Propantheline

Drug notes

Propantheline

James Barry1 MBBS, MRes, Foundation Doctor Sympathetic preganglionic Sympathetic postganglionic neuron (cholinergic) neuron (cholinergic) Gerry McKay1 BSc(Hons), FRCP, Consultant Physician

Miles Fisher1 MD, FRCP, Consultant Physician

1Glasgow Royal Infirmary, Glasgow, UK Acetylcholine Correspondence to: Dr James Barry, Foundation Doctor, Department of Acetylcholine Diabetes, Endocrinology & Clinical Pharmacology, Propantheline Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, UK; email: [email protected]

Muscarinic receptors

Sweat gland

Figure 1. Propantheline acts as an antagonist to acetylcholine at the muscarinic receptor within the sweat gland

Introduction has a direct musculotropic effect Sweating, or diaphoresis, is an essen- causing relaxation of smooth muscle. tial mechanism of thermoregulation. Propantheline is the isopropyl ana- Aberrant diaphoresis is a recognised logue of methantheline and has up complication of diabetic autonomic to five times the antimuscarinic neuropathy which is manifest at the activity, a longer duration of action time of eating (gustatory sweating). and a smaller side effect profile. This has potentially debilitating phys- Propantheline undergoes exten- iological, social and psychological sive first pass metabolism, reducing effects and is difficult to treat. If bioavailability significantly to between avoidance of triggering foods does 10–25%. Metabolism is mainly via not improve symptoms, a trial of hydrolysis with studies demonstrating drug therapy may be indicated. peak plasma levels at 2 hours and Propantheline has been used for elimination half-life between 2–3 many years to treat gustatory sweat- hours post single-dose administration. ing, but its effectiveness compared to The pharmacological effect is seen at more novel agents and multi-modal- 1 hour and persists until 6 hours post ity therapies is uncertain.1 dose. Elimination is mainly via renal excretion as inactive metabolites Pharmacology (70%) with up to 10% remaining as Propantheline bromide (Pro- intact propantheline. Banthine) is a synthetic analogue of The dual mechanism of action methantheline bromide (Banthine), produces an array of effects with which was used in the past for the possible clinical benefits, including treatment of peptic ulcer disease. It decreased secretions (anaesthesia), is a synthetic quaternary ammonium decreased gastric acid production compound which acts via two distinct (peptic ulcer disease) and smooth pathways. It is a non-specific acetyl- muscle relaxation (enuresis/gastro- choline antagonist at the muscarinic intestinal spasm disorders). Specific M1–3 receptors (Figure 1), but it also benefits for hyperhidrosis (excessive

sweating) and gustatory sweating axillary sweat production was 99mg are attributed to its antagonism of for methantheline bromide and Key points acetylcholine at M3 receptors of 130mg for placebo compared with glandular tissue. 168mg and 161mg respectively at ● Propantheline is a licensed medication Tolerability of anticholinergic baseline (p=0.004).2 Quality of life for hyperhidrosis side effects is widely reported as a scores were also improved. Tolerability ● The use of propantheline to treat limiting factor. These include dry was good for both groups. The most gustatory sweating in patients with mouth, bradycardia, constipation frequent adverse event was dry mouth. diabetic autonomic neuropathy is mainly and urinary retention among No such study has been performed historic, and evidence for its use is limited others. The elderly population are for propantheline. ● Randomised trials and comparative particularly susceptible to intensi- Oxybutynin and glycopyrrolate studies with newer therapies such as fied symptoms due to polyphar- are anticholinergic drugs that may topical glycopyrrolate and botulinum macy and comorbidities. Awareness also be used to treat hyperhidrosis injections are required of precautions and contraindica- although not licensed for this indi- tions including gastrointestinal cation. In a head-to-head study of obstructive diseases and closed- patients with enuresis, propanthe- one of several drug therapies which angle glaucoma is necessary. line was described as a less effective may be used to reduce symptoms. Toxicity due to delayed gastro but more tolerable therapy than Its use is historically based and paresis is reported with digoxin. oxybutynin. Both symptom improve- evidence of its efficacy, safety and Propantheline overdose will result ment and adverse events were signif- superiority over other treatment in intensification of usual side icantly greater for oxybutynin than modalities is lacking.4 effects, but at extreme doses pro- propantheline; 58.2% versus 44.7%, As a result of the high preva- pantheline exhibits nicotinic action and 63% versus 44%, respectively. lence of side effects with oral thera- that may result in paralysis through pies, other treatment modalities neuromuscular blocking. Specific evidence for use have been explored. These include Propantheline is the only anti- in diabetes topical glycopyrrolate, topical antimuscarinic and oral therapy licensed No evidence of trials supporting the perspirants, botulinum injections, for the treatment of hyperhidrosis use of propantheline in gustatory and in patients with severe and in the UK. sweating could be found although it disabling symptoms surgery may be is referred to as a possible treatment considered. Comparative studies of Trials of safety and efficacy within review articles of diabetes oral and topical antimuscarinic The use of antimuscarinic drugs for and diabetic autonomic neuropa- medication and other treatment excessive sweating developed from a thy. A single metabolic study was modalities in gustatory sweating case report in 1950 where dry hands found investigating growth hor- and hyperhidrosis are required. were observed as a side effect when mone suppression with atropine methantheline was prescribed for and propantheline in people with Declaration of interests the treatment of peptic ulcer dis- diabetes and concluded that pro- There are no conflicts of interest ease. In a mechanistic study, both pantheline was ineffective with a declared. methantheline and propantheline high incidence of adverse events.3 reduced the production of sweat in References response to galvanic skin stimula- Discussion 1. Watkins PJ, Thomas PK. Diabetes mellitus and the tion compared to placebo. Case Gustatory sweating is an increas- nervous system. J Neurol Neurosurg Psychiatry reports of generalised hyperhidrosis ingly recognised complication of 1998;65:620–32. 2. Muller C, et al. Efficacy and safety of methantheline in two patients following spinal cord diabetic autonomic neuropathy. bromide (Vagantin®) in axillary and palmar hyper- injury, and of one patient with gus- Currently, it is thought to be irre- hidrosis: results from a multicenter, randomized, tatory sweating post thyroidectomy, versible and treatment consists of placebo-controlled trial. J Eur Acad Dermatol Venereol 2013;27:1278–84. reported propantheline as effective symptom control. Propantheline 3. Hyer SL, et al. Failure to suppress GH secretion after in reducing symptoms. may be an effective treatment for 2 weeks treatment with atropine or propanthelene In a multi-centre, randomised, some patients if avoidance of trig- in diabetics with proliferative retinopathy. Acta Endocrinol (Copenh) 1988;119:61–8. placebo-controlled trial of methan- gering food does not reduce symp- 4. Lee KYC, Levell NJ. Turning the tide: a history and theline bromide, 339 patients were toms. Although the only licensed review of hyperhidrosis treatment. JRSM Open randomised. On day 28±1, the mean oral treatment, propantheline is 2014;5:1–4. Letter to the Editor Letters on any aspects of diabetes care are welcomed and should be addressed to: The Editor, Practical Diabetes, John Wiley & Sons, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK. Email: [email protected]