Journal of Human (1997) 11, 629–635  1997 Stockton Press. All rights reserved 0950-9240/97 $12.00

REVIEW ARTICLE : 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 , and adverse effect profile. With a growing num- to reduce . 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 . In ine represents a significant advance in hypertension this review we examine the ’s , clini- management. cal , efficacy as an antihypertensive

Keywords: moxonidine; hypertension; imidazoline; I1 imidazoline

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 , one of the first antihypertensive agents which depleted peripheral sympathetic neurones of noradrenaline and also interfered with central ␣ monoamine neurotransmission. The 2- clonidine and (via its metabolite ␣- 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 ␣ potent 2-agonists such as 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- ␣ nergic binding site, termed the 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, ␣ 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, , 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 ␣-methyldopa and clonidine) are 4 ␣ 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-.18 It

injection of the I1 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 for these receptor sites may be .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- ␣ 8 3 3 vation of 2-adrenoceptors in the brainstem. The Radioligands H-clonidine H-idazoxan development of more potent ␣ -adrenoceptor agon- 3H-moxonidine 2 3H-p-aminoclonidine ists, such as guanabenz, 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 = Ͼ is almost entirely devoid of hypoten- Drug affinities Clonidine idazoxan = ϾϾ guanabenz ϾϾ sive effect while being a powerful sedative. idazoxan Ͼ clonidine ϾϾ Structure-activity relationship studies were sub- rilmenidine = epinephrine sequently performed which showed that when moxonidine Ͼ injected into the medulla of anaesthetised animals, efaroxan ϾϾ epinephrine only imidazoline drugs, and not , 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, , Cerebral cortex, zolines but insensitive to catecholamines was first adrenal medulla, astrocytes, , demonstrated in 1987.10 Further studies with the ␣ - 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 ␣ 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 ␮g moxonid- ␣ 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- 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 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 ine is accompanied by a reduction in the plasma lev- derivative, around 85–90% of the drug is excreted els of and noradrenaline, and in plasma 25 unchanged, and the metabolites have less than 10% renin activity. of the antihypertensive potency of the parent drug. As imidazoline receptors are widely distributed The total clearance following oral administration throughout different tissues, moxonidine may be has been calculated at 12.8 ± 2.5 ml/min/kg expected to have other pharmacological actions (Table 2).34 besides BP reduction. Studies in rats have confirmed Multiple oral dosing in normal subjects, with a potent reduction in gastric acid and pepsin pro- 200 ␮g of moxonidine twice daily, does not appear duction and protection against gastric mucosal 26 to alter the pharmacokinetics, and drug accumu- injury. Again in rats, moxonidine reduced ischae- lation does not occur.35 In renal impairment, how- mia-induced cardiac arrhythmias and dose-depen- ever, the excretion half-life, Cmax and area under the dently increased the number of rats that survived curve all rise significantly, the levels being inversely without developing arrhythmias following ligation 25 27 proportional to the glomerular filtration rate. Close of a coronary artery. This anti-arrhythmic effect is observation has been suggested in these patients, most likely a result of reduced sympathetic outflow with use of lower doses titrated to individual BP as moxonidine does not directly alter cardiac refrac- 2 responses. In elderly patients, Tmax and AUC rise, toriness or ECG intervals. and total clearance falls, although renal clearance Further animal studies have confirmed that like remains unchanged.33 This is interpreted as being the older centrally-acting agents, moxonidine 1 a result of reduced metabolism in the elderly. The increases sodium excretion and induces a diuresis. changes in the pharmacokinetics of moxonidine By reducing sympathetic tone through a central 25 with advanced age are nevertheless small, and no action, moxonidine lowers plasma renin activity, drug accumulation has been observed if standard and thus would be expected to reduce aldosterone doses are used and the patient’s renal function is production. There is also evidence for a peripheral normal.33 natriuretic action—intrarenal injection of moxonid- 28 Only around 7% of the circulating drug is plasma ine and other I1-imidazoline receptor-selective 33 29,30 protein-bound. As a consequence, few drug inter- compounds in rats induces natriuresis. A study actions would be expected with moxonidine. In in healthy human volunteers, however, revealed no studies in humans, no drug–drug interaction has effect of moxonidine on renal excretory function or 31 been demonstrated between moxonidine and renal haemodynamics. The importance of any digoxin, or glibenclamide.33 natriuretic action of moxonidine in its hypotensive effect in humans is thus unclear. New antihypertensive drugs are developed with neutral, or preferably, beneficial metabolic effects. Moxonidine has been shown to significantly reduce Table 2 Pharmacokinetic parameters of moxonidine after oral body weight, cholesterol, triglycerides and and intravenous administration of 0.2 mg dose in 18 healthy indi- levels in the obese spontaneously hypertensive rat, viduals a putative model for the human syndrome X.32 Short term studies in humans suggest that moxonidine is Parameter Oral Intravenous at least metabolically ‘neutral’ in that no effect on t (h) 0.56 ± 0.28 – , cholesterol or triglyceride levels was seen max Cmax (ng/ml) 1.50 ± 0.65 3.97 ± 1.34 18 ± ± after 1 year of treatment. AUC0–(ng·h/ml) 3.67 1.01 4.20 1.21 ± ± t1/2 (h) 1.98 0.68 2.18 0.44 Vc (L/kg) 0.78 ± 0.58 0.44 ± 0.31 Pharmacokinetics Vss (L/kg) 1.79 ± 0.66 1.83 ± 0.44 Cl (ml/min/kg) 12.8 ± 2.5 11.2 ± 2.3 The clinical pharmacokinetics of moxonidine have Ae (24 h) (% of dose) 51 ± 13 61 ± 16 been extensively studied in healthy volunteers and (Reproduced with permission from reference 34). patient sub-populations (for review see reference = = Cl total clearance; AUC0– area under the plasma concen- 33). After oral administration, the drug is rapidly tration-time curve extrapolated to infinity; Ae = amount of drug and almost completely absorbed from the gastro- excreted renally unchanged; Vss = volume of distribution at ste- intestinal tract, with absolute esti- ady state; Vc = volume of distribution in central compartment. Moxonidine: a review STW Morris and JL Reid 632 Clinical studies compared for efficacy and tolerability with enalapril in 140 patients over an 8-week period.42 After a pla- ± (Results are expressed as mean s.d.). Pilot studies cebo run-in period, patients were randomised in a using moxonidine in mild-to-moderate hyperten- double-blind fashion to either placebo, moxonidine sion have suggested that an appropriate starting 200 ␮g once daily or enalapril 5 mg once daily, if ␮ 36,37 dose is 200 g once daily. One of the largest mean DBP was у85 mm Hg as measured by ABPM. initial studies was an open multicentre study, in Drug doses were doubled after a further 2 weeks. A ␮ which 141 patients initially received 200 g moxon- response to therapy was defined as sitting DBP р90 38 idine after a placebo washout. The dose was mm Hg or a fall in DBP of at least 10 mm Hg. In ␮ increased up to a maximum of 800 g if diastolic BP addition, 24-h ABPM allowed measurement of ± remained above 90 mm Hg. BP fell from 170 13.6/ trough:peak ratios. One hundred and thirty-three ± ± ± 103.2 6.3 mm Hg to 147.5 12.1/88.4 5.9 mm Hg patients completed the study protocol. over a 12-month treatment period in which 58.2% Response rates were similar in the two treatment ␮ of patients were maintained on 200 g/day and arms: 66% with enalapril and 60% with moxonid- ␮ 37.6% on 400 g/day. ine, and both drugs were significantly superior to A small single-blind, placebo-controlled, cross- placebo. Twenty-four hour DBP was lowered by ␮ over study with 250 g moxonidine once daily, 10.1 ± 9.8 mm Hg wtih moxonidine and by showed average reductions in systolic and diastolic 12.6 ± 10.5 mm Hg with enalapril. A trough to peak BP (SBP/DBP) of 23.1 and 17.5 mm Hg respect- ratio of 0.73 for moxonidine (0.70 for enalapril) indi- 25 ively. In a larger double-blind placebo-controlled cates that the drug can effectively be given once 39 ␮ study, the effects of moxonidine 200 g twice daily. The commonest adverse effect reported with ␮ daily, moxonidine 400 g once daily and placebo moxonidine was dry mouth (5/47), but there were a were compared in 49 patients with mild to moderate similar number of adverse effects reported with both hypertension over a 6-week period. Treatment with moxonidine (36.2%) and enalapril (31.9%). It moxonidine significantly reduced both systolic and should be noted, however, that 28.9% of patients on diastolic BP throughout the 24-h period, and both placebo experienced adverse effects. dosage regimes were equally effective. No significant change in heart rate was detected. Left ventricular hypertrophy (LVH) is an inde- (ii) Beta-blockers pendent predictor of adverse outcome in patients A randomised, double-blind, parallel group trial with , through its association compared the antihypertensive efficacy of moxonid- with congestive cardiac failure, myocardial ischae- ine with that of .43 After a 4-week placebo mia and malignant ventricular arrhythmias. While run-in period, patients were randomised to either no large scale studies have been performed with 200 ␮g moxonidine once daily or 50 mg atenolol moxonidine, a study involving 20 patients utilised once daily if DBP lay within the range 95–105 cardiac magnetic resonance imaging to assess the mm Hg. Over an 8-week treatment phase, doses were 40 ability of moxonidine to induce regression of LVH. doubled if DBP did not fall below 90 mm Hg. The Moxonidine reduced mean interventricular septal treatment phase was then followed by a further 2- thickness from 22.5 mm to 19.1 mm over 6 months, week placebo phase. Seventy-nine patients were with no significant change in ejection fraction. entered in total, 63 entered the treatment phase and Moxonidine has been compared for efficacy and 48 completed the full protocol. BP decreased from tolerability with all major existing classes of antihy- 166 ± 10/100 ± 5 to 149 ± 21/90 ± 9 mm Hg in the pertensive agent: moxonidine group and from 169 ± 11/101 ± 6to 149 ± 21/87 ± 8 mm Hg in the atenolol group. The reduction in BP was not significantly different (i) ACE inhibitors between the two groups, and a similar number of A randomised double-blind parallel group study adverse effects were reported in each group: 20.6% used 24-h ambulatory BP monitoring (ABPM) to with moxonidine and 26.5% with atenolol. This compare the effects of moxonidine 200 ␮g twice study did not, however, include a placebo group. daily with those of captopril 25 mg twice daily in 26 patients with a DBP of 85–105 mm Hg over a 4- (iii) Calcium antagonists week period.41 In the moxonidine group, mean 24- h ambulatory BP was reduced from a baseline of In one of the largest double-blind studies to date, 144.6 ± 15.8/91.4 ± 5.4 mm Hg to 139.7 ± 18.5/ Wolf44 compared moxonidine (200–400 ␮g once 86.8 ± 9.7 mm Hg, and in the captopril group from daily) to sustained-release nifedipine (20–40 mg 146.7 ± 10.6/91.5 ± 4.1 mm Hg to 141.0 ± 13.7/ once daily) in 229 patients over a 6-month period. 87.1 ± 7.1 mm Hg. The fall in BP was mainly attribu- A response was defined as a fall in DBP to Ͻ90 table to a fall in daytime pressure and was not sig- mm Hg or by 10 mm Hg. At the end of the study, nificantly different between the two groups. No 81.5% in the moxonidine group and 90.7% in the change in heart rate was detected, and no rebound nifedipine had responded. This difference was not hypertension was seen on withdrawal of either drug. statistically significant. BP fell from 168.4 ± 14.9/ Eight of 14 patients on moxonidine reported adverse 102.3 ± 7.2 mm Hg to 144.6 ± 18.9/86.0 ± 11.5 effects (most commonly nausea) compared with 8 of mm Hg in the moxonidine group, and from 12 on captopril (most commonly dizziness). 167.6 ± 15.2/102.1 ± 6.5 mm Hg to 139.8 ± 15.4/ In a placebo-controlled study, moxonidine was 83.1 ± 9.1 mm Hg in the nifedipine group. Slightly Moxonidine: a review STW Morris and JL Reid 633 more patients reported adverse effects in the nifedi- males entered this study; single doses of moxonid- pine group, but it was proposed by the authors that ine 200 ␮g, clonidine 200 ␮g or placebo were given most adverse effects were not likely to be drug- in a random order. During the study day, clonidine related. Again, no placebo group was included for and moxonidine lowered BP, with a significantly comparison, and these conclusions remain to be greater reduction achieved with clonidine. No confirmed. change in heart rate was detected with either drug. Drowsiness and dry mouth were twice as common with clonidine, but equi-effective hypotensive doses (iv) diuretics were not being compared. Moxonidine has been studied in combination with thiazide diuretics. In a placebo-controlled double- Adverse effects blind parallel group study in 160 patients with mild- to-moderate hypertension, the effects of 400 ␮g The main dose-limiting adverse effects of most cen- moxonidine once daily, hydrochlorothiazide 25 mg trally-acting antihypertensive agents are sedation once daily, a combination of the two or placebo were and dry mouth. Moxonidine therapy is said to be compared. Both moxonidine and hydrochlorothiaz- less frequently associated with these adverse effects. ide were shown to be equi-effective at reducing BP, In a double-blind study comparing equipotent anti- but the combination was superior with a mean hypertensive doses of moxonidine and clonidine, reduction in BP of 27 ± 16/16 ± 7.9 mm Hg.45 30% of patients experienced side effects with moxonidine compared to 53% with clonidine.48 Dry mouth and oedema were significantly less common (v) Alpha-blockers with moxonidine, but there was no statistically sig- An intra-individual study compared the efficacy and nificant reduction in the reporting of sedation. A tolerability of moxonidine with .46 Thirty double-blind crossover study in 20 patients revealed patients with mild-to-moderate hypertension were that while clonidine withdrawal was associated treated with 200– 400 ␮g/day moxonidine for 4 with rapid reversal and even overshoot (rebound) weeks. This was followed by a wash-out period of hypertension, this was not observed for moxonidine. 2 weeks, and then a further 4-week treatment period This finding confirms the lack of rebound hyperten- with prazosin 1–3 mg/day. A similar reduction in sion seen in animal models with moxonidine.50 In BP was obtained with the two drugs, but dose this same study, tiredness was significantly more titration took longer with prazosin. In addition, the common with clonidine, and patients reported a majority of patients were maintained on once-daily general feeling of well-being on moxonidine but not moxonidine, while the majority on prazosin on clonidine.47 Other reported adverse effects with required three times daily dosing. General well- moxonidine are sleep disturbance, nausea and dizzi- being was reported as being better with moxonidine, ness. and there were significantly more adverse effects When compared to the four main classes of cur- with prazosin therapy, the commonest being pos- rent antihypertensive agents (ACE inhibitors, tural , tiredness and nervousness. Dry diuretics, calcium antagonists, beta-blockers), over- mouth and tiredness were the most frequently all patient acceptability with moxonidine was at reported adverse effects with moxonidine. As yet, least as good41,45 if not better.43,44 In a total of 970 no comparison has been made with . patients who have received moxonidine in con- trolled clinical trials, nine serious adverse events have been documented: six were felt to be unrelated (vi) Clonidine to the drug and three were thought related (cardiac Moxonidine was originally introduced as an alterna- failure, unstable angina and syncope).51 tive to clonidine. The first study to compare the two Standard toxicology studies suggest that moxo- drugs was by reported by Pla¨nitz in 1984,47 where nidine is devoid of any mutagenic, carcinogenic or a double-blind crossover design was used. Twenty teratogenic effects.52 Nevertheless, it is excreted in hypertensive patients were treated with either 200 breast milk and is contraindicated in pregnancy or micrograms of clonidine or moxonidine for 2 weeks, breast-feeding. the dose being increased until DBP was Ͻ90 mm Hg. After 2 weeks, the drugs were switched for a further Conclusion 2 weeks without a wash-out period. Both drugs were equi-effective at BP reduction, with a mean daily Moxonidine is the first UK-licensed member of a dose of 300 ␮g. Six patients reported adverse effects new class of centrally-acting antihypertensive agent, with moxonidine compared to 17 with clonidine; the I1 imidazoline receptor agonists. Short and dry mouth and tiredness were the commonest medium-term studies show that the drug is as effec- adverse effects. tive at BP reduction as most of the current antihy- In a further double-blind, parallel-group compari- pertensives on the market. While dry mouth occurs son, moxonidine was again as effective as clonidine in around 10% of patients treated with moxonidine, at BP reduction, but adverse effects were signifi- other adverse effects are considerably less common, cantly more common in the clonidine group.48 and in particular, rebound hypertension, a phenom- A similar crossover study compared haemody- enon reported after abrupt withdrawal of clonidine namic and behavioural parameters with clonidine therapy, does not seem to occur. Furthermore, and moxonidine.49 Nine healthy normotensive moxonidine causes less sedation than the older cen- Moxonidine: a review STW Morris and JL Reid 634 trally-acting drugs, and does not appear to interfere 11 Ernsberger PR, Giuliano R, Willette RN, Reiss DJ. Role to any great extent with motor skills such as driv- of imidazoline receptors in the vasodepressor response ing.53 to clonidine analogs in the rostral ventrolateral med- While short and medium-term studies are encour- ulla. J Pharmacol Exp Ther 1990; 253: 408–418. aging, data are lacking for long-term safety, and sur- 12 De Vos H et al. Imidazoline receptors, non- vival studies have not been performed. In addition, idazoxan binding sites and alpha 2-adrenoceptors in the human central nervous system. Neuroscience the data sheet recommends that moxonidine be avo- 1994; 59: 589–598. ided in patients with Raynaud’s phenomenon, per- 13 Regunathan S, Meeley MP, Reis DJ. Expression of non- ipheral vascular disease, cardiac conduction defects, adrenergic imidazoline sites in chromaffin cells and unstable angina and severe cardiac failure. As the mitochondrial membranes of bovine adrenal medulla. drug is renally excreted, it must be used with care Biochem Pharmacol 1993; 45: 1667–1675. in moderate renal impairment. Small studies have, 14 Zonnenchein R, Diamant S, Atlas D. Imidazoline however, confirmed the drug’s tolerability in receptors in rat liver cells—a novel receptor or a sub- patients with cardiac failure54 and with asthma.55 type of alpha 2-adrenoceptors? Eur J Pharmacol 1990; Moxonidine may be a useful addition to the arma- 190: 203–215. mentarium of drugs at the physician’s disposal. Its 15 Langin D, Lafontan M. (3H)idazoxan binding at non- use as a first line treatment for uncomplicated essen- alpha 2-adrenoceptors in rabbit adipocyte membranes. tial hypertension could be justified, in that it is Eur J Pharmacol 1989; 159: 199–203. effective and probably has no more adverse effects 16 Yablonsky F, Riffaud JP, Lacolle JY, Dausse JP. Evi- dence for non-adrenergic binding sites for than many drugs already on the market. Although it (3H)idazoxan in the smooth muscle of rabbit urethra. is considerably more costly than or generic Eur J Pharmacol 1988; 154: 209–212. beta-blockers, it may be indicated in patients who 17 Chan Sl, Brown CA, Scarpello KE, Morgan NG. The are intolerant of, or who fail to respond to, other imidazoline site involved in control of insulin

classes of antihypertensive agent. Moxonidine does secretion: characteristics that distinguish it from I1 and offer an alternative strategy in hypertension manage- I2 sites. Br J Pharmacol 1994; 112(4): 1065–1070. ment—tolerable central sympathetic inhibition—to 18 Michel MC, Ernsberger P. Keeping an eye on the I site: add to the peripheral actions of drugs which inter- imidazoline-preferring receptors. Trends Pharmacol fere with the renin angiotensin system or peripheral Sci 1992; 13: 369–370. adrenergic blockers. 19 Bousquet P. Imidazoline receptors: from basic con- cepts to recent developments. J Cardiovasc Pharmacol References 1995; 26 (Suppl 2): S1–S6. 20 Li G et al. Agmatine: an endogenous clonidine-dis- 1 Armah BI, Hofferber E, Stenzel W. General pharma- placing substance in the brain. Science 1994; 263: cology of the novel centrally-acting antihypertensive 966–969. agent moxonidine. Drug Res 1988; 38: 1426–1434. 21 Ernsberger P, Westbrooks L, Christen O, Scha¨fer SG. A 2 Ziegler D et al. Pharmacology of moxonidine, an I1- second generation of centrally-acting antihypertensive Imidazoline receptor agonist. J Cardiovasc Pharmacol agents act on putative I1-Imidazoline receptors. J Car- 1996; 27 (Suppl 3): S26–S37. diovasc Pharmacol 1992; 20: S1–S10. 3 Haxhiu MA, Dreshaj I, Scha¨fer SG, Ernsberger P. Selec- 22 Mitrovic V, Patyna W, Hu¨ ting J, Schlepper W. Haemo- tive antihypertensive action of moxonidine is dynamic and neurohumoral effects of moxonidine in mediated mainly by I1-Imidazoline receptors in the patients with essential hypertension. Cardiovasc rostral ventrolateral medulla. J Cardiovasc Pharmacol Drugs Ther 1991; 5: 967–972. 1994; 24 (Suppl 1): S1–S8. 23 Hu¨ ting J, Mitrovic V, Bahavar H, Schlepper M. Vergle- 4 Reis DJ, Morrison S, Ruggiero DA. The C1 area of the ich der Wirkungen von Moxonidin und Nifedipin die brainstem in tonic and reflex control of blood pressure: linskventricula¨re Funktion bei Monotherapie der state of the art lecture. Hypertension 1988; 11 (Suppl essentiellen Hypertonie. Herz Kreislauf 1992; 24: 1): 8–13. 132–136. 5 Reis DJ. Neurons and receptors in the rostroventrolat- 24 Klepzig H Jr et al. Akuter und chronischer Einfluss von eral medulla mediating the anti-hypertensive actions Moxonidin auf Blutdruck und linskventricula¨re Funk- of drugs acting at imidazoline receptors. J Cardiovasc tion in Ruhe und unter Belastung. In: Hayduk K, Pharmacol 1996; 27 (Suppl 3): S11–S18. Stumpe KO (eds). Ein neues Therapieprinzip zur 6 Haxhiu MA et al. Vasodepression elicited in hyperten- Behandlung der Hypertonie. Schattauer: Stuttgart, sive rats by the selective I -imidazoline agonist moxon- 1 1992, pp 23–30. idine administered into the rostral ventrolateral med- ulla. J Cardiovasc Pharmacol 1992; 20 (Suppl 4): 25 Kirch W, Hutt H-J, Pla¨nitz V. Pharmacodynamic action S11–S15. and pharmacokinetics of moxonidine after single oral 7 Bousquet P, Feldman J, Schwartz J. Central cardio- administration to hypertensive patients. J Clin Pharm- vascular effects of ␣ adrenergic drugs: differences acol 1990; 30: 1088–1095. between catecholamines and imidazolines. J Pharm 26 Glavin GB, Smyth DD. Effects of the selective I1 imida- Exp Ther 1984; 230: 230–236. zoline receptor agonist, moxonidine, on gastric ␣ secretion and gastric mucosal injury in rats. Br J Pharm 8 Timmermans PBMW, Van Zwieten PA. 2 adrenocep- tors: classification, localization, mechanisms and tar- 1995; 114(4): 51–754. gets for drugs. J Med Chem 1982; 25: 1389–1401. 27 Lepran I, Papp JG. Effect of moxonidine on arrythmias 9 Mosqueda-Garcia R. Guanfacine: a second generation induced by coronary artery occlusion and reperfusion. ␣ 2 adrenergic blocker. Am J Med Sci 1990; 299: 73–76. J Cardiovasc Pharmacol 1994; 24 (Suppl 1): S9–S15. 10 Ernsberger PR, Meeley MP, Mann JJ, Reis DJ. Clonidine 28 Allan DR, Penner SB, Smyth DD. Renal imidazoline ␣ binds to imidazole binding sites as well as to 2 adre- preferring sites and solute excretion in the rat. Br J noceptors in the ventrolateral medulla. Eur J Pharma- Pharmacol 1993; 108: 870–875. col 1987; 134: 1–13. 29 Smyth DD, Penner SB. Renal I1-imidazoline receptor- Moxonidine: a review STW Morris and JL Reid 635 selective compounds mediate natriuresis in the rat. J moxonidine and atenolol in the management of Cardiovasc Pharmacol 1995; 26 (Suppl 2): S63–S67. patients with mild-to-moderate hypertension. J Car-

30 Penner SB, Smyth DD. Central and renal I1-imidazo- diovasc Pharmacol 1992; 20 (Suppl 4): S85–S93. line preferring receptors: two unique sites mediating 44 Wolf R. The treatment of hypertensive patients with a natriuresis in the rat. Br J Pharmacol 1994; 112: calcium antagonist or moxonidine. J Cardiovasc Phar- 1089–1994. macol 1992; 20 (Suppl 4): S79–S84. 31 Wiecek A, Fliser D, Nowicki M, Ritz E. Effect of 45 Frei M et al. Moxonidine and hydrochlorothiazide in moxonidine on urinary electrolyte excretion and renal combination: a synergistic antihypertensive effect. J haemodynamics in man. Eur J Clin Pharmacol 1995; Cardio Pharmacol 1994; 24 (Suppl 1): S25–S28. 48: 203–208. 46 Pla¨nitz V. Intraindividual comparison of moxonidine 32 Ernsberger P, Koletsky RJ, Collins LA, Bedol D. Sym- and prazosin in hypertensive patients. Eur J Clin Phar- pathetic nervous system in salt-sensitive and obese macol 1986; 29: 645–650. hypertension: amelioration of multiple abnormalities 47 Pla¨nitz V. Crossover comparison of moxonidine and by a central agent. Cardiovasc Drug clonidine in mild to moderate hypertension. Eur J Clin Ther 1996; 10 (Suppl 1): 275–282. Pharmacol 1984; 27: 147–152. 33 Weimann H-J, Rudolph M. Clinical pharmacokinetics 48 Pla¨nitz V. Comparison of moxonidine clonidine HCl of moxonidine. In: Scha¨fer SG, Christen MO, in treating patients with hypertension. J Clin Pharm Ernsberger PR (eds). New Perspectives in the Treat- 1987; 27(1): 46–51. ment of Hypertension/The Imidazoline Receptor 49 Macphee GJA, Howie CA, Elliott HL, Reid JL. A com- Agonist Moxonidine. Raven Press: New York, 1992, parison of the haemodynamic and behavioural effects pp 69–77. of moxonidine and clonidine in normotensive sub- 34 Theodor R, Weimann H-J, Weber W, Michaelis K. jects. Br J Clin Pharm 1992; 33: 261–267. Absolute bioavailability of moxonidine. Eur J Drug 50 Rupp H, Maisch B, Brilla CG. Drug withdrawal and Metab Pharmacokinet 1991; 16: 153–159. rebound hypertension: differential action of the cen- 35 Trenk D, Wagner F, Ja¨hnchen E, Pla¨nitz V. Pharmacok- tral antihypertensive drugs moxonidine and clonidine. inetics of moxonidine after single and repeated daily Cardiovasc Drug Ther 1996; 10: 251–262. doses in healthy volunteers. J Clin Pharmacol 1987; 51 Webster J, Koch HF. Aspects of tolerability of cen- 27: 988–993. trally-acting antihypertensive drugs. J Cardiovasc Pharmacol 1996; 27 (Suppl 3): S49–S54. 36 Pla¨nitz V, Hoffman K. First clinical data on moxonid- 52 Hamilton CA. Chemistry, mode of action and experi- ine hydrochloride for treatment of mild to moderate mental pharmacology of moxonidine. In: van Zwieten hypertension. Nauyn Schmiedeberg Arch Pharmacol PA, Hamilton CA, Jahu S, Prichard BNC (eds). The II 1983; 342 (Suppl): R79. imidazoline receptor agonist moxonidine: a new anti- 37 Planitz V. Treatment of hypertonia using various doses ¨ hypertensive. 2nd Ed, Royal Society of Medicine Press of moxonidine. Report on a moxonidine pilot study Ltd: London, 1994, pp 1–41. regarding the dosage interval. Kali-Chemie AG 1986: 53 Schmidt U et al. Hypertension: a possible risk in road Report 220.5904. traffic. J Cardiovasc Pharmacol 1992; 20 (Suppl 4): 38 Schwartz W, Kandziora J. Long-term experience with S50–S56. moxonidine, a new anti-hypertensive agent. Fortschr 54 Mitrovic V et al. Haemodynamic effects of moxonidine Med 1990; 108: 616–620. in patients with congestive cardiac failure during the 39 Oldenbroek C. Double-blind, placebo-controlled, first three hours after administration of a single 0.4 mg multicenter parallel group prospectively randomised dose [abstract]. 3rd Cardiovascular Pharmacology study of the antihypertensive effects of moxonidine in International Symposium, Kyoto 1989. patients with essential hypertension. Kali Chemi AG ␣ 55 Wilkens H et al. Effect of moxonidine, an 2 adrenergic 1991: Report K.220.5004. agonist, on histamine-induced bronchial constriction 40 Eichsta¨dt H et al. Demonstration of hypertrophy: and ventilatory occlusion responses to carbon dioxide regression with magnetic resonance tomography under in asthmatics [abstract]. 3rd Cardiovascular Pharma- the new adrenergic inhibitor moxonidine. Cardiovasc cology International Symposium. Kyoto 1989.

Drugs Ther 1989; 3 (Suppl 2): 583. 56 Ernsberger P et al.I1-Imidazoline receptors: definition, 41 Kraft K, Vetter H. Twenty-four-hour blood pressure characterization, distribution and transmembrane sig- profiles in patients with mild-to-moderate hyperten- nalling. Annals New York Academy of Sciences 1995; sion: moxonidine versus captopril. J Cardiovasc Phar- 763: 22–42. macol 1994; 24 (Suppl 1): S29–S33. 57 Regunathan S, Reis DJ. Imidazoline receptors and their 42 Ku¨ppers HE et al. Placebo-controlled comparison of endogenous ligands. Annu Rev Pharmacol Toxicol the efficacy and tolerability of once-daily moxonidine 1996; 36: 511–544. and enalapril in mild-to-moderate essential hyperten- 58 van Zwieten PA. Central imidazoline receptors as a sion. J Hypertens 1997; 15: 93–97. target for centrally acting antihypertensive drugs. 43 Prichard BNC et al. A double-blind comparison of Pharm World Sci 1995; 17(6): 186–190.