Drug Safety 2008; 31 (2): 109-126 REVIEW ARTICLE 0114-5916/08/0002-0109/$48.00/0 © 2008 Adis Data Information BV. All rights reserved. Drug-Induced Hyperhidrosis and Hypohidrosis Incidence, Prevention and Management William P. Cheshire Jr1 and Robert D. Fealey2 1 Department of Neurology, Autonomic Reflex Laboratory, Mayo Clinic, Jacksonville, Florida, USA 2 Department of Neurology, Thermoregulatory Sweating Laboratory, Mayo Clinic, Rochester, Minnesota, USA Contents Abstract ....................................................................................109 1. Clinical Importance ......................................................................110 1.1 Hyperhidrosis ........................................................................110 1.2 Hypohidrosis .........................................................................111 2. Sites of Drug Action ......................................................................112 3. Drug-Induced Hyperhidrosis ...............................................................114 3.1 Anticholinesterases ..................................................................114 3.2 Antidepressants......................................................................114 3.3 Antiglaucoma Agents ................................................................115 3.4 Bladder Stimulants ...................................................................115 3.5 Drugs for Dementia ..................................................................115 3.6 Opioids .............................................................................115 3.7 Sialogogues .........................................................................116 3.8 Rebound Effects .....................................................................116 4. Drug-Induced Hypohidrosis ...............................................................116 4.1 Anticholinergics .....................................................................116 4.2 Antidepressants......................................................................118 4.3 Antiepileptics ........................................................................118 4.4 Antihistamines .......................................................................118 4.5 Antihypertensives ....................................................................119 4.6 Antipsychotics and Antiemetics .......................................................119 4.7 Botulinum Toxins .....................................................................119 4.8 Ganglionic Antagonists ...............................................................119 4.9 Intoxication .........................................................................119 5. Measurement of Hypohidrosis .............................................................120 6. Management of Hyperhidrosis .............................................................120 7. Management of Hypohidrosis .............................................................122 8. Conclusion ..............................................................................123 Abstract The human sweating response is subject to the influence of diverse classes of drugs. Some act centrally at the hypothalamus or at spinal thermoregulatory centres, while others act at sympathetic ganglia or at the eccrine-neuroeffector junction. Pharmacological disturbances of sweating have broad clinical implica- 110 Cheshire & Fealey tions. Drugs that induce hyperhidrosis, or sweating in excess of that needed to maintain thermoregulation, can cause patient discomfort and embarrassment, and include cholinesterase inhibitors, selective serotonin reuptake inhibitors, opioids and tricyclic antidepressants. Drugs that induce hypohidrosis, or deficient sweat- ing, can increase the risk of heat exhaustion or heat stroke and include antimus- carinic anticholinergic agents, carbonic anhydrase inhibitors and tricyclic antidepressants. As acetylcholine is the principal neuroeccrine mediator, anhidrosis is one of the clinical hallmarks by which acute anticholinergic toxicity may be recognized. The symptom of dry mouth often accompanies the less apparent symptom of hypohidrosis because the muscarinic M3 acetylcholine receptor type predominates at both sweat and salivary glands. Management options include dose reduction, drug substitution or discontinuation. When com- pelling medical indications require continuation of a drug causing hyperhidrosis, the addition of a pharmacological agent to suppress sweating can help to reduce symptoms. When hypohidrotic drugs must be continued, deficient sweating can be managed by avoiding situations of heat stress and cooling the skin with externally applied water. The availability of clinical tests for the assessment of sudomotor dysfunction in neurological disease has enhanced recognition of the complex effects of drugs on sweating. Advances in the understanding of drug- induced anhidrosis have also enlarged the therapeutic repertoire of effective treatments for hyperhidrosis. Sweating is the principal means of thermoregula- 1.1 Hyperhidrosis tory heat dissipation in response to heat stress in humans. Although numerous drugs can influence Hyperhidrosis refers to sweating in excess of that the sweating response, very few studies have evalu- needed to maintain a constant body temperature. ated the effects of medications specifically on sweat Under normal conditions, when increased metabolic production. activity or exposure to high ambient temperatures It is important to consider the potential role of raises the internal temperature of the body beyond sweat-promoting drugs in patients who complain of the range of physiological tolerance, the sympathet- unpleasant increased sweating, or of sweat-inhib- ic nervous system responds with a coordinated set of iting drugs in patients who present with hyperther- reflexes resulting in vasodilatation, hyperpnoea and mia or heat-related illness. In patients without symp- generalized sweating.[1-3] In this way, evaporative toms of altered sweating, it is also important to heat loss lowers body temperature to restore thermal consider the potential effects of drugs when clinical normality and maintain homeostasis. tests of sweat function are undertaken in an auto- Sweating in excess of thermoregulatory need or nomic laboratory for the purpose of evaluating auto- that occurs during routine daily activities usually nomic disorders or detecting small fibre neuro- does not lead to hypothermia but can be quite un- pathies. Knowledge of the effects of drugs on sweat- comfortable and socially embarrassing to the pa- ing is also useful in managing the patient with a tient. In these patients, generalized sweating may sweating disorder. occur at a lowered threshold with excessive loss of 1. Clinical Importance body fluids resulting in the potential for dehydration or electrolyte depletion. A number of common The clinical importance of sweating falls into two medications occasionally cause hyperhidrosis (table distinct categories, hyperhidrosis and hypohidrosis. I). © 2008 Adis Data Information BV. All rights reserved. Drug Safety 2008; 31 (2) Drug-Induced Hyperhidrosis and Hypohidrosis 111 Table I. Drugs that can cause hyperhidrosis Drug Class Common examples Mechanism Anticholinesterases Pyridostigmine Cholinesterase inhibition Antidepressants: selective serotonin reuptake Citalopram Serotonergic effect on hypothalamus or spinal cord inhibitors Duloxetine Escitalopram Fluoxetine Fluvoxamine Mirtazapine Paroxetine Trazodone Venlafaxine Antidepressants: tricyclics Amitriptyline Norepinephrine reuptake inhibition with stimulation of Desipramine peripheral adrenergic receptors Doxepin Imipramine Nortriptyline Protriptyline Antiglaucoma agents Physostigmine Physostigmine = cholinesterase inhibition Pilocarpine Pilocarpine = muscarinic receptor agonism Bladder stimulants Bethanechol Muscarinic receptor agonism Opioids Fentanyl Histamine release Hydrocodone Methadone Morphine Oxycodone Sialogogues Cevimeline Muscarinic receptor agonism Pilocarpine A US survey estimated the prevalence of hyper- temperature in conditions of strenuous physical ac- hidrosis in the general population at 2.8% but did tivity or in hot environments. When evaporative not assess whether, or to what degree, drugs might cooling is impaired, heat stress is more likely to lead have contributed.[4] Although the incidence of drug- to hyperthermia, heat exhaustion or heat stroke. induced hyperhidrosis is unknown, it is probably Core temperatures in excess of 38–40°C are not only less than that of essential hyperhidrosis. unpleasant for the patient but, if sustained, can cause There is no evidence that drugs that promote cellular dysfunction or death. The brain is especially sweating facilitate acclimatization to high ambient vulnerable to hyperthermia, and summer heat waves [5] temperatures or enhance the thermoregulatory ef- have taken the lives of large numbers of people.[7] ficiency of sweating during exercise.[6] Most patients remain unaware of hypohidrosis unless it renders them heat intolerant, in which case 1.2 Hypohidrosis they are less likely to notice the absence of sweating The second category is hypohidrosis, or de- than the positive symptoms of flushing, dizziness, creased sweating in response to a proportionate ther- exhaustion, dyspnoea and mild confusion resulting mal or pharmacological stimulus. Its complete form from overheating. Any drug that suppresses the pa- is termed anhidrosis, or the absence of sweating. tient’s ability