiting factor for elimination Drug metabolism follows first order kinetics. o At higher concentration of drug, elimination pathways become saturated and are a limiting factor for drug elimination --) Drug metabolism follows zero order kinetics. So, the drug whose elimination pathway become saturated at higher concentration follows zero order kinetics at higher concentration. Examples are Aspirin, Alcohol, Warfarin, Theophylline, Tolbutamide. o It should be kept in the mind that non-linear kinetics (zero-order) is not: only due to saturation of metabolism, it may also occur due to saturation of other elimination pathway e.g. Renal excretion, Biliary secretion. Process saturated Drugs o Metabolism Phenytoin, alcohol, theophylline, warfarine, aspirin, toibutamide o Renal excretion Naproxen, mezlocillin o Biliary secretion Cimitidine, Isotretinoin, BSA o Absorption Riboflavin, Peniefilins
Metabolism of phenytoin
Biliary secretion of bromosulfthalein (BSP)
Glomerular filtration of naproxen
Metabolism of diazepam