Journal of Human Hypertension (1997) 11, 629–635 1997 Stockton Press. All rights reserved 0950-9240/97 $12.00 REVIEW ARTICLE Moxonidine: a review STW Morris and JL Reid Department of Medicine and Therapeutics, University of Glasgow, and The Renal Unit, Western Infirmary, Glasgow Moxonidine is an imidazoline compound which acts on agent including comparative studies with pre-existing I1 imidazoline ‘receptors’ in the central nervous system drugs, and adverse effect profile. With a growing num- to reduce blood pressure. This novel mechanism of ber of effective antihypertensive agents already avail- action is claimed to lead to fewer adverse effects than able to the clinician, it is not yet clear whether moxonid- the older centrally-acting agents such as clonidine. In ine represents a significant advance in hypertension this review we examine the drug’s pharmacology, clini- management. cal pharmacokinetics, efficacy as an antihypertensive Keywords: moxonidine; hypertension; imidazoline; I1 imidazoline receptor agonist Introduction The use of drugs which act in the central nervous system (CNS) to lower blood pressure (BP) is not a new concept. From the shrub Rauwolfia was derived reserpine, one of the first antihypertensive agents which depleted peripheral sympathetic neurones of noradrenaline and also interfered with central a monoamine neurotransmission. The 2-agonists clonidine and methyldopa (via its metabolite a- methylnoradrenaline) followed, and for many years were utilised as effective antihypertensive agents. As newer drugs came along, these centrally-acting drugs fell from favour owing to their adverse effects which included dry mouth, sedation and rebound or overshoot hypertension on cessation of therapy. It was through experimentation with clonidine and methyldopa that a role of central noradrenergic synapses in BP control was initially suspected. Both drugs reduced the firing of efferent sympathetic neu- rones from the CNS, and when injected directly into the medulla oblongata or fourth ventricle, produced profound falls in BP at lower doses than would be required systemically. Surprisingly, when more a potent 2-agonists such as guanabenz were developed it was found that the antihypertensive effect was less pronounced. Examination of the imidazoline structure of cloni- dine (Figure 1) and studies with other imidazoline compounds led to the concept of a central non-adre- Figure 1 Structures of moxonidine, clonidine and related mol- a nergic binding site, termed the imidazoline receptor ecules that bind to I1 imidazoline and/or 2 adrenoreceptors. or binding site. Moxonidine has been developed as a novel centrally-acting antihypertensive which by virtue of its selectivity for the imidazoline receptor, a was expected to have fewer 2-related adverse effects (sedation and dry mouth). Moxonidine and now licenced and marketed in several European another imidazoline compound, rilmenidine, are countries. In this review we examine the pharma- cology of the drug and its clinical efficacy as an anti- Correspondence: Dr Scott TW Morris, The Renal Unit, Western hypertensive. Infirmary, Dumbarton Rd, Glasgow G11 6NT, UK Received 1 May 1997; revised and accepted 29 June 1997 Moxonidine: a review STW Morris and JL Reid 630 Pharmacology Evidence for a central site of action Moxonidine is an imidazoline compound (Figure 1) which exerts its antihypertensive effect by an action in the CNS. There are several pieces of evidence from animal work which unequivocally demonstrate that the drug has a central site of action. Firstly, in anaesthetised rabbits, there is a 30-fold increase in the dose required intravenously compared to that required intracisternally to produce the same fall in BP.1 In cats, injection of a single dose of moxonidine into the vertebral artery produced a considerably greater hypotensive effect than the same dose injected into the femoral artery.1 In addition, moxonidine has no hypotensive effect in pithed rats and in cats following spinal cord transection.2 The site of action of moxonidine in the CNS is thought to be the rostral ventrolateral medulla (RVLM),3 an area of the medullary reticular forma- Figure 2 Illustrates that hypotensive effect of moxonidine is mediated via I1 imidazoline receptors, while sedation and dry tion that contains neurones which control the pre- mouth (commonly seen with a-methyldopa and clonidine) are 4 a ganglionic sympathetic neurones in the spinal cord. mediated via 2 adrenoreceptors. (Adapted from reference 57). Maintenance of arteriolar smooth muscle tone and thus of peripheral resistance is dependent on the tonic discharge of neurones in this area.5 The RVLM ceptor stimulation led to adverse effects such as sed- is also the site of termination of afferent barorecep- ation11 (Figure 2). tor neurones, and this area orchestrates the reflex Imidazoline receptor sites have subsequently been control of BP. Micro-injection of moxonidine into demonstrated in several different species and the RVLM in rats produces profound falls in BP.6 tissues,12–17 and have been classified into at least Furthermore, following intravenous administration two subclasses termed I1 and I2 receptors based on of moxonidine in spontaneously hypertensive rats, affinity for 3H-clonidine and 3H-idazoxan.18 It injection of the I1 receptor antagonist efaroxan into should be noted that these receptors have thus far the RVLM blocks the hypotensive action of moxoni- only been defined by radioligand binding studies dine.3 It is therefore apparent that moxonidine can and drug-displacement profiles, and that the actual lower BP by an action at sites located in the RVLM. receptor proteins and second messenger systems have not been fully identified.19 Characteristics of the two receptor types are summarised in Table 1. Imidazoline receptors The endogenous ligand for these receptor sites may be agmatine.20 The existence of imidazoline receptors was first pro- posed in 1984 following examination of structure- activity relationships of various compounds synthe- Table 1 Characteristics of imidazoline receptors sized to avoid the adverse effects of clonidine.7 Until then it was assumed that the central hypotensive I1-receptor I2-receptor effect of clonidine was mediated solely through acti- a 8 3 3 vation of 2-adrenoceptors in the brainstem. The Radioligands H-clonidine H-idazoxan development of more potent a -adrenoceptor agon- 3H-moxonidine 2 3H-p-aminoclonidine ists, such as guanabenz, guanfacine and medetomid- Endogenous Agmatine Agmatine ine, did not, however, herald more potent antihyper- ligand tensives. In fact, these compounds are considerably Subcellular Plasma membrane Mitochondria less effective at BP reduction than methyldopa,9 and localization = . medetomidine is almost entirely devoid of hypoten- Drug affinities Clonidine Cirazoline idazoxan phentolamine = .. guanabenz .. sive effect while being a powerful sedative. idazoxan . clonidine .. Structure-activity relationship studies were sub- rilmenidine = epinephrine sequently performed which showed that when moxonidine . injected into the medulla of anaesthetised animals, efaroxan .. epinephrine only imidazoline drugs, and not catecholamines, Signal Unknown, possibly Unknown, possibly 7 were capable of lowering BP. The existence of bind- transduction prostaglandin release regulation of MAO ing sites in the RVLM which were specific to imida- Distribution Brainstem, kidney, Cerebral cortex, zolines but insensitive to catecholamines was first adrenal medulla, astrocytes, liver, demonstrated in 1987.10 Further studies with the a - platelets adrenal medulla, 2 platelets, colon, adrenoceptor antagonist SKF 86466 and imidazoline urethra, adipocytes, receptor antagonist idazoxan, demonstrated that prostate, kidney imidazoline receptors were responsible for the a hypotensive effects of clonidine, while 2-adreno- (Data from references 56 and 57). Moxonidine: a review STW Morris and JL Reid 631 Pharmacological actions of moxonidine mated at 88%34 and absorption is unaffected by food.33 In a study involving 18 healthy male volun- Moxonidine is a selective I1-receptor agonist with an teers who received an oral dose of 200 mg moxonid- a 21 I1: 2 affinity ratio of 40:1 to 70:1. Through an ine, the peak plasma concentration (Cmax) was action in the RVLM, it reduces sympathetic outflow 1.50 ± 0.65 ng/ml, the time to maximum plasma con- and lowers peripheral vascular resistence.22 Haemo- ± centration (Tmax) was 0.56 0.28 hours, and the half- dynamic studies have confirmed that BP reduction life (t ) 1.98 ± 0.68 hours.34 The volume of distri- is not accompanied by any significant change in 1/2 22 bution was calculated after intravenous adminis- heart rate or cardiac output. There has been a tration to be 1.83 L/kg with 0.44 L/kg apportioned to suggestion that moxonidine may actually produce a 14 23,24 the central compartment. A C radiolabelled study slight rise in cardiac output and there is growing showed only modest metabolism, and excretion of interest in the potentially beneficial neuro-humoral moxonidine and its metabolites is almost entirely by effects of moxonidine in the treatment of cardiac the renal route.33 While two metabolites were ident- failure. The reduction in BP obtained with moxonid- ified, 4,5-dehydromoxonidine and a guanidine ine is accompanied by a reduction in the plasma lev- derivative, around 85–90% of the drug is excreted els of adrenaline and noradrenaline, and in plasma 25 unchanged, and the metabolites have less than 10% renin activity. of the antihypertensive potency of the parent