Interações medicamentosa mediadas pela CYP 450 em pacientes críticos: ênfase em antifúngicos triazólicos
##plugins.themes.bootstrap3.article.sidebar##
Publicado
Jun 29, 2023
##plugins.themes.bootstrap3.article.main##
Resumo
objetivo: Fornecer informações sobre as principais alterações fisiológicas que podem influenciar as propriedades farmacológicas em pacientes críticos e das interações medicamentosas de relevância clínica mediadas pelas enzimas do citocromo P450, com ênfase nos antifúngicos triazólicos. Revisão bibliográfica: Os pacientes internados na Unidade de Terapia Intensiva (UTI) apresentam frequentemente alterações fisiológicas que ocasionam modificações no perfil farmacológico de diversos medicamentos. A presença de disfunções hepáticas, renais, hipóxia e isquemia periférica, distúrbios circulatórios, elevação de marcadores inflamatórios, hipoalbunemia e obesidade alteram parâmetros de absorção, distribuição, metabolização e excreção de farmacos. Essas modificações aliadas ao uso concomitantemente de diversos fármacos representam um grande desafio para a abordagem farmacoterapêutica destes pacientes. Dentre a ampla variedade de classes farmacológicas, enfatizamos os antifúngicos triazólicos, devido ao seu grande impacto e uso em UTI. Considerações finais: O conhecimento das alterações farmacocinéticas em pacientes críticos e sobre a modulação das enzimas do citocromo P450 é uma valiosa ferramenta para prevenir e manejar possíveis interações medicamentosas, principalmente nas UTI. A atuação em conjunto dos intensivistas e dos farmacêuticos clínicos pode otimizar consideravelmente o tratamento farmacoterapêutico.
##plugins.themes.bootstrap3.article.details##
Como Citar
MoraesS. S. de, ManaçasL. R. A., & BadinR. C. (2023). Interações medicamentosa mediadas pela CYP 450 em pacientes críticos: ênfase em antifúngicos triazólicos. Revista Eletrônica Acervo Saúde, 23(6), e13085. https://doi.org/10.25248/reas.e13085.2023
Seção
Revisão Bibliográfica
Copyright © | Todos os direitos reservados.
A revista detém os direitos autorais exclusivos de publicação deste artigo nos termos da lei 9610/98.
Reprodução parcial
É livre o uso de partes do texto, figuras e questionário do artigo, sendo obrigatória a citação dos autores e revista.
Reprodução total
É expressamente proibida, devendo ser autorizada pela revista.
Referências
1. ALVIM MM, et al. Eventos adversos por interações medicamentosas potenciais em unidade de terapia intensiva de um hospital de ensino. Revista Brasileira de Terapia Intensiva, 2015; 27: 353-359.
2. ARENAS R, et al. Classification of subcutaneous and systemic mycoses. Clinics in dermatology, 2012, 30 (4), 369-371.
3. BADIN RC, et al. Pharmacological profile and potential drug interactions in ovarian cancer hospitalized patients. Journal of Oncology Pharmacy Practice, 2022; 10781552221091298.
4. BELLMANN R e SMUSZKIEWICZ P. Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of patients. Infection, 2017; 45(6): 737-779.
5. BERARDINELLI MBM, et al. Potenciais repercussões clínicas decorrentes de interações medicamentosas em terapia intensiva. Enfermagem em Foco, 2020; 11(2).
6. BERTO C, et al. Bases da resistência antifúngica: uma revisão comentada. Revista Uningá, 2018; 55(3): 52-71.
7. BHATTACHARYA M, et al. Posaconazole. Journal of Postgraduate Medicine, 2010; 56(2): 163.
8. BIBI Z. Role of cytochrome P 450 in drug interactions. Nutrition & Metabolim, 2008; 5: 1-10.
9. BLUM S, et al. Lack of pharmacokinetic basis of weight-based dosing and intra-operative re-dosing with cefazolin surgical prophylaxis in obese patients: implications for antibiotic stewardship. Surgical Infections, 2019; 20(6): 439-443.
10. CÂNDIDO SHS, et al. Retrato do uso de carbapenêmicos em um hospital pertencente ao sistema único de saúde. Research, Society and Development, 2022; 11(9): e16811931647.
11. CARIBÉ RA, et al. Potenciales interacciones medicamentosas en pacientes con sepsis internados en la unidad de terapia intensiva. Farmacia hospitalaria, 2013; 37(5): 383-387.
12. CHAI MG, et al. What are the current approaches to optimising antimicrobial dosing in the intensive care unit? Pharmaceutics, 2020; 12(7): 638.
13. CHAMBOKO CR, et al. Human Cytochrome P450 1, 2, 3 Families as Pharmacogenes with Emphases on Their Antimalarial and Antituberculosis Drugs and Prevalent African Alleles. International Journal of Molecular Sciences, 2023; 24(4): 3383.
14. CHEN L, et al. Pharmacokinetics and pharmacodynamics of posaconazole. Drugs, 2020; 80(7): 671-695.
15. DE PAEPE P, et al. Pharmacokinetic and pharmacodynamics considerations when treating patients with sepsis and septic shock. Clin. Pharmacokinet., 2002; 41(14): 1135-1151.
16. DOLTON MJ, et al. Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring. Antimicrobial agents and chemotherapy, 2012; 56(6): 2806-2813.
17. DONNELLY JP e DE PAUW BE. Voriconazole—a new therapeutic agent with an extended spectrum of antifungal activity. Clinical Microbiology and Infection, 2004; 10: 107-117.
18. EL-SOLH AA. Clinical approach to the critically ill, morbidly obese patient. Am J Respir Crit Care Med., 2004; 169: 557-561.
19. FRANCO GCN, et al. Interações medicamentosas: fatores relacionados aos pacientes - Parte I. Rev. Cir. Traumatol. Buco-Maxilo- fac., 2007; 7(1): 17-28.
20. GARNACHO-MONTERO J e PARRILLA FJ. Interacciones farmacológicas en el paciente crítico. ¿ Un factor relevante para usar micafungina? Enfermedades Infecciosas y Microbiología Clínica, 2011; 29: 33-37.
21. GARSKE CCD, et al. Avaliação das interações medicamentosas potenciais em prescrições de pacientes em unidade de terapia intensiva. Saúde e Pesquisa, 2016; 9(3): 483-490.
22. GILMAN PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. British Journal of Pharmacology. 2007; 151(6): 737-48.
23. HERSH EV, et al. Fluconazole-Warfarin Interaction: A case report with deadly consequences. Australasian Medical Journal (Online), 2017; 10(6): 544.
24. HOLT A, et al. Bleeding Risk Following Systemic Fluconazole or Topical Azoles in Patients with Atrial Fibrillation on Apixaban, Rivaroxaban, or Dabigatran. The American Journal of Medicine, 2022; 135(5): 595-602.
25. IORIS LMD e BACCHI AD. Interações medicamentosas de interesse em odontologia. Revista da Faculdade de Odontologia-UPF, 2019; 24(1): 148-154.
26. JARRAR YB e LEE S. Molecular functionality of cytochrome P450 4 (CYP4) genetic polymorphisms and their clinical implications. International journal of molecular sciences, 2019, 20 (17), 4274.
27. KIANG TKL, et al. UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacology & Therapeutics, 2005; 106(1): 97-132.
28. KIELSTEIN JT, et al. Pharmacokinetics and total elimination of meropenem and vancomycin intensive care unit patients undergoing extended daily dialysis. Crit Care Med., 2006; 34(1): 51-56.
29. KOPS CB, et al. GLORYx: prediction of the metabolites resulting from phase 1 and phase 2 biotransformations of xenobiotics. Chemical research in toxicology, 2020; 34(2): 286-299.
30. KULMATYCKI KM e JAMALI F. Drug disease interactions: role of inflammatory mediators in disease and variability in drug response. J Pharm Pharmaceut Sci, 2005; 8(5): 602-625.
31. LIPAROTI G, et al. Individualizing doses of antiepileptic drugs. Expert Opinion on Drug Metabolism & Toxicology, 2022; 18(3): 219-233.
32. MANN HJ. Drug-associated disease: cytochrome P450 interactions. Crit Care Clin., 2006; 22(2): 329-345.
33. MARZI M, et al. A Recent Overview of 1, 2, 3-Triazole-Containing Hybrids as Novel Antifungal Agents: Focusing on Synthesis, Mechanism of Action, and Structure-Activity Relationship (SAR). Journal of Chemistry, 2022.
34. MEYER MR e MAURER HH. Absorption, distribution, metabolism and excretion pharmacogenomics of drug of abuse. Pharmacogenomics, 2011; 12(2): 215-233.
35. MORAES SS e BADIN, RC. Isavuconazol: um novo fármaco para tratamento de aspergilose invasiva e mucormicose: Isavuconazole: a new drug for the treatment of invasive aspergillosis and mucormycosis. Brazilian Journal of Health Review, 2022; 5(4): 16644-16655.
36. NOCUA-BÁEZ LC, et al. Azoles de antes y ahora: una revisión. Revista chilena de infectología, 2020; 37(3): 219-230.
37. OLIVEIRA MB, et al. Interações medicamentosas potenciais em prescrições de pacientes internados em unidade de terapia intensiva. Brazilian Journal of Development, 2023; 9(1): 4912–4929.
38. ORR STM, et al. Mechanism- Based Inactivation (MBI) of Cytochrome P450 enzymes: structure-activity relationship and discovery strategies to mitigate drug-drug interaction risks. Journal Medicinal Chemistry, 2012; 55(11): 4896-4933.
39. PAI MP e BEARDEN DT. Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy., 2007; 27(8): 1081-1091.
40. PACHOLAK A, et al. Evaluating the effect of azole antifungal agents on the stress response and nanomechanical surface properties of ochrobactrum anthropi Aspcl2. 2. Molecules, 2020; 25(15): 3348.
41. PEA F e VIALE P. The antimicrobial therapy puzzle: could pharmacokinetic- pharmacodynamic relationships be helpful in addressing the issue of appropriate pneumonia treatment in critically ill patients? Clin Infect Dis., 2006; 42(12): 1764-1771.
42. PISTOLESI V, et al. A guide to understanding antimicrobial drug dosing in critically ill patients on renal replacement therapy. Antimicrobial agents and chemotherapy, 2019; 63(8): e00583-19.
43. RENTON KW. Cytochrome P450 regulation and drug biotransformation during inflammation and infection. Curr Drug Metab, 2004; 5(3): 235-243.
44. RICHTER DC, et al. Antibiotic stewardship and therapeutic drug monitoring of β-lactam antibiotics: Is there a link? An opinion paper. Therapeutic Drug Monitoring, 2022; 44(1): 103-111.
45. ROBERTS JA e LIPMAN J. Antibacterial dosing in intensive care: pharmacokinetic, degree of disease and pharmacodynamics of sepsis. Clin. Pharmacokinet., 2006; 45(8): 755-773.
46. ROCHA APS, et al. Perfil epidemiológico das leveduroses sistêmicas em Unidades de Terapia Intensiva de hospitais públicos da cidade do Recife–PE, Brasil. Brazilian Journal of Health Review, 2020; 3(6): 19098-19111.
47. SAARI TI, et al. Effect of voriconazole and fluconazole on the pharmacokinetics of intravenous fentanyl. European journal of clinical pharmacology, 2008; 64(1): 25-30.
48. SARAVOLATZ LD, et al. Voriconazole: a new triazole antifungal agent. Clinical infectious diseases, 2003; 36(5): 630-637.
49. SARI S, et al. Discovery of new azoles with potent activity against Candida spp. and Candida albicans biofilms through virtual screening. European journal of medicinal chemistry, 2019; 179: 634-648.
50. SILVA LA, et al. Potenciais de interações medicamentosas em pacientes cirúrgicos de um hospital universitário. Research, Society and Development, 2022; 11(9): e16111931544.
51. SCORZONI L, et al. Current and promising pharmacotherapeutic options for candidiasis. Expert Opinion on Pharmacotherapy, 2021; 22(7): 887-888.
52. SPRIET I, et al. Mini-series: II. Clinically relevant CYP450- mediated drug interactions in the ICU. Intensive Care Med., 2009; 35(4): 603-12.
53. TEIXEIRA LHS, et al. Interações medicamentosas em unidades de terapia intensiva do Brasil: Revisão integrativa. Brazilian Journal of Health Review, 2021; 4(2): 7782–7796.
54. TORNIO A, et al. Clinical studies on drug–drug interactions involving metabolism and transport: methodology, pitfalls, and interpretation. Clinical Pharmacology & Therapeutics, 2019; 105(6): 1345-1361.
55. TROISI C, et al. Measuring Creatinine Clearance Is the Most Accurate Way for Calculating the Proper Continuous Infusion Meropenem Dose for Empirical Treatment of Severe Gram-Negative Infections among Critically Ill Patients. Pharmaceutics, 2023; 15(2): 551.
56. TROTMAN RL, et al. Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy. Clin Infec Dis., 2005; 41(8): 1159-1166.
57. VOLPATO DC, et al. Idade e polifarmácia como fatores de risco para potenciais interações de drogas psicotrópicos via CYP450. Revista Contexto & Saúde, 2022; 22(46): e9543.
58. WARING RH. Cytochrome P450: genotype to phenotype. Xenobiotica, 2020; 50(1): 9-18.
59. WILKINSON GR. Drug Metabolism and variability among patients in drug response. N Engl J Med., 2005; 352: 2211-2221.
60. ZAGLI G, et al. Altered pharmacology in the intensive care unit patient. Fundamental & Clinical Pharmacology, 2008; 22(5): 493-501.
2. ARENAS R, et al. Classification of subcutaneous and systemic mycoses. Clinics in dermatology, 2012, 30 (4), 369-371.
3. BADIN RC, et al. Pharmacological profile and potential drug interactions in ovarian cancer hospitalized patients. Journal of Oncology Pharmacy Practice, 2022; 10781552221091298.
4. BELLMANN R e SMUSZKIEWICZ P. Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of patients. Infection, 2017; 45(6): 737-779.
5. BERARDINELLI MBM, et al. Potenciais repercussões clínicas decorrentes de interações medicamentosas em terapia intensiva. Enfermagem em Foco, 2020; 11(2).
6. BERTO C, et al. Bases da resistência antifúngica: uma revisão comentada. Revista Uningá, 2018; 55(3): 52-71.
7. BHATTACHARYA M, et al. Posaconazole. Journal of Postgraduate Medicine, 2010; 56(2): 163.
8. BIBI Z. Role of cytochrome P 450 in drug interactions. Nutrition & Metabolim, 2008; 5: 1-10.
9. BLUM S, et al. Lack of pharmacokinetic basis of weight-based dosing and intra-operative re-dosing with cefazolin surgical prophylaxis in obese patients: implications for antibiotic stewardship. Surgical Infections, 2019; 20(6): 439-443.
10. CÂNDIDO SHS, et al. Retrato do uso de carbapenêmicos em um hospital pertencente ao sistema único de saúde. Research, Society and Development, 2022; 11(9): e16811931647.
11. CARIBÉ RA, et al. Potenciales interacciones medicamentosas en pacientes con sepsis internados en la unidad de terapia intensiva. Farmacia hospitalaria, 2013; 37(5): 383-387.
12. CHAI MG, et al. What are the current approaches to optimising antimicrobial dosing in the intensive care unit? Pharmaceutics, 2020; 12(7): 638.
13. CHAMBOKO CR, et al. Human Cytochrome P450 1, 2, 3 Families as Pharmacogenes with Emphases on Their Antimalarial and Antituberculosis Drugs and Prevalent African Alleles. International Journal of Molecular Sciences, 2023; 24(4): 3383.
14. CHEN L, et al. Pharmacokinetics and pharmacodynamics of posaconazole. Drugs, 2020; 80(7): 671-695.
15. DE PAEPE P, et al. Pharmacokinetic and pharmacodynamics considerations when treating patients with sepsis and septic shock. Clin. Pharmacokinet., 2002; 41(14): 1135-1151.
16. DOLTON MJ, et al. Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring. Antimicrobial agents and chemotherapy, 2012; 56(6): 2806-2813.
17. DONNELLY JP e DE PAUW BE. Voriconazole—a new therapeutic agent with an extended spectrum of antifungal activity. Clinical Microbiology and Infection, 2004; 10: 107-117.
18. EL-SOLH AA. Clinical approach to the critically ill, morbidly obese patient. Am J Respir Crit Care Med., 2004; 169: 557-561.
19. FRANCO GCN, et al. Interações medicamentosas: fatores relacionados aos pacientes - Parte I. Rev. Cir. Traumatol. Buco-Maxilo- fac., 2007; 7(1): 17-28.
20. GARNACHO-MONTERO J e PARRILLA FJ. Interacciones farmacológicas en el paciente crítico. ¿ Un factor relevante para usar micafungina? Enfermedades Infecciosas y Microbiología Clínica, 2011; 29: 33-37.
21. GARSKE CCD, et al. Avaliação das interações medicamentosas potenciais em prescrições de pacientes em unidade de terapia intensiva. Saúde e Pesquisa, 2016; 9(3): 483-490.
22. GILMAN PK. Tricyclic antidepressant pharmacology and therapeutic drug interactions updated. British Journal of Pharmacology. 2007; 151(6): 737-48.
23. HERSH EV, et al. Fluconazole-Warfarin Interaction: A case report with deadly consequences. Australasian Medical Journal (Online), 2017; 10(6): 544.
24. HOLT A, et al. Bleeding Risk Following Systemic Fluconazole or Topical Azoles in Patients with Atrial Fibrillation on Apixaban, Rivaroxaban, or Dabigatran. The American Journal of Medicine, 2022; 135(5): 595-602.
25. IORIS LMD e BACCHI AD. Interações medicamentosas de interesse em odontologia. Revista da Faculdade de Odontologia-UPF, 2019; 24(1): 148-154.
26. JARRAR YB e LEE S. Molecular functionality of cytochrome P450 4 (CYP4) genetic polymorphisms and their clinical implications. International journal of molecular sciences, 2019, 20 (17), 4274.
27. KIANG TKL, et al. UDP-glucuronosyltransferases and clinical drug-drug interactions. Pharmacology & Therapeutics, 2005; 106(1): 97-132.
28. KIELSTEIN JT, et al. Pharmacokinetics and total elimination of meropenem and vancomycin intensive care unit patients undergoing extended daily dialysis. Crit Care Med., 2006; 34(1): 51-56.
29. KOPS CB, et al. GLORYx: prediction of the metabolites resulting from phase 1 and phase 2 biotransformations of xenobiotics. Chemical research in toxicology, 2020; 34(2): 286-299.
30. KULMATYCKI KM e JAMALI F. Drug disease interactions: role of inflammatory mediators in disease and variability in drug response. J Pharm Pharmaceut Sci, 2005; 8(5): 602-625.
31. LIPAROTI G, et al. Individualizing doses of antiepileptic drugs. Expert Opinion on Drug Metabolism & Toxicology, 2022; 18(3): 219-233.
32. MANN HJ. Drug-associated disease: cytochrome P450 interactions. Crit Care Clin., 2006; 22(2): 329-345.
33. MARZI M, et al. A Recent Overview of 1, 2, 3-Triazole-Containing Hybrids as Novel Antifungal Agents: Focusing on Synthesis, Mechanism of Action, and Structure-Activity Relationship (SAR). Journal of Chemistry, 2022.
34. MEYER MR e MAURER HH. Absorption, distribution, metabolism and excretion pharmacogenomics of drug of abuse. Pharmacogenomics, 2011; 12(2): 215-233.
35. MORAES SS e BADIN, RC. Isavuconazol: um novo fármaco para tratamento de aspergilose invasiva e mucormicose: Isavuconazole: a new drug for the treatment of invasive aspergillosis and mucormycosis. Brazilian Journal of Health Review, 2022; 5(4): 16644-16655.
36. NOCUA-BÁEZ LC, et al. Azoles de antes y ahora: una revisión. Revista chilena de infectología, 2020; 37(3): 219-230.
37. OLIVEIRA MB, et al. Interações medicamentosas potenciais em prescrições de pacientes internados em unidade de terapia intensiva. Brazilian Journal of Development, 2023; 9(1): 4912–4929.
38. ORR STM, et al. Mechanism- Based Inactivation (MBI) of Cytochrome P450 enzymes: structure-activity relationship and discovery strategies to mitigate drug-drug interaction risks. Journal Medicinal Chemistry, 2012; 55(11): 4896-4933.
39. PAI MP e BEARDEN DT. Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy., 2007; 27(8): 1081-1091.
40. PACHOLAK A, et al. Evaluating the effect of azole antifungal agents on the stress response and nanomechanical surface properties of ochrobactrum anthropi Aspcl2. 2. Molecules, 2020; 25(15): 3348.
41. PEA F e VIALE P. The antimicrobial therapy puzzle: could pharmacokinetic- pharmacodynamic relationships be helpful in addressing the issue of appropriate pneumonia treatment in critically ill patients? Clin Infect Dis., 2006; 42(12): 1764-1771.
42. PISTOLESI V, et al. A guide to understanding antimicrobial drug dosing in critically ill patients on renal replacement therapy. Antimicrobial agents and chemotherapy, 2019; 63(8): e00583-19.
43. RENTON KW. Cytochrome P450 regulation and drug biotransformation during inflammation and infection. Curr Drug Metab, 2004; 5(3): 235-243.
44. RICHTER DC, et al. Antibiotic stewardship and therapeutic drug monitoring of β-lactam antibiotics: Is there a link? An opinion paper. Therapeutic Drug Monitoring, 2022; 44(1): 103-111.
45. ROBERTS JA e LIPMAN J. Antibacterial dosing in intensive care: pharmacokinetic, degree of disease and pharmacodynamics of sepsis. Clin. Pharmacokinet., 2006; 45(8): 755-773.
46. ROCHA APS, et al. Perfil epidemiológico das leveduroses sistêmicas em Unidades de Terapia Intensiva de hospitais públicos da cidade do Recife–PE, Brasil. Brazilian Journal of Health Review, 2020; 3(6): 19098-19111.
47. SAARI TI, et al. Effect of voriconazole and fluconazole on the pharmacokinetics of intravenous fentanyl. European journal of clinical pharmacology, 2008; 64(1): 25-30.
48. SARAVOLATZ LD, et al. Voriconazole: a new triazole antifungal agent. Clinical infectious diseases, 2003; 36(5): 630-637.
49. SARI S, et al. Discovery of new azoles with potent activity against Candida spp. and Candida albicans biofilms through virtual screening. European journal of medicinal chemistry, 2019; 179: 634-648.
50. SILVA LA, et al. Potenciais de interações medicamentosas em pacientes cirúrgicos de um hospital universitário. Research, Society and Development, 2022; 11(9): e16111931544.
51. SCORZONI L, et al. Current and promising pharmacotherapeutic options for candidiasis. Expert Opinion on Pharmacotherapy, 2021; 22(7): 887-888.
52. SPRIET I, et al. Mini-series: II. Clinically relevant CYP450- mediated drug interactions in the ICU. Intensive Care Med., 2009; 35(4): 603-12.
53. TEIXEIRA LHS, et al. Interações medicamentosas em unidades de terapia intensiva do Brasil: Revisão integrativa. Brazilian Journal of Health Review, 2021; 4(2): 7782–7796.
54. TORNIO A, et al. Clinical studies on drug–drug interactions involving metabolism and transport: methodology, pitfalls, and interpretation. Clinical Pharmacology & Therapeutics, 2019; 105(6): 1345-1361.
55. TROISI C, et al. Measuring Creatinine Clearance Is the Most Accurate Way for Calculating the Proper Continuous Infusion Meropenem Dose for Empirical Treatment of Severe Gram-Negative Infections among Critically Ill Patients. Pharmaceutics, 2023; 15(2): 551.
56. TROTMAN RL, et al. Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy. Clin Infec Dis., 2005; 41(8): 1159-1166.
57. VOLPATO DC, et al. Idade e polifarmácia como fatores de risco para potenciais interações de drogas psicotrópicos via CYP450. Revista Contexto & Saúde, 2022; 22(46): e9543.
58. WARING RH. Cytochrome P450: genotype to phenotype. Xenobiotica, 2020; 50(1): 9-18.
59. WILKINSON GR. Drug Metabolism and variability among patients in drug response. N Engl J Med., 2005; 352: 2211-2221.
60. ZAGLI G, et al. Altered pharmacology in the intensive care unit patient. Fundamental & Clinical Pharmacology, 2008; 22(5): 493-501.