Explain the difference and the clinical relevance, between zero and first order kinetics. (60% marks) Give an example that is relevant to intensive care practice. (40% marks)
For a good answer it was expected that candidates would mention that if mechanisms for
elimination of a given drug become saturated, the kinetics approaches zero order, in which a constant amount of drug is eliminated per unit of time. First-order kinetics, is where a
constant fraction of drug in the body is eliminated per unit of time – that is, systems for
elimination of drugs such as metabolizing enzymes and transporters are not saturated, and
thus the absolute rate of elimination of the drug is essentially a linear function of its
concentration in plasma. Clearance varies with the concentration of drug. Drugs with a target concentration is more than the concentration at which half the maximal rate of elimination is reached have a narrow therapeutic index and zero order kinetics and therapeutic drug monitoring is most important – low therapeutic index and variable half life. In contrast to capacity-limited drug elimination, some drugs are cleared very readily by the organ of elimination, so that at any clinically realistic concentration of the drug, most of the drug in the blood perfusing the organ is eliminated on the first pass of the drug through it. The elimination of these drugs will thus depend primarily on the rate of drug delivery to the organ of elimination – have a high-extraction. Phenytoin provides an example of a drug for which metabolism becomes saturated in the therapeutic range of concentrations, and half-life can vary between 7 and 42 hours.
Syllabus – II 2a
Reference: Goodman and Gillman Chp 1
Definitions and difference between first-order and zero-order kinetics:
It might be helpful for the candidate to draw a crude diagram to illustrate what they mean:
Clinical relevance of these concepts:
Examples relevant to intensive care practice:
Richens, Alan. "Clinical pharmacokinetics of phenytoin." Clinical pharmacokinetics 4.3 (1979): 153-169.
Richens, Alan, and Andrew Dunlop. "Serum-phenytoin levels in management of epilepsy." The Lancet 306.7928 (1975): 247-248.
Barza, Michael, et al. "Predictability of blood levels of gentamicin in man." Journal of Infectious Diseases 132.2 (1975): 165-174.
Goncalves‐Pereira, J., A. Martins, and P. Povoa. "Pharmacokinetics of gentamicin in critically ill patients: pilot study evaluating the first dose." Clinical Microbiology and Infection 16.8 (2010): 1258-1263.
Rangno, R. E., J. H. Kreeft, and D. S. Sitar. "Ethanol ‘dose‐dependent’elimination: Michaelis‐Menten v classical kinetic analysis." British Journal of Clinical Pharmacology 12.5 (1981): 667-673.
Cederbaum, Arthur I. "Alcohol metabolism." Clinics in liver disease 16.4 (2012): 667-685.