Renewed interest in centrally acting antihypertensive drugs

Cardiovasc J S Afr. 2000 Aug;11(4):225-229.


Classic centrally acting drugs such as clonidine and alpha-methyldopa induce peripheral sympatho-inhibition via the stimulation of alpha(2)-adrenoceptors in the brainstem. From a haemodynamic point of view this appears to be a useful mechanism to lower elevated blood pressure in hypertensives. Although not known in full detail, a complex relationship exists between the sympathetic nervous system and hypertensive disease; sympathetic inhibition therefore appears to be a logical target of antihypertensive drug treatment. Numerous attempts have been made to improve the unfavourable side-effect profile of the centrally actingalpha(2)-adrenoceptor stimulants. None of these attempts were successful, since both the central antihypertensive activity and the major side-effects (sedation, dry mouth) are mediated by alpha(2)-adrenoceptors. A new approach in this field has been offered by the introduction of centrally acting antihypertensives which interact with central imidazoline (I(1))-receptors and thus cause peripheral sympatho-inhibition. As such they offer haemodynamic benefits similar to those of the classic alpha(2)-adrenoceptor agonists. However, it is hoped that their side-effect profile will be more favourable because of their much weaker affinity for alpha(2)-adrenoceptors. Moxonidine and rilmenidine are the prototypes of centrally acting I(1)-receptor stimulants. The antihypertensive activity of these agents is caused by vasodilatation and a reduction of peripheral vascular resistance. Left ventricular end-diastolic and end-systolic volumes are reduced, whereas heart rate, stroke volume, cardiac output and pulmonary artery pressures are largely unchanged. Left ventricular hypertrophy (LVH) is reduced in the long term. Both drugs when applied in a once-daily dosage schedule appear to control hypertension in most patients. Both drugs have been compared with representative agents from the major classes of antihypertensives in controlled trials and have been found to be equally effective with respect to blood pressure control. The incidence and severity of side-effects is lower than for clonidine, in particular with respect to sedation. A rebound (withdrawal) phenomenon has so far not been reported for moxonidine and rilmenidine. In conclusion, I(1)-receptor stimulants appear to offer the potential to be developed as centrally acting agents with a better side-effect profile than the classic alpha(2)-adrenoceptor stimulants, but with similar haemodynamic properties.