Verapamil


Article Author:
Sequoya Fahie


Article Editor:
Manouchkathe Cassagnol


Editors In Chief:
Mitchell Farrell
Brian Froelke


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
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Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
6/27/2019 12:54:49 PM

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

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,
  • Should be used with caution in patients with high gradients, advanced heart failure or sinus bradycardia.

Idiopathic Ventricular Tachycardia (IVT):

The chronic use of oral verapamil for verapamil-sensitive idiopathy LVT has been reported to 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 a decrease in 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 sprinkled on 1 tablespoon of applesauce. Patients should be instructed to swallow immediately with a full glass of cool water. For sustained Verapamil products take with food and swallow whole (should not be chewed or crushed).  When given intravenously, verapamil administration must be over at least a two-minute timeframe. 

Hypertension[7][8][7]

  • 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
  • For geriatric patients consider lower initial doses and titrate to response
    • 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[9]: 

  • Dosed orally, Verapamil (immediate release) should be given 80 mg to 160 mg three times a day (TID) 

Atrial Fibrillation (AF)[10][11]:

  • Intravenous
    • 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 does produce an adequate response to the initial (or repeat bolus) dose, then initiate a continuous infusion
  • Oral 
    • 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[12][13][14][15]:

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

Cluster Headaches[16][17]:

  • 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

PSVT prophylaxis[18]: 

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

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 [19][18][19]:

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
  • The maximum total dose is 20 to 30 mg

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[19][20][21][22]

  • May cause first-degree AV block, higher degrees of AV block could occur in patients with a sick sinus syndrome - consider a dosage reduction or discontinue verapamil therapy
  • Considered contraindicated in patients with wide complex tachycardias unless it can be proven to be supraventricular in origin; severe hypotension could occur upon administration
  • Avoid use in patients with heart failure, particularly heart failure with a reduced ejection fraction, due to a higher risk than benefit in the use of calcium channel blockers overall
  • 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

Pregnancy[23][21][18][24][18]:

  • Verapamil can cross the placenta
  • Pregnancy category C 
  • Use during pregnancy may cause adverse effects towards the fetus(e.g., bradycardia, heart block, hypotension)
  •  Women with HCM who are 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
  •  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
  • If treatment for hypertension during pregnancy is needed, it is recommended to look change to an alternative agent. (ACOG 2013)

Breast-Feeding[25][26][27][28][29]:

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 %. Therefore, breastfeeding is acceptable for verapamil[28][25][29][26], though some manufacturers are against it.  

  • The RID of verapamil was calculated by the authors of several case reports 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 contained 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 is a result of a supraventricular tachycardia responsive to verapamil) 
  • Concomitant use of intravenous beta-blockers

Monitoring

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

Goals of Therapy[30]:

  • Blood pressure is an important indicator of how the patient with confirmed hypertension is doing with verapamil. The ASCVD risk and comorbidities of the patient must be examined to evaluate the specific blood pressure goal for the patient.
  • 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 recommended, but reasonable

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 inhibition in 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 to be 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 inotropic

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 due to its delivering three times the amount of calcium than in 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, and doctors) who prescribe and distribute this medication should be aware of the side effects, sound alike look-alike issues between the verapamil brand names and monitor, heart rate and blood pressure. Pharmacists should educate patients on the side effects and what to do if they feel these side effects. 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 to use with caution when converting from one route to another. When a doctor 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. 


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Verapamil - Questions

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Which medication used for angina most often causes constipation?



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The mode of action of verapamil is blockage of which of the following?



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Which calcium channel blocker has a negative inotropic action?



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Which of the following medications is most likely to cause orthostatic hypotension in the elderly?



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Which of following medications is a class IV antiarrhythmic drug?



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Verapamil is what type of drug?



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Why is verapamil given intravenously?



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What is the mechanism of action of verapamil?



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Which of the following is a class IV antiarrhythmic agent?



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Which of the following drugs is a non-dehydropyridine calcium channel blocker?



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Which of the following cardiovascular drugs has negative chronotropic properties?



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Which of the following drugs is a class IV antiarrhythmic?



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A patient currently taking verapamil and nebivolol begins to experience shortness of breath, edema, bradycardia, and dyspnea on exertion. What is a possible cause of these symptoms?



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Verapamil and atropine are considered to have which one of the following?



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What drug treats both high blood pressure and atrial arrhythmias?



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Which antihypertensive drug product is designed to follow the human circadian rhythm?



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Which antihypertensive drug is dosed and administered based on circadian rhythm?



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In which drug class does verapamil belong?



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Verapamil - References

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