Continuing Education Activity

The Food and Drug Administration (FDA) approved indications for verapamil include angina (chronic stable, vasospastic or Prinzmetal variant), unstable angina (crescendo, preinfarction), hypertension as add-on therapy, paroxysmal supraventricular tachycardia (PSVT) prophylaxis, and supraventricular tachycardia (SVT). Verapamil also has numerous non-FDA-approved indications. This activity outlines the indications, mechanism of action, administration methods, significant adverse effects, contraindications, toxicity, and monitoring, of verapamil so providers can direct patient therapy where it is indicated as part of the interprofessional team.

Objectives:

• Describe the mechanism of action of verapamil.
• Summarize the approved and off-label indications for verapamil.
• Identify the potential adverse effects associated with therapy with verapamil.
• Review interprofessional team strategies for improving care coordination and communication to properly use typhoid verapamil to improve patient outcomes for indicated conditions.

Indications

The Food and Drug Administration (FDA) Approved Indications for Verapamil are as Follows

• Angina (chronic stable, vasospastic [prinzmetal variant], unstable angina [cresendo,preinfarction]) 
• Hypertension (as add on therapy) 
• Paroxysmal supraventricular tachycardia (PSVT) prophylaxis
• Supraventricular tachycardia (SVT)

The non-FDA-approved Indications for Verapamil are as Follows

Acute Coronary Syndrome (ACS)

Given as initial treatment in patients with: (1) Non-ST elevation acute coronary syndrome(NSTE-ACS, (2) continuing or frequently recurring ischemia and are unable to use beta-blockers (e.g., contraindication, suffered from unacceptable adverse effects, beta-blockers were insufficient for treatment) in the absence of:

• Clinically significant LV dysfunction,
• Increased risk for cardiogenic shock,
• PR interval greater than 24 seconds, or
• Second or third-degree AV block without a cardiac pacemaker

Furthermore, long-acting calcium channel blockers and nitrates are recommended in patients with coronary artery spasm (short-acting calcium channel antagonists should be avoided).[1]

Cluster Headaches

Verapamil can be used as a first-line prophylactic at a minimum dosage of 240 mg per day per recommendation to reduce headache severity and decrease the frequency of episodes during a cluster period.[2]

Hypertrophic Cardiomyopathy (HCM)[3]

Recommended for the treatment of symptoms (e.g., angina or dyspnea) in patients with obstructive or non-obstructive HCM who are unable to take beta-blockers (e.g., side effects/contraindications to beta-blockers, unresponsive to beta-blockers).

• Should be initiated at a low dose and titrated up to 480 mg/day,
• Its use requires caution in patients with high gradients, advanced heart failure, or sinus bradycardia.

Idiopathic Ventricular Tachycardia (IVT)

There are reports that the chronic use of oral verapamil for verapamil-sensitive idiopathy LVT can control IVT in many patients in both adults and children.[4]

Mechanism of Action

Verapamil is a non-dihydropyridine calcium channel blocker. Calcium channel blockers inhibit the entry of calcium ions into the slow L-type calcium channels in the myocardium and vascular smooth muscle during depolarization. This inhibition will produce relaxation of coronary vascular smooth muscle as well as coronary vasodilation, which is helpful in patients with hypertension. Verapamil also increases myocardial oxygen delivery, which helps patients with vasospastic angina. Verapamil correlates with negative chronotropic effects and decreased sympathetic nervous system activity.[5][6]

Administration

Verapamil can be administered either orally (sustained release or immediate release) or intravenously. It is possible to open sustained-release verapamil capsules, and the contents are sprinkled on one tablespoon of applesauce. Patients should receive instructions to swallow immediately with a full glass of cool water. For sustained verapamil products, take with food and swallow whole (they should not be chewed or crushed). When given intravenously, verapamil administration must be over at least a two-minute timeframe. 

Hypertension

• For immediate-release formulations, the usual dose range is 120 to 360 mg/day given in three divided doses; the maximum dose is 480 mg/day.[7]
• For geriatric patients, consider lower initial doses and titrate to response.[8]
  • For immediate-release oral formulations, the initial dose is 40 mg three times daily (TID).
  • For extended-release oral formulations, give an initial dose of 120 mg once daily in the morning or 100 mg once daily at bedtime.

Angina

• For oral dosing, verapamil (immediate-release) should be given 80 mg to 160 mg three times a day (TID).[9]

Atrial Fibrillation (AF)

• Intravenous[10]
  • Administer an initial bolus of 0.075 to 0.15 mg/kg over at least 2 minutes.
  • If the patient does not produce an adequate response, administer an additional 10 mg after 15 to 30 minutes.
  • If the patient produces an adequate response to the initial (or repeat bolus) dose, initiate a continuous infusion.
• Oral[11]
  • For extended-release formulations, initiate a maintenance dose of 180 to 480 mg once daily. 
  • For immediate release formulations, initiate a dose of 240 to 480 mg daily in 3 to 4 divided doses; the maximum daily dose should be 480 mg/day.

IVT

• Intravenous 
  • Administer 2.5 to 5.0 mg every 15 to 30 minutes[12][13]
• Oral 
  • For immediate-release, formulations administer 360 mg/day in three divided doses.
  • For extended-release formulations, administer 240 to 480 mg once daily.[14][15]

Cluster Headaches

• Oral: For immediate release formulations, administer 240 mg in three divided doses; if this dose does not produce an adequate response, increase the dose by 80 mg every 1 to 2 weeks until symptoms have alleviated or adverse reactions occur.[16][17]

PSVT Prophylaxis

• Dosed orally For immediate release formulations, the usual dosage range is between 240 mg and 480 mg in 3 to 4 divided doses.[18]

Ongoing Management of SVT

• For immediate release formulations, administer an initial dose of 120 mg in divided doses; the maximum maintenance dose is 480 mg/day. 

Acute Treatment of Supraventricular Tachycardia

ACLS Guidelines

• Administer 2.5 to 5 mg over 2 minutes (over 3 minutes in geriatric patients) administer a second dose of 5 to 10 mg (approximately 0.15 mg/kg) may be given 15 to 30 minutes after the initial dose only if: the patient does not experience any adverse reactions but does not respond to initial treatment.[18]
• The maximum total dose is 20 to 30 mg.[19]

ACC/AHA/HRS SVT Guidelines

• Administer 5 to 10 mg (0.075 to 0.15 mg/kg) over 2 minutes
• If the patient has no response to this dose, a second dose can be given 30 minutes after the initial dose, followed by an infusion of 0.005 mg/kg/minute.

Adverse Effects

Adverse Effects

• Gingival hyperplasia 
• Constipation 
• Peripheral edema
• Hypotension
• Fatigue
• Dyspepsia

Precautions

• May cause first-degree AV block; higher degrees of AV block could occur in patients with sick sinus syndrome - consider a dosage reduction or discontinue verapamil therapy.[19]
• It is considered contraindicated in patients with wide complex tachycardias unless it can be proven to be supraventricular in origin; severe hypotension could occur upon administration.[20]
• Avoid use in patients with heart failure, particularly heart failure with a reduced ejection fraction, due to a higher risk than benefit in using calcium channel blockers overall.[21]
• Use with caution in patients with HCM with outflow tract obstruction, including those:
  • With high gradients
  • Advanced heart failure
  • Sinus bradycardia
  • Verapamil should not be used in those with HCM and systemic hypotension or severe difficulty breathing at rest.[22]

Pregnancy

• Verapamil can cross the placenta.
• Pregnancy Category C[23]
• Use during pregnancy may cause adverse effects on the fetus(e.g., bradycardia, heart block, hypotension)
•  Women with HCM controlled with verapamil before pregnancy may continue therapy, but it is recommended to monitor the fetus for slow heart rate, low blood pressure, and heart block.[21]
•  It may be used intravenously for the acute treatment of SVT in pregnant women when adenosine or beta-blockers are ineffective or contraindicated. Verapamil may also be used for the ongoing management of SVT in highly symptomatic patients; the recommendation is for the lowest effective dose; avoid use during the first trimester if possible.[18]
• If treatment for hypertension during pregnancy is needed, it is recommended to change to an alternative agent. (ACOG 2013)[24]

Breast-Feeding

Although verapamil is present in breast milk, the relative infant dose of verapamil is less than or equal to 1% of the weight-adjusted maternal dose, which is below the required RID limit of less than 10 %.[25][26] Therefore, breastfeeding is acceptable for verapamil, though some manufacturers are against it.[27][28][29][25]  

• The authors of several case reports calculated the RID of verapamil following maternal use of verapamil 80 to 120 mg three times daily in women less than or equal to 3 months postpartum. Adverse events were not observed in breastfed infants.

Contraindications

Oral Formulation

• If the patient has hypersensitivity to verapamil or any component in the verapamil formulation (immediate-release or extended-release)
• Severe dysfunction of the left ventricle
• Severe hypotension, defined as a systolic blood pressure reading of less than 90 mmHg or cardiogenic shock (except in patients with a functioning artificial ventricular pacemaker)
• Sick sinus syndrome and second or third-degree atrioventricular block (the main exception being in patients who have a functioning artificial ventricular pacemaker)
• Atrial flutter/fibrillation with an accessory bypass tract (Lown-Ganong-Levine syndrome, Wolff-Parkinson-White [WPW] syndrome)

Intravenous Formulation

• Severe heart failure (unless the heart failure results from a supraventricular tachycardia responsive to verapamil)
• Concomitant use of intravenous beta-blockers

Monitoring

The clinician should monitor their blood pressure, heart rate, and liver function tests for patients who are on verapamil.

Goals of Therapy

• Blood pressure is an essential indicator of how the patient with confirmed hypertension is doing with verapamil. The ASCVD risk and comorbidities of the patient require an evaluation to evaluate the specific blood pressure goal for the patient.[30]
• If the patient with confirmed hypertension has known cardiovascular disease or a 10-year ASCVD risk greater than or equal to 10%, then the recommended target blood pressure is less than 130/80 mm Hg - for patients without markers of increased ASCVD risk, a target blood pressure less than 130/80 is not a recommendation but is a reasonable goal.[30]

Special Populations

• Renal Impairment: If repeated intravenous injections are necessary for therapy, monitor blood pressure, and PR readings  
• Liver Impairment (Cirrhosis): Monitor ECG and reduce dose to:
  • 20% in oral formulations
  • 50% in intravenous formulations

Toxicity

Like all calcium channel blockers, an overdose of verapamil can lead to negative inotropic and chronotropic effects, dilation of arterial vasculature, and hypotension. Additionally, verapamil’s blockade of slow calcium channels in pancreatic beta cells can lead to inhibited insulin release, thereby causing hyperglycemia. If a patient experiences bradycardia with hypotension/metabolic acidosis and hyperglycemia is indicative of verapamil toxicity. The most serious complications from a verapamil overdose are bradycardia and hypotension, as both can lead to death if the patient is left untreated.

If a patient presents with verapamil toxicity within 1 hour, two decontamination procedures exist; gastric lavage and single-dose activated charcoal.[31][32] If a patient presents with verapamil toxicity after 1 hour of ingestion has elapsed, whole bowel irrigation using polyethylene glycol electrolyte solution is a viable decontamination procedure.[33] According to experimental and clinical studies, ipecac and cathartics have not proven beneficial decontamination procedures.[33][34][35]

Treatment of Calcium Channel Blocker Overdose[36]

Patients with symptoms should undergo treatment with the prioritization of first-line therapy. Determination of which treatment is first-line depends upon the desired effect to include:

• Intravenous calcium
• High dose insulin monotherapy (in patients with myocardial dysfunction)
• Norepinephrine or epinephrine if the patient is suffering from shock (norepinephrine is preferable in patients with vasodilatory shock)

Patients refractory to first-line therapies:

• Fat emulsion therapies
• Incremental doses of high dose insulin therapy – in patients with myocardial dysfunction
• Use of a pacemaker – in patients with unstable bradycardia/high-grade AV block without significant alteration in cardiac inotropy

Patients with refractory shock/precardiac-arrest:   

• Incremental doses of high dose insulin
• Fat emulsion therapy
• Venoarterial extracorporeal membrane oxygenation (only to be used when the refractory shock contains a significant cardiogenic component)

Administration of calcium chloride or calcium gluconate in symptomatic patients is another therapeutic alternative. Calcium chloride is used in nonacidotic patients because it delivers three times the amount of calcium than calcium gluconate. In contrast, calcium gluconate is used in acidotic patients because calcium chloride could worsen the acidosis. Both calcium formulations must have IV administration.  

Enhancing Healthcare Team Outcomes

Healthcare professionals (pharmacists, nurses, mid-level practitioners, and doctors) who prescribe and distribute this medication should be aware of the side effects and sound-alike look-alike issues between the verapamil brand names; these concerns require monitoring of heart rate and blood pressure. Pharmacists should educate patients regarding the drug's side effects and how to identify and what to do if they experience them. Further, they should keep track of other medications that the patient is taking to avoid drug-drug interactions. Pharmacists should also educate doctors and nurses on the differences between oral and IV dosing and exercise caution when converting from one route to another. When a clinician decides to switch from oral formulation to intravenous formulation, the total daily dose of verapamil will remain the same unless the strength of the formulation does not allow for direct mg for mg conversion. Therefore, nurses and clinicians should engage the pharmacist when prescribing or counseling on the dosing and administration of the various formulations, and nursing should understand this information for their counseling. This type of interprofessional communication among healthcare team members will improve outcomes using verapamil. [Level 5]