Download Mecamylamine (Inversine )

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
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.
Journal of Human Hypertension (2002) 16, 453–457. doi:
10.1038/sj.jhh.1001416
Keywords: mecamylamine; nicotine; smoking; Inversine; cardiovascular disease; nicotinic receptor
Introduction
Aceytlcholinergic nicotinic receptors (nAChR) have
been implicated in adverse pulmonary and cardiovascular changes associated with tobacco smoking.1–3
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
Correspondence: D Shytle, PhD, Center for Aging and Brain
Repair, Department of Neurosurgery, MDC-78, 12901 Bruce B.
Downs Blvd., University of South Florida College of Medicine,
Tampa, FL 33613, USA. E-mail: dshytle얀hsc.usf.edu
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 10mg 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’.
Mecamylamine (Inversine)
RD Shytle et al
454
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,12–15 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
Journal of Human Hypertension
duration of continuous smoking abstinence. At 1year 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
Mecamylamine (Inversine)
RD Shytle et al
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 reninangiotensin system and smoking found that cigarette
smoking-induced activation of the sympathetic nervous system was not blunted by acute angiotensinconverting 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 adrenalinereleasing 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 nonsmokers, 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.41–43 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.
455
Conclusions
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.
Acknowledgements
Three of the authors (RDS, AAS and PRS) are inventors on a patent owned by USF that covers the use
of nicotinic receptor antagonists for the treatment of
nicotine-responsive neuropsychiatric disorders. The
authors are also scientific consultants for Layton
BioScience, who owns the trade name and marketing rights to mecamylamine (Inversine).
Journal of Human Hypertension
Mecamylamine (Inversine)
RD Shytle et al
456
References
1 Schuller HM, Jull BA, Sheppard BJ, Plummer HK.
Interaction of tobacco-specific toxicants with the neuronal alpha(7) nicotinic acetylcholine receptor and its
associated mitogenic signal transduction pathway:
potential role in lung carcinogenesis and pediatric
lung disorders. Eur J Pharmacol 2000; 393: 265–277.
2 Plummer HK, 3rd, Sheppard BJ, Schuller HM. Interaction of tobacco-specific toxicants with nicotinic cholinergic regulation of fetal pulmonary neuroendocrine
cells: implications for pediatric lung disease. Exp Lung
Res 2000; 26: 121–135.
3 Villablanca AC. Nicotine stimulates DNA synthesis
and proliferation in vascular endothelial cells in vitro.
J Appl Physiol 1998; 84: 2089–2098.
4 Saareks V et al. Clinical pharmacology of eicosanoids,
nicotine induced changes in man. J Physiol Pharmacol
2000; 51: 631–642.
5 Stone CA, Torchiana ML, Navarro A, Beyer KH.
Ganglionic blocking properties of 3-methylaminoisocamphane hydrochloride (mecamylamine): a secondary amine. J Pharmacol 1956; 117: 169–183.
6 Baer JE, Paulson SF, Russo HF, Beyer KH. Renal elimination of 3-methylaminoisocamphane hydrochloride
(mecamylamine). Am J Physiol 1956; 186: 180–186.
7 Martin BR, Onaivi ES, Martin TJ. What is the nature
of mecamylamine’s antagonism of the central effects of
nicotine? Biochem Pharmacol 1989; 38: 3391–3397.
8 Young JM, Shytle RD, Sanberg PR, George TP. Mecamylamine: new therapeutic uses and toxicity/risk profile. Clin Ther 2001; 23: 532–565.
9 Papke RL, Sanberg PR, Shytle RD. Analysis of mecamylamine stereoisomers on human nicotinic receptor
subtypes. J Pharmacol Exp Ther 2001; 297: 646–656.
10 Reid MS, Mickalian JD, Delucchi KL, Berger SP. A nicotine antagonist, mecamylamine, reduces cue-induced
cocaine craving in cocaine-dependent subjects. Neuropsychopharmacology 1999; 20: 297–307.
11 Blomqvist O, Engel JA, Nissbrandt H, Soderpalm B.
The mesolimbic dopamine-activating properties of
ethanol are antagonized by mecamylamine. Eur J Pharmacol 1993; 249: 207–213.
12 Rose JE, Sampson A, Levin ED, Henningfield JE. Mecamylamine increases nicotine preference and attenuates
nicotine discrimination. Pharmacol Biochem Behav
1989; 32: 933–938.
13 Rose JE et al. Mecamylamine combined with nicotine
skin patch facilitates smoking cessation beyond nicotine patch treatment alone. Clin Pharmacol Therapeut 1994; 56: 86–99.
14 Rose JE, Behm FM, Westman EC. Nicotine-mecamylamine treatment for smoking cessation: the role of precessation therapy. Exp Clin Psychopharmacol 1998; 6:
331–343.
15 Rose J, Behm F, Westman E. Brand-switching and gender effects in mecamylamine/nicotine smoking cessation treatment. In: 5th Annual Meeting of the Society
for Research on Nicotine and Tobacco; 1999 March,
1999; San Diego, US: Society for Research on Nicotine
and Tobacco; 1999.
16 Newman MB et al. Corticosterone-attenutating and
anxiolytic properties of mecamylamine in the rat.
Neuro-Psychopharmacol Biol Psych 2000; 25: 609–
620.
17 Yokota T et al. Nicotine-sensitive paresis. Neurology
1992; 42: 382–388.
Journal of Human Hypertension
18 Newman M et al. Nicotine induced seizures blocked
by (±)-mecamylamine and its stereoisomers. Life Sci
2001; 69: 2583–2591.
19 Silver AA et al. Multi-center double blind placebo
controlled study of mecamylamine monotherapy for
Tourette’s disorder. J Am Acad Child Adolescent
Psych 2001; 40: 1101–1110.
20 Shytle RD, Silver AA, Sanberg PR. Comorbid bipolar
disorder in tourette syndrome responds to nicotinic
receptor antagonist, mecamylamine (Inversine. Biol
Psych 2000; 48: 1028–1031.
21 Shytle RD et al. Neuronal nicotinic receptor inhibition
for treating mood disorders: preliminary controlled
evidence with mecamylamine. Depression Anxiety
2002; (in press).
22 Shytle R et al. Nicotinic acetylcholine receptors as targets for antidepressants. Mol Psych 2002; (in press).
23 Braddom RL, Johnson EW. Mecamylamine in control
of hyperreflexia. Arch Phys Med Rehabil 1969; 50:
448– 453 passim.
24 Braddom RL, Rocco JF. Autonomic dysreflexia. A survey of current treatment. Am J Phys Med Rehabil 1991;
70: 234 –241.
25 Rose JE et al. Mecamylamine combined with nicotine
skin patch facilitates smoking cessation beyond nicotine patch treatment alone. Clin Pharmacol Ther
1994; 56: 86–99.
26 Tennant FS, Jr., Tarver AL, Rawson RA. Clinical evaluation of mecamylamine for withdrawal from nicotine
dependence. NIDA Res Monogr 1984; 49: 239–246.
27 Tennant Jr, FS, Tarver AL. Withdrawal from nicotine
dependence using mecamylamine: comparison of
three-week and six-week dosage schedules. NIDA Res
Monogr 1984; 55: 291–297.
28 Rose JE, Sampson A, Levin ED, Henningfield JE. Mecamylamine increases nicotine preference and attenuates
nicotine discrimination. Pharmacol Biochem Behavr
1989; 32: 933–938.
29 Perkins KA. Smoking cessation in women. Special
considerations. CNS Drugs 2001; 15: 391– 411.
30 Dale LC et al. Bupropion for smoking cessation: predictors of successful outcome. Chest 2001; 119:
1357–1364.
31 Slemmer JE, Martin BR, Damaj MI. Bupropion is a nicotinic antagonist. J Pharmacol Exp Ther 2000; 295:
321–327.
32 Villablanca AC, McDonald JM, Rutledge JC. Smoking
and cardiovascular disease. Clin Chest Med 2000; 21:
159–172.
33 Omvik P. How smoking affects blood pressure. Blood
Press 1996; 5: 71–77.
34 Fogari R, Zoppi A, Malamani GD, Corradi L. Effects of
calcium channel blockers on cardiovascular responses
to smoking in normotensive and hypertensive smokers. Int J Clin Pharmacol Res 1992; 12: 81–88.
35 Ottesen MM, Worck R, Ibsen H. Captopril does not
blunt the sympathoadrenal response to cigarette smoking in normotensive humans. Blood Press 1997; 6:
29–34.
36 Trap-Jensen J, Carlsen JE, Svendsen TL, Christensen
NJ. Cardiovascular and adrenergic effects of cigarette
smoking during immediate non-selective and selective
beta adrenoceptor blockade in humans. Eur J Clin
Invest 1979; 9: 181–183.
37 Zevin S, Jacob P, 3rd, Benowitz NL. Nicotine-mecamylamine interactions. Clin Pharmacol Ther 2000; 68:
58–66.
Mecamylamine (Inversine)
RD Shytle et al
38 Craig WY, Palomaki GE, Haddow JE. Cigarette smoking
and serum lipid and lipoprotein concentrations: an
analysis of published data. Br Med J 1989; 298: 784 –
788.
39 Augustin J, Beedgen B, Sophr U, Winkel F. The influence of smoking on plasma lipoproteins. Inner Med
1982; 9: 104 –108.
40 Largue G et al. Nicotine gum and the lipid profile.
Patholog Biol 1989; 37: 937–941.
41 Burch Jr., EA, Kadowitz PJ, Kother Copes SMC, Namara Jr. DB. The effect of alcoholism and smoking on
platelet eicosanoid production in vitro, prostaglandins, leukotrienes essential. Fatty Acids 1991; 42:
39– 44.
42 Booyse FM, Osikowicz G, Qarfoot AJ. Effect of Chronic
Oral Consumption of Nicotine on the Rabbit Aortic
Endothelium. Am J Pathol 1981; 102: 229–238.
43 Cluette-Brown J et al. Oral nicotine induces an atherogenic lipoprotein profile. Proc Soc Exp Biol Med
1986; 182: 409– 413.
44 Kavitharaj NK, Vijayammal PL. Nicotine Administration induced changes in the gonadal functions in
male rats. Pharmacology 1999; 58: 2–7.
45 Smith TH, Rossi GV. The effect of reserpine and mecamylamine on experimental atheromatosis in the normotensive and hypertensive rat. J Pharmacol Exp Ther
1962; 135: 367–373.
457
Journal of Human Hypertension