Drug-Associated Heat Stroke

Mauricio Martinez, MD, Lisa Devenport, MD, Jullette Saussy, MD, Jorge Martinez, MD


South Med J. 2002;95(8) 

In This Article

Effects of Certain Drugs on Heat Exposure

Anticholinergic drugs or drugs with anticholinergic effects are frequently associated with hyperpyrexia and heat illness. These drugs inhibit sweating, thereby reducing heat elimination.[3] Other anticholinergic effects include tachycardia, dry flushed skin, dilated pupils, decreased gastrointestinal motility, and urinary retention. In anticholinergic overdose, mental status changes with delirium may be present. Seizures, myoclonus, and dysrhythmias can also occur. Medications with anticholinergic properties include antihistamines, parkinsonism medication, atropine/scopolamine and the other belladonna alkaloids, neuroleptics, antispasmodics, and many species of plants. Tricyclic antidepressants have known quinidine-like sodium channel blockade, but they exert anticholinergic effects as well.

The clinical effects of sympathomimetics are similar to those of the anticholinergics, but the mechanisms are different. While anticholinergics block acetylcholine at the postsynaptic receptor, the sympathomimetics stimulate the a and b sympathetic receptors by releasing or preventing the reuptake of neurotransmitters. The effects include the tachycardia, hypertension, midriasis, and mental status changes in overdose. Drugs with sympathomimetic properties include cocaine, amphetamines, and ephedrine/pseudoephedrine, which are present in over-the-counter decongestants and popular dietary agents (ma huang). Methylxanthines, such as caffeine and theophylline, are indirect sympathomimetics. While not directly stimulating receptors, they potentiate sympathomimetic effects by inhibiting phosphodiesterase. Theophylline is also believed to be an inhibitor of adenosine, but effects on heat regulation have not been studied.

Sympathomimetics elevate body temperature by two main mechanisms. First, cutaneous blood flow is decreased by vasoconstriction, reducing heat loss. Second, heat production is increased by expanded muscular activity from agitation and seizure activity.[19]

The neuroleptics are a broad category of drugs with antipsychotic effects. Most of their psychiatric effects are attributed to dopamine blockade. Many of the neuroleptics have been associated with heat illness, including heat stroke and neuroleptic malignant syndrome. The same mechanism that treats psychosis may create heat illness.

In heat illness, phenothiazines are the best-studied class of antipsychotic medication. Commonly used phenothiazines include thioridazine, chlorpromazine, promethazine, and prochlorperazine. They gained widespread use in the early 1950s for the treatment of psychiatric illness because they were believed to be safe. In 1954, Berti and Cima[20] published their report of lethal temperature deregulation in mice given chlorpromazine. This was followed in 1956 by a case report by Ayd,[21] who described a patient who died as a result of hyperthermia while using chlorpromazine. Since that time, several other reports have described heat stroke in patients using phenothiazine medication.[22,23,24]

Phenothiazines have combined anticholinergic and central thermoregulatory effects. They inhibit afferent neuronal input to the hypothalamus.[25,26] This inhibition decreases the hypothalamus's normal compensatory effect of increasing cutaneous blood flow to aid in heat dissipation. Heat elimination is therefore reduced, leading to systemic heat alteration.

Thioxanthenes are physiologically and structurally similar to the phenothiazines. Their effects on heat illnesses have not been studied well, but they may have similar effects due to their structural and physiologic similarities. Commonly used thioxanthenes include chlorprothixene and thiothixene.

Butyrophenones include haloperidol in the class. This class of antipsychotic medication blocks dopamine receptors and may mimic -aminobutyric acid and oppose the action of glutamic acid in areas of the extrapyramidal system. Some of the known side effects are dystonias and the development of parkinsonian type symptoms. Regarding heat illness, they have not been shown to induce heat stroke, but temperature dysregulation in animal models has been shown.[27]


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