Kritik Hastalığın İlaç Farmokokinetiği Üzerine Etkisi
Özet
Kritik hastalıklar, hastaların sürekli değişen fizyolojileri nedeniyle ilaçların absorpsiyon, dağılım, biyotransformasyon (metabolizma) ve eliminasyon (atılım) süreçlerinden oluşan farmakokinetik profillerini önemli ölçüde değiştirmekte ve bu durum sağlıklı bireylerden alınan standart farmakokinetik verilerin bu hastalarda geçersiz kalmasına yol açmaktadır. Absorpsiyon aşamasında; perfüzyonun azalması, vazopressör kullanımı, yavaşlayan gastrointestinal motilite ve enteral beslenme tüpü uygulamaları gibi faktörler özellikle intravenöz dışı ilaçların emilimini ve etkisini ciddi şekilde azaltır. Dağılım aşamasında; yoğun sıvı resüsitasyonu ve kapiller kaçak gibi durumlar, vankomisin ve beta-laktamlar gibi hidrofilik ilaçların dağılım hacmini (Vd) artırarak serum konsantrasyonlarını düşürürken; hipoalbüminemi ise albümine yüksek oranda bağlanan ilaçların serbest fraksiyonlarını artırır. İlaç metabolizması ise karaciğer kan akımındaki dalgalanmalar ile sepsis, siroz, ciddi yanıklar, travma ve hipotermi gibi durumlarda CYP450 enzim aktivitesinin değişmesinden doğrudan etkilenmektedir. Son olarak eliminasyon süreci; sepsisin erken hiperdinamik evresinde artan renal kan akımıyla hızlanıp ilaç düzeylerini düşürürken, hipodinamik evrelerde veya gelişen akut böbrek hasarında yavaşlayarak toksisite riskini artırır. Bu karmaşık fizyolojik değişimler nedeniyle klinisyenlerin, tedavide biyoyararlanımı korumak adına intravenöz yolu tercih etmeleri, yükleme dozlarını değişen dağılım hacmine göre planlamaları ve tedaviyi terapötik ilaç izlemi (Tİİ) ile optimize etmeleri gerekmektedir.
Critical illnesses significantly alter the pharmacokinetic profiles of drugs—comprising absorption, distribution, biotransformation (metabolism), and elimination (excretion)—due to patients' constantly changing physiologies, rendering standard pharmacokinetic data derived from healthy individuals inapplicable to this group. In the absorption phase, factors such as reduced perfusion, vasopressor use, delayed gastrointestinal motility, and enteral feeding tube applications severely decrease the absorption and onset of non-intravenous drugs. During the distribution phase, conditions like intensive fluid resuscitation and capillary leak increase the volume of distribution (Vd) of hydrophilic drugs, such as vancomycin and beta-lactams, thereby lowering their serum concentrations, while hypoalbuminemia increases the free fraction of highly protein-bound drugs. Drug metabolism is directly influenced by fluctuations in hepatic blood flow and alterations in CYP450 enzyme activity caused by conditions like sepsis, cirrhosis, severe burns, trauma, and hypothermia. Lastly, the elimination process accelerates with increased renal blood flow in the early hyperdynamic phase of sepsis—reducing drug levels—but slows down during hypodynamic phases or acute kidney injury, increasing the risk of toxicity. Due to these complex physiological shifts, it is crucial for clinicians to prefer the intravenous route to maintain bioavailability, plan loading doses according to the altered Vd, and optimize treatment through therapeutic drug monitoring (TDM).
Referanslar
İskit A. Antibiyotik tedavisinin farmakokinetik/farmakodinamik yönü: temel kavramlar ve parametreler. J Crit Intensive Care. 2007;7(1):11-6.
Smith BS, Yogaratnam D, Levasseur-Franklin KE et al. Introduction to drug pharmacokinetics in the critically ill patient. Chest. 2012;141(5):1327-36.
Sürmelioğlu N, Demirkan K. Septik hastaların tedavisinde polifarmasinin ve ilaç etkileşimlerinin değerlendirilmesi. Turk J Intensive Care. 2020. DOI: 10.4274/tybd.galenos.2020.36844
Roberts JA, Roberts MS, Semark A et al. Antibiotic dosing in the 'at risk' critically ill patient: Linking pathophysiology with pharmacokinetics/pharmacodynamics in sepsis and trauma patients. BMC Anesthesiol. 2011;11:3-7.
Boucher BA, Wood GC, Swanson JM. Pharmacokinetic changes in critical illness. Crit Care Clin. 2006;22(2):255-71.
Ariano RE, Sitar DS, Zelenitsky SA et al. Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza. CMAJ. 2010;182(4):357-63.
Jochberger S, Mayr V, Luckner G et al. Antifactor Xa activity in critically ill patients receiving antithrombotic prophylaxis with standard dosages of certoparin: a prospective, clinical study. Crit Care. 2005;9(5):R541-8.
Nguyen NQ, Ng MP, Chapman M et al. The impact of admission diagnosis on gastric emptying in crit- ically ill patients. Crit Care. 2007;11(1):R16.
Pea F, Pavan F, Furlanut M. Clinical relevance of pharmacokinetics and pharmacodynamics in cardiac critical care patients. Clin Pharmacokinet. 2008;47(7):449-462
Maka DA, Murphy LK. Drug-nutrient interactions: a review. AACN Clin Issues. 2000;11(4):580-589.
Ekincioğlu Bayraktar A, Demirkan K. Clinical nutrition and drug interactions. Turk J Surg. 2013;29(4):177-86.
Gonzalez DJ, Conrado D, Theuretzbacher U et al. The effect of critical illness on drug distribution. Curr Pharm Biotechnol. 2011; 12(12): 2030-2036.
Triginer C, Izquierdo I, Fernandez R et al. Gentamicin volume of distribution in critically ill septic patients. Intensive Care Med. 1990;16(5):303-6.
Varghese JM, Roberts JA, Lipman J. Antimicrobial pharmacokinetic and pharmacodynamic issues in the critically ill with severe sepsis and septic shock. Crit Care Clin. 2011;27(1):19-34.
Joukhadar C, Frossard M, Mayer BX et al. Impaired target site penetration of beta-lactams may account for therapeutic failure in patients with septic shock. Crit Care Med. 2001;29(2):385-91.
Roberts JA, Lipman, J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med. 2009;37(3):840-851.
Rall DP, Stabenau JR, Zubrod CG. Distribution of drugs between blood and cerebrospinal fluid: general methodology and effect of pH gradients. J Pharmacol Exp Ther. 1959; 125(3):185-193.
Cheifetz IM. Cardiorespiratory interactions: the relationship between mechanical ventilation and hemodynamics. Respir Care. 2014;59(12):1937-45.
Perkins MW, Dasta JF, DeHaven B. Physiologic implications of mechanical ventilation on pharmacokinetics. DICP. 1989;23(4):316-23.
Richard C, Berdeaux A, Delion F et al. Effect of mechanical ventilation on hepatic drug pharmacokinetics. Chest. 1986;90(6):837-41.
HA Michael A, SIEG Adam C. Evaluation of altered drug pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation. Pharmacotherapy. 2017;37(2):221-235.
Shekar K., Fraser JF, Smith MT et al. Pharmacokinetic changes in patients receiving extracorporeal membrane oxygenation. J Crit Care. 2012;27(6):741-e9.
Richard C, Berdeaux A, Delion F et al. Effect of mechanical ventilation on hepatic drug pharmacokinetics. Chest. 1986;90(6):837-41.
Da Paepe P, Belpaire FM, Buylaert WA. Pharmacokinetic and pharmacodynamic considerations when treating patients with sepsis and septic shock. Clin Pharmacokinet. 2002;41(14):1135-1151.
Roberts JA, Lipman J. Antibacterial dosing in intensive care: pharmacokinetics, degree of disease and pharmacodynamics of sepsis. Clin Pharmacokinet. 2006;45(8):755-773.
Delcò F, Tchambaz L, Schlienger R et al. Dose adjustment in patients with liver disease. Drug Saf. 2005;28(6):529-545.
McKindley DS, Hanes S, Boucher BA. Hepatic drug metabolism in critical illness. Pharmacotherapy. 1998;18(4):759-778.
Pugh RN, Murray-Lyon IM, Dawson JL et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646-649.
Blanchet B, Jullien V, Vinsonneau C et al. Influence of burns on pharmacokinetics and pharmacodynamics of drugs used in the care of burn patients. Clin Pharmacokinet. 2008; 47(10):635-654.
Sun H, Frassetto L, Benet LZ. Effects of renal failure on drug transport and metabolism. Pharmacol Ther. 2006;109(1-2): 1-11.
Vilay AM, Churchwell MD, Mueller BA. Clinical review: drug metabolism and nonrenal clearance in acute kidney injury. Crit Care. 2008;12(6):235.
Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008;64(12):1147-1161.
Delcò F, Tchambaz L, Schlienger R et al. Dose adjustment in patients with liver disease. Drug Saf. 2005;28(6):529-545.
Haas CE, Kaufman DC, Jones CE et al. Cytochrome P450 3A4 activity after surgical stress. Crit Care Med. 2003;31(5):1338-1346.
Harbrecht BG, Frye RF, Zenati MS et al. Cytochrome P-450 activity is differentially altered in severely injured patients. Crit Care Med. 2005;33(3):541-546.
Tortorici MA, Kochanek PM, Poloyac SM. Effects of hypo- thermia on drug disposition, metabolism, and response: a focus of hypothermia-mediated alterations on the cytochrome P450 enzyme system. Crit Care Med. 2007;35(9):2196-2204.
Van den Broek MPH, Groenendaal F, Egberts ACG et al. Effects of hypothermia on pharmacoki- netics and pharmacodynamics: a systematic review of pre-clinical and clinical studies. Clin Pharmacokinet. 2010;49(5): 277-294.
Koyner JL, Murray PT. Mechanical ventilation and the kidney. Blood Purif. 2010;29(1):52-68.
Udy AA, Roberts JA, Lipman J. Clinical implications of antibiotic pharmacokinetic principles in the critically ill. Intensive Care Med. 2013;39(12):2070-82.
Shah S, Barton G, Fischer A. Pharmacokinetic considerations and dosing strategies of antibiotics in the critically ill patient. J Intensive Care Soc. 2015;16(2):147-53.
Pannu N, Mehta RL. Effect of mechanical ventilation on the kidney. Best Pract Res Clin Anaesthesiol. 2004;18(1):189-203.
