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• First order elimination kinetics: a constant proportion (eg. a percentage) of drug is eliminated per unit
time
• Zero order elimination kinetics: a constant amount (eg. so many milligrams) of drug is eliminated per
unit time
• First order kinetics is a concentration-dependent process (i.e. the higher the concentration, the faster the
clearance), whereas zero order elimination rate is independent of concentration.
• Michaelis-Menten kinetics describes enzymatic reactions where a maximum rate of reaction is reached
when drug concentration achieves 100% enzyme saturation.
• Non-linear elimination kinetics is the term which describes drig clearance by Michaelis-
Menten processes, where a drug at low concentration is cleared by first-order kinetics and at high
concentrations by zero order kinetics (eg. phenytoin or ethanol).
• At high concentrations, the rate of reaction remains the same because all
the enzyme molecules are "busy", i.e. the system is saturated.
• With a small dose of the drug, apparent first-order kinetics are observed,
because no saturation kinetics occur (curve B).
• The curves should exhibit parallel slopes if the drug follows dose-
independent kinetics. Alternatively, a plot of the areas under the plasma
level–time curves at various doses should be linear.
• Where:
• –Vmax is the maximum elimination rate.
• –KM is the Michaelis constant that reflects the capacity of the enzyme
system.
• With these drugs, elimination kinetics are first-order with very small
doses, mixed order at higher doses, and may approach zero-order with
very high therapeutic doses.
• No longer can we increase the dose by some fraction, for example 25%,
and expect the concentration to increase by the same fraction. The
calculations are more complex and must be done carefully.
• With non-linear kinetics, this time will increase with concentration just as
this psuedo half-life increases with concentration.
• Typical Vm values are 300 to 700 mg/day. These are the maximum
amounts of drug which can be eliminated by these patients per day. Giving
doses approaching these values or higher would cause very dangerous
accumulation of drug.