Sodium blocking agents and antiarrhythmic drugs class I

All sodium channel-blocking agents affect impulse conduction across the myocardium by altering the movement of ions through the cell membrane.

Sodium, potassium, and calcium ions flow through channels in the myocardial cell membrane, contributing to the various phases of the action potential.

All class I antiarrhythmic agents block fast sodium channels (phase 0) during open, inactive, or resting states.

Blocking these sodium channels decreases the slope of phase 0 of action potential, leads to the QRS complex's widening. The most potent sodium channel blockers are Cass Ic antiarrhythmic drugs.

Common sodium channel-blocking drugs include:

- Antiarrhythmic drugs (class Ia, Ib, Ic)

- Chloroquine

- Quinine

- Propoxyphene

- Tricyclic antidepressants

- Phenothiazines

- Antihistamines

- Cocaine

- Propranolol

- Carbamazepine

Ia drugs: Moderate sodium channel blockade (QRS interval prolongation).

Increase effective refractory period (ERP) due to decreased outward potassium channel activity, leading to QT interval prolongation.

Ib drugs: Weak sodium channel blockade.

Decrease ERP by inhibiting slow sodium current, resulting in QT interval shortening.

Ic drugs: Potent sodium channel blockade (QRS interval prolongation).

No effect on ERP, leading to less impact on QT interval.

Class Ia antiarrhythmic drugs

Cass Ia drugs are moderate-potency inhibitors of fast sodium channels and their effects are dose-dependent.

The depression of slow inward calcium and outward potassium channels leads to prolonged repolarization and reduced action potential plateau.

This results in the prolongation of the QRS complex and QTc interval.

Quinidine

Fallen out due to adverse effects.

Pharmacokinetics

Absorption: good bioavailability, peak plasma concentration at 90 minutes.
Distribution: highly protein-bound, Vd 3 L/kg. (A higher Vd indicates the drug is more distributed into soft tissue.)
Metabolism: via CYP3A4. The primary metabolite of quinidine is 3-hydroxy-quinidine.
Excretion: 40% in the kidneys (less than 20% of the drug is excreted unchanged in the urine) and 60% in the liver.

Quinidine syncope: Noted in individuals experiencing prolongation of both QRS and QT intervals. (VT 2-4%)

Hypotension is multifactorial, with dose-dependent myocardial suppression and peripheral alpha-1 receptor antagonists leading to vasodilation.

As serum concentration rises, QT interval prolongation occurs initially, followed by QRS complex prolongation. This is associated with bundle branch block, AV block, sinus arrest, and junctional or ventricular escape rhythm.

The antimuscarinic effect can enhance conduction through the AV node. Potassium channel blockade increases insulin release from the pancreatic islet cells, which may result in hypoglycemia.

Coma and seizures can occur with toxic concentration.

Antimuscarinic effect: sinus tachycardia, blurred vision, altered mental status, urinary retention, ileus.

Chloroquine, quinine, and quinidine can exhibit indistinguishable cardiotoxicity.

Procainamide

It is commonly used to treat atrial and ventricular arrhythmia.

Procainamide does not have any AV nodal-blocking effect, so it is indicated in patients with atrial fibrillation with Wolf-Parkinson-White syndrome for acute termination of antidromic AV re-entrant tachycardia in stable patients. Because using an AV nodal-blocking agent in this patient population could enhance conduction down the accessory pathway.

Pharmacokinetics

Absorption: good bioavailability, peak plasma concentration 10-30 min.
Distribution: Vd 2 L/kg. Vd of NAPA 1.25 L/lg
Metabolism: via CYP2D6. The active metabolite is NAPA (N-acetyl procainamide), which has cardiac activity.
Excretion: The half-life of procainamide is 2.5 to 5 hrs. Excreted as NAPA, which accumulate in patients with CKD .(plasma half-life of NAPA is 4-15 hours)

N-acetyl procainamide (NAPA) is an electrophysiologically active product with antiarrhythmic class III. NAPA prolongs the action potential by blocking the potassium rectifier current but does not exhibit sodium channel blockade.

Cardiotoxicity resembles quinidine, leading to myocardial depression, ventricular tachycardia, and hypotension at doses of 20 mg/min., as well as a high-pacing threshold in patients intoxicated with procainamide.

Acute overdoses include seizures and antimuscarinic effects(sinus tachycardia, blurred vision, altered mental status, urinary retention, ileus.).

Structurally similar substances to amphetamine may result in a false-positive urine drug screen for amphetamine.

Lupus-like syndrome, agranulocytosis, thrombocytopenia, hemolytic anemia.

Disopyramide

Disopyramide is used in the treatment of patients with HCM.

Pharmacokinetics

Absorption: peak plasma concentration for several hours.
Distribution: protein-bound 50%, Vd <1 L/kg.
Metabolism: The plasma half-life is 6 to 8 hours, mediated by CYP3A4. The primary metabolite is mono-N-dealkaylated disopyramide (little cardiac activity but has increased antimuscarinic effects.
Excretion: Both hepatic and renal. The half-life of disopyramide is prolonged in patients with severe renal dysfunction, ranging from 14 to 43 hours.

Disopyramide lowers cells' diastolic depolarization rate (phase 4), augmented automaticity, and upstroke velocity (phase 1).

It blocks the sodium channel and the rapid component of the delayed rectifier potassium current, prolonging the QT interval.

Drugs of choice for vagally mediated atrial fibrillation, such as sleep-induced or atrial fibrillation in athlete groups due to anticholinergic activity.

Potassium channel blockade increases insulin release from the pancreatic islet cells, which may result in hypoglycemia.

Antimuscarinic effect: sinus tachycardia, blurred vision, altered mental status, urinary retention, ileus.

Rare (<1%) adverse events: agranulocytosis, cholestatic jaundice, malignant arrhythmia, and other electrocardiographic abnormalities.

Class Ib antiarrhythmic drugs

Class Ib suppression automaticity is like Ia but possesses the highest affinity for the Na channel in an inactivated state and the highest on-off binding kinetics for myocardial sodium channels. Meanwhile, Ia and Ic drugs block sodium channels in both activated and inactivated states.

This characteristic of Ib drugs is important because these drugs are beneficial for arrhythmias in ischemic myocardium. Ischemia leads to slow cellular depolarization, which inactivates sodium channels, enhancing the binding of Ib drugs.

Ib drugs weak affect the phase 0 action potential (weak sodium channel blockade) and block small sodium plateau current (shortened QT interval).

Lidocaine

Predominantly used as a local anesthetic and treat VT.

Pharmacokinetics

Absorption: significant first-pass effect, with oral bioavailability at only 30-35%; well absorbed topically through the epithelium and via endotracheal administration.
Distribution: Vd 1.3 L/kg.
Metabolism: The elimination half-life is 2 hours, and the liver metabolizes all. The active metabolite is monoethylglycinexylidide (MEGX), which has a half-life of 2 hours.
Excretion: The liver metabolizes virtually.

Both lidocaine and MEGX are poisoning in cardiovascular and CNS toxicity and can cause seizures and apnea.

Lidocaine can pass the blood-brain barrier and manifest CNS dysfunction.

Early signs of lidocaine intoxication include tongue or perioral numbness, lightheadedness, agitation, confusion, hallucination, dysarthria, and progress to seizure and coma.

CVS toxicity: Suppresses cardiac pacemaker, delayed conduction, and myocardial suppression.

Large doses result in asystole, complete AV block, and refractory hypotension.

Lidocaine Dosage Guide

Phenytoin

Most commonly used in the management of seizure disorders.

Pharmacokinetics

Absorption: Peak level can be delayed up to 24 hours or more.
Distribution: 90% protein binding, Vd is 0.5 L/kg. In patients with hypoalbuminemia, there is an increased risk of phenytoin toxicity.
Metabolism: Zero order kinetics. Drug elimination is constant. ( The elimination rate is not affected by the drug concentration in the blood.). The half-life may increase to several days. Metabolized to nontoxic metabolite by the liver.
Excretion: Liver.

Neurotoxicity: drowsiness, ataxia, dysarthria, nystagmus, coma, seizure.

Propylene glycol (parenteral vehicle in intravenous solution): Propylene glycol is a cardiac depressant, and rapid infusions can lead to bradycardia, hypotension, and asystole.

Class Ic antiarrhythmic drugs

Class Ic drugs (flecainide, propafenone) bind sodium channels in an activated state.

The most potent sodium channel-blocking effect.

Flecainide

Flecainide, a procainamide derivative, is usually used to treat atrial fibrillation or SVT in patients who do not have structural heart disease.

Propafenone blocks β-receptors and is a weak potassium channel blocker. This drug usually slows conduction and prolongs the refractoriness of most cardiac conduction system tissue.

Pharmacokinetics

Absorption: Bioavailability: 80-90%, Peak serum time: 2-3 hours
Distribution: 40-50% protein binding, Vd is 5-9 L/kg.
Metabolism: primarily metabolized by the hepatic cytochrome P450 CYP2D6 system to Meta-O-dealkylated flecainide, meta-O-dealkylated lactam of flecainide (inactive)
Excretion: 12 to 27hr; t1/2 increased in renal impairment. In those with a creatinine clearance ≤35 mL/min/1.73 m2, the recommended starting dose is 100 mg daily or 50 mg twice daily.

The toxicity typically marked QRS prolongation without QT interval prolongation.

Flecainide has a negative inotropic effect that may worsen heart failure.

Flecainide toxicity is treated the same as a tricyclic antidepressant overdose. Sodium bicarbonate is administered to maintain the pH between 7.5 and 7.55 in order to reverse the effects of sodium channel blockade.

Rhythm control atrial fibrillation

Flecainide 1-2 mg/kg i.v. over 10 min

200-300 mg, then 50-150 mg two times daily.

Propafenone

Propafenone blocks β-receptors and is a weak potassium channel blocker. This drug usually slows conduction and prolongs the refractoriness of most cardiac conduction system tissue.

Pharmacokinetics

Absorption: Bioavailability: 3.4%, Peak serum time: 2-3.5 hours
Distribution: 90% protein binding, Vd is 2-3 L/kg.
Metabolism: Via CYP2D6 to 5-hydroxypropafenone; via CYP1A2 and CYP3A4 to N-depropylpropafenone
Excretion: Urine; feces

Rhythm control atrial fibrillation

Propafenone 1.5-2 mg/kg i.v. over 10 min

450-600 mg, then 150-300 mg two- three times daily.

References

David L. Brown (Eds.). (2019). Cardiac Intensive Care (3nd ed.). Elsevier. https://doi.org/10.1016/C2014-0-03291-1

Jain A, SISODIA JITENDRA. Quinidine. [Updated 2023 Aug 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.

Pritchard B, Thompson H. Procainamide. [Updated 2023 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.

Sundjaja JH, Makaryus AN. Disopyramide. [Updated 2023 May 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.

Iorga A, Horowitz BZ. Phenytoin Toxicity. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-.