First order kinetics
First order kinetics at low drug concentrations (fixed percentage of drug metabolized during a per unit time) Zero order kinetics at higher concentrations (fixed amount of drug metabolized per unit time – rate is independent of the concentration of the reactants) This is due to Saturation Kinetics involving CYP450 isoenzymes. The consequences of this are that…
Duration of action is more strongly dependent on dose than with drugs that do not show saturation metabolism Relationship between dose and the steady state plasma concentration is steep and therefore unpredictable The maximum rate of metabolism sets a limit to the rate at which the drug can be administered – if this rate is exceeded the amount of drug in the body would in principle increase indefinitely and never reach steady state (but in practice this doesn’t actually happen due to other non saturating pathways of metabolism or renal excretion). Metabolism can be enhanced or competitively inhibited by drugs that share the same hepatic enzyme Ethanol has a dual effect: Initially it competitively inhibits the metabolism of phenytoin Then as induction takes time, it later reduces the pharmacological activity of phenytoin So if a person who does not often consume alcohol drinks a moderate or large amount, the level of phenytoin in the blood may be significantly increased. On the other hand, a person who chronically abuses alcohol may experience decreased levels of phenytoin and be more susceptible to seizures.
All of this means that there is considerable variation in the plasma concentration achieved at a given dose and that a small increase in dose may lead to a large increase in drug concentration as elimination becomes saturated. Monitoring with a radioimmunoassay for phenytoin in plasma helps achieve optimal therapeutic effects.