The difficulties of Polytherapy: examples from antimicrobial chemotherapy

Abstract

Medical therapy in patients with more than one pathology means using more pharmaceuticals, which results in a higher risk of drug interactions which are modifications in the action of one drug when it is administered in the presence of another. The consequences can be diminished therapeutic effect or increased adverse reactions. The pharmacological interactions can be either physico-chemical, pharmacokinetic or pharmacodynamic, on the basis of their mechanisms. Pharmacokinetic interactions are the most important and can emerge during various phases of absorption, distribution, metabolism and drug elimination. The absorption of many antimicrobial agents can be modified through various mechanisms. Some drugs (for example the anticholinergics and opiates) or food can slow gastric motility, slowing the absorption and reducing maximum concentrations of the antibiotic. Variations in gastric pH can alter the solubility or chemical stability of molecules such as the beta-lactams, the natural macrolides and some azoles. The bioavailability of these drugs can be reduced due to molecules used to raise gastric pH. Antibiotics such as tetracycline or the fluoroquinolones have reduced bioavailability due to chelation from bi- and trivalent cations. The primary number of clinically relevant pharmacological interactions is correlated with modifications of biotransformation of drugs due to Cytochrome P450 (CYP) hepatic enzymes which are involved in oxidative drug processes, including lipophilic antimicrobial drugs such as the macrolides, the fluoroquinolones (to be considered amphoteric) and the antifungal azole derivatives. CYP3A is probably one of the most important isoenzymes since it contributes to at least the partial transformation of 60% of drugs that undergo oxidation: erythromycin and clarithromycin are CYP3A4 substrates. Many isoenzymes can also be inhibited by antimicrobial drugs, including both antibacterials and antifungals (for example the macrolides, fluoroquinolones, metronidazole, sulfonamides and azole derivatives) with a consequent reduction in the metabolism of other drugs, thus increasing their blood concentrations and possible correlated adverse reactions. On the other hand, rifampicin, rifabutin and some anticonvulsants can induce enzymatic metabolism, causing reduced blood concentrations and lower AUC of itraconazole and voriconazole with possibly lower therapeutic efficacy. This brief review of pharmacological interactions among certain chemotherapeutic agents leads us to believe that this problem is destined to occur with more frequency in daily clinical practice. What is needed is basic knowledge of drug interactions on the part of all physicians who work in the fields of clinical therapeutics with the goal of reducing the high number of medical errors.

Small-Cell Lung Cancer Comorbid with Pulmonary <b><i>Mycobacterium avium</i></b> Infection: A Case Report

“…Meanwhile, MAC infection is primarily treated with CAM and RFP. CAM suppresses drug metabolism by suppressing CYP3A4 [6], while RFP accelerates drug metabolism by inducing CYP 3A4 [6]. Thus, simultaneous administration of these drugs is risky because the influence of CAM and RFP on the metabolism of etoposide cannot be predicted.…”

“…CAM and RFP/PBT drug metabolism influences cytochrome P-450 (CYP) [6]. Therefore, treatment for pulmonary MAC infection coexisting with another disease that requires drugs metabolized by CYP is often difficult.…”

Evaluación de interacción medicamentosa de voriconazol-ciclosporina en pacientes pediátricos que reciben trasplante de precursores hematopoyéticos (2013-2014)

“…Nuestra sugerencia para estos pacientes es disminuir en 20% la dosis de ciclosporina al inicio de una terapia concomitante con voriconazol y controlar las concentraciones plasmáticas de ciclosporina luego de 72 h o a la 5° vida media de inicio del tratamiento, ya sea cuando los pacientes sean expuestos a terapias de ciclosporina o voriconazol, para evitar dosis sub-terapéuticas o sobredosis que pudiesen traducirse en interacciones medicamentosas y potenciales RAM que pusieran en riesgo la seguridad de nuestros pacientes. (3)(4)(5)(6), peso promedio: 20 kg (17-30). Se analizaron 63 concentraciones plasmáticas de CsA, 27 eran concentraciones de CsA previas al uso de VCZ y 36 concentraciones plasmáticas de CsA concomitantes con VCZ.…”

“…Esto puede producir alteraciones en la actividad farmacológica, es decir que el medicamento sea más o menos eficaz o que produzca efectos adversos no deseados" 1 , comprometiendo el objetivo del tratamiento y afectando la seguridad de administración y ser potencial de reacciones adversas a medicamentos (RAM), definida como todo efecto de un medicamento que es perjudicial y no deseado, que ocurre a dosis terapéuticas, profilácticas o de diagnóstico, según la OMS 2 . Los factores de riesgo para producir una IM son: edad, complejidad del tratamiento, polifarmacia, gravedad de la enfermedad, co-morbilidades y otros factores relacionados a la farmacoterapia [3][4][5] .…”

“…En diferentes etapas del TPH, los pacientes son tratados con agentes inmunosupresores, entre otros medicamentos, lo que aumenta el riesgo potencial de IM y RAM, ya que son particularmente susceptibles a IM [3][4][5] . Se observó en un estudio la frecuencia potencial de IM relacionada con el uso de un mayor número de medicamentos, siendo los antifúngicos azoles y ciclosporina los que se asocian a la ocurrencia de éstas 5 .…”