Review Article

Mecamylamine (Inversine®): an old antihypertensive with new research directions

Abstract

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.

Introduction

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.

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.

References

  1. 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

    CAS  Article  Google Scholar 

  2. 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

    CAS  Article  Google Scholar 

  3. 3

    Villablanca AC . Nicotine stimulates DNA synthesis and proliferation in vascular endothelial cells in vitro J Appl Physiol 1998; 84: 2089–2098

    CAS  Article  Google Scholar 

  4. 4

    Saareks V et al. Clinical pharmacology of eicosanoids, nicotine induced changes in man J Physiol Pharmacol 2000; 51: 631–642

    CAS  PubMed  Google Scholar 

  5. 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

    CAS  Google Scholar 

  6. 6

    Baer JE, Paulson SF, Russo HF, Beyer KH . Renal elimination of 3-methylaminoisocamphane hydrochloride (mecamylamine) Am J Physiol 1956; 186: 180–186

    CAS  Article  Google Scholar 

  7. 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

    CAS  Article  Google Scholar 

  8. 8

    Young JM, Shytle RD, Sanberg PR, George TP . Mecamylamine: new therapeutic uses and toxicity/risk profile Clin Ther 2001; 23: 532–565

    CAS  Article  Google Scholar 

  9. 9

    Papke RL, Sanberg PR, Shytle RD . Analysis of mecamylamine stereoisomers on human nicotinic receptor subtypes J Pharmacol Exp Ther 2001; 297: 646–656

    CAS  PubMed  Google Scholar 

  10. 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

    CAS  Article  Google Scholar 

  11. 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

    CAS  Article  Google Scholar 

  12. 12

    Rose JE, Sampson A, Levin ED, Henningfield JE . Mecamylamine increases nicotine preference and attenuates nicotine discrimination Pharmacol Biochem Behav 1989; 32: 933–938

    CAS  Article  Google Scholar 

  13. 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

    CAS  Article  Google Scholar 

  14. 14

    Rose JE, Behm FM, Westman EC . Nicotine-mecamylamine treatment for smoking cessation: the role of pre- cessation therapy Exp Clin Psychopharmacol 1998; 6: 331–343

    CAS  Article  Google Scholar 

  15. 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. 16

    Newman MB et al. Corticosterone-attenutating and anxiolytic properties of mecamylamine in the rat Neuro-Psychopharmacol Biol Psych 2000; 25: 609–620

    Article  Google Scholar 

  17. 17

    Yokota T et al. Nicotine-sensitive paresis Neurology 1992; 42: 382–388

    CAS  Article  Google Scholar 

  18. 18

    Newman M et al. Nicotine induced seizures blocked by (±)-mecamylamine and its stereoisomers Life Sci 2001; 69: 2583–2591

    CAS  Article  Google Scholar 

  19. 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

    Google Scholar 

  20. 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

    CAS  Article  Google Scholar 

  21. 21

    Shytle RD et al. Neuronal nicotinic receptor inhibition for treating mood disorders: preliminary controlled evidence with mecamylamine Depression Anxiety 2002; (in press)

  22. 22

    Shytle R et al. Nicotinic acetylcholine receptors as targets for antidepressants Mol Psych 2002; (in press)

  23. 23

    Braddom RL, Johnson EW . Mecamylamine in control of hyperreflexia Arch Phys Med Rehabil 1969; 50: 448–453 passim

    CAS  PubMed  Google Scholar 

  24. 24

    Braddom RL, Rocco JF . Autonomic dysreflexia. A survey of current treatment Am J Phys Med Rehabil 1991; 70: 234–241

    CAS  Article  Google Scholar 

  25. 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

    CAS  Article  Google Scholar 

  26. 26

    Tennant FS Jr ., Tarver AL, Rawson RA. Clinical evaluation of mecamylamine for withdrawal from nicotine dependence NIDA Res Monogr 1984; 49: 239–246

    PubMed  Google Scholar 

  27. 27

    Tennant FS Jr, Tarver AL . Withdrawal from nicotine dependence using mecamylamine: comparison of three-week and six-week dosage schedules NIDA Res Monogr 1984; 55: 291–297

    PubMed  Google Scholar 

  28. 28

    Rose JE, Sampson A, Levin ED, Henningfield JE . Mecamylamine increases nicotine preference and attenuates nicotine discrimination Pharmacol Biochem Behavr 1989; 32: 933–938

    CAS  Article  Google Scholar 

  29. 29

    Perkins KA . Smoking cessation in women. Special considerations CNS Drugs 2001; 15: 391–411

    CAS  Article  Google Scholar 

  30. 30

    Dale LC et al. Bupropion for smoking cessation: predictors of successful outcome Chest 2001; 119: 1357–1364

    CAS  Article  Google Scholar 

  31. 31

    Slemmer JE, Martin BR, Damaj MI . Bupropion is a nicotinic antagonist J Pharmacol Exp Ther 2000; 295: 321–327

    CAS  PubMed  Google Scholar 

  32. 32

    Villablanca AC, McDonald JM, Rutledge JC . Smoking and cardiovascular disease Clin Chest Med 2000; 21: 159–172

    CAS  Article  Google Scholar 

  33. 33

    Omvik P . How smoking affects blood pressure Blood Press 1996; 5: 71–77

    CAS  Article  Google Scholar 

  34. 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

    CAS  PubMed  Google Scholar 

  35. 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

    CAS  Article  Google Scholar 

  36. 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

    CAS  Article  Google Scholar 

  37. 37

    Zevin S, Jacob P 3rd, Benowitz NL . Nicotine-mecamylamine interactions Clin Pharmacol Ther 2000; 68: 58–66

    CAS  Article  Google Scholar 

  38. 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

    CAS  Article  Google Scholar 

  39. 39

    Augustin J, Beedgen B, Sophr U, Winkel F . The influence of smoking on plasma lipoproteins Inner Med 1982; 9: 104–108

    Google Scholar 

  40. 40

    Largue G et al. Nicotine gum and the lipid profile Patholog Biol 1989; 37: 937–941

    Google Scholar 

  41. 41

    Burch EA Jr, Kadowitz PJ, Kother Copes SMC, Namara DB Jr . The effect of alcoholism and smoking on platelet eicosanoid production in vitro, prostaglandins, leukotrienes essential Fatty Acids 1991; 42: 39–44

    CAS  Article  Google Scholar 

  42. 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

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Cluette-Brown J et al. Oral nicotine induces an atherogenic lipoprotein profile Proc Soc Exp Biol Med 1986; 182: 409–413

    CAS  Article  Google Scholar 

  44. 44

    Kavitharaj NK, Vijayammal PL . Nicotine Administration induced changes in the gonadal functions in male rats Pharmacology 1999; 58: 2–7

    CAS  Article  Google Scholar 

  45. 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

    CAS  PubMed  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to R D Shytle.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Keywords

  • mecamylamine
  • nicotine
  • smoking
  • Inversine®
  • cardiovascular disease
  • nicotinic receptor

Further reading

Search