Which of the following about phenytoin is true
It follows zero order kinetics [Ref KDT 6th/e p. 403-405J There are three pharmacokinetic characteristic of phenytoin: -- Marked binding to serum protein - Nonlinearity of its elimination kinetics (1t.follows saturation kinetics) - Metabolism by the CY P'S Phenytoin follows saturation kinetics: ? - At their therapeutic concentrations most of the drugs occupy only a small fraction of their metabolizing sites so their metabolic rate increases as the drug concentration increase. - In such cases the metabolic rate of the drug is a constant fraction of the drug present in the body (rather than a constant amount of drug/h) i.e., the drug has a specific half life. This is.first order kinetics. For example If the concentration of the drug is 500 mg at time zero - After metabolism at 1 hr the drug concentration would be -4250mg - After metabolism at 2hr the drug concentration would be 125 mg However - When most of the enzymes are occupied metabolism occurs at a maximal rate i.e., it is saturated and does not change in propoion to the drug concentration i.e., a fixed amount of drug is metabolized per unit time. This is zero order kinetics. For example - Drug concentration at time zero --> 500 mg - After metabolism at 1 hr --> 450 mg - After metabolism at 2 hr --> 400 mg As the drug concentration increases metabolic sites and their metabolism shifts from first order to zero order. The drug whose kinetic changes from first order to zero at therapeutic concentration are said to follow zero? order kinetics saturation kinetics now small increase in drug dose produces marked side effects. - Phenvtoin is one of the few drug whose elimination varies as a function of its concentration i.e., the rate is nonlinear, as the drug concentration increases the kinetics shift to zero order. Phenytoin is hydroxylated extensively in the liver and this process becomes saturated at about doses needed for therapeutic effects. - Thus phenytoin at low doses exhibit. - First order kinetics - As the therapeutic concentration increases - Zero order kinetic develops. - Now a small increment in dose produces dispropoionate rise in steady state plasma concentration. - Thus dose increments should become smaller as the dose increased. Enzyme induction and inhibition We have seen above that the metabolism of phenytoin is saturable i.e., the enzymes metabolizing it gets saturated. - Because its metabolism is saturable, the other drugs that are metabolized by these enzymes can inhibit the metabolism of phenytoin and increase its concentration. Conversely the degradation rate of other drugs that are substrates for these enzymes can be inhibited by phenytoin. One such drug is warfarin - And addition of phenytoin to a patient receiving warfarin can lead to bleeding disorders. Another mechanism for drug interaction in phenytoin:- It arises from phenytoins ability to induce diverse CYPs. -Phenytoin is a potent inducer of hepatic enzymes that metabolize other drugs. - Coadministration of phenytoin and medication metabolized by these enzymes can lead to an increased degradation of such medication. - Of paicular note in this regard are oral contraceptive. - Treatment with phenytoin could enhance the metabolism of oral contraceptives and lead to unplanned pregnancy. Phenytoin is highly bound to proteins (90%) mainly albumin - Small variations in the percentage of phenytoin that is bound dramatically affect the absolute amount of free (active) drug. Therefore increased propoion of free drug are evident in Patients with hypoalbuminemia, uremic patients and neonates. TeratoRenic effects of phenytoin The total plasma level decreases when the percentage that is bound decreases as in uremia or hypoalbuminemia. Phenytoin is metabolized to Arene oxide compound that is responsible for its teratogenic effect (Fetal hydantion syndrome) :- - Hypoplastic phalanges - Cleft palate - Hair lip - Microcephaly
It follows zero order kinetics
Not a hepatic enzyme inducer
It is excreted unchanged in urine
It is not teratogenic