|Year : 2019 | Volume
| Issue : 2 | Page : 75-82
Review of oral anticholinergics in the treatment of palmoplantar hyperhidrosis
Swetalina Pradhan1, Bhushan Madke2, Chandra Sekhar Sirka3
1 Department of Dermatology and Venereology, All India Institute of Medical Sciences, Patna, Bihar, India
2 Department of Dermatology, Venereology and Leprosy, Jawaharlal Nehru Medical College and AVBR Hospital, Wardha, Maharashtra, India
3 Department of Dermatology and Venereology, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
|Date of Web Publication||16-Dec-2019|
Dr. Bhushan Madke
Department of Dermatology, Venereology and Leprosy, Jawaharlal Nehru Medical College and AVBR Hospital, Sawangi, Wardha - 442 001, Maharashtra
Source of Support: None, Conflict of Interest: None
Hyperhidrosis (HH) is the excessive production of sweating, which can be primary and focal or secondary. The most commonly affected sites are the armpits, palms, soles, and face. It causes much discomfort and affects self-esteem and quality of life. Many treatment options have been proposed, both medical and surgical. Several recent studies have documented the effectiveness of oral anticholinergics in both focal and generalized HH regardless of age, gender, and weight. This article is an attempt to update the current status of oral anticholinergics in the treatment of palmoplantar HH.
Keywords: Hyperhidrosis, oral anticholinergics, review
|How to cite this article:|
Pradhan S, Madke B, Sirka CS. Review of oral anticholinergics in the treatment of palmoplantar hyperhidrosis. Indian J Drugs Dermatol 2019;5:75-82
|How to cite this URL:|
Pradhan S, Madke B, Sirka CS. Review of oral anticholinergics in the treatment of palmoplantar hyperhidrosis. Indian J Drugs Dermatol [serial online] 2019 [cited 2020 Jun 1];5:75-82. Available from: http://www.ijdd.in/text.asp?2019/5/2/75/272960
| Introduction|| |
Hyperhidrosis (HH) is a disorder characterized by the increased production of sweat disproportionate to the amount required to compensate for environmental conditions or thermoregulatory needs. Studies from several parts of the world have been addressing the epidemiology of HH, but in most of them, a limited portion of populations has been analyzed, thus their conclusions cannot be generalized.
HH can be primary or secondary in nature and may have general, regional, or focal manifestations. Primary HH is most often focal and generally causes idiopathic, symmetrically bilateral excessive sweating of the axillae, palms, soles, or craniofacial region. Secondary HH manifests most often as generalized excessive sweating that is related to an underlying medical condition or use of medications. HH results in a decrease in quality of life, may cause impairment in the ability to carry out daily functions, and, in some cases, may increase the risk of cutaneous infections.,
Magnitude of problem
There have been contradictory reports from various studies conducted in various countries such as Japan, Germany, Poland, and Canada regarding gender distribution in HH.,,, However, in majority of the studies, men have been found to have higher incidence and intensity of HH compared to women.,,, Men are more likely to have craniofacial HH or “additional areas” involved, whereas women are more likely to have axillary HH.
| Management of Hyperhidrosis|| |
Therapeutic options for HH are divided into several categories including topical, oral, and injectable drugs and medical devices.
Antiperspirant preparations containing aluminum salts, glycopyrrolate 2%, formaldehyde, and glutaraldehyde salts are the commonly used topical preparations for HH. Aluminum salts are the first-line treatment for HH because of their safety profile, cost-effectiveness, and efficacy.,, Antiperspirants work by obstructing the distal eccrine sweat gland ducts and long-term blockage, leading to functional and structural degeneration of the eccrine acini and thereby reducing sweat production., Skin irritation is a common limiting adverse event with aluminum chloride hexahydrate.,
Topical glycopyrrolate 2% improves HH because of its anticholinergic action by competitively binding the muscarinic acetylcholine receptors (Ach R). Studies and case reports suggest good results in facial HH, whereas results on axillary HH were inconsistent.,, Formaldehyde and glutaraldehyde are not commonly used in the treatment of primary focal HH because of their side effects such as localized skin irritation, allergic sensitization, and central nervous system toxicity.,
Botulinum toxin is an acetylcholine release inhibitor and a neuromuscular blocking agent. Various types of botulinum toxins have been tried in axillary and palmoplantar HH.,,,,,,,,,, The administration of botulinum toxin requires multiple injections, and expertise to inject proper amount of the toxin at proper site and the procedure is painful. Apart from discomfort, it is costly and unaffordable by patients in resourcepoor settings.,, Therapeutic failure owing to antibody formation is possible but extremely rare.
Tap water iontophoresis (TPI) has been used as a mode of treatment for HH where an ionized substance is used for passing through the intact skin with the help of a device that delivers 15–20 mA of current through tap water.,
According to proposed hypotheses, it acts through the inhibition of sympathetic nerve transmission, ion deposition obstructing the sweat gland, and local alterations of pH inhibiting the sweat gland.,,, Although TPI is found to be effective, it requires multiple sessions and maintenance therapy and is very time-consuming. In addition, it can cause discomfort, vesiculation, and erythema.
Apart from TPI, various emerging modalities, for example, microwave technology, lasers, microneedle radiofrequency, and ultrasound, are recently used for a focused area of thermotherapy targeting the eccrine sweat glands. However, they are cumbersome and costly and require multiple sessions and expertise.,,,,,
Sympathectomy is used especially in palmar HH. Wolosker et al. evaluated quality of life in 453 patients prospectively for 5 years following endoscopic thoracic sympathectomy and found that 409 patients (90.3%) had improved quality of life and only 3.1% of the patients had worsening results. In a study, more than 90% of patients had improved quality of life following sympathectomy and severe compensatory HH occurred in 5.4% of patients. Age did not affect these outcomes. Although long-term improvement has been found in 79% of cases, the procedure has the drawback of development of compensatory HH in body areas that are not supplied by the upper nerve trunk. In addition, there is a risk of surgery-related complications such as hemothorax, pneumothorax, Horner's syndrome, injury to the thoracic duct, and damage to the phrenic nerve.
For axillary HH, removal of axillary sweat glands by complete axillary curettage or liposuction has been tried, with success rate being 90%., However, the procedure needs skilled expertise and carries a risk of postprocedural complications of wound infection, scar formation, skin necrosis, and skin discoloration.
All the above-mentioned therapeutic approaches show a specific safety and effective profile to control primary HH localized at the axilla, the palms of the hands, the soles of the feet, and the face, and some of them have also demonstrated efficacy in segmental compensatory HH. Generalized HH requires systemic treatment and other modalities can be used as an adjuvant. Oral anticholinergics, beta-blockers, benzodiazepines, methanthelinium bromide, and clonidine have been used for the treatment of HH and among them, oral anticholinergics are commonly used for HH. In this review, we will discuss various types of oral anticholinergics in the management of HH.
| Oral Anticholinergics|| |
HH is believed to be caused by overactive cholinergic input to the eccrine glands.
Overexpression of acetylcholine and α 7-nicotinic receptors in sympathetic ganglia has been demonstrated in HH patients. Among oral anticholinergics, oxybutynin and glycopyrrolate have been studied widely for the management of HH.
Over the years, several studies have demonstrated good results of oxybutynin in focal HH (axillary, facial, and palmoplantar) and generalized HH.,,,,
Mechanism of action
Oxybutynin is an oral anticholinergic medication having antagonistic action on M1, M2, and M3 subtypes of the muscarinic acetylcholine receptor (Ach R). Its antimuscarinic effect on HH was first reported in 1988.,
Oxybutynin is rapidly absorbed, achieving the maximum concentration within an hour of oral intake after which plasma concentration decreases. The effective half-life of the drug is approximately 2–3 h. The absolute bioavailability of oxybutynin is reported to be about 6% (range, 1.6–10.9). Food delays the absorption and thereby increases the bioavailability of oxybutynin by 25%.
Oxybutynin is widely distributed in body tissues following systemic absorption. The major binding protein is α-1 acid glycoprotein.,, The drug can cross blood–brain barrier.
Oxybutynin is metabolized primarily by the cytochrome P450 enzyme systems, particularly CYP3A4, found mostly in the liver and gut wall. The metabolism results in one pharmacologically active product des-ethyl oxybutynin and a pharmacologically inactive product phenylcyclohexylglycolic acid.,,
Oxybutynin is extensively metabolized by the liver, with <0.1% of the administered dose excreted unchanged in the urine and <0.1% of the administered dose excreted as the metabolite des-ethyl oxybutynin.,,
Oxybutynin is a pregnancy category B drug. Oxybutynin chloride should not be given to pregnant women unless, in the judgment of the physician, the probable clinical benefits outweigh the possible hazards.,,
The concomitant use of oxybutynin with other anticholinergic drugs or with other agents which produce side effects similar to anticholinergics should be avoided.,, Due to anticholinergic effect on gastrointestinal (GI) motility, oxybutynin may alter the absorption of some concomitantly administered drugs. Ketoconazole being a potent CYP3A4 inhibitor increases the mean oxybutynin chloride plasma concentrations three- to four-fold. Other inhibitors of the cytochrome P450 3A4 enzyme system, such as antimycotic agents (e.g., itraconazole and miconazole) or macrolide antibiotics (e.g., erythromycin and clarithromycin), may alter the oxybutynin's mean pharmacokinetic parameters (i.e., maximum concentration and area under the curve).,,
Different studies have followed the following regimen – oral oxybutynin 2.5 mg daily for the 1st week, then 2.5 mg twice daily from day 8 to day 21, and 5 mg twice daily starting at day 22 up to 6 months for HH.,, The drug can be taken with or without food.
- Absolute contraindication: Angle-closure glaucoma
- Relative contraindication: Urinary retention, severe bladder outflow obstruction, gastric retention, GI obstruction, severe toxic megacolon, and hypersensitivity to the drug substance or other components of the product.
Side effect profile
Side effects are mainly due to the antimuscarinic effects of the drug. Dry mouth is experienced by 70%–100% of the patients treated with oxybutynin for HH. Other adverse events observed include constipation in up to 31% of the patients and drowsiness in up to 18%, while a feeling of mild urinary retention, dry eyes, dizziness, blurred vision, diarrhea, mydriasis, dry skin, rash, photosensitivity, and flushing are seen rarely.
The anticholinergic effects are more frequent with doses over 15 mg/day. A maximum dose of 10 mg/day reached through slow and progressive increase in dosage over a period of 3 weeks lowers the incidence of side effects, maintaining effectiveness and improving compliance to treatment. Schedules of a 1.25-mg initial dose and an increase by 1.25 mg every 4 days up to 7.5 mg/day, or 2.5 mg/day for the 1st week, 2.5 mg twice a day for the next 2 weeks, and 5 mg twice daily for the rest of the treatment have been successfully employed in literature.
Glycopyrrolate (pyrrolidinium 3-[(cyclopentylhydroxy/phenylacetyl) oxyl]-1, l-dimethyl bromide; glycopyrronium bromide) is a quaternary ammonium anticholinergic drug.
Mechanism of action
It competitively inhibits the action of acetylcholine at muscarinic receptors, which are prominent in glandular tissue. It also induces smooth muscle relaxation. It is a known antisecretory drug, thereby reducing gastric, pharyngeal, tracheal, and bronchial secretions.
Following oral administration, absorption from the GI tract is poor. Only 10%–25% of the drug is absorbed after oral intake. There is poor penetration of the drug across the blood–brain barrier. Both animal and human studies showed that placental transfer is limited.,
Metabolism and excretion
The major metabolic pathway is hydroxylation of the cyclopentyl ring and oxidation of the hydroxyl group in the mandelic acid residue which occurs in liver. The drug is chiefly excreted through urine and bile.
In various studies, the effective mean dose of glycopyrrolate in adult patients with primary HH was 2 mg once to twice daily., The efficacy is higher in children than in adults in controlling HH (90% efficacy with a mean dosage of 2 mg daily), and significant side effects in children are unusual.
The drug may antagonize the GI effects of prokinetic drugs (metoclopramide and domperidone).
Pregnancy category: Category B
Side effects of glycopyrrolate include xerostomia, loss of taste, nausea, vomiting, constipation, erectile dysfunction, headache, urinary retention and hesitancy, tachycardia, feeling of bloating, ocular effects (dry eyes and cycloplegia), and dizziness. Potentially fatal result can occur due to severe anaphylaxis.
The drug should be used with caution in those with close-angle glaucoma, bladder outflow obstruction, gastro-esophageal reflux disease, and cardiac insufficiency. It is contraindicated in those with myasthenia gravis, paralytic ileus, and pyloric stenosis.
Current literature on the efficacy of oral anticholinergic drugs are summarized in [Table 1] and [Table 2].
| Conclusion|| |
Oral anticholinergic drugs are safe therapeutic options in the treatment of focal HH, especially in resource-poor settings. Oxybutynin and glycopyrrolate are currently available in the Indian market. The drugs need close monitoring for their side effect profile. The authors suggest a tailor-made dosing schedule in real clinical settings.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]