Rate of drug metabolism

Question 1

Zero order kinetics = elimination at a constant rate

Answer 1

Zero order kinetics is where the plasma concentration of a drug decreases at a constant rate, despite the concentration of the drug. For drugs which follow zero order kinetics there is no fixed half-life. These types of reactions are typically found when the material needed for the reaction to proceed (e.g. enzyme) is saturated. Ethanol and Phenytoin are good examples of this. This process is described as non-linear (see below ‘A note about linearity’).

Question 2

First order kinetics = elimination at a proportional rate

Answer 2

In first order kinetics, a constant fraction of the drug in the body is eliminated per unit time. The rate of elimination is proportional to the amount of drug in the body. The majority of drugs are eliminated in this way. Drugs that follow first order kinetics have a fixed half-life. Most drugs tend to follow first order reactions. Note however that if a drug which is normally eliminated by first order kinetics is present in a high concentration then it may follow zero order kinetics if its metabolic pathway is saturated. This process is described as linear (see below ‘A note about linearity’).

The half-life of a drug is the time taken for its concentration to fall to one half of its value. Drugs with long half-lives sometimes require a loading dose to ensure therapeutic plasma concentrations are achieved rapidly. Without a loading dose it takes 4.5 half-lives to reach steady state plasma levels.

The steady state is achieved when the amount of drug eliminated from the body is the same as the amount being administered.

Question 3

Linearity

Answer 3

Linearity is a clinical pharmacological concept thats that causes us psychiatrists much confusion. Our advice is to learn and accept but for those of you insistent on torturing yourself please feel free to read on.

The term linear simply means that if the dose is increased, the plasma concentration or area under the plasma concentration-time curve (AUC) will be increased proportionally. However, for some drugs, this may not be valid. For example, when the dose of phenytoin is increased by 50 percent in a patient from 300 mg/day to 450 mg/day, the average steady state concentration may increase by as much as tenfold. This dramatic increase in the concentration is due to the nonlinear pharmacokinetics of phenytoin. For these drugs (drugs with nonlinear kinetics or dose-dependent kinetics), the kinetic parameters, such as clearance, volume of distribution, and half-life, may vary depending on the administered dose. This is because one or more of the kinetic processes of the drug (absorption, distribution, and/or elimination) may be via a process other than simple first-order kinetics. For these drugs, the relationship between the AUC or CSS and dose is not linear. Additionally, different doses of these drugs may not result in parallel plasma concentration-time courses expected for drugs with linear pharmacokinetics.
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