I1 imidazoline agonists. General clinical pharmacology of imidazoline receptors: implications for the treatment of the elderly.

In recent years evidence has accumulated for the existence of central imidazoline (I1) receptors that influence blood pressure. While there is some controversy, it has been suggested that clonidine exerts its blood pressure-lowering effect mainly by activation of imidazoline I1 receptors in the rostral ventrolateral medulla, while its sedative effect is mediated by activation of central alpha2-receptors. Moxonidine and rilmenidine are 2 imidazoline compounds with 30-fold greater specificity for I1 receptors than for alpha2-receptors. In comparison, clonidine displays a 4-fold specificity for I1 receptors compared with alpha2 receptors. Moxonidine and rilmenidine lower blood pressure by reducing peripheral resistance. They reduce circulating catecholamine levels and moxonidine reportedly reduces sympathetic nerve activity in patients with hypertension. Moxonidine and rilmenidine modestly reduce elevated blood glucose levels and moxonidine has been reported to reduce insulin resistance in hypertensive patients with raised insulin resistance. Small reductions in plasma levels of total cholesterol, low density lipoprotein-cholesterol and triglycerides have been reported with rilmenidine. Both moxonidine and rilmenidine are well absorbed after oral administration and are eliminated unchanged by the kidneys. The elimination half-life (t(1/2)) of rilmenidine and moxonidine is 8 and 2 hours, respectively, but trough/peak plasma concentration ratios indicate that moxonidine can be administered once daily, suggesting possible CNS retention. As would be expected, t(1/2) values are increased in patients with reduced renal function, and in elderly individuals. Both drugs have been compared with established antihypertensive drugs from all the major groups. Studies, almost all of which were of a double-blind, parallel-group design, indicate that blood pressure control with moxonidine or rilmenidine is similar to that with established drugs, i.e. alpha-blocking drugs, calcium antagonists, ACE inhibitors, beta-blocking drugs and diuretic agents. There have been few studies conducted solely in elderly patients. However, evidence clearly suggests that the antihypertensive effect of the imidazoline compounds is not reduced in elderly patients. The overall adverse effect profile of moxonidine and rilmenidine compares reasonably with established agents. In accord with the receptor-binding studies, drowsiness and dry mouth are observed less often with these drugs than with other centrally acting drugs, although the symptoms occur more often than with placebo. An overshoot of blood pressure was seen when treatment with clonidine, but not moxonidine, was abruptly discontinued in conscious, spontaneously hypertensive rats. Clinical evidence of withdrawal reaction with moxonidine or rilmenidine is scant but caution should be observed pending more formal studies.