Pharmacology and clinical use of moxonidine, a new centrally acting sympatholytic antihypertensive agent.

Moxonidine is a centrally acting antihypertensive. Its action is mediated by imidazoline I1 receptors located in the rostral ventro-lateral medulla (RVLM). Animal experiments show much smaller amounts are required to reduce blood pressure (BP) when it is given intracisternally, or injected directly into the RVLM, compared to intravenous dose. The antihypertensive action of microinjection of moxonidine into the RVLM in the spontaneously hypertensive rat (SHR) is abolished by pretreatment with imidazoline I1 blockade from efaroxan, but alpha(2) blockade from SKF 86466 has much less effect. Similarly the fall of BP in the SHR from intravenous moxonidine is reversed by the microinjection of efaroxan into the RVLM. Receptor binding studies demonstrate that moxonidine binds with an affinity for the imidazoline I1 receptor that is thirty-three times more effective than is alpha(2) receptor binding, while for clonidine the difference is only four times. Moxonidine reduces adrenaline, noradrenaline and renin levels in man, a finding consistent with central inhibition of sympathetic tone. Acute haemodynamic studies indicate that moxonidine results in a fall of BP due to a decline in systemic vascular resistance, while the heart rate, cardiac output, stroke volume and pulmonary artery pressures are not affected. Left ventricular end systolic and diastolic volumes are reduced. Left ventricular hypertrophy has been found to regress after 6 months treatment with moxonidine. After oral administration Tmax is about 1 h, bioavailability approaches 90%. Moxonidine is mostly excreted unchanged, biotransformation is unimportant. The T1/2 is 2.5 h, which is prolonged by renal insufficiency. However, suggesting possible retention in the central nervous system (CNS), the antihypertensive effect lasts longer than would be expected from the half-life, as moxonidine is suitable for once daily administration. Moxonidine is an effective antihypertensive agent. It has been compared with representatives from each important class of antihypertensive drugs, with clonidine, diuretics, both alpha- and beta-blocking drugs, calcium antagonists and ACE inhibitors. BP control has been similar with moxonidine and these other agents. The side effect profile of moxonidine is favourable, its lack of effect on central alpha(2) receptors is important in this regard.