title: Effects of hypothermia on pharmacokinetics and pharmacodynamics: a systematic review of preclinical and clinical studies.
abstract: Examples of clinical applications of therapeutic hypothermia in modern clinical medicine include traumatic cardiac arrest, ischaemic stroke and, more recently, acute perinatal asphyxia in neonates. The exact mechanism of (neuro)protection by hypothermia is unknown. Since most enzymatic processes exhibit temperature dependency, it can be expected that therapeutic hypothermia may cause alterations in both pharmacokinetic and pharmacodynamic parameters, which could result in an increased risk of drug toxicity or therapy failure. Generalizable knowledge about the effect of therapeutic hypothermia on pharmacokinetics and pharmacodynamics could lead to more appropriate dosing and thereby prediction of clinical effects. This article reviews the evidence on the influence of therapeutic hypothermia on individual pharmacokinetic and pharmacodynamic parameters. A literature search was conducted within the PubMed, Embase and Cochrane databases from January 1965 to September 2008, comparing pharmacokinetic and/or pharmacodynamic parameters in hypothermia and normothermia regarding preclinical (animal) and clinical (human) studies. During hypothermia, pharmacokinetic parameters alter, resulting in drug and metabolite accumulation in the plasma for the majority of drugs. Impaired clearance is the most striking effect. Based on impaired clearance, dosages should be decreased considerably, especially for drugs with a low therapeutic index. Hypothetically, high-clearance compounds are affected more than low-clearance compounds because of the additional effect of impaired hepatic blood flow. The volume of distribution also changes, which may lead to therapy failure when it increases and could lead to toxicity when it decreases. The pH-partitioning hypothesis could contribute to the changes in the volumes of distribution for weak bases and acids, depending on their acid dissociation constants and acid-base status. Pharmacodynamic parameters may also alter, depending on the hypothermic regimen, drug target location, pharmacological mechanism and metabolic pathway of inactivation. The pharmacological response changes when target sensitivity alters. Rewarming patients to normothermia can also result in toxicity or therapy failure. The integrated effect of hypothermia on pharmacokinetic and pharmacodynamic properties of individual drugs is unclear. Therefore, therapeutic drug monitoring is currently considered essential for drugs with a low therapeutic index, drugs with active metabolites, high-clearance compounds and drugs that are inactivated by enzymes at the site of effect. Because most of the studies (74%) included in this review contain preclinical data, clinical pharmacokinetic/pharmacodynamic studies are essential for the development of substantiated dose regimens to avoid toxicity and therapy failure in patients treated with hypothermia.
authors.affiliation: Department of Clinical Pharmacy, Division of Laboratory Medicine & Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands. m.p.h.vandenbroek@umcutrecht.nl
authors.forename: Marcel P H
authors.initials: MP
authors.lastname: van den Broek
authors.forename: Floris
authors.initials: F
authors.lastname: Groenendaal
authors.forename: Antoine C G
authors.initials: AC
authors.lastname: Egberts
authors.forename: Carin M A
authors.initials: CM
authors.lastname: Rademaker
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D007035:Hypothermia / Q000188:drug therapy* / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology
chemical_list: D004364:Pharmaceutical Preparations
references.citation: Crit Care Med. 2009 Jan;37(1):263-9
references.pmid: 19050605
references.citation: Pediatrics. 2008 Apr;121(4):e844-9
references.pmid: 18381513
references.citation: Clin Pharmacokinet. 1987 Mar;12(3):145-67
references.pmid: 3555939
references.citation: J Pharmacol Exp Ther. 1965 Feb;147:260-9
references.pmid: 14259505
references.citation: Arch Pediatr. 2008 Mar;15(3):229-35
references.pmid: 18329254
references.citation: Anesth Analg. 1994 May;78(5):973-7
references.pmid: 7909212
references.citation: Pharmacol Ther. 2008 Oct;120(1):43-53
references.pmid: 18718848
references.citation: J Pharmacol Exp Ther. 1969 Nov;170(1):145-52
references.pmid: 5350998
references.citation: J Pharmacol Exp Ther. 1968 Feb;159(2):389-98
references.pmid: 5638659
references.citation: J Appl Physiol (1985). 2006 Feb;100(2):457-64
references.pmid: 16210439
references.citation: Epilepsia. 2009 Nov;50(11):2355-61
references.pmid: 19744111
references.citation: Anesth Analg. 1995 May;80(5):1007-14
references.pmid: 7726398
references.citation: J Neurosurg. 1993 Sep;79(3):363-8
references.pmid: 8360732
references.citation: J Pediatr. 1982 Apr;100(4):655-60
references.pmid: 7062221
references.citation: Br J Clin Pharmacol. 1991 Dec;32(6):697-704
references.pmid: 1768562
references.citation: Ther Drug Monit. 2001 Jun;23(3):192-7
references.pmid: 11360024
references.citation: Anesthesiology. 2002 Jul;97(1):90-5
references.pmid: 12131108
references.citation: Crit Care Med. 2006 Mar;34(3):785-91
references.pmid: 16521272
references.citation: Acta Anaesthesiol Scand. 1995 Feb;39(2):199-204
references.pmid: 7793187
references.citation: Pediatrics. 2009 Jul;124(1):310-5
references.pmid: 19564314
references.citation: Curr Drug Metab. 2008 Jul;9(6):574-80
references.pmid: 18680478
references.citation: Pharmacology. 1980;20(2):95-100
references.pmid: 7384193
references.citation: J Pharmacol Exp Ther. 1965 Feb;147:252-9
references.pmid: 14259504
references.citation: Mol Pharmacol. 1976 Nov;12(6):977-86
references.pmid: 63911
references.citation: Clin Pharmacokinet. 2006;45(11):1077-97
references.pmid: 17048973
references.citation: J Pharmacol Exp Ther. 1968 Dec;164(2):396-404
references.pmid: 5699100
references.citation: Biochim Biophys Acta. 1990 Oct 8;1031(3):261-75
references.pmid: 2223818
references.citation: Cell Death Differ. 2005 Feb;12(2):162-76
references.pmid: 15592434
references.citation: Am J Physiol. 1978 Aug;235(2):H136-43
references.pmid: 28676
references.citation: Clin Pharmacokinet. 1982 May-Jun;7(3):234-51
references.pmid: 7047043
references.citation: Crit Care Med. 1985 Oct;13(10):844-7
references.pmid: 4028756
references.citation: West J Med. 1983 Feb;138(2):227-32
references.pmid: 6837026
references.citation: Biochem Pharmacol. 1992 Dec 15;44(12):2323-31
references.pmid: 1472097
references.citation: Anesthesiology. 1983 Apr;58(4):357-61
references.pmid: 6220624
references.citation: Anesth Analg. 2005 Apr;100(4):996-1002
references.pmid: 15781513
references.citation: Anesthesiology. 2000 Jan;92(1):84-93
references.pmid: 10638903
references.citation: J Neurochem. 1995 Oct;65(4):1704-11
references.pmid: 7561868
references.citation: Drug Metab Pharmacokinet. 2009;24(1):16-24
references.pmid: 19252333
references.citation: Brain Res. 2007 Jun 11;1153:188-95
references.pmid: 17482580
references.citation: J Clin Pharmacol. 1988 Sep;28(9):860-4
references.pmid: 3230153
references.citation: Am J Physiol. 1953 Apr;173(1):100-2
references.pmid: 13050769
references.citation: Pediatrics. 2009 Jan;123(1):170-2
references.pmid: 19117878
references.citation: Acta Anaesthesiol Scand. 1957;1(1-2):1-13
references.pmid: 13487086
references.citation: Curr Drug Metab. 2008 Mar;9(3):193-8
references.pmid: 18336221
references.citation: Life Sci. 1998;63(26):2365-71
references.pmid: 9877226
references.citation: Can Anaesth Soc J. 1982 Jan;29(1):16-23
references.pmid: 7055740
references.citation: Neonatology. 2008;94(3):203-10
references.pmid: 18832856
references.citation: Anesthesiology. 2001 Feb;94(2):270-9
references.pmid: 11176092
references.citation: Biol Neonate. 2000;77(1):50-7
references.pmid: 10658831
references.citation: Pediatr Neurol. 2005 Jan;32(1):18-24
references.pmid: 15607599
references.citation: BMC Pediatr. 2008 Apr 30;8:17
references.pmid: 18447921
references.citation: Am J Physiol. 1977 Nov;233(5):H605-12
references.pmid: 920823
references.citation: J Pharm Pharmacol. 1986 Feb;38(2):122-5
references.pmid: 2870155
references.citation: J Pharm Pharmacol. 1989 Feb;41(2):125-6
references.pmid: 2568421
references.citation: Clin Sci Mol Med. 1976 Dec;51(6):583-8
references.pmid: 1070422
references.citation: Resuscitation. 2004 Feb;60(2):225-30
references.pmid: 15036742
references.citation: Gen Pharmacol. 1977;8(5-6):305-10
references.pmid: 23978
references.citation: Pharmacol Toxicol. 1990 May;66(5):354-60
references.pmid: 2371241
references.citation: Mol Pharm. 2007 Nov-Dec;4(6):929-35
references.pmid: 17927262
references.citation: Indian Pediatr. 2005 Sep;42(9):928-34
references.pmid: 16208054
references.citation: Indian J Pediatr. 2008 Apr;75(4):385-91
references.pmid: 18536895
references.citation: J Pharm Sci. 1987 Sep;76(9):688-91
references.pmid: 11002802
references.citation: Biochem Biophys Res Commun. 1995 Dec 26;217(3):1193-9
references.pmid: 8554576
references.citation: Anesthesiology. 1978 Nov;49(5):324-9
references.pmid: 736287
references.citation: J Cancer Res Clin Oncol. 1988;114(4):335-40
references.pmid: 3410874
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1973;280(1):71-8
references.pmid: 4273671
references.citation: J Thorac Cardiovasc Surg. 1965 Mar;49:511-6
references.pmid: 14265966
references.citation: Crit Care Med. 2007 Sep;35(9):2196-204
references.pmid: 17855837
references.citation: J Physiol. 1970 Feb;206(2):38P-39P
references.pmid: 5498490
references.citation: Curr Neurol Neurosci Rep. 2008 Nov;8(6):508-17
references.pmid: 18957189
references.citation: J Thorac Cardiovasc Surg. 2004 May;127(5):1270-5
references.pmid: 15115982
references.citation: Anesth Analg. 2002 May;94(5):1298-303, table of contents
references.pmid: 11973207
references.citation: Neuropharmacology. 2008 Sep;55(3):363-89
references.pmid: 18308347
references.citation: Biol Pharm Bull. 2007 Sep;30(9):1763-7
references.pmid: 17827736
references.citation: Anesth Analg. 2001 Jul;93(1):234-8
references.pmid: 11429373
references.citation: Anesthesiology. 1991 May;74(5):815-9
references.pmid: 1673591
references.citation: Cancer Chemother Pharmacol. 1997;40(5):419-24
references.pmid: 9272119
references.citation: Ann Thorac Surg. 1992 Jun;53(6):957-64
references.pmid: 1596156
references.citation: Anesth Analg. 1990 Aug;71(2):158-70
references.pmid: 2375517
references.citation: Resuscitation. 1974;3(4):265-71
references.pmid: 4467280
references.citation: J Clin Pharmacol. 2008 Oct;48(10):1226-36
references.pmid: 18559487
references.citation: J Matern Fetal Neonatal Med. 2007 May;20(5):407-10
references.pmid: 17674246
references.citation: J Pharmacol Exp Ther. 1978 Nov;207(2):532-8
references.pmid: 712635
references.citation: Chest. 2008 May;133(5):1267-74
references.pmid: 18460529
references.citation: Pharm Res. 1987 Jun;4(3):248-50
references.pmid: 3509290
references.citation: Br J Anaesth. 2000 Apr;84(4):443-9
references.pmid: 10823093
references.citation: Neonatology. 2009;96(4):211-8
references.pmid: 19407466
references.citation: Br J Anaesth. 1987 Nov;59(11):1459-64
references.pmid: 2825743
references.citation: Perfusion. 2004 Jan;19(1):53-63
references.pmid: 15072256
references.citation: J Hepatol. 1987 Apr;4(2):259-68
references.pmid: 3295021