Mecamylamine (Inversine ): an Old Antihypertensive with New Research Directions

Home , Hexamethonium, Mecamylamine, Pentolinium

Journal of Human Hypertension (2002) 16, 453–457  2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh REVIEW ARTICLE Mecamylamine (Inversine): an old antihypertensive with new research directions

RD Shytle1,2,4,5, E Penny6, AA Silver4, J Goldman4 and PR Sanberg1–5 Center for Aging and Brain Repair, 1Department of Neurosurgery, University of South Florida College of Medicine, Tampa, FL, USA; 2Department of Pharmacology, University of South Florida College of Medicine, Tampa, FL, USA; 3Department of Neurology, University of South Florida College of Medicine, Tampa, FL, USA; 4Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, FL, USA; 5Neuroscience Program, University of South Florida College of Medicine, Tampa, FL, USA; 6Layton Bioscience, Tampa Division, FL, USA

Mecamylamine (Inversine), the first orally available treatment of hypertension. Tobacco smoking is a strong antihypertensive agent, is now rarely used. Although risk factor for cardiovascular morbidity, including accel- celebrated in the 1950s, mecamylamine fell out of favour erated atherosclerosis and increased risk of heart because of its widespread ganglionic side effects at attacks. Though currently untested, the available evi- antihypertensive doses (30–90 mg/day). However, dence suggests that low-dose mecamylamine therapy recent studies suggest that mecamylamine is very effec- might reduce blood pressure variability and athero- tive at relatively low doses (2.5–5 mg b.i.d.) for blocking genetic lipid profile in smokers. With this in mind, meca- the physiological effects of nicotine and improving mylamine should be an important research tool in the abstinence rates in smoking cessation studies, parti- field of hypertension research, particularly in recalci- cularly for women. When these lower doses of mecamyl- trant smokers with mild to moderate hypertension. amine are given, patients do not experience the severity Journal of Human Hypertension (2002) 16, 453–457. doi: of side effects that made the drug unpopular for the 10.1038/sj.jhh.1001416

Keywords: mecamylamine; nicotine; smoking; Inversine; cardiovascular disease; nicotinic receptor

Introduction agents, such as trimethaphan, hexamethonium and pentolinium, which are not well absorbed from the Aceytlcholinergic nicotinic receptors (nAChR) have gastrointestinal track and do not cross the blood– been implicated in adverse pulmonary and cardio- 1–3 brain barrier, mecamylamine is almost completely vascular changes associated with tobacco smoking. absorbed and readily crosses the blood–brain barrier The adverse effects of nicotine on the cardiovascular 6,7 4 where it acts as an nAChR antagonist. system are numerous. As nAChRs are ubiquitous in There is a substantial history of wide clinical use both the peripheral and central nervous system, a of mecamylamine.8 Between 1954 and 1984, Merck broadly affecting anticholinergic that can cross the distributed both 10-mg and 2.5-mg tablets. The 10- blood–brain barrier and act specifically as an nAChR mg tablet was discontinued in March 1984. Unfortu- antagonist may reduce the adverse cardiovascular nately, mecamylamine distribution statistics are not changes associated with smoking and may also aid available for the period of greatest drug usage as an in smoking cessation. One such drug is mecamylam-  antihypertensive agent (1954 to 1960). However, ine (Inversine ). Introduced as a therapeutic agent from 1961 until 1996, Merck distributed 41 572 046 for the treatment of hypertension in the 1950s, and 7 029 400 of the 2.5-mg and 10 mg tablets, mecamylamine was the first useful ganglionic block-  ing agent that was not a quarternary ammonium respectively. In 1996, Merck sold the Inversine compound.5 Unlike other ganglionic blocking NDA to Layton Bioscience. The FDA has since approved a new manufacturing site and Layton Bioscience redistributed mecamylamine on the US market in May 2000.8 Correspondence: D Shytle, PhD, Center for Aging and Brain Repair, Department of Neurosurgery, MDC-78, 12901 Bruce B. Mecamylamine is currently approved for ‘the Downs Blvd., University of South Florida College of Medicine, management of moderately severe hypertension and Tampa, FL 33613, USA. E-mail: dshytleȰhsc.usf.edu uncomplicated cases of malignant hypertension’. Mecamylamine (Inversine) RD Shytle et al 454 The antihypertensive effects of mecamylamine duration of continuous smoking abstinence. At 1- reflect its blockade of impulse transmission at sym- year follow-up, smoking abstinence was achieved in pathetic ganglia due to competition for nAChRs and 37.5% of subjects. Furthermore, this combination stabilization of postsynaptic membranes against reduced ad-lib smoking, smoking satisfaction and excitation by ACh. This sympathetic ganglionic smoking craving. The most common side effect in blockade causes blood vessels to dilate and periph- these studies was mild constipation, which eral blood flow to increase, resulting in a reduction responded well to dosage reduction and/or over the in blood pressure. At therapeutic antihypertensive counter laxatives. doses (30–90 mg/day), mecamylamine also has para- Rose et al14 also found that daily administration sympathetic-blocking activity, causing nuisance of mecamylamine alone for 4 weeks prior to the quit side effects such as constipation, urinary retention, date was also more effective than nicotine patches dryness of the mouth and skin, dilation of the in reducing smoking satisfaction, cigarette craving pupils, and loss of visual accommodation in some and measures of continuous abstinence over several patients. weeks. In a recent study investigating gender effects Recently, there is considerable interest in evaluat- in the treatment of smoking cessation, Rose et al15 ing mecamylamine for the treatment of other clinical found that administration of mecamylamine prior to indications.8 The principal focus of research on quitting smoking may be necessary to extinguish the other clinical indications largely involves mecamyl- influence of environmental cues previously amine’s potent blockade of brain nicotinic receptors reinforced by smoking. Moreover, they found that at doses that do not have a significant effect on para- abstinence rates were much higher for women sympathetic function (2.5–10 mg/day).9 Potential receiving mecamylamine than for men. Because indications currently under investigation include results from other forms of smoking cessation ther- treatment of cocaine10 and ethanol abuse,11 to facili- apy including nicotine replacement therapy29 and tate smoking cessation,12–15 and to treat various neu- oral bupropion administration,30 indicate that ropsychiatric disorders including anxiety,16 epi- women have a more difficult time remaining absti- lepsy,17,18 Tourette’s disorder,19 bipolar disorder20 nent from smoking than men, these new findings and major depression.21,22 Mecamylamine also suggest that pre-cessation mecamylamine treatment appears to be well suited for the prophylactic treat- may be uniquely beneficial for women.15 Ongoing ment of autonomic dysreflexia.23,24 clinical studies at Duke University are investigating The purpose of this paper is to critically review this unique property of mecamylamine. the research available regarding the possible use of Although there is some evidence that bupropion mecamylamine as an aid to smoking cessation and (Zyban) may function to selectively block certain to propose testable hypotheses that could be studied nicotinic receptors in the brain,31 mecamylamine in recalcitrant smokers with mild to moderate (Inversine) is the only orally active well established hypertension. nicotinic receptor blocker currently available on the US market. Mecamylamine as an aid to smoking cessation New research directions for mecamylamine: smoking and While mecamylamine is still in phase III clinical trials and not yet indicated by the FDA for smoking cardiovascular disease cessation, there are several published studies that It is well known that cigarette smoking contributes conclude that mecamylamine, particularly in combi- to human diseases including coronary and periph- nation with transdermal nicotine, increases the rates eral vascular disease and stroke.32 Also long known of smoking abstinence14,25 especially in women.15 is that blood pressure and heart rate increase during Mecamylamine was one of the first medications smoking. These effects are specifically associated studied for smoking cessation treatment at the with nicotine, while the other components of ciga- National Institutes of Drug Abuse. Unfortunately, rette smoking seem to be of minor importance.33 intolerable side effects including constipation, Nicotine activates both parasympathetic and sym- drowsiness, and dry month caused by the high doses pathetic ganglia by mimicking the actions of acetyl- employed (mean of 26.7 mg/day) outweighed the choline at nicotinic receptors. Nicotine primarily drug’s beneficial effects on smoking cessation.26,27 acts through the sympathetic nervous system to However, Rose et al28 found that a very low dose of raise blood pressure and increase cardiac output and mecamylamine (2.5 mg/day), which was well toler- total peripheral vascular resistance. Heart rate can ated, reduced the subjective desire to smoke. increase by 20–30% shortly after smoking while Rose et al14,25 have also demonstrated the thera- blood pressure increases by about 10%.33 peutic utility of combining mecamylamine with While most studies have found that smokers do transdermal nicotine for the treatment of smoking not have a higher prevalence of hypertension than cessation. They have demonstrated that mecamyla- do non-smokers, it is clear that smokers exhibit a mine, given orally (2.5 to 5 mg b.i.d.) in combination persistent activation of the sympathetic nervous sys- with nicotine patches, significantly prolonged the tem throughout the day along with marked blood

Journal of Human Hypertension Mecamylamine (Inversine) RD Shytle et al 455 pressure variability. This suggests that smoking the remainder of the 21-week experiment. Mecamyl- results in transient blood pressure elevations with amine at a low dose (0.2 mg/kg) was administered each cigarette causing blood flow to be more turbu- orally once per day, 7 days per week from weeks 11 lent in smokers.33 Since blood pressure variability to 21 inclusive. Mecamylamine had no significant bears a direct positive relationship with target tissue blood pressure effects in the normotensive groups damage, it would be highly desired to treat habitual on regular or atherogenic diet, but reduced the sys- smokers with an antihypertensive medication that tolic blood pressure of hypertensive rats to near nor- could reduce this variability. While at least one mal levels regardless of diet. Furthermore, mecamyl- study found that some calcium channel blockers amine treatment reduced serum cholesterol levels to reduced blood pressure variability in smokers, near normal in the rats fed the atherogenic diet, and acceleration of heart rate due to smoking was not significantly reduced the development of aortic significantly affected.34 A recent study investigating atheromatous lesions (as assessed at the conclusion whether an interaction exists between the renin- of the 21 week study) in both normotensive and angiotensin system and smoking found that cigarette hypertensive animals receiving the high choles- smoking-induced activation of the sympathetic ner- terol diet. vous system was not blunted by acute angiotensin- In summary, these preclinical findings support the converting enzyme (ACE)-inhibition by captopril.35 testable hypothesis that low-dose mecamylamine Moreover, the smoking related increase in blood therapy may reduce both blood pressure variability pressure is exaggerated by propanolol, a non-selec- and adverse lipid profiles in smokers. tive beta-blocker.36 In summary, there is limited evidence that existing antihypertensive therapy is effective in reducing blood pressure variability in smokers. Since a long-acting nicotinic receptor Conclusions antagonist such as mecamylamine should be more Mecamylamine, the first orally available ganglionic selective in minimising cardiovascular variability in blocker developed for severe hypertension is rarely smokers, future studies could be designed to deter- used anymore. However, when doses 1/3rd or less mine the safety and efficacy of low-dose mecamyla- of the antihypertensive dose are used, patients do mine therapy in smokers with mild to moderate not experience the severity of side effects that made hypertension. In a recent pharmacokinetic study by the mecamylamine unpopular for the treatment of Zevin, Jacob and Benowitz,37 mecamylamine was hypertension. Mecamylamine has been found to found to reduce the volume of distribution of nic- potently block the physiological effects of nicotine otine and the cardioacceleratory and adrenaline- and to aid in the treatment of smoking cessation, releasing effects of nicotine in cigarette smoking particularly in women. Tobacco smoking is a strong subjects. This effect, the authors suggest, indicates risk factor for cardiovascular morbidity, including that in addition to the well-known nicotinic recep- accelerated atherosclerosis and increased risk of tor blocking properties, part of mecamylamine’s nic- heart attacks. These risks are particularly strong for otine blocking action may be due to a decrease in recalcitrant smokers with hypertension. Animal nicotine transport into the brain. studies suggest that various adverse consequences of Though currently untested clinically, mecamyla- smoking are primarily due to the pharmacological mine could potentially reduce adverse lipid profile actions of nicotine through acetylcholinergic nic- in smokers. Smokers on average have been found to otinic receptor activation. A broadly affecting antic- have a more atherogenetic lipid profile than do non- holinergic, such as mecamylamine, that can cross smokers, with increased low-densitity lipoprotein the blood–brain barrier and act specifically as a nic- and decreased high-density lipoprotein.38 The otinic antagonist, may not only reduce the desire to adverse lipid profile in smokers appears to be smoke, but also alleviate the adverse cardiovascular caused by nicotine because it has also been found in changes associated with smoking. With this in humans receiving nicotine gum,39,40 and in animals mind, controlled clinical trials involving low-dose receiving nicotine alone.41–43 Nicotine-induced mecamylamine therapy should be considered for increases in cholesterol, triacylglycerol, phospholi- smokers with mild to moderate hypertension. pid and fatty acids in the liver and testes of rats are counteracted by co-administration of the nicotinic receptor antagonist, mecamylamine.44 Preclinically, mecamylamine has been studied for its effect on Acknowledgements experimental atheromatosis in normal and hypertensive male Sherman rats.45 Hypertension was Three of the authors (RDS, AAS and PRS) are inven- induced unilateral nephrectomy, renal compression tors on a patent owned by USF that covers the use and subcutaneous implantation of desoxycortisone of nicotinic receptor antagonists for the treatment of acetate. All animals were maintained on regular diet nicotine-responsive neuropsychiatric disorders. The from weeks 1 to 5 inclusive and then half of the nor- authors are also scientific consultants for Layton motensive rats and half of the hypertensive rats were BioScience, who owns the trade name and market- switched to a high cholesterol atherogenic diet for ing rights to mecamylamine (Inversine).

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