Influence of burns on pharmacokinetics and pharmacodynamics of drugs used in the care of burn patients.
The pharmacokinetics and pharmacodynamics of drugs are significantly altered in the burn patient, and the burn patient population shows wide inter- and intraindividual variation in drug handling. Burn injury evolves in two phases. The first phase corresponds to the burn shock, which occurs during the first 48 hours after thermal injury. In this phase, hypovolaemia, oedema, hypoalbuminaemia and a low glomerular filtration rate are observed, which result in a slower rate of drug distribution and lower renal clearance. The second phase (beyond 48 hours after injury) is a hyperdynamic state with high blood flow in the kidneys and liver, an increased alpha1-acid-glycoprotein level and loss of the drug with exudate leakage. As a result, protein binding, drug distribution and clearance may be altered. Because of the alteration in these variables, wide intraindividual variation of pharmacokinetic parameters occurs depending upon the time since thermal injury and fluid resuscitation. Interindividual variations may be correlated with the percentage of the body surface area that is burnt, creatinine clearance, albuminaemia or the alpha1-acid-glycoprotein level. A number of important variations in pharmacodynamic parameters have been described, but their mechanisms are poorly understood. From a practical point of view, for the subpopulation of burn patients who eliminate drugs extremely rapidly, higher doses and/or shorter dosing intervals are required to avoid treatment inefficacy. Drug concentration measurements help to take into account interindividual variability. However, adaptation of doses based on Bayesian methods is frequently not possible because the distribution of pharmacokinetic parameters is poorly characterized in this population. Methods based only on individual data or on a surrogate marker for efficacy may be used to optimize the dosing regimen in this population.
Blanchet
Benoit
B
Department of Pharmacy-Toxicology, GH Cochin-Saint Vincent-de-Paul, Paris, France.
Jullien
Vincent
V
Vinsonneau
Christophe
C
Tod
Michel
M
D000700:Analgesics / Q000493:pharmacokinetics* / Q000494:pharmacology; D000777:Anesthetics / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D000890:Anti-Infective Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D000897:Anti-Ulcer Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000494:pharmacology; D002056:Burns / Q000503:physiopathology*; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000494:pharmacology; D004334:Drug Administration Schedule; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D003473:Neuromuscular Nondepolarizing Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D010672:Phenytoin / Q000493:pharmacokinetics / Q000494:pharmacology
D000700:Analgesics; D000777:Anesthetics; D000890:Anti-Infective Agents; D000897:Anti-Ulcer Agents; D000927:Anticonvulsants; D007166:Immunosuppressive Agents; D003473:Neuromuscular Nondepolarizing Agents; D010672:Phenytoin; D016572:Cyclosporine
J Burn Care Rehabil. 1990 Sep-Oct;11(5):391-4
2246307
Anesthesiology. 1989 May;70(5):752-5
2719307
J Trauma. 1976 Oct;16(10):824-8
994263
Clin Pharmacol Ther. 1988 Mar;43(3):250-5
3345616
Int J Clin Pharmacol Ther. 2007 Mar;45(3):133-42
17416108
Eur J Clin Pharmacol. 1999 Sep;55(7):515-9
10501821
Pathol Biol (Paris). 1987 May;35(5):603-7
2956565
Eur J Clin Pharmacol. 1989;36(4):361-7
2737228
J Clin Pharmacol. 1986 Feb;26(2):147-51
3950058
Am J Physiol. 1988 Nov;255(5 Pt 2):H1069-74
3189570
J Pharmacol Exp Ther. 1980 Apr;213(1):97-9
7359372
Clin Pharmacol Ther. 1992 Apr;51(4):408-14
1563210
Antimicrob Agents Chemother. 1996 Jan;40(1):139-45
8787895
Int J Antimicrob Agents. 2006 Sep;28(3):226-30
16908121
Presse Med. 1984 Mar 29;13(13):805-7
6231599
Anesthesiology. 1996 Mar;84(3):526-32
8659779
J Clin Pharmacol. 1990 Jul;30(7):632-7
2391394
J Clin Pharmacol. 2007 Jun;47(6):674-80
17428913
Pathol Biol (Paris). 1987 Jun;35(5 Pt 2):777-80
3309814
J Burn Care Rehabil. 2005 May-Jun;26(3):207-27
15879742
Arch Surg. 1983 Mar;118(3):295-302
6824430
J Trauma. 1976 Oct;16(10):819-23
994262
J Antimicrob Chemother. 1991 Nov;28(5):747-52
1778877
J Burn Care Rehabil. 1994 Mar-Apr;15(2):95-103
8195267
J Trauma. 1993 Sep;35(3):394-8
8371297
Clin Pharmacol Ther. 1990 Aug;48(2):130-7
2379384
Br J Clin Pharmacol. 2003 Dec;56(6):629-34
14616422
Burns. 2000 Feb;26(1):109-10
10630329
J Antimicrob Chemother. 1989 Nov;24 Suppl B:121-9
2606814
Antimicrob Agents Chemother. 1990 May;34(5):792-5
2360818
Drugs Exp Clin Res. 1989;15(4):177-84
2776659
Antimicrob Agents Chemother. 1999 Dec;43(12):2848-54
10582870
Zhonghua Zheng Xing Shao Shang Wai Ke Za Zhi. 1994 Sep;10(5):385-8
7712387
Anesthesiology. 1981 May;54(5):378-82
7224206
Clin Pharmacol Ther. 1984 Apr;35(4):535-9
6705453
J Burn Care Rehabil. 1989 Sep-Oct;10(5):425-8
2793921
Res Commun Chem Pathol Pharmacol. 1986 Oct;54(1):87-99
3797808
J Pharmacokinet Biopharm. 1976 Apr;4(2):183-95
950590
Br J Anaesth. 1992 Nov;69(5):447-50
1467073
Burns. 1993 Dec;19(6):529-30
8292242
Antimicrob Agents Chemother. 1993 May;37(5):1073-81
8517694
Scand J Infect Dis Suppl. 1990;72:29-34
2151064
Presse Med. 1994 Nov 5;23(34):1554-8
7824489
Ann Pharmacother. 2001 Dec;35(12):1588-92
11793627
J Trauma. 1982 Nov;22(11):944-9
7143501
Int J Clin Pharmacol Ther. 2007 Oct;45(10):529-38
17966838
Burns. 1996 Jun;22(4):255-74
8781717
N Engl J Med. 1978 Oct 26;299(17):915-9
692596
Eur J Clin Pharmacol. 1988;35(5):543-9
3069478
Ann Fr Anesth Reanim. 1989;8 Suppl:R157
2604116
J Dermatol. 1993 Apr;20(4):208-13
8315110
Antimicrob Agents Chemother. 1993 May;37(5):1065-72
8517693
J Antimicrob Chemother. 1997 Jun;39(6):677-86
9222035
Br J Clin Pharmacol. 2007 Jul;64(1):27-35
17324245
Antimicrob Agents Chemother. 1998 Apr;42(4):930-3
9559811
Antimicrob Agents Chemother. 1993 May;37(5):1132-6
8517702
Clin Pharmacol Ther. 1984 Aug;36(2):228-33
6744781
J Clin Pharmacol. 1990 Jan;30(1):70-5
2303584
Ann Fr Anesth Reanim. 1997;16(4):374-7
9750583
J Burn Care Rehabil. 1997 Mar-Apr;18(2):116-24
9095420
J Antimicrob Chemother. 2000 Mar;45(3):337-42
10702553
DICP. 1991 Jul-Aug;25(7-8):713-5
1949924
Ann Surg. 1980;192(4):570-80
6775605
Clin Pharmacol Ther. 1988 Jul;44(1):9-13
3292106
J Antimicrob Chemother. 2001 May;47(5):720
11328796
Pathol Biol (Paris). 1999 May;47(5):486-90
10418024
Anesth Analg. 1982 Mar;61(3):241-6
7199837
Anesth Analg. 1983 Mar;62(3):293-7
6402956
Acta Anaesthesiol Scand. 2005 Jan;49(1):85-91
15675988
Burns Incl Therm Inj. 1985 Oct;12(1):1-7
4063865
J Clin Pharmacol. 1986 Nov-Dec;26(8):680-5
2947935
J Antimicrob Chemother. 2000 Aug;46(2):315-7
10933661
J Burn Care Rehabil. 1990 Sep-Oct;11(5):410-8
2246310
Antimicrob Agents Chemother. 2006 Jun;50(6):1937-45
16723549
J Antimicrob Chemother. 1996 Mar;37(3):545-53
9182111
Clin Pharmacol Ther. 1977 Mar;21(3):362-9
837654
Antimicrob Agents Chemother. 1996 May;40(5):1153-6
8723457
Anesthesiology. 1986 Nov;65(5):517-20
3777482
Br J Clin Pharmacol. 1990 Dec;30(6):901-5
2288837
Antimicrob Agents Chemother. 1982 Sep;22(3):391-4
7137982
Fundam Clin Pharmacol. 2003 Dec;17(6):645-50
15015709
J Burn Care Rehabil. 1993 Nov-Dec;14(6):666-9
8300702
Antimicrob Agents Chemother. 1991 Jan;35(1):57-61
2014982
JAMA. 1985 Mar 1;253(9):1288-91
3968854
Therapie. 1986 Nov-Dec;41(6):417-20
3810536
Nouv Presse Med. 1979 Oct 31;8(42):3503-6
537906
Clin Pharmacol Ther. 1986 Jun;39(6):631-4
3709027
Surgery. 1978 Nov;84(5):603-8
715674