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Heat Exposure and Drugs

A Review of the Effects of Hyperthermia on Pharmacokinetics

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  • Drug Interactions
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Abstract

Acute heat loading is encountered in several everyday situations, during physical exercise or work in a hot climate are just 2 examples. Special forms of heat exposure include different types of steam baths and saunas. External heating induces changes in haemodynamics, body fluid volume and blood flow distribution, which in turn may affect the pharmacokinetics of a drug and the therapeutic response. Documentation of the effects of heat exposure on the pharmacokinetics of drugs in humans is very limited, but based on the documentation some general conclusions can be drawn.

The effects of external heating on absorption and elimination of those orally administered drugs which have been studied (e.g. midazolam, ephedrine, propranolol and tetracycline), have been minor. Systemic absorption of transdermally and subcutaneously administered drugs [insulin, nitroglycerin (glyceryl trinitrate) and nicotine] is in most cases enhanced by external heating, leading to higher plasma drug concentrations.

In general, pharmacokinetic interactions between heat exposure and drug therapy are rare and limited to special situations, in which local blood flow (for example, over the skin) is enhanced many-fold because of hyperthermia. When pharmacodynamics are concerned, in most cases the probability of interactions is low, but in the treatment of malignant tumours hyperthermia may potentiate cytotoxic effects of drugs without enhancement of myelosuppressive effects.

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References

  1. Bull JMC. An update on the anticancer effects of a combination of chemotherapy and hyperthermia. Cancer Res 1984; 44 Suppl.: 4853s–6s.

    PubMed  CAS  Google Scholar 

  2. Vuori I. Sauna bather’s circulation. Ann Clin Res. 1988; 20: 249–56.

    PubMed  CAS  Google Scholar 

  3. Leppäluoto J. Human thermoregulation in sauna. Ann Clin Res. 1988; 20: 240–3.

    PubMed  Google Scholar 

  4. Rowell LB, Brengelmann GL, Murray JA. Cardiovascular responses to sustained high skin temperature in resting man. J Appl Physiol. 1969; 27(5): 673–80.

    PubMed  CAS  Google Scholar 

  5. Shoenfeld Y, Sohar E, Ohry A, et al. Heat stress: comparison of short exposure to severe dry and wet heat in saunas. Arch Phys Med Rehabil. 1976; 57: 126–9.

    PubMed  CAS  Google Scholar 

  6. Kukkonen-Harjula K, Oja P, Laustiola K, et al. Haemodynamic and hormonal responses to heat exposure in a Finnish sauna bath. Eur J Appl Physiol. 1989; 58: 543–50.

    Article  CAS  Google Scholar 

  7. Kauppinen K. Sauna, shower and ice water immersion: physiological responses to brief exposures to heat, cool and cold. Part III: body temperatures. Arctic Med Res. 1989; 48: 75–86.

    PubMed  CAS  Google Scholar 

  8. Harrison MH. Plasma volume changes during acute exposure to high environmental temperature. J Appl Physiol. 1974; 37(1): 38–42.

    PubMed  CAS  Google Scholar 

  9. Kauppinen K. Sauna, shower and ice water immersion: physiological responses to brief exposures to heat, cool and cold. Part I: body fluid balance. Arctic Med Res. 1989; 48: 55–63.

    PubMed  CAS  Google Scholar 

  10. Leppäluoto J, Arjamaa O, Vuolteenaho O, et al. Passive heat exposure leads to delayed increase in plasma levels of atrial natriuretic peptide in humans. J Appl Physiol. 1991; 71(2): 716–20.

    PubMed  Google Scholar 

  11. Ahonen E, Nousiainen U. The sauna and body fluid balance. Ann Clin Res. 1988; 20: 257–61.

    PubMed  CAS  Google Scholar 

  12. van Beaumont W, Underkofler S, van Beaumont S. Erythrocyte volume, plasma volume, and acid-base changes in exercise and heat dehydration. J Appl Physiol. 1981; 50(6): 1255–62.

    PubMed  Google Scholar 

  13. Rowell LB. Cardiovascular adjustments to thermal stress. In: Shephard JT, Abbound FM, editors. Handbook of physiology. Section 2: the cardiovascular system. Vol 3: peripheral circulation and organ blood flow. Part 2. Chapter 27. Bethesda: American Physiological Society, 1983: 967–1023.

    Google Scholar 

  14. Rowell LB, Brengelmann GL, Blackmon JR, et al. Redistribution of blood flow during sustained high skin temperature in resting man. J Appl Physiol. 1970; 28(4): 415–20.

    PubMed  CAS  Google Scholar 

  15. Rowell LB, Detry J-ML, Profant GR, et al. Splanchnic vasoconstriction in hyperthermic man: role of falling blood pressure. J Appl Physiol. 1971; 31(6): 864–9.

    PubMed  CAS  Google Scholar 

  16. Swartz RD, Sidell FR, Cucinell SA. Effects of physical stress on the disposition of drugs eliminated by the liver in man. J Pharmacol Exp Ther. 1974; 188(1): 1–7.

    PubMed  CAS  Google Scholar 

  17. Vanakoski J, Idänpään-Heikkilä JJ, Seppälä T. Exposure to high environmental temperature in the sauna does not change plasma indocyanine green (ICG) clearance in healthy subjects. Pharmacol Toxicol. 1996; 78: 94–8.

    Article  PubMed  CAS  Google Scholar 

  18. Kukkonen-Harjula K, Kauppinen K. How the sauna affects the endocrine system. Ann Clin Res. 1988; 20: 262–6.

    PubMed  CAS  Google Scholar 

  19. Laatikainen T, Salminen K, Kohvakka A, et al. Response of plasma endorphins, prolactin and catecholamines in women to intense heat in a sauna. Eur J Appl Physiol. 1988; 57: 98–102.

    Article  CAS  Google Scholar 

  20. Kukkonen-Harjula K, Oja P, Vuori I, et al. Cardiovascular effects of atenolol, scopolamine and their combination on healthy men in Finnish sauna baths. Eur J Appl Physiol. 1994; 69: 10–15.

    Article  CAS  Google Scholar 

  21. Adlercreutz H, Kuoppasalmi K, Kosunen K, et al. Plasma cortisol, growth hormone (GH) and prolactin levels during exposure to intense heat. IRCS J Med Sci. 1976; 4: 546.

    CAS  Google Scholar 

  22. Leppäluoto J, Huttunen P, Hirvonen J, et al. Endocrine effects of repeated sauna bathing. Acta Physiol Scand. 1986; 128: 467–70.

    Article  PubMed  Google Scholar 

  23. Barkve TF, Langseth-Manrique K, Bredesen JE, et al. Increased uptake of transdermal glyceryl trinitrate during physical exercise and during high ambient temperature. Am Heart J. 1986; 112(3): 537–41.

    Article  PubMed  CAS  Google Scholar 

  24. Danon A, Ben-Shimon S, Ben-Zvi Z. Effect of exercise and heat exposure on percutaneous absorption of methyl salicylate. Eur J Clin Pharmacol. 1986; 31: 49–52.

    Article  PubMed  CAS  Google Scholar 

  25. Formenti SC, Shrivastava PN, Sapozink M, et al. Abdominopelvic hyperthermia and intraperitoneal carboplatin in epithelial ovarian cancer: feasibility, tolerance and pharmacology. Int J Radiat Oncol Biol Phys. 1996; 35(5): 993–1001.

    Article  PubMed  CAS  Google Scholar 

  26. Fujimura A, Sasaki M, Harada K, et al. Influences of bathing and hot weather on the pharmacokinetics of a new transdermal clonidine, M-5041T. J Clin Pharmacol. 1996; 36: 892–6.

    PubMed  CAS  Google Scholar 

  27. Gerad H, Egorin MJ, Whitacre M, et al. Renal failure and platinum pharmacokinetics in three patients treated with cisdiamminedichloroplatinum(II) and whole-body hyperthermia. Cancer Chemother Pharmacol. 1983; 11: 162–6.

    Article  PubMed  CAS  Google Scholar 

  28. Koivisto VA. Sauna-induced acceleration in insulin absorption from subcutaneous injection site. BMJ. 1980; 280: 1411–3.

    Article  PubMed  CAS  Google Scholar 

  29. Koivisto VA. Influence of heat on insulin absorption: different effects on amorphous and soluble insulin. Acta Diabetol Lat. 1983; 20: 175–8.

    Article  PubMed  CAS  Google Scholar 

  30. Robins HI, Cohen JD, Schmitt CL, et al. Phase I clinical trial of carboplatin and 41.8°C whole-body hyperthermia in cancer patients. J Clin Oncol. 1993; 11(9): 1787–94.

    PubMed  CAS  Google Scholar 

  31. Robins HI, Rushing D, Kurtz M, et al. Phase I clinical trial of melphalan and 41.8°C whole-body hyperthermia in cancer patients. J Clin Oncol. 1997; 15(1): 158–64.

    PubMed  CAS  Google Scholar 

  32. Rönnemaa T, Koivisto VA. Combined effect of exercise and ambient temperature on insulin absorption and postprandial glycemia in type I patients. Diabetes Care. 1988; 11(10): 769–73.

    Article  PubMed  Google Scholar 

  33. Schlaeffer F, Engelberg I, Kaplanski J, et al. Effect of exercise and environmental heat on theophylline kinetics. Respiration. 1984; 45: 438–42.

    Article  PubMed  CAS  Google Scholar 

  34. Vanakoski J, Strömberg C, Seppälä T. Effects of a sauna on the pharmacokinetics and pharmacodynamics of midazolam and ephedrine in healthy young women. Eur J Clin Pharmacol. 1993; 45: 377–81.

    Article  PubMed  CAS  Google Scholar 

  35. Vanakoski J, Seppälä T. Effects of a Finnish sauna on the pharmacokinetics and haemodynamic actions of propranolol and captopril in healthy volunteers. Eur J Clin Pharmacol. 1995; 48: 133–7.

    Article  PubMed  CAS  Google Scholar 

  36. Vanakoski J, Idänpään-Heikkilä JJ, Olkkola K, et al. Effects of heat exposure in a Finnish sauna on the pharmacokinetics and metabolism of midazolam. Eur J Clin Pharmacol. 1996; 51: 335–8.

    Article  PubMed  CAS  Google Scholar 

  37. Vanakoski J, Seppälä T, Sievi E, et al. Exposure to high ambient temperature increases absorption and plasma concentrations of transdermal nicotine. Clin Pharmacol Ther. 1996; 60(3): 308–15.

    Article  PubMed  CAS  Google Scholar 

  38. Vanakoski J, Seppälä T. Renal excretion of tetracycline is transiently decreased during short-term heat exposure. Int J Clin Pharmacol Ther. 1997; 35(5): 204–7.

    PubMed  CAS  Google Scholar 

  39. Wiedemann GJ, d’Oleire F, Knop E, et al. Ifosfamide and carboplatin combined with 41.8°C whole-body hyperthermia in patients refractory sarcoma and malignant teratoma. Cancer Res. 1994; 54: 5346–50.

    PubMed  CAS  Google Scholar 

  40. Neufer PD, Young AJ, Sawka MN. Gastric emptying during exercise: effects of heat stress and hypohydration. Eur J Appl Physiol. 1989; 58: 433–9.

    Article  CAS  Google Scholar 

  41. Rehrer NJ, Beckers EJ, Brouns F, et al. Effects of dehydration on gastric emptying and gastrointestinal distress while running. Med Sci Sports Exerc. 1990; 22(6): 790–5.

    PubMed  CAS  Google Scholar 

  42. Klemsdal TO, Gjesdal K, Bredesen J-E. Heating and cooling of the nitroglycerin patch application area modify the plasma level of nitroglycerin. Eur J Clin Pharmacol. 1992; 43: 625–8.

    Article  PubMed  CAS  Google Scholar 

  43. Brockmöller J, Roots I. Assessment of liver metabolic function. Clin Pharmacokinet. 1994; 27(3): 216–48.

    Article  PubMed  Google Scholar 

  44. Ballard BE. Pharmacokinetics and temperature. J Pharm Sci. 1974; 63(9): 1345–58.

    Article  PubMed  CAS  Google Scholar 

  45. Fabre G, Crevat-Pisano P, Dragna S, et al. Involvement of the macrolide antibiotic inducible cytochrome P-450 LM3c in the metabolism of midazolam by microsomal fractions prepared from rabbit liver. Biochem Pharmacol. 1988; 37(10): 1947–53.

    Article  PubMed  CAS  Google Scholar 

  46. Kronbach T, Mathys D, Umeno M, et al. Oxidation of midazolam by and triazolam by human liver cytochrome P450IIIA4. Mol Pharmacol. 1989; 36: 89–96.

    PubMed  CAS  Google Scholar 

  47. Hasan J, Karvonen MJ, Piironen P. Special review: Part II. Physiological effects of extreme heat as studied in the Finnish ’sauna’ bath. Am J Phys Med. 1967; 46(2): 1226–46.

    CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Helsinki, P.O. Box 8 (Siltavuorenpenger 10), FIN-00014, Helsinki, Finland

    Jyrki Vanakoski

  2. Laboratory of Pharmacology and Toxicology, National Public Health Institute, Helsinki, Finland

    Jyrki Vanakoski & Timo Seppälä

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  1. Jyrki Vanakoski
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  2. Timo Seppälä
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Vanakoski, J., Seppälä, T. Heat Exposure and Drugs. Clin Pharmacokinet 34, 311–322 (1998). https://doi.org/10.2165/00003088-199834040-00004

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