Determinants of drug onset

Abstract

The timing and magnitude of drug onset can be influenced by factors in the chain of drug delivery from the site of administration to the site of effect. This review examines recent evidence regarding the contribution and significance of these factors. It is apparent that drug formulations and mixtures can play a significant role in drug onset. An extension of this is the effect of coadministration of drugs, which can influence drug effect both by altering the physiology underlying drug delivery and by an effect at the target organ. Of the physiological variables, cardiac output and its distribution are clearly important. Cardiac output is a significant source of variability in drug response, and indeed has been successfully incorporated into pharmacokinetic models. The pattern of cardiac output distribution is also relevant. In particular, the blood flow to target organs will influence both the timing and magnitude of the effect of some anaesthetic drugs. In addition, the role of the lung in affecting drug distribution may be important for some drugs. At the site or organ of effect itself, variability in drug distribution, drug-receptor interactions, and the influence of other drugs, can all impact on the profile of drug onset. Factors in the chain of drug delivery have been demonstrated to affect the nature of drug onset, and can account for some of the observed variability in response. The significance to dosing guidelines and strategies, and to predictions of variability in response, remains to be explored.