Verapamil and Diltiazem

Mechanism

Pharmacological Class and Group

Antianginal drugs, Class IV antiarrhythmics and antihypertensives belonging to the class of Non-Dihydropyridine L-Type Calcium Channel Blockers (Phenylalkylamines [Verapamil] and Benzothiazpines [Diltiazem]).

Mechanism of Action

Unlike dihydropyridines, non-dihydropyridine calcium antagonists exhibit a balanced or preferential selectivity profile for Cav1.2 channels expressed in specialized conduction and contraction myocardial tissue, exerting marked control of central cardiac function.

Myocardial and Nodal Molecular Mechanism of Action

1. Differential allosteric binding in the Cav1.2 channels of the myocyte and conduction system: Verapamil and diltiazem bind to specific and independent sites within the internal pore of the L-type channel of the α₁ subunit, with higher affinity when the channel is in high firing frequency states (frequency dependence or use), blocking the channel from its internal face.

2. Conduction Delay in the AV Node (Class IV Antiarrhythmic Effect): They selectively decrease calcium influx during the slow diastolic depolarization phase (phase 4) and phase 0 depolarization of the slow response action potential in the cells of the sinus and atrioventricular nodes:

↓ Slope of Phase 4 and Phase 0 in AV Node ↑ Effective Refractory Period (Negative dromotropic conduction)

This blockade of conduction velocity and the prolongation of the refractory period of the AV node annul the atrioventricular reentry circuits and decrease the ventricular response in uncontrolled atrial tachyarrhythmias.

3. Negative Inotropic Effect (Verapamil > Diltiazem): By decreasing the availability of cytoplasmic calcium in ventricular myocytes, they limit the activation of the ryanodine receptor of the sarcoplasmic reticulum, reducing the global systolic cardiac contraction force.

Pharmacokinetics

High Resolution Pharmacokinetics

• Verapamil: Rapid oral absorption greater than 90%. It has a low net bioavailability (20% - 35%) due to an extensive first hepatic metabolic step mediated in a mixed manner by the cytochrome isoenzymes CYP3A4, CYP1A2 and CYP2C9, transforming norverapamil into its active metabolite (which has 20% of the potency of the parent molecule). High protein binding (90%). Elimination half-life of 4 to 9 hours. It is excreted 70% in the urine as conjugated metabolites and 16% in the bile.
• Diltiazem: Rapid oral absorption with bioavailability of 40% to 60% secondary to the first hepatic passage mediated by CYP3A4 to its active metabolite desacetyldiltiazem. Plasma half-life of 3 to 5 hours, with extended-release formulations allowing dosing every 24 hours. Mostly biliary excretion of 65% and urinary excretion of 35%.

Indicators and dose

Clinical Indications and Uses

• Heart Rate Control in Atrial Fibrillation and Atrial Flutter: First line in patients with preserved ejection fraction.
• Paroxysmal Supraventricular Tachycardia (PSVT): Acute conversion and prevention of recurrence due to re-entry into the AV node.
• Chronic Stable Angina Pectoris and Vasospastic Angina: They reduce myocardial oxygen consumption by reducing heart rate and afterload in a coordinated manner.
• Systemic Arterial Hypertension: Especially useful in hypertensive patients with ischemic heart disease or concurrent tachyarrhythmias.

Dosage and Clinical Adjustment

Verapamil:

• Control of AF / Angina: Oral dose of 120 mg to 480 mg per day, divided into 3 or 4 immediate-release doses, or as a single daily dose using extended-release formulations.
• Arrhythmic Urgency (TSVP): 5 mg to 10 mg slowly intravenously to pass over 2 minutes; An additional 10 mg dose can be repeated after 30 minutes if hemodynamically tolerated.

Diltiazem:

• Hypertension/Angina: Oral dosage of 180 mg to 360 mg daily, preferably using extended-release formulations once daily.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Heart failure with reduced ejection fraction (HFrEF): Its potent negative inotropic effect can precipitate cardiogenic shock or acute fulminant pulmonary edema.
• Baseline severe bradycardia or second or third degree AV block without pacemaker.
• Wolff-Parkinson-White syndrome associated with atrial fibrillation: Verapamil and diltiazem preferentially block conduction in the AV node without affecting the accessory pathway, redirecting the flow of impulses through the fast anomalous pathway and precipitating lethal ventricular fibrillation.

Relative Contraindications

• Moderate arterial hypotension.
• Severe chronic constipation (very common complication with verapamil due to inhibition of calcium-dependent colonic intestinal peristalsis).

Adverse Effects and Toxicity

• Severe Constipation (Verapamil 25%): Dose-dependent, of physiological origin due to blockage of calcium channels in the smooth muscle of the colon. Requires active dietary management.
• Extreme Bradycardia and AV Block: Require initial electrocardiographic monitoring.
• Maleolar Edema and Facial Blushing: Lower intensity compared to conventional dihydropyridines.

Critical Toxicity: Risk of Hemodynamic Collapse due to Dual Use with Beta-Blockers

Concomitant intravenous or oral administration of verapamil (or diltiazem) together with a beta-blocker (such as carvedilol or metoprolol) dramatically suppresses the two main pathways of control of myocardial conduction and contraction:

Verapamil + Beta-Blocker Dual blockade of Ca²⁺ entry and Adrenergic stimulation Asystole and Cardiac Arrest

The combination is formally contraindicated in outpatient clinical practice, except in exceptional specialty situations with intensive baseline electrocardiographic monitoring.

Relevant Drug Interactions

• Potent CYP3A4 and P-glycoprotein Inhibitors and Substrates (Digoxin, Cyclosporin, Statins): Verapamil and diltiazem are potent inhibitors of CYP3A4 and P-glycoprotein (P-gp). Its concomitant use critically increases the levels of digoxin (up to a 60% to 70% increase) and statins (atorvastatin, simvastatin), increasing the risk of rhabdomyolysis and digitalis poisoning.
• Azole and Macrolide Antifungals: Increase the concentrations of verapamil and diltiazem by reciprocal inhibition of their hepatic clearance metabolism.