Relationship between pharmacokinetics and pharmacodynamics of organic nitrates

The pharmacological effect of drugs can usually be described as a dose- or concentration-response relationship. With respect to organic nitrates there are many confounding factors which can modify or even mask the existence of such a relationship. The antianginal effect of these drugs is the result of hemodynamic changes caused by their action on different parts of the vascular system. These effects are thought to have different concentration-response relationships and to participate to a different degree in the antianginal efficacy. Counterregulatory mechanisms and development of tolerance may further modify these concentration-response relationships. The formation of active metabolites makes it necessary to consider each drug species separately with respect to the time course and magnitude of effect. Evidence also exists that for glycerol trinitrate the time course of drug concentration at the site of action may be different from that in the plasma. Furthermore, not only the actual plasma concentration but also its rate of change may determine the magnitude of effect. This can cause the efficacy to depend also on the route of administration. Therefore, it is not surprising that for organic nitrates large intersubject differences exist in the plasma concentration-response relationship and that it is difficult to define a therapeutic plasma concentration range.