Mecamylamine (Inversine®), the first orally available antihypertensive agent, is now rarely used. Although celebrated in the 1950s, mecamylamine fell out of favour because of its widespread ganglionic side effects at antihypertensive doses (30–90 mg/day). However, recent studies suggest that mecamylamine is very effective at relatively low doses (2.5–5 mg b.i.d.) for blocking the physiological effects of nicotine and improving abstinence rates in smoking cessation studies, particularly for women. When these lower doses of mecamylamine are given, patients do not experience the severity of side effects that made the drug unpopular for the treatment of hypertension. Tobacco smoking is a strong risk factor for cardiovascular morbidity, including accelerated atherosclerosis and increased risk of heart attacks. Though currently untested, the available evidence suggests that low-dose mecamylamine therapy might reduce blood pressure variability and atherogenetic lipid profile in smokers. With this in mind, mecamylamine should be an important research tool in the field of hypertension research, particularly in recalcitrant smokers with mild to moderate hypertension.
Aceytlcholinergic nicotinic receptors (nAChR) have been implicated in adverse pulmonary and cardio- vascular changes associated with tobacco smoking.1,2,3 The adverse effects of nicotine on the cardiovascular system are numerous.4 As nAChRs are ubiquitous in both the peripheral and central nervous system, a broadly affecting anticholinergic that can cross the blood–brain barrier and act specifically as an nAChR antagonist may reduce the adverse cardiovascular changes associated with smoking and may also aid in smoking cessation. One such drug is mecamylamine (Inversine®). Introduced as a therapeutic agent for the treatment of hypertension in the 1950s, mecamylamine was the first useful ganglionic blocking agent that was not a quarternary ammonium compound.5 Unlike other ganglionic blocking agents, such as trimethaphan, hexamethonium and pentolinium, which are not well absorbed from the gastrointestinal track and do not cross the blood–brain barrier, mecamylamine is almost completely absorbed and readily crosses the blood–brain barrier where it acts as an nAChR antagonist.6,7
There is a substantial history of wide clinical use of mecamylamine.8 Between 1954 and 1984, Merck distributed both 10-mg and 2.5-mg tablets. The 10-mg tablet was discontinued in March 1984. Unfortunately, mecamylamine distribution statistics are not available for the period of greatest drug usage as an antihypertensive agent (1954 to 1960). However, from 1961 until 1996, Merck distributed 41 572 046 and 7 029 400 of the 2.5-mg and 10 mg tablets, respectively. In 1996, Merck sold the Inversine® 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
Mecamylamine is currently approved for ‘the management of moderately severe hypertension and uncomplicated cases of malignant hypertension’. The antihypertensive effects of mecamylamine reflect its blockade of impulse transmission at sympathetic ganglia due to competition for nAChRs and stabilization of postsynaptic membranes against excitation by ACh. This sympathetic ganglionic blockade causes blood vessels to dilate and peripheral blood flow to increase, resulting in a reduction in blood pressure. At therapeutic antihypertensive doses (30–90 mg/day), mecamylamine also has parasympathetic-blocking activity, causing nuisance side effects such as constipation, urinary retention, dryness of the mouth and skin, dilation of the pupils, and loss of visual accommodation in some patients.
Recently, there is considerable interest in evaluating mecamylamine for the treatment of other clinical indications.8 The principal focus of research on other clinical indications largely involves mecamylamine's potent blockade of brain nicotinic receptors at doses that do not have a significant effect on parasympathetic function (2.5–10 mg/day).9 Potential indications currently under investigation include treatment of cocaine10 and ethanol abuse,11 to facilitate smoking cessation,12,13,14,15 and to treat various neuropsychiatric disorders including anxiety,16 epilepsy,17,18 Tourette's disorder,19 bipolar disorder20 and major depression.21,22 Mecamylamine also appears to be well suited for the prophylactic treatment of autonomic dysreflexia.23,24
The purpose of this paper is to critically review the research available regarding the possible use of mecamylamine as an aid to smoking cessation and to propose testable hypotheses that could be studied in recalcitrant smokers with mild to moderate hypertension.
Mecamylamine as an aid to smoking cessation
While mecamylamine is still in phase III clinical trials and not yet indicated by the FDA for smoking cessation, there are several published studies that conclude that mecamylamine, particularly in combination with transdermal nicotine, increases the rates of smoking abstinence14,25 especially in women.15
Mecamylamine was one of the first medications studied for smoking cessation treatment at the National Institutes of Drug Abuse. Unfortunately, intolerable side effects including constipation, drowsiness, and dry month caused by the high doses employed (mean of 26.7 mg/day) outweighed the drug's beneficial effects on smoking cessation.26,27 However, Rose et al28 found that a very low dose of mecamylamine (2.5 mg/day), which was well tolerated, reduced the subjective desire to smoke.
Rose et al14,25 have also demonstrated the therapeutic utility of combining mecamylamine with transdermal nicotine for the treatment of smoking cessation. They have demonstrated that mecamylamine, given orally (2.5 to 5 mg b.i.d.) in combination with nicotine patches, significantly prolonged the duration of continuous smoking abstinence. At 1-year follow-up, smoking abstinence was achieved in 37.5% of subjects. Furthermore, this combination reduced ad-lib smoking, smoking satisfaction and smoking craving. The most common side effect in these studies was mild constipation, which responded well to dosage reduction and/or over the counter laxatives.
Rose et al14 also found that daily administration of mecamylamine alone for 4 weeks prior to the quit date was also more effective than nicotine patches in reducing smoking satisfaction, cigarette craving and measures of continuous abstinence over several weeks. In a recent study investigating gender effects in the treatment of smoking cessation, Rose et al15 found that administration of mecamylamine prior to quitting smoking may be necessary to extinguish the influence of environmental cues previously reinforced by smoking. Moreover, they found that abstinence rates were much higher for women receiving mecamylamine than for men. Because results from other forms of smoking cessation therapy including nicotine replacement therapy29 and oral bupropion administration,30 indicate that women have a more difficult time remaining abstinent from smoking than men, these new findings suggest that pre-cessation mecamylamine treatment may be uniquely beneficial for women.15 Ongoing clinical studies at Duke University are investigating this unique property of mecamylamine.
Although there is some evidence that bupropion (Zyban®) may function to selectively block certain nicotinic receptors in the brain,31 mecamylamine (Inversine®) is the only orally active well established nicotinic receptor blocker currently available on the US market.
New research directions for mecamylamine: smoking and cardiovascular disease
It is well known that cigarette smoking contributes to human diseases including coronary and peripheral vascular disease and stroke.32 Also long known is that blood pressure and heart rate increase during smoking. These effects are specifically associated with nicotine, while the other components of cigarette smoking seem to be of minor importance.33 Nicotine activates both parasympathetic and sympathetic ganglia by mimicking the actions of acetylcholine at nicotinic receptors. Nicotine primarily acts through the sympathetic nervous system to raise blood pressure and increase cardiac output and total peripheral vascular resistance. Heart rate can increase by 20–30% shortly after smoking while blood pressure increases by about 10%.33
While most studies have found that smokers do not have a higher prevalence of hypertension than do non-smokers, it is clear that smokers exhibit a persistent activation of the sympathetic nervous system throughout the day along with marked blood pressure variability. This suggests that smoking results in transient blood pressure elevations with each cigarette causing blood flow to be more turbulent in smokers.33 Since blood pressure variability bears a direct positive relationship with target tissue damage, it would be highly desired to treat habitual smokers with an antihypertensive medication that could reduce this variability. While at least one study found that some calcium channel blockers reduced blood pressure variability in smokers, acceleration of heart rate due to smoking was not significantly affected.34 A recent study investigating whether an interaction exists between the renin-angiotensin system and smoking found that cigarette smoking-induced activation of the sympathetic nervous system was not blunted by acute angiotensin-converting enzyme (ACE)-inhibition by captopril.35 Moreover, the smoking related increase in blood pressure is exaggerated by propanolol, a non-selective 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 antagonist such as mecamylamine should be more selective in minimising cardiovascular variability in smokers, future studies could be designed to determine the safety and efficacy of low-dose mecamylamine therapy in smokers with mild to moderate hypertension. In a recent pharmacokinetic study by Zevin, Jacob and Benowitz,37 mecamylamine was found to reduce the volume of distribution of nicotine and the cardioacceleratory and adrenaline-releasing effects of nicotine in cigarette smoking subjects. This effect, the authors suggest, indicates that in addition to the well-known nicotinic receptor blocking properties, part of mecamylamine's nicotine blocking action may be due to a decrease in nicotine transport into the brain.
Though currently untested clinically, mecamylamine could potentially reduce adverse lipid profile in smokers. Smokers on average have been found to have a more atherogenetic lipid profile than do non-smokers, with increased low-densitity lipoprotein and decreased high-density lipoprotein.38 The adverse lipid profile in smokers appears to be caused by nicotine because it has also been found in humans receiving nicotine gum,39,40 and in animals receiving nicotine alone.41,42,43 Nicotine-induced increases in cholesterol, triacylglycerol, phospholipid 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 experimental atheromatosis in normal and hypertensive male Sherman rats.45 Hypertension was induced unilateral nephrectomy, renal compression and subcutaneous implantation of desoxycortisone acetate. All animals were maintained on regular diet from weeks 1 to 5 inclusive and then half of the normotensive rats and half of the hypertensive rats were switched to a high cholesterol atherogenic diet for the remainder of the 21-week experiment. Mecamylamine at a low dose (0.2 mg/kg) was administered orally once per day, 7 days per week from weeks 11 to 21 inclusive. Mecamylamine had no significant blood pressure effects in the normotensive groups on regular or atherogenic diet, but reduced the systolic blood pressure of hypertensive rats to near normal levels regardless of diet. Furthermore, mecamylamine treatment reduced serum cholesterol levels to near normal in the rats fed the atherogenic diet, and significantly reduced the development of aortic atheromatous lesions (as assessed at the conclusion of the 21 week study) in both normotensive and hypertensive animals receiving the high cholesterol diet.
In summary, these preclinical findings support the testable hypothesis that low-dose mecamylamine therapy may reduce both blood pressure variability and adverse lipid profiles in smokers.
Mecamylamine, the first orally available ganglionic blocker developed for severe hypertension is rarely used anymore. However, when doses 1/3rd or less of the antihypertensive dose are used, patients do not experience the severity of side effects that made the mecamylamine unpopular for the treatment of hypertension. Mecamylamine has been found to potently block the physiological effects of nicotine and to aid in the treatment of smoking cessation, particularly in women. Tobacco smoking is a strong risk factor for cardiovascular morbidity, including accelerated atherosclerosis and increased risk of heart attacks. These risks are particularly strong for recalcitrant smokers with hypertension. Animal studies suggest that various adverse consequences of smoking are primarily due to the pharmacological actions of nicotine through acetylcholinergic nicotinic receptor activation. A broadly affecting anticholinergic, such as mecamylamine, that can cross the blood–brain barrier and act specifically as a nicotinic antagonist, may not only reduce the desire to smoke, but also alleviate the adverse cardiovascular changes associated with smoking. With this in mind, controlled clinical trials involving low-dose mecamylamine therapy should be considered for smokers with mild to moderate hypertension.
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Shytle, R., Penny, E., Silver, A. et al. Mecamylamine (Inversine®): an old antihypertensive with new research directions. J Hum Hypertens 16, 453–457 (2002). https://doi.org/10.1038/sj.jhh.1001416
- cardiovascular disease
- nicotinic receptor
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