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![Mechanism based pharmacokinetic/pharmacodynamic modeling of β-blockers according to the model proposed by Snelder et al. [61]. MAP is determined by both physiological functions: CO and TPR. Traditional β-blockers reduce MAP by inhibiting the production of CO by myocardial β 1 -adrenergic antagonism. Vasodilatory β-blockers reduce MAP by inhibiting both the production of CO and the production of TPR due its ability to induce relaxation of vascular smooth muscle. CO: Cardiac output; MAP: Mean arterial pressure; TPR: Total peripheral resistance. Adapted with permission from [61] © British Journal of Pharmacology, The British Pharmacological Society (2013).](profile/Julieta-Del-Mauro/publication/308768354/figure/fig3/AS:741796875337728@1553869565273/Mechanism-based-pharmacokinetic-pharmacodynamic-modeling-of-b-blockers-according-to-the.png)
Mechanism based pharmacokinetic/pharmacodynamic modeling of β-blockers according to the model proposed by Snelder et al. [61]. MAP is determined by both physiological functions: CO and TPR. Traditional β-blockers reduce MAP by inhibiting the production of CO by myocardial β 1 -adrenergic antagonism. Vasodilatory β-blockers reduce MAP by inhibiting both the production of CO and the production of TPR due its ability to induce relaxation of vascular smooth muscle. CO: Cardiac output; MAP: Mean arterial pressure; TPR: Total peripheral resistance. Adapted with permission from [61] © British Journal of Pharmacology, The British Pharmacological Society (2013).
Source publication
β-blockers play a central role in the treatment of the various main cardiovascular diseases, including hypertension, coronary artery disease and systolic heart failure. As a therapeutic class, β-blockers form a heterogeneous family that differs in their pharmacokinetic (PK) and pharmacodynamic (PD) properties, highlighting the relevance of the exte...
Contexts in source publication
Context 1
... recently, Snelder et al. have developed a mechanism-based PK/PD model for the characterization of the effects of cardiovascular drugs with different mechanisms of action, including β-blockers, on the interrelationship between mean arterial pressure (MAP), CO and total peripheral resistance (TPR) (Figure 3) [61]. Considering that MAP = CO × TPR, the model includes two indirect physiological models to describe the time course of change in CO and TPR. ...
Context 2
... that MAP = CO × TPR, the model includes two indirect physiological models to describe the time course of change in CO and TPR. In these equations, K in_CO and K in_TPR represent the zero-order production rate constants and k out_CO and k out_TPR represent the first-order dissipation rate constants of CO and TPR, respectively (Figure 3). In addition, two feedback constants are introduced in order to take into account the magnitude of the negative feedback of MAP on CO and TPR (Figure 3) [61]. ...
Context 3
... these equations, K in_CO and K in_TPR represent the zero-order production rate constants and k out_CO and k out_TPR represent the first-order dissipation rate constants of CO and TPR, respectively (Figure 3). In addition, two feedback constants are introduced in order to take into account the magnitude of the negative feedback of MAP on CO and TPR (Figure 3) [61]. During the development of the novel mechanism based PK/ PD model, the authors consider that antihypertensive drugs selectively influence either CO or TPR and that all compounds influence the production rates of CO or TPR rather than the dissipation rates [61]. ...
Context 4
... proposed model may predict the effects of a particular β-blocker on blood pressure based on preclinical data [61]. Although the mechanism-based PK/PD model seems to be suitable for the evaluation of cardiovascular actions of most β-blockers, it requires modifications for vasodilatory β-blockers, considering the fact that the blood pressure reduction induced by these agents depends not only on the effects on CO but also on TPR (Figure 3). ...
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Citations
... 13 There are several PK−PD models for β-blockers, especially carvedilol, using clinical data. 14 One PK−PD model demonstrated the relationship between (S)-carvedilol and HR reduction in exercise-induced tachycardia. 15 Another study investigated the relationship between carvedilol concentration and blood pressure. ...
Background:
Carvedilol is a beta-adrenergic receptor antagonist primarily metabolized by cytochromes P450 (CYP) 2D6. This study established a carvedilol population pharmacokinetic (PK)-pharmacodynamic (PD) model to describe the effects of CYP2D6 genetic polymorphisms on the inter-individual variability of PK and PD.
Methods:
The PK-PD model was developed from a clinical study conducted on 21 healthy subjects divided into three CYP2D6 phenotype groups, with six subjects in the extensive metabolizer (EM, *1/*1, *1/*2), seven in the intermediate metabolizer-1 (IM-1, *1/*10, *2/*10), and eight in the intermediate metabolizer-2 (IM-2, *10/*10) groups. The PK-PD model was sequentially developed, and the isoproterenol-induced heart rate changes were used to establish the PD model. A direct effect response and inhibitory Emax model were used to develop a carvedilol PK-PD model.
Results:
The carvedilol PK was well described by a two-compartment model with zero-order absorption, lag time, and first-order elimination. The carvedilol clearance in the CYP2D6*10/*10 group decreased by 32.8% compared with the other groups. The inhibitory concentration of carvedilol estimated from the final PK-PD model was 16.5 ng/mL regardless of the CYP2D6 phenotype.
Conclusion:
The PK-PD model revealed that the CYP2D6 genetic polymorphisms were contributed to the inter-individual variability of carvedilol PK, but not PD.
... On the other hand, the variation of the therapeutic target during the day, for example, the expression of an enzyme or receptor, produces a variation in response to pharmacological treatment and consequently changes the dose-response curves [12]. Classical PK-PD models have been developed for β-blockers (BB), ARBs, CCBs, and ACE inhibitors [13][14][15][16], and some of the PK-PD models of antihypertensive medications have included the circadian variation of BP by coupling an indirect effect model with circadian variation [15,17,18]. But the simultaneous estimation of the circadian BP and PD parameters can lead to biased results due to the high correlation between some of them. ...
Blood pressure (BP) follows a circadian variation, increasing during active hours, showing a small postprandial valley and a deeper decrease during sleep. Nighttime reduction of 10–20% relative to daytime BP is defined as a dipper pattern, and a reduction of less than 10%, as a non-dipper pattern. Despite this BP variability, hypertension’s diagnostic criteria and therapeutic objectives are usually based on BP average values. Indeed, studies have shown that chrono-pharmacological optimization significantly reduces long-term cardiovascular risk if a BP dipper pattern is maintained. Changes in the effect of antihypertensive medications can be explained by circadian variations in their pharmacokinetics (PK) and pharmacodynamics (PD). Nevertheless, BP circadian variation has been scarcely included in PK-PD models of antihypertensive medications to date. In this work, we developed PK-PD models that include circadian rhythm to find the optimal dosing time ( Ta ) of first-line antihypertensive medications for dipper and non-dipper patterns. The parameters of the PK-PD models were estimated using global optimization, and models were selected according to the lowest corrected Akaike information criterion value. Simultaneously, sensitivity and identifiability analysis were performed to determine the relevance of the parameters and establish those that can be estimated. Subsequently, Ta parameters were optimized to maximize the effect on BP average, BP peaks, and sleep-time dip. As a result, all selected models included at least one circadian PK component, and circadian parameters had the highest sensitivity. Furthermore, Ta with which BP>130/80 mmHg and a dip of 10–20% are achieved were proposed when possible. We show that the optimal Ta depends on the therapeutic objective, the medication, and the BP profile. Therefore, our results suggest making chrono-pharmacological recommendations in a personalized way.
Postoperative atrial fibrillation is one of the most recognised complications of cardiac surgery. Although its exact pathophysiology remains unknown, evidence suggests that it is multifactorial and that it directly affects patient outcomes post cardiac surgery. It is associated with an increased risk of heart failure, renal failure, stroke and mortality. Pharmacological agents such as beta blockers and antiarrhythmic drugs are well established and extensively used for both the prevention and treatment of postoperative atrial fibrillation. This article will explore the pharmacological treatment of postoperative atrial fibrillation with specific reference to metoprolol and amiodarone, along with the pharmacokinetic and pharmacodynamic effects of both drugs. It will briefly discuss the evidence reviewed regarding the effectiveness of these drugs for postoperative atrial fibrillation and the recommendations from the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery on how postoperative atrial fibrillation should be treated.
