RESUMEN
Doxapram is an analeptic that induces ventilatory stimulation and increases blood pressure and cardiac output (CO). Its mechanism of action is the blockade of background K+ -channels expressed on type 1 carotid body cells. In the randomized controlled trial, the authors explored the role of the increase in CO by doxapram (plasma concentration (Cp) 1,000-3,500 ng/mL) on the pharmacokinetics (PKs) and pharmacodynamics (PDs) of the potent opioid alfentanil (Cp 100-200 ng/mL). Population PK-PD analyses were performed on the doxapram PK-CO data and the alfentanil PK-antinociception data. The analyses showed that the doxapram-induced increase in CO explained the increase in alfentanil distribution and elimination clearances causing a significant reduction in plasma alfentanil Cp and antinociception. This novel approach in which one PK-PD model effectively drives another PK-PD model highlights the importance of physiological influences on PK and PD of a potent opioid with rapid onset of effect and low clinical margin of safety.
Asunto(s)
Alfentanilo , Doxapram , Insuficiencia Respiratoria , Adulto , Alfentanilo/efectos adversos , Alfentanilo/sangre , Alfentanilo/farmacocinética , Analgésicos/administración & dosificación , Analgésicos/farmacocinética , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/sangre , Analgésicos Opioides/farmacocinética , Presión Sanguínea/efectos de los fármacos , Gasto Cardíaco/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/farmacocinética , Doxapram/administración & dosificación , Doxapram/farmacocinética , Voluntarios Sanos , Humanos , Masculino , Tasa de Depuración Metabólica , Insuficiencia Respiratoria/inducido químicamente , Insuficiencia Respiratoria/prevención & control , Fármacos del Sistema Respiratorio/administración & dosificación , Fármacos del Sistema Respiratorio/farmacocinética , Resultado del TratamientoRESUMEN
Opioid-induced respiratory depression (OIRD) is a serious and potentially life-threatening complication of opioid overdose, abuse, and misuse. An option to avert OIRD is to treat patients on strong opioids with respiratory stimulants that do not interact with the opioid system and consequently do not compromise opioid analgesic efficacy. The BK-channel blocker GAL021 is a respiratory stimulant acting at K(+) -channels expressed on type 1 carotid body cells. The authors performed a population pharmacokinetic-pharmacodynamic (PKPD) analysis on the ability of GAL021 to reverse alfentanil-induced respiratory depression in 12 male volunteers using an isohypercapnic experimental design. The analysis showed that (1) GAL021 interacts in a multiplicative fashion with alfentanil and GAL021, which predicts that GAL021 efficacy is reduced at low ventilation levels; (2) GAL021 has a rapid onset/offset with a blood-effect site equilibration half-life not different from zero; and (3) GAL021 displays ceiling in its efficacy to reverse OIRD.
