Mathematical modeling of antihypertensive therapy

Abstract

Hypertension is a multifactorial disease arising from complex pathophysiological pathways. Individual characteristics of patients result in different responses to various classes of antihypertensive medications. Therefore, evaluating the efficacy of therapy based on in silico predictions is an important task. This study is a continuation of research on the modular agent-based model of the cardiovascular and renal systems (presented in the previously published article). In the current work, we included in the model equations simulating the response to antihypertensive therapies with different mechanisms of action. For this, we used the pharmacodynamic effects of the angiotensin II receptor blocker losartan, the calcium channel blocker amlodipine, the angiotensin-converting enzyme inhibitor enalapril, the direct renin inhibitor aliskiren, the thiazide diuretic hydrochlorothiazide, and the β-blocker bisoprolol. We fitted therapy parameters based on known clinical trials for all considered medications, and then tested the model’s ability to show reasonable dynamics (expected by clinical observations) after treatment with individual drugs and their dual combinations in a group of virtual patients with hypertension. The extended model paves the way for the next step in personalized medicine that is adapting the model parameters to a real patient and predicting his response to antihypertensive therapy. The model is implemented in the BioUML software and is available at https://gitlab.sirius-web.org/virtual-patient/antihypertensive-treatment-modeling.

Mathematical modeling of the influence ofACE I/Dpolymorphism on blood pressure and antihypertensive therapy

“…All blood counts listed in Table 1, except for sodium, are constant in the model. To account for the fact that thiazide diuretics reduce sodium reabsorption (Duarte and Cooper-DeHoff, 2010; Akbari and Khorasani-Zadeh, 2023), we previously included the corresponding effect of hydrochlorothiazide in the model (Kutumova et al, 2022). As a result, in the current study, we observed a slight decrease in circulating sodium levels with hydrochlorothiazide-based therapy (Supplementary File 1, Figure S31 and Table S48).…”

“…The correspondence of the simulated response of cardiovascular and renal parameters to single-drug treatment with experimental observations was carried out in our previous study on modeling antihypertensive therapy (Kutumova et al, 2022). The dynamics of model parameters in the case of double and triple drug combinations in the present research were a consequence of cross-drug effects.…”

“…In addition, we considered the following representatives of other classes of antihypertensive medications to analyze their combined action with RAAS inhibitors: the β-blocker bisoprolol (5 mg), the calcium channel blocker amlodipine (5 mg), and the thiazide diuretic hydrochlorothiazide (12.5 mg). An extension of the primary model to account for the effects of these drugs was described previously (Kutumova et al, 2022). Briefly, we identified target variables in the model for all listed medications.…”

“…The pharmacodynamic functions of aliskiren, enalapril, losartan, and amlodipine were taken unchanged from the study by Kutumova et al (2022). We also retained the hydrochlorothiazide targets in the model, but re-estimated the kinetic parameters in the influence functions to better fit clinical trials (MacKay et al, 1996).…”

“…Primary model incorporated the processes of blood circulation and the cardiac cycle, neurohumoral regulation, oxygen exchange between blood and tissue, the renin-angiotensin-aldosterone system (RAAS), renal microcirculation and sodium transport along the nephron, renal sympathetic nerve activity, and regulation of water and sodium balance. The model was further improved to account for the effects of various antihypertensive agents, including RAAS blockers such as the direct renin inhibitor aliskiren, the ACE inhibitor enalapril, and the angiotensin II receptor blocker losartan, as well as drugs with other mechanisms of action, such as the β-blocker bisoprolol, the calcium channel blocker amlodipine, and the thiazide diuretic hydrochlorothiazide (Kutumova et al, 2022).…”