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CLINICAL PHARMACOLOGY APPROACH TO THE USE OF ANTIARRHYTHMIC DRUGS
Odiljonova Aziza Bakhtiyorjon kizi
Assistant intern at the Department of "Pharmacology, clinical pharmacology and medical biotechnologies", ASMI https://doi.org/10.5281/zenodo.14557063
ABSTRACT
Received: 19th December 2024 Accepted: 25th December 2024 Online: 26th December 2024
KEYWORDS Antiarrhythmic drugs, clinical pharmacology, cardiac
arrhythmias, sodium channel blockers, beta-blockers,
potassium channel blockers.
This article explores the clinical pharmacology of antiarrhythmic drugs, focusing on their classification, mechanisms of action, and clinical applications in managing cardiac arrhythmias. The pharmacokinetics and pharmacodynamics of key drug classes, including sodium channel blockers, beta-blockers, potassium channel blockers, and calcium channel blockers, are discussed. Special attention is given to the selection of antiarrhythmic agents based on the type of arrhythmia, patient-specific factors, and potential side effects. The article also highlights the role of evidence-based approaches in optimizing therapy and minimizing proarrhythmic risks.
INTRODUCTION
In recent decades, due to a significant increase in cardiovascular pathology, the frequency of use of antiarrhythmic drugs (AAD) has increased significantly [1]. In the process of using such drugs, severe side effects have become more common, since their complex drug-drug interactions, organ specificity, proarrhythmogenicity, pharmacokinetics and pharmacodynamics, features of use depending on gender and age, as well as existing background cardiac and extracardiac pathology are often not taken into account [2]. In this report, the attention of practicing physicians is drawn precisely to these aspects of AAD use. It is known that most AADs act on ion channels, changing their structure and function. According to the Singh-Vaughan-Williams classification [3], four classes of antiarrhythmics are distinguished: fast Na+ channel blockers (class I), p-adrenergic receptor antagonists (class II), drugs that predominantly block K+ channels, prolonging the repolarization phase and not affecting intracardiac conduction (class III), and non-dihydropyridine L-type Ca2+ channel blockers (class IV). In addition, class I AADs are divided into three subclasses: those that increase (IA), shorten (IB), and do not affect (IC) the duration of the repolarization phase.
MATERIALS AND METHODS
It is important to remember that any of the AAPs may worsen the patient's condition in the presence of previous bradycardia or conduction disturbances, and therefore their use should be strictly regulated.
Features of the use of antiarrhythmic drugs depending on the clinical characteristics of the patient
Gender and age
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Although the effectiveness of AAPs is the same in men and women [4], the risk of developing proarrhythmias in women is still higher. The female gender is associated with an increased risk of developing polymorphic ventricular tachycardia (VT) of the "pirouette" type when using AAPs of classes I and III. This is facilitated by an increase in the corrected QT interval, greater QT hysteresis and the absence of the protective antiarrhythmic effect of androgens. To minimize the risk of developing torsades de pointes VT in women, it is recommended to use the lowest effective doses of AADs and avoid concomitant use of drugs that prolong QT. Given the increased risk of proarrhythmias in women receiving class III AADs, their use should be avoided if patients have additional risk factors for developing polymorphic VT, including heart failure [5]. If proarrhythmias are suspected, 24-hour Holter monitoring is indicated due to the clear inverse relationship between the use of class III AADs and the tendency to develop proarrhythmias during nocturnal bradycardia. Finally, patients should be advised to promptly seek medical attention if they experience dizziness or palpitations [5]. The incidence of proarrhythmias increases significantly in elderly patients and with physiological changes caused by old age, which significantly alter the pharmacokinetics of AAP.
RESULTS AND DISCUSSION
In children and patients with congenital heart defects (CHD), the use of AADs (except for P-blockers and verapamil) should be avoided due to their negative inotropic effect, as well as due to the small evidence base for the efficacy and safety of their use [5]. The question of the safety of using AADs in individuals with left ventricular (LV) hypertrophy also remains open. It has been demonstrated that such patients have a higher transmural dispersion of repolarization and, accordingly, a higher risk of developing VT of the "pirouette" type. Due to the development of a possible proarrhythmogenic effect, many experts warn against the use of class IC and III AADs in individuals with significant LV hypertrophy. Thus, in accordance with the 2016 European Society of Cardiology (ESC) guidelines for the management of patients with atrial fibrillation (AF), the use of dronedarone, sotalol, and amiodarone is an acceptable alternative for patients with AF and LV hypertrophy. However, in patients with HF, only amiodarone is used, which is also an alternative when other AADs are ineffective [2].
Thus:
- the use of class IA, IC, and III AADs (except amiodarone or sotalol) should be avoided in patients with significant structural heart disease (cardiomyopathy, LV dysfunction, myocardial infarction, and myocardial ischemia).
- class IA, IC and III should be avoided except for amiodarone, dronedarone, sotalol and disopyramide in patients with severe LV hypertrophy (>1.4 cm);
- disopyramide is recommended for the treatment of patients with obstructive hypertrophic cardiomyopathy (in combination with P-blockers) to improve the clinical picture; but with caution in patients with AF, where it may increase ventricular rate;
- the use of AADs in CHD (especially complex defects) is indicated only in special cases, since they are often poorly tolerated due to the negative inotropic effect, other side effects, and due to insufficient evidence regarding their efficacy and safety in these patient cohorts.
When deciding to use AAP in a patient on hemodialysis, the key point is drug dialysability, which depends on the molecular size, protein binding, volume of distribution,
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water solubility and plasma clearance. Some technical aspects of the dialysis procedure can affect the degree of elimination of the antiarrhythmic drug. The usual approach requires knowledge of the "sieving coefficient", which is the ratio of the concentration of the substance in the filtrate to the total concentration of the test substance in the plasma at the entrance and exit of the hemodialyzer. The closer this coefficient is to unity, the more complete the removal of the drug during dialysis [2]. In patients on hemodialysis, the use of procainamide and sotalol should be avoided, the dose of flecainide should be at least 50% of the usual recommended dose, and dialysis has little effect on the clearance of amiodarone and does not require dose adjustment [3]. Thus:
- renal function should be assessed in all patients who are indicated for AAP therapy;
- glomerular filtration rate is estimated using the Cockcroft-Gault formula, MDRD (modification of diet in kidney disease) or CKD-EPI equation, and the AAP dosage should be adapted to the results obtained, taking into account the pharmacokinetic characteristics of a particular drug [2].
Pregnancy
There are few data from some studies on the use of AAP during pregnancy. Most AAPs are classified as FDA category C, which indicates that animal studies have shown adverse effects on the fetus and adequate and well-controlled studies in pregnant women have not been conducted, but the potential benefit associated with the use of a class C antiarrhythmic in pregnant women may justify its use despite the presumably small and poorly defined risk.
In pregnant women, the first line of therapy to stop an attack of supraventricular tachycardia should be carotid sinus massage, then, if ineffective, adenosine may be administered, followed by a p-blocker (metoprolol). The latter can also be used to prevent relapse in a minimal dosage. Some guidelines prohibit the use of p-blockers in the first trimester (except in cases of existing prolongation of the QT interval) in order to minimize the risk of intrauterine growth retardation of the fetus [3]. If therapy with p-blockers is unsuccessful, the possibility of using sotalol or flecainide can be considered (sotalol has recently been found to be effective in the treatment of supraventricular tachycardia in the fetus) [4]. Propafenone has not been adequately studied in pregnancy, although there is no evidence of increased prenatal risk associated with its use.
Hemodynamically significant VT in pregnant women should be treated with cardioversion, while hemodynamically stable VT may be treated with forced rhythm (if CVD is available) or intravenous lidocaine. Procainamide or quinidine may also be used if lidocaine is ineffective. However, amiodarone (FDA category D) should be avoided due to significant fetal risks, including hypothyroidism, intrauterine growth retardation, and preterm labor [5].
Thus:
- due to the potential risk to the fetus, treatment of arrhythmias in pregnancy should be limited to cases with recurrent, hemodynamically significant arrhythmias;
- when drugs are ineffective, second-line therapy is catheter ablation with minimal fluoroscopy. In this case, the surgical team should also include an obstetrician-gynecologist and a neonatologist.
Safety issues for patients receiving antiarrhythmic drugs
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