Rytmonorm Mechanism of Action

Pharmacotherapeutic group: Antiarrhythmics, class 1C. ATC Code: C01 BC 03.
Pharmacology: Pharmacodynamics: Propafenone hydrochloride is a class 1c antiarrhythmic drug with some structural similarities to beta-blocking agents.
Propafenone hydrochloride is an antiarrhythmic agent with membrane-stabilizing, sodium channel blocking properties (Vaughan Williams, class 1c). It also possesses weak beta blocking efficacy (class II according to Vaughan Williams). Propafenone hydrochloride reduces the rate of rise of the action potential thereby slowing down impulse conduction (negative dromotropic effect). The refractory periods in the atrium, atrioventricular (AV) node and ventricles are prolonged. Propafenone hydrochloride prolongs the refractory periods in the accessory pathways in patients with WPW syndrome.
Pharmacokinetics: Propafenone is a racemic mixture of S- and R-propafenone.
Absorption: Maximal plasma concentrations are reached between two to three hours following the administration of propafenone hydrochloride. Propafenone is known to undergo extensive and saturable presystemic biotransformation (CYP2D6 hepatic first pass effect) which results in a dose- and dosage form-dependent absolute bioavailability. Although food increased the maximal plasma concentration and bioavailability in a single dose study, during multiple dose administration of propafenone to healthy subjects, food did not change bioavailability significantly.
Distribution: Propafenone distributes rapidly. The steady-state volume of distribution is 1.9 to 3.0 L/kg. The degree of plasma protein binding of propafenone is concentration dependent and decreased from 97.3% at 0.25 μg/mL to 81.3% at 100 μg/mL.
Biotransformation and elimination: There are two genetically determined patterns of propafenone metabolism. In over 90% of patients, the drug is rapidly and extensively metabolized with an elimination half-life from two to ten hours (i.e. extensive metabolizers). These patients metabolize propafenone into two active metabolites: 5-hydroxypropafenone which is formed by CYP2D6 and N-depropylpropafenone (norpropafenone) which is formed by CYP3A4 and CYP1A2. In less than 10% of patients, metabolism of propafenone is slower because the 5-hydroxy metabolite is not formed or is minimally formed (i.e., poor metabolizers). Slow metabolizers had higher propafenone plasma concentrations which they required for suppression of arrhythmia since they did not produce the active metabolite 5-hydroxypropafenone (5-OHP). These higher propafenone plasma concentrations may lead to clinically evident beta-blockade. The estimated propafenone elimination half-life ranges from two to ten hours for extensive metabolizers and from ten to 32 hours for poor metabolizers. Clearance of propafenone is 0.67 to 0.81 L/h/kg.
Because steady state is reached after three to four days of dosing of propafenone hydrochloride, the recommended dosing regimen of propafenone is the same regardless of the metabolic status (i.e., poor or extensive metabolizers) for all patients.
Linearity/non-linearity: In extensive metabolizers, the saturable hydroxylation pathway (CYP2D6) results in nonlinear pharmacokinetics. In slow metabolizers, propafenone pharmacokinetics are linear.
Inter/intra subject variability: With propafenone hydrochloride, there is a considerable degree of individual variability in pharmacokinetics which is due in large part to the first pass hepatic effect and non-linear pharmacokinetics in extensive metabolizers. The large variability in blood levels requires that the dose be titrated carefully in patients, paying close attention to clinical and electrocardiographic evidence of toxicity.
Elderly population: Propafenone exposure in elderly subjects with normal renal function was highly variable, and not significantly different from healthy young subjects.
Renal impairment: In patients with renal impairment, exposure to propafenone and 5-hydroxypropafenone was similar to that in healthy controls, while accumulation of glucuronide metabolites was observed. Propafenone hydrochloride should be administered cautiously in patients with renal disease.
Liver impairment: Propafenone shows an increased oral bioavailability and half-life in patients with liver impairment. The dosage must be adjusted in patients with liver disease.
Toxicology: Pre-clinical safety data: Pre-clinical safety data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential or toxicity to reproduction.