Diltiazem

1. Drug Name

• Generic Name: Diltiazem

• Brand Names: Cardizem, Dilacor XR, Tiazac, Tiamate, and others.

2. Drug Classification

• Class: Calcium Channel Blocker (CCB)

• Subclass: Non-dihydropyridine Calcium Channel Blocker

3. Mechanism of Action

Diltiazem is a non-dihydropyridine calcium channel blocker that exerts its effects by inhibiting the influx of calcium ions into both vascular smooth muscle and cardiac myocytes via L-type calcium channels. The detailed mechanisms include:

• Vascular Smooth Muscle Relaxation: By blocking calcium entry into vascular smooth muscle cells, diltiazem reduces the contraction of these muscles, leading to vasodilation. This results in a decrease in systemic vascular resistance, lowering blood pressure.

• Heart Rate and Contractility Reduction: In the heart, diltiazem affects calcium-dependent processes in the conduction system, particularly within the sinoatrial (SA) and atrioventricular (AV) nodes. By slowing conduction through the AV node, diltiazem reduces heart rate and the force of contraction, which is useful in managing conditions like atrial fibrillation or angina.

• Coronary Artery Vasodilation: Diltiazem causes dilation of coronary arteries, improving oxygen delivery to the myocardium, which helps relieve angina symptoms, particularly in coronary artery disease.

• Modulation of Electrical Activity: Diltiazem has antiarrhythmic properties due to its ability to slow conduction and inhibit the spontaneous firing of pacemaker cells, particularly in atrial arrhythmias.

4. Pharmacokinetics

• Absorption: Diltiazem is well absorbed after oral administration, but it undergoes significant first-pass metabolism in the liver, leading to approximately 40-60% bioavailability. Extended-release formulations help mitigate this effect and provide a sustained release of the drug.

• Distribution: Diltiazem has a moderate volume of distribution (Vd) of about 3-4 L/kg and is extensively bound to plasma proteins (about 70-80%), primarily albumin. It is distributed to the heart, liver, lungs, and kidneys.

• Metabolism: The drug is primarily metabolized in the liver by cytochrome P450 enzymes (especially CYP3A4), resulting in the formation of both active and inactive metabolites. Impaired liver function can lead to an increased concentration of diltiazem and its metabolites.

• Excretion: Diltiazem is eliminated through the liver, and its metabolites are excreted in the urine. The elimination half-life (t½) ranges from 3.5 to 9 hours for immediate-release formulations, and up to 12 hours for extended-release forms.

• Special Considerations: The drug’s pharmacokinetics can be altered by hepatic impairment, necessitating dose adjustments. In elderly patients, caution is recommended due to reduced liver function and slower drug clearance.

5. Indications

• Primary Indications:

  • Hypertension: Diltiazem is used to manage high blood pressure, either alone or in combination with other antihypertensive agents.

  • Angina Pectoris: Diltiazem is effective in treating both stable angina and vasospastic (Prinzmetal’s) angina by decreasing myocardial oxygen demand and improving coronary blood flow.

  • Atrial Fibrillation and Atrial Flutter: As a rate control agent, diltiazem is used to slow the ventricular response rate in patients with atrial fibrillation or flutter.

• Off-Label Uses:

  • Raynaud's Phenomenon: Diltiazem may be used to treat this condition by relaxing the vasospastic blood vessels and improving blood flow.

  • Supraventricular Tachycardias (SVT): Diltiazem can be used for the management of certain types of SVT due to its AV node-blocking properties.

• Special Populations:

  • Diltiazem is particularly beneficial in patients with both hypertension and concomitant arrhythmias, such as atrial fibrillation, where its ability to control heart rate provides a dual benefit.

6. Dosage and Administration

• Adult Dosing:

  • Hypertension:

    • Immediate-release: 30-60 mg orally 3-4 times daily.

    • Extended-release: 120-240 mg once daily, with a typical maximum dose of 360 mg.

  • Angina Pectoris:

    • Immediate-release: 30-60 mg orally 3-4 times daily.

    • Extended-release: 120-240 mg once daily.

  • Atrial Fibrillation/Flutter:

    • Immediate-release: 30-60 mg orally 3 times daily, titrated to effect.

    • Extended-release: 120-180 mg once daily.

• Pediatric Dosing:

  • Diltiazem can be used in children for hypertension and arrhythmias, with doses typically adjusted based on weight. Pediatric dosing usually starts with 1-2 mg/kg/day divided into 2-3 doses.

• Renal and Hepatic Impairment:

  • In patients with liver impairment, dose reduction is required. For renal dysfunction, lower doses may be necessary, and patients should be closely monitored for side effects.

• Maximum Safe Dose: The maximum dose is typically 360 mg for extended-release formulations in hypertension and angina.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity: Known allergy to diltiazem or any of its components.

  • Severe Bradycardia: Diltiazem should not be used in patients with a resting heart rate less than 40 bpm.

  • Severe Hypotension: Use is contraindicated in patients with systolic blood pressure <90 mmHg.

  • Heart Block: In patients with second- or third-degree atrioventricular block (unless they have a pacemaker).

  • Acute Myocardial Infarction (in certain settings): Diltiazem should be avoided in acute MI with concomitant severe left ventricular dysfunction.

• Relative Contraindications:

  • Heart Failure: Diltiazem should be used with caution in patients with heart failure due to its negative inotropic effect.

  • Pregnancy and Lactation: Although Category C (risk cannot be ruled out), it should only be used in pregnancy when the benefits outweigh the risks.

8. Warnings and Precautions

• Black Box Warnings: None.

• Special Warnings:

  • Bradycardia and AV Block: As a rate-limiting agent, diltiazem can cause or worsen bradycardia and AV block, particularly in patients with pre-existing conduction system disease.

  • Hypotension: Caution is needed when using diltiazem in patients with low blood pressure or those receiving other antihypertensives.

  • Liver Disease: In patients with liver disease, dose adjustments are necessary because diltiazem is metabolized extensively by the liver.

• Monitoring Parameters:

  • Blood pressure and heart rate should be monitored regularly during treatment, especially during the initiation phase and when adjusting doses.

  • Liver function tests should be monitored periodically in patients with hepatic impairment.

9. Adverse Effects

• Common Adverse Effects:

  • Peripheral edema

  • Headache

  • Dizziness

  • Flushing

  • Bradycardia

• Less Common but Clinically Significant Side Effects:

  • AV block

  • Hypotension

  • Fatigue or weakness

  • Constipation

• Rare/Serious Adverse Reactions:

  • Severe hypotension

  • Acute heart failure exacerbation

  • Severe liver toxicity

  • Gingival hyperplasia

10. Drug Interactions

• Major Drug Interactions:

  • CYP3A4 Inhibitors (e.g., ketoconazole, itraconazole, ritonavir): These can increase the plasma concentration of diltiazem by inhibiting its metabolism. Dose adjustment may be required.

  • CYP3A4 Inducers (e.g., rifampin, phenytoin): These may reduce the efficacy of diltiazem by enhancing its metabolism.

  • Beta-blockers: When used together, beta-blockers and diltiazem can result in excessive bradycardia and AV block.

  • Digoxin: Diltiazem may increase digoxin levels, increasing the risk of digoxin toxicity.

• Food-Drug Interactions:

  • Grapefruit juice can increase diltiazem plasma levels by inhibiting CYP3A4, leading to a higher risk of adverse effects.

11. Clinical Pharmacology

• Pharmacodynamics: Diltiazem’s ability to block calcium influx into vascular smooth muscle and cardiac cells leads to vasodilation and a reduction in heart rate, blood pressure, and myocardial oxygen demand. It also helps in controlling atrial fibrillation by modulating AV nodal conduction.

• Additional Effects: In addition to its cardiovascular effects, diltiazem has been shown to reduce smooth muscle tone in the bronchi, which may have a beneficial effect in certain respiratory conditions.

12. Special Populations

• Pregnancy: Category C. Diltiazem should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Lactation: It is excreted in breast milk; therefore, its use in breastfeeding mothers should be avoided unless absolutely necessary.

• Geriatrics: Older patients are at greater risk of developing adverse effects such as hypotension and bradycardia. Reduced hepatic function in the elderly may necessitate dose adjustments.

• Renal Impairment: Diltiazem requires caution and potential dose reduction in patients with severe renal impairment.

13. Therapeutic Uses

• Hypertension: Used alone or with other antihypertensive agents as a first-line therapy.

• Angina: Effective for both stable and variant angina (Prinzmetal’s angina).

• Atrial Fibrillation: Diltiazem is useful in controlling ventricular rate in patients with atrial fibrillation.

14. Monitoring and Follow-Up

• Lab Tests: Liver function tests, kidney function tests, and ECG to monitor heart rate and rhythm should be performed at regular intervals.

• Symptoms to Monitor: Report any symptoms of excessive bradycardia, hypotension, or heart failure exacerbation.

15. Overdose Management

• Symptoms: Severe bradycardia, hypotension, AV block, and dizziness.

• Treatment:

  • Supportive care, including IV fluids and vasopressors.

  • Atropine for bradycardia.

  • Temporary pacemaker may be required for severe heart block.

16. Patient Counseling Information

• Key Points:

  • Take the medication as prescribed, either with or without food.

  • Do not abruptly discontinue the medication as this may worsen angina or cause rebound hypertension.

  • Monitor your blood pressure regularly.

• Immediate Medical Attention: Seek medical attention if you experience significant dizziness, fainting, chest pain, or shortness of breath.