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Drugs

Check with a doctor about the effects of sun and heat when taking prescription drugs, especially diuretics or antihistamines.”  (Texas Department of State Health Services, Public Health Preparedness, 2007)

Many classes of drugs, whether prescribed, over-the-counter, recreational, or illicit can predispose their users to heat-related illnesses, including heat stroke (a medical emergency). Among heat-interacting medications are antidepressants, antihistamines, antipsychotics, and diuretics (detailed below). Unfortunately, many who prescribe these drugs, as well as those who dispense and those who use them, may be unaware of the risk presented by their use under conditions of extreme heat.1

Drugs and Heat

Drugs can interfere with normal thermoregulatory function in multiple ways, mediated through:

  • the hypothalamus, which sets normal body temperature;
  • heat perception, leading to behavioural change (heat avoidance);
  • changes in cardiac output;
  • changes in peripheral vasodilation;
  • changes in sweat rate;
  • changes due to renal function and/or body dehydration.

In terms of direct heat effects, the most critical pharmacological consequence is via the impact (decrease) on sweat rate. Since 90% of the body’s ability to cool itself at extreme temperatures relies on the evaporation of sweat, a disrupted capacity to sweat may be critical. Drugs with these side-effects act upon the muscarinic nerve endings of the cholinergic nerve fibres that innervate the sweat glands (of which there are several million in the body) and are therefore said to be antimuscarinic and/or anticholinergic. In addition, a number of drugs can directly introduce hyperthermic states (e.g., neuroleptic malignant syndrome); thus, the presence of environmental heat would provide an exacerbating effect.

Prescribing Medications in the Heat

The critical heat-related information for prescribing should (in principle) be available to the clinician who performs a thorough review of product monographs. Detailed information about effects of some drugs on thermoregulation, photosensitivity, anticholinergic effects or hydration status is included in the Canadian Compendium of Pharmaceuticals and Specialties (CPS) monographs. Examples include: phenothiazines, such as chlorpromazine; anticholinergics, such as antihistamines; antiparkinson drugs; atropine; MAO inhibitors and tricyclic antidepressants; and olanzapine (an atypical anti-psychotic). However, a number of CPS monographs for hyperthermic drugs make no mention of heat as an environmental issue of concern.2

In some cases, different drugs within a class may affect thermoregulation to differing degrees, although human data is lacking in this respect. For example, a study of the effect of various anticholinergic medications on core temperature elevation in rats found that scopolamine, often used as an antinauseant in humans, has the highest relative potency and therefore the highest impact on core temperature elevation (Table 1).3

Table 1: Relative impact of anticholinergic drugs on core temperature regulation

Drug Relative Potency
Imipramine 0.004
Amitriptyline 0.02
Chlorpromazine 0.1
Atropine 1
L-hyoscyamine 2
Atropine methyl nitrate 4
Scopolamine 16

In addition to being aware that prescribing certain drugs can limit patients’ life-styles and therefore requires appropriate warning, the clinician should bear in mind that some drugs of the same class can have opposite effects on the thermoregulatory mechanism, depending on type/dose. For example, tricyclic antidepressants (depending on the specific type) can cause hypohidrosis (deficient sweating) or hyperhidrosis (excessive sweating). Low doses of opioids may induce hyperthermia, whereas higher doses may cause hypothermia.4 These anomalies underscore the complex interplay between brain serotonin, dopamine, norepinephrine, thyroxine, and cortisol that impact on the maintenance of normal body temperature.

Epidemiologic Research on Drugs and Heat

A wealth of scientific information about the effects of drugs on thermoregulation has been derived from epidemiologic studies of the 2003 European Extreme Heat Event (EHE).

It was found that of 1405 patients treated at the emergency department (ER) of a hospital in Bordeaux, France during the August 2003 EHE, 4% were identified as experiencing heat stroke or hyperthermia.5 When compared with community controls who were not treated at the ER but were taking at least one prescription drug , ER cases with heat-related illness were more likely to have been prescribed anti-cholinergics, anti-psychotics, and anxiolytics  (when the use of other psycho-active medications were adjusted in analyses).

Table 2: Relationship between drugs and hospital admissions for heat-related illness

 Drug Class Odds Ratio 95% Confidence Interval
 Anticholinergics  6.0  1.8–19.6
 Antipsychotics  4.6  1.9–11.2
 Anxiolytics  2.4  1.3–4.4

Among 345 people admitted with heatstroke to intensive care units during August 2003 in France, univariate analysis showed that the use of diuretics, but not anxiolytics, antidepressants or alcohol, was associated with significantly increased chance of death.5 It was also found that none of the commonly-cited risk factors (older age, respiratory or neurologic co-morbidity, pre-existing use of neuroleptics or anxiolytics, alcohol abuse) was an independent predictor of mortality.

In a case-control study that considered deaths just prior to (August 1–4) and during (August 5–13) the 2003 French EHE, univariate analysis showed that several drug classes were more frequently used among individuals aged 70 to100 years who died during the heat event (Table 3).6

Table 3: Relationship between drugs and heat-related mortality during EHE 

Drug Class Odds Ratio 95% Confidence Interval
Antidepressants 1.75 1.62-1.90
Tricyclics 2.2 1.80-2.69

Antipsychotics
(except thioxanthenes)

2.19 1.96-2.45

Hypnotics:
     Non-benzodiazepene
     Benzodiazepenes


1.70
1.01
 

1.48-1.49 [sic]
0.95–1.08  i.e. not significant
 

Thus, three major pharmacological classes were associated with increased risk of heat-related mortality during the heat event.

Research Challenges

Much of the literature on the relationship between drugs and heat exposure is comprised of individual case studies where, in some cases, there is dubious association between the two. For example, one published study was conducted in a sauna at air temperatures in excess of 80 °C.7 Similarly, given the close relationship between medical diagnoses and specific therapies, epidemiological studies cannot effectively distinguish between the classic chicken-and-egg question – was it the drug or the underlying medical condition (including its socio-demographic elements) that led to the occurrence of heat-related illness? It is also difficult to ascribe causality to the presence of a drug, since heat stroke and consequent deaths also occur in those who are not taking any medications.8

Case Reports of Drugs and Heat

In cases where multiple drugs are administered (polypharmacy) and two or more of them in combination might be responsible for the reported symptoms, it is not possible to attribute individual causal relationships. The following case studies outline some reports of patients, taking multiple implicated drugs, who experienced heat stroke.

  • Fatal heat strokes were experienced by two men; one taking pimozide and clomipramine, the other taking zuclopenthixol, dexetimide, droperidol, promethzine and propranolol. These have anticholinergic and antidopaminergic effects; the latter can increase the core body temperature set point.9  
  • A man taking chlorpromazine and benztropine mesylate collapsed under hot outdoor conditions. He was found to be hyperthermic (42.9 °C, rectal) and, despite intensive intervention, died 16 hours after admission.10
  • An 11 year old girl, taking two amphetamines (phentermine and propylhexedrine hydrochloride) for weight loss, (as well as a diuretic, bumetanide; with last dose taken 3 days earlier) went on a 4 km hike with 107 classmates, during an ambient temperature of 34 °C. She collapsed and became delirious, ultimately losing consciousness. Although she was in hospital within 45 minutes (body temperature 42 °C), cooling methods had been applied in the interim, and there were numerous therapeutic efforts in both hospitals that she attended, she died some 19 hours after her initial collapse. None of the other children on the hike suffered any significant ill effects. The authors attribute the death to the peripheral vasoconstrictive and endogenous heat-producing effects of the two amphetamines that she was taking. Given the half-life and last administration of the diuretic, it is not believed to have made a contribution.11

Vulnerable Groups

It is clear that there are certain groups who may be particularly at risk for drug-induced heat-related adverse effects. Certain medical conditions increase risk of heat-related illness and are treated by medications that affect thermoregulation. For example, individuals taking antipsychotics may have diminished capacity to respond to extremely hot weather in addition to facing risks associated with their medication.

Summary

Shown below is an example in each of several drug classes that have been associated with this effect.  The list is representative only and by no means exhaustive.

Table 4: Some Examples of Drugs with Thermoregulatory Effects*

Class  Generic Name  Thermoregulatory Effects
 Antiadrenergics (ß-blockers)  Propranolol12  Decreased cardiac output
 Anticholinergics  Scopolomine4,13  Anti-muscarinic
 Antidepressants  Desipramine14  Anti-muscarinic
 Antiepileptics  Topiramate2,4,13,15,16  Central & inhibit carbonic   anhydrase
 Antihistamines     Diphenhydramine4,13  Anti-muscarinic
 Antihypertensives  Clonidine17  Central & anti-adrenergic
 Antiparkinsonics  Benztropine2,13  Anti-muscarinic
 Antipsychotics  Chlorpromazine2,4,13  Anti-muscarinic
 Anxiolytics (Non-benzodiazepines)18  Buspirone  
 Bladder antispasmodics     Oxybutinin4,13,19  Anti-muscarinic
 Diuretics  Acetazolamide13  Inhibit carbonic anhydrase & dehydration
 Natural Health Products     Ephedra20  Anti-muscarinic
 Recreational drugs  Fentanyl2,4  Hypothalamic set point
 Sympathomimetics  Pseudoephedrine  Inhibit peripheral vasodilation

* Table does not include cases where polypharmacy was implicated.

In summary, many classes of drugs that have an essential therapeutic use also have the adverse effect of putting the user at risk with respect to a hyperthermia as a result of exposure to high environmental heat and/or exercise-induced metabolic heat strain.  It behooves the prescriber and/or dispenser (especially when over the counter) of such drugs to appropriately advise the user.  This will become increasingly important as the frequency, duration, and severity of extreme heat events occur with climate change.

Recreational and Illicit Drugs

There are many drugs (including some of the medicinals mentioned above) that are used for recreational purposes.  Although they are too numerous to be elaborated here, such drugs could have similar effects as those described above, despite the applied purpose. As they are pharmacologically diverse, no single mechanistic basis is implicated. 

Two drugs that are obtained by illicit means, such as cocaine and “Ecstasy” (MDMA) certainly put the user at increased hyperthermic risk.  There may be various factors at play, including (as in the case of cocaine) a decreased awareness of the heat (and thereby lack of avoidance mechanisms), as well as decreased peripheral vasodilation and sweating.21  In the case of Ecstasy, the typical rave exertional activities are associated with considerable sweat loss which can lead (in those advised to drink a lot of water) to hyponatremia; hyperthermic effects appear to be mediated through an interaction of neurotransmitters.22

Unfortunately, given the nature whereby such drugs are acquired and used, informing the user is more problematic.

Gaps and Questions

  • At what minimum dose does a given drug exert hyperthermic effects?
  • What is the degree of heat strain at which specific drugs compound the heat effect?
  • Are drugs of different classes, and with different mechanistic bases, less likely to have interactive effects?

References

  1. Lomax P, Schonbaum E. The effects of drugs on thermoregulation during exposure to hot environments. Prog Brain Res. 1998;115:193-204.
  2. Canadian Pharmacists Association. CPS. Compendium of pharmaceuticals and specialties. The Canadian drug reference for health professionals. Gray J, editor. Ottawa, ON: Canadian Pharmacists Association; 2009.
  3. Matthew CB, Hubbard RW, Francesconi RP. A heat-stressed rat model to determine relative anticholinergic and anticholinesterase drug potency. Aviat Space Environ Med. 1986;57(11):1061-5.
  4. Cheshire WP, Fealey RD. Drug-induced hyperhidrosis and hypohidrosis: Incidence, prevention and management. Drug Saf. 2008;31(2):109-26.
  5. Misset B, De Jonghe B, Bastuji-Garin S, Gattolliat O, Boughrara E, Annane D, et al. Mortality of patients with heatstroke admitted to intensive care units during the 2003 heat wave in France: A national multiple-center risk-factor study. Crit Care Med. 2006;34(4):1087-92.
  6. Nordon C, Martin-Latry K, de Roquefeuil L, Latry P, Begaud B, Falissard B, et al. Risk of death related to psychotropic drug use in older people during the European 2003 heatwave: a population-based case-control study. Am J Geriatr Psychiatry. 2009;17(12):1059-67.
  7. Vanakoski J, Idänpään-Heikkilä JJ, Olkkola KT, Seppälä T. Effects of heat exposure in a Finnish sauna on the pharmacokinetics and metabolism of midazolam. Eur J Clin Pharmacol. 1996;51(3-4):335-8.
  8. Sherman R, Copes R, Stewart RK, Dowling G, Guidotti TL. Occupational death due to heat stroke: report of two cases. Can Med Assoc J. 1989;140(9):1057-8.
  9. Fijnheer R, van de Ven PJ, Erkelens DW. [Psychiatric drugs as risk factor in fatal heat stroke].[see comment]. Ned Tijdschr Geneeskd. 1995;139(27):1391-3.
  10. Stadnyk AN, Glezos JD. Drug-induced heat stroke. Can Med Assoc J. 1983;128(8):957-9.
  11. Kew MC, Hopp M, Rothberg A. Fatal heat-stroke in a child taking appetite-suppressant drugs. A case report. S Afr Med J. 1982;62(24):905-6.
  12. Gordon NF, Duncan JJ. Effect of beta-blockers on exercise physiology: Implications for exercise training. Med Sci Sports Exerc. 1991;23(6):668-76.
  13. Cuddy ML. The effects of drugs on thermoregulation. AACN Clin Issues. 2004;15(2):238-53.
  14. Popper CW, Elliott GR. Sudden death and tricyclic antidepressants: clinical considerations for children. J Child Adolesc Psychopharmacol. 1990;1(2):125-32.
  15. Boussemart T, Flurin V, Labay-Bruneau F, Bonardi JM. [Heat stroke and topiramate]. Arch Pediatr. 2008;15(4):416-8.
  16. Nieto-Barrera M, Nieto-Jiménez M, Candau R, Ruiz del Portal L. Anhydrosis and hyperthermia associated with treatment with topiramate. Rev Neurol. 2002;34(2):114-6.
  17. Fujimura A, Sasaki M, Harada K, Kumagai Y, Ohashi KI, Ebihara A. Influences of bathing and hot weather on the pharmacokinetics of a new transdermal clonidine, M-5041T. J Clin Pharmacol. 1996;36(10):892-6.
  18. Martin-Latry K, Goumy MP, Latry P, Gabinski C, Begaud B, Faure I, et al. Psychotropic drugs use and risk of heat-related hospitalisation. Eur Psychiatry. 2007;22(6):335-8.
  19. Adubofour KO, Kajiwara GT, Goldberg CM, King-Angell JL. Oxybutynin-induced heatstroke in an elderly patient. Ann Pharmacother. 1996;30(2):144-7.
  20. Holstege CP, Mitchell K, Barlotta K, Furbee RB. Toxicity and drug interactions associated with herbal products: ephedra and St. John's Wort. Med Clin North Am. 2005;89(6):1225-57.
  21. Crandall CG, Vongpatanasin W, Victor RG. Mechanism of cocaine-induced hyperthermia in humans. Ann Intern Med. 2002;136(11):785-91.
  22. Salzmann J, Marie-Claire C, Noble F. [Acute and long-term effects of ecstasy]. Presse Médicale (Paris, France: 1983). 2004;33(18 Suppl):24-32.

September 2010