15.6
Relación farmacocinética-farmacodinámica: problemas
El enfoque empírico para la optimización de la farmacoterapia se basa en correlacionar la respuesta farmacológica con la dosis administrada. Este enfo…
La relación farmacocinético-farmacodinámica, o PK–PD, vincula la respuesta farmacológica a la concentración del fármaco en el sitio objetivo, reflejada en los niveles plasmáticos de fármacos.
La modelización puede volverse compleja debido a la presencia de mezclas racémicas, la influencia de la unión a proteínas, el impacto de la distribución tardía, la formación de metabolitos activos y el desarrollo de tolerancia adquirida.
Muchos fármacos se administran como mezclas racémicas, en las que solo un isómero activo impulsa la respuesta, lo que hace que la proporción de isómeros sea crucial para la eficacia.
Además, la respuesta al fármaco se correlaciona con mayor precisión con la concentración plasmática no unida, ya que la unión a proteínas altera los niveles de fármacos libres y complica el modelado PK–PD.
Además de la unión a proteínas, muchos fármacos actúan sobre el tejido extravascular, requiriendo tiempos de equilibrio más largos y retrasando la respuesta.
Algunos fármacos producen metabolitos farmacológicamente activos en el organismo. Los niveles plasmáticos de estos metabolitos pueden correlacionarse mejor con la respuesta terapéutica que los del fármaco principal.
Además, el uso crónico de algunos fármacos puede conducir a una tolerancia adquirida, ya sea mediante un metabolismo acelerado o una respuesta disminuida, alterando la relación PK–DP con el tiempo.
View the full transcript and gain access to JoVE Core videos
Q1: Why is unbound drug concentration more important than total plasma concentration in PK-PD modeling?
Drug response correlates more accurately with unbound plasma concentration because protein binding alters free drug levels available to act at the target site. Total plasma concentration includes both bound and unbound drug, but only unbound drug can produce a pharmacological effect. Variations in protein binding between patients complicate PK-PD modeling when based solely on total concentration measurements.
Q2: How do active metabolites complicate the relationship between drug concentration and therapeutic response?
Some drugs produce pharmacologically active metabolites in the body whose plasma levels may correlate better with therapeutic response than the parent drug itself. Basing the PK-PD relationship solely on parent drug concentration can obscure the true concentration-response relationship. Examples include imipramine, amitriptyline, and propranolol, where metabolite activity significantly contributes to the overall therapeutic effect.
Q3: What causes delayed response in drugs acting on extravascular tissues?
Many drugs act on extravascular tissue rather than plasma, requiring longer equilibration times between the plasma and the site of action. This distribution delay means the pharmacological response lags behind plasma drug concentration changes. For example, the anticoagulant effect of dicoumarol shows long delays because it is an indirect measure of drug effect at the tissue level.
Q4: Why does the isomer ratio matter in racemic drug mixtures?
Many drugs are administered as racemic mixtures containing two optically active enantiomers, but typically only one active isomer drives the pharmacological response. A change in the ratio of active to inactive isomers can lead to significant differences in pharmacological response and efficacy. The isomer ratio is therefore crucial to predicting and maintaining consistent therapeutic outcomes.
Q5: How does acquired tolerance alter the PK-PD relationship over time?
Chronic use of some drugs may lead to acquired tolerance through either enhanced metabolism or diminished pharmacodynamic response. Pharmacokinetic tolerance involves increased drug elimination, while pharmacodynamic tolerance reflects reduced tissue responsiveness. Both mechanisms alter the PK-PD relationship, meaning the same plasma concentration may produce a weaker effect with repeated dosing.
Q6: What advantage does PK-PD modeling offer over empirical dose-response approaches?
PK-PD modeling correlates pharmacological response with plasma drug concentration or body drug amount rather than administered dosage, providing more precise predictions. Empirical approaches are costly, time-consuming, and often yield poor correlation due to formulation factors and drug elimination variability. Modeling assumes response is proportional to drug concentration at the site of action, reflected in plasma levels.
Q7: How does the duration of therapeutic action sometimes exceed plasma drug concentration persistence?
In some drugs like reserpine, the therapeutic action outlasts the measurable plasma drug concentration, creating a disconnect between plasma levels and observed effect duration. This occurs when drugs bind tightly to tissue receptors or produce sustained biochemical changes that persist after the drug is eliminated. Understanding this relationship is essential for predicting dosing intervals and the influence of elimination half-life on effect duration.