Pathophysiology and pharmacokinetics following burn injury.
Therapy for inpatient burn victims is a clear challenge for the clinician, since directly following injury the pharmacokinetic parameters of many drugs will change drastically. Blood flow to the tissues is decreased; the rate of distribution and elimination of intravenous drugs administered during this time is reduced, and absorption of oral drugs may be slowed. Approximately 48 hours after injury, the blood flow increases, as does internal core temperature; the rates may increase as a result. Immediately after injury, plasma albumin level rapidly decreases and remains significantly depressed even at 60 days post-burn. Thus, the protein binding of acidic and neutral drugs will decrease and higher amounts of free fraction will be available at the biophase. On the other hand, alpha 1-acid glycoprotein increases in concentration and remains elevated at least 20 days post-burn. Basic drugs exhibit increased protein binding and will most probably need an increased dosage to achieve the appropriate pharmacological effect. Hepatic metabolism is also affected: the rate of phase I metabolism will decrease while phase II metabolism is unimpaired and may possibly increase. Other liver functions, such as protein synthesis, are also impaired. The effect on phase I drug metabolism is believed to be due to oxygen-derived free radicals released during the course of injury. In those patients with full-thickness burns, the epidermal layer is destroyed. Topical drugs have less of a barrier to cross and, consequently, less drug is needed to achieve effectiveness. In addition, the stomach has been found to secrete excess protons which will eventually lead to ulcers in the majority of patients. Hyperchlorhydria may affect the dissolution and disintegration of orally administered drugs in tablet form, as well as the partitioning of the neutral un-ionised species between the stomach and bloodstream. In the small intestine decreased nutrient absorption and DNA synthesis occurs, but the effect this may have on drug absorption is questionable. This paper focuses on the epidemiology of burn injuries and the way in which the pathophysiology following such injury alters the pharmacokinetics of a drug. Specific examples are provided. Some mention is made of burn management, therapeutic drug monitoring in burn patients, experimental design considerations, and future research topics.
Bonate
P L
PL
Department of Pharmacology/Toxicology, College of Pharmacy, Washington State University, Pullman.
D000818:Animals; D002056:Burns / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D006801:Humans; D010599:Pharmacokinetics