Pharmacokinetic-Pharmacodynamic Relationships of ??-Adrenoceptor Antagonists

Abstract

Competitive alpha1-adrenoceptor antagonists are effective in the treatment of both hypertension and cardiac failure. Prazosin has both a short half-life and a short duration of action, but other related quinazoline derivatives, such as doxazosin and terazosin, have pharmacokinetic and pharmacodynamic profiles which make them potentially suitable for once-daily administration. Acute reductions in blood pressure have been correlated with plasma concentrations of prazosin but in most instances, particularly during long term therapy, there is no simple, direct relationship between drug concentration and the fall in blood pressure. Using integrated pharmacokinetic-pharmacodynamic analysis, correlations have been described not only for reductions in blood pressure during short and long term treatment but also for alpha1-adrenoceptor antagonist activity. Furthermore, this integrated approach defines the drug concentration-effect relationship in individual subjects and provides a mathematical description of response that is potentially useful for investigating the factors (both kinetic and dynamic) which influence the inter- and intrasubject variability in antihypertensive effect of alpha-adrenergic blockers. Preliminary data suggest that the long term response to treatment with prazosin and doxazosin is mainly dependent upon the height of the pretreatment blood pressure and the response to the first dose.

The response to the first dose of an angiotensin converting enzyme inhibitor in uncomplicated hypertension‐a placebo controlled study utilising ambulatory blood pressure recording.

“…Although attempts have been made to define predictive factors (Hodsman et al, 1983) the exact nature is still unclear with only a few indicators of predisposition such as heart failure or severe salt or volume depletion. The fall in blood pressure may be dose related or it may reflect a wide individual range of responsiveness, as has been noted with other antihypertensive agents (Donnelly et al, 1989). It may be a consequence of idiosyncratic vagal activation (Mark, 1983;Semple et al, 1988).…”

Concentration‐effect relationships and individual responses to doxazosin in essential hypertension.

“…Very little is known about factors which determine the response to treatment with an a-adrenoceptor blocker Stokes et al, 1980;Donnelly et al, 1989) but variability in kinetic as well as dynamic parameters accounts for much of the interindividual differences in antihypertensive effect. The fall in blood pressure is related to antagonism of a1-adrenoceptors in the peripheral vasculature but, acutely, reflex increases in heart rate tend to counteract the fall in blood pressure and if the heart rate response is attenuated, for example with a 3-adrenoceptor antagonist, the acute hypotensive effect of prazosin is enhanced (Elliott et al, 1981).…”

α₁-Adrenoceptor Selectivity: The North American Experience

“…3 or 4 way, singleblind, crossover studies were used to compare the effects of a randomised single dose of placebo, or an alpha-blocker on phenylephrine (PE)-induced changes in BP or P Ura . In each case attenuation of increasing doses of agonist (PE) was used to establish the dose response and receptor responsiveness of the agents [12, 13]. …”