Diltiazem


Article Author:
Om Talreja


Article Editor:
Manouchkathe Cassagnol


Editors In Chief:
Lawrence Lee
Michael Firstenberg
Lawrence Greiten


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Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
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Heba Mahdy
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Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
10/2/2019 9:43:14 AM

Indications

Diltiazem is an oral and parenteral non-dihydropyridine calcium channel blocker. It is useful in many clinical scenarios as an antihypertensive, anti-arrhythmic, and as an anti-anginal.[1]

FDA-approved Indications:

  • Atrial arrhythmia 
  • Hypertension
  • Paroxysmal supraventricular tachycardia
  • Chronic stable angina

Diltiazem also has utility in numerous off-label indications. A select few are listed below.

Non-FDA-approved Indications[2]:

  • Anal fissures
  • Migraine prophylaxis
  • Cramps in lower leg related to rest
  • Pulmonary hypertension

Diltiazem is available in many dosage forms and strengths, making it imperative to be cautious when prescribing, dispensing, and administering this medication. There are umerous brand names for oral diltiazem (capsules and tablets), and available strengths include 30mg, 60mg, 90mg, 120mg, 180mg, 240mg, 300mg, 360mg, 420mg.

Mechanism of Action

Diltiazem is a non-dihydropyridine calcium channel blocker. Therapeutic effects occur through various mechanisms. Primarily, diltiazem inhibits the inflow of calcium ions into the cardiac smooth muscle during depolarization. Reduced intracellular calcium concentrations equate to increased smooth muscle relaxation resulting in arterial vasodilation and therefore, decreased blood pressure. Diltiazem is a potent coronary artery vasodilator and is therefore used for chronic angina and in those patients with coronary vasospasm. Vasospasm of the coronary arteries can lead to debilitating conditions such as myocardial infarction.

Diltiazem is a negative inotrope (decreased force) and negative chronotrope (decreased rate). The combination, along with coronary artery vasodilation, leads to decreased myocardial oxygen demand, decreased heart rate, and reduced blood pressure.

Administration

In the United States, diltiazem is FDA-approved as an oral and intravenous formulation. Compounded topical preparations of diltiazem are used off-label.[3][4]

Consult the package insert for the formulation you are using by brand name because pharmacokinetics vary significantly between different brands. The following represent the dosing variances by condition using generic names under various trade names.

Recommended Dosages

Hypertension

  • Diltiazem hydrochloride (various brands)
    • Initial dose:       180 mg - 240 mg once daily
    • Maximum dose: 480 mg once daily
  • Diltiazem HCl (various brands)
    • Initial dose:       120 mg - 240 mg once daily
    • Maximum dose: 540 mg once daily
  • Diltiazem HCl extended-release (various brands)
    • Initial dose:       180 mg - 240 mg once daily
    • Maximum dose:  540 mg once daily

 Chronic Stable Angina

  • Diltiazem hydrochloride (various brands)
    • Initial dose: 30 mg four times daily*
  • Diltiazem HCl (various brands)
    • Initial dose:      120 mg - 180 mg once daily
    • Maximum dose: 480 mg once daily
  • Diltiazem HCl (various brands)
    • Initial dose:      120 mg - 180 mg once daily
    • Maximum dose: 540 mg once daily
  • Diltiazem HCl extended-release (various brands)*
    • Initial dose:      180 mg once daily
  • Diltiazem HCl extended-release (various brands)
    • Initial dose:      120 mg once daily
    • Maximum dose: 480 mg once daily

Atrial Arrhythmia/Paroxysmal Supraventricular Tachycardia

  • Initial dose: IV bolus 0.25 mg/kg ABW IV over 2 minutes
    • If needed, repeat dose at 0.35 mg/kg ABW IV after 15 minutes
  • Maintenance dose: IV continuous infusion 10mg/hr
    • Increase dose at 5mg/hr to max 15mg/hr
    • Max infusion time is 24 hours 

*Increase based on clinical response to 180mg-360mg/day

Adverse Effects

Common adverse effects of diltiazem therapy include edema, bradycardia, dizziness, headache, and fatigue. Rarer, yet more severe adverse effects include congestive heart failure, myocardial infarction, and hepatotoxicity. Diltiazem is indicated for the treatment of arrhythmias and consequently the potential to worsen or create new arrhythmias such as extrasystole and AV block. 

Diltiazem is extensively metabolized through the CYP450 system and requires careful medication profile review. Concomitant use alongside potent CYP450 inhibitors may increase diltiazem concentrations leading to adverse effects even at clinically recommended doses. Concomitant administration with agents that slow cardiac conduction can further potentiate adverse effects such as AV block or bradycardia. 

Contraindications

Specific clinical scenarios are contraindicated to the use of diltiazem. Due to its mechanism of actions, patients with a systolic blood pressure of less than 90mmHg are ineligible for diltiazem pharmacotherapy. Additional contraindications include sick sinus syndrome and second/third degree AV block, without a functioning ventricular pacemaker and acute myocardial infarction with pulmonary congestion on X-ray.

Additional contraindications are in place for intravenous administration. These include concomitant or recent administration of intravenous beta blockers; cardiogenic shock; atrial fibrillation or flutter associated with an accessory bypass tract (i.e., Wolff-Parkinson-White syndrome); and ventricular tachycardia. 

Monitoring

Therapeutic monitoring includes periodic assessments of blood pressure, heart rate, and electrocardiograms. When treating hypertension and arrhythmias, objective findings are used to assess the efficacy of therapy while subjective findings, such as a patient's frequency and severity of chest pain, are used to assess efficacy when treating chronic angina. A complete blood count (CBC) lab test is also performed at baseline to track potential changes in electrolytes and kidney and liver function. 

For the treatment of hypertension during pregnancy, recommendations state to use an alternative agent as diltiazem has shown adverse fetal effects in animal studies. If a patient is controlled on diltiazem for the treatment of hypertrophic cardiomyopathy, diltiazem may be continued, but additional fetal monitoring is required. 

Additional monitoring is required when using diltiazem parenterally. When treating arrhythmias, an IV bolus is administered over two minutes. Continuous blood pressure and ECG monitoring are warranted during the bolus administration. 

Toxicity

Potential diltiazem overdose can lead to profound bradycardia and conduction delays by suppression of SA and AV nodes. These may manifest as dizziness, lightheadedness, and fatigue. Further toxicities can lead to worsened arrhythmias, hyperglycemia and end-organ dysfunction. Moderate toxicity can be treated with fluids but ACLS protocol may be required when treating severe bradycardia and hypotension.[5][6]

Diltiazem is a substrate of the CYP450 enzyme and careful monitoring is warranted when given concomitantly with inducers or inhibitors. Potent inducers/inhibitors can lead to new arrhythmias or worsen existing arrhythmias. Potent inhibitors can increase diltiazem concentration leading to mentioned toxicities. A medication profile review should be conducted when initiating new medications for patients on diltiazem.[7]

Enhancing Healthcare Team Outcomes

Diltiazem has been widely used in practice for many clinical indications. Proper dosage and frequency are essential to enhance patient care and improve outcomes. Providers should verify drug, dose, and patient factors prior to administration. One common error that occurs with diltiazem therapy is incorrect dose administered to the patient. Diltiazem is available in many brand names with differing recommended dosages and differing maximum daily doses. Double-checking doses can help ensure the patient is being therapeutically managed in both the inpatient and outpatient setting. Pharmacists and other providers should also check for potential drug interactions with other medications of the patient's profile. This will limit the potential drug interactions. 

Diltiazem possesses negative inotropic effects and is generally avoided in patients with congestive heart failure, but diltiazem is also on the Beers Criteria. This highlights the importance to avoid diltiazem in heart failure patients, especially in the elderly, due to potential fluid retention and heart failure exacerbation. 


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Diltiazem - Questions

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Which antihypertensive agent is not associated with elevated lipid levels?



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A patient on telemetry is receiving several medications, including a diltiazem 30 mg by mouth, three times a day. The electrocardiogram on telemetry shows a second-degree AV block type II, with a rate of 48 beats per minute. Which of the following is the most appropriate action?



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Which antihypertensive agent can cause severe constipation?



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Which of the following medications has a negative inotropic effect?



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Which of the following calcium channel blockers have negative chronotropic properties?



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Which of the following should be monitored in a patient who is taking diltiazem?



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



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Which directly affects the cardiovascular system?



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Which of the following generic drugs is branded as Cardizem?



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Diltiazem is in which drug class?



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Diltiazem - References

References

Weiner DA,Cutler SS,Klein MD, Efficacy and safety of sustained-release diltiazem in stable angina pectoris. The American journal of cardiology. 1986 Jan 1     [PubMed]
Islam S,Masiakos P,Schnitzer JJ,Doody DP,Ryan DP, Diltiazem reduces pulmonary arterial pressures in recurrent pulmonary hypertension associated with pulmonary hypoplasia. Journal of pediatric surgery. 1999 May     [PubMed]
Knight JS,Birks M,Farouk R, Topical diltiazem ointment in the treatment of chronic anal fissure. The British journal of surgery. 2001 Apr     [PubMed]
Sajid MS,Whitehouse PA,Sains P,Baig MK, Systematic review of the use of topical diltiazem compared with glyceryltrinitrate for the nonoperative management of chronic anal fissure. Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 2013 Jan     [PubMed]
Levine M,Boyer EW,Pozner CN,Geib AJ,Thomsen T,Mick N,Thomas SH, Assessment of hyperglycemia after calcium channel blocker overdoses involving diltiazem or verapamil. Critical care medicine. 2007 Sep     [PubMed]
Ahmad S, Diltiazem and hyperglycemia-coma. Journal of the American College of Cardiology. 1985 Aug     [PubMed]
St-Onge M,Dubé PA,Gosselin S,Guimont C,Godwin J,Archambault PM,Chauny JM,Frenette AJ,Darveau M,Le Sage N,Poitras J,Provencher J,Juurlink DN,Blais R, Treatment for calcium channel blocker poisoning: a systematic review. Clinical toxicology (Philadelphia, Pa.). 2014 Nov     [PubMed]

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