Nifedipine

1. Drug Name

  • Generic Name: Nifedipine

  • Brand Names: Adalat, Procardia, Nifed, and others.

2. Drug Classification

  • Class: Calcium Channel Blocker (CCB)

  • Subclass: Dihydropyridine Calcium Channel Blocker

3. Mechanism of Action

Nifedipine is a dihydropyridine calcium channel blocker, primarily acting on vascular smooth muscle to induce vasodilation. It works by inhibiting the influx of calcium ions into the smooth muscle cells through L-type calcium channels. The detailed effects include:

  • Vasodilation: By blocking calcium entry into vascular smooth muscle, nifedipine causes relaxation and dilation of the blood vessels, reducing systemic vascular resistance and blood pressure. This is particularly pronounced in peripheral arterioles, leading to reduced afterload.

  • Reduction in Myocardial Oxygen Demand: Nifedipine’s vasodilatory effects lead to reduced systemic vascular resistance (afterload), which decreases the workload on the heart and helps reduce myocardial oxygen consumption. This makes nifedipine useful in angina management.

  • Coronary Artery Vasodilation: Nifedipine also causes dilation of coronary arteries, which can increase blood flow to the heart muscle and relieve symptoms of angina, especially in patients with coronary artery disease.

  • Minimal Effect on Cardiac Conduction: Nifedipine primarily affects the vasculature rather than the heart itself. Unlike non-dihydropyridine CCBs (e.g., verapamil, diltiazem), nifedipine has minimal effect on heart rate or AV nodal conduction.

4. Pharmacokinetics

  • Absorption: Nifedipine is well absorbed after oral administration, but it undergoes significant first-pass metabolism in the liver, resulting in about 45-65% bioavailability. Extended-release formulations are available to reduce peak-trough fluctuations and provide a more sustained effect.

  • Distribution: Nifedipine has a high volume of distribution (Vd) of about 1-3 L/kg and is extensively bound to plasma proteins (approximately 90-98%), particularly albumin. It is distributed widely to tissues, including the heart and lungs.

  • Metabolism: Nifedipine is extensively metabolized in the liver by cytochrome P450 enzymes (particularly CYP3A4) to inactive metabolites. Liver dysfunction can lead to decreased clearance and higher plasma concentrations of nifedipine.

  • Excretion: The drug is primarily excreted in the urine as inactive metabolites. Its half-life (t½) is about 2-5 hours for immediate-release formulations, and up to 8 hours for extended-release preparations.

  • Special Considerations: The plasma concentration of nifedipine can be significantly altered by hepatic impairment, so dose adjustments are necessary in patients with liver disease. Renal dysfunction has less impact on nifedipine metabolism but should still be monitored.

5. Indications

  • Primary Indications:

    • Hypertension: Nifedipine is used to manage hypertension by relaxing blood vessels, which lowers blood pressure.

    • Angina Pectoris: It is used for both chronic stable angina and vasospastic angina (Prinzmetal’s angina), by reducing myocardial oxygen demand and improving coronary blood flow.

  • Off-Label Uses:

    • Raynaud’s Phenomenon: Nifedipine can help relieve the symptoms of Raynaud’s phenomenon, where blood vessels in the fingers and toes constrict, leading to color changes and pain.

    • Premature Labor: Nifedipine has been used off-label for its tocolytic effects to delay premature labor by relaxing uterine smooth muscle.

  • Special Populations:

    • Nifedipine is particularly useful in patients who have concomitant hypertension and angina, especially when other classes of antihypertensives (e.g., ACE inhibitors, beta-blockers) are not tolerated or contraindicated.

6. Dosage and Administration

  • Adult Dosing:

    • Hypertension:

      • Immediate-release: 10-20 mg orally 3 times daily, adjusted based on clinical response. The maximum dose is 120 mg daily.

      • Extended-release: 30-60 mg once daily, with a typical maximum dose of 120 mg daily.

    • Angina Pectoris:

      • Immediate-release: 10-20 mg orally 3 times daily.

      • Extended-release: 30-60 mg once daily.

  • Pediatric Dosing:

    • Use in children is limited, but the typical pediatric dose for hypertension is 0.25 mg/kg to 1 mg/kg per day, based on clinical need.

  • Renal and Hepatic Impairment:

    • In patients with liver impairment, the dose should be reduced, particularly for the immediate-release form. Nifedipine should be used with caution in patients with renal dysfunction, as the drug is eliminated primarily through the liver.

  • Maximum Safe Dose: The maximum dose is typically 120 mg/day for both hypertension and angina, though the exact dose may vary based on individual patient needs.

7. Contraindications

  • Absolute Contraindications:

    • Hypersensitivity: Known hypersensitivity to nifedipine or other dihydropyridine calcium channel blockers.

    • Severe Hypotension: Nifedipine should not be used in patients with a systolic blood pressure less than 90 mmHg.

    • Cardiogenic Shock: Nifedipine is contraindicated in patients in a state of shock due to its vasodilatory effects.

    • Acute Myocardial Infarction (IM) or Unstable Angina (immediate-release form): The use of immediate-release nifedipine in acute MI or unstable angina may lead to a reflex tachycardia, exacerbating myocardial ischemia.

  • Relative Contraindications:

    • Heart Failure: Nifedipine should be used cautiously in patients with heart failure, as it can cause reflex tachycardia and worsen symptoms in some cases.

8. Warnings and Precautions

  • Black Box Warnings: None.

  • Special Warnings:

    • Hypotension: Nifedipine can cause a significant drop in blood pressure, especially in patients who are already on antihypertensive therapy or those with renal or hepatic impairment.

    • Reflex Tachycardia: In the immediate-release form, nifedipine can cause a reflex tachycardia, potentially exacerbating angina in some patients.

    • Gingival Hyperplasia: Chronic use may be associated with gingival hyperplasia (overgrowth of gum tissue).

  • Monitoring Parameters:

    • Regular monitoring of blood pressure and heart rate is essential during treatment, especially after dose adjustments.

    • Monitor for signs of peripheral edema, a known side effect of nifedipine, which may require dose adjustment.

9. Adverse Effects

  • Common Adverse Effects:

    • Peripheral edema

    • Headache

    • Dizziness

    • Flushing

  • Less Common but Clinically Significant Side Effects:

    • Reflex tachycardia (especially with immediate-release formulations)

    • Gingival hyperplasia (long-term use)

    • Hypotension (especially in patients with volume depletion or who are on other antihypertensive medications)

  • Rare/Serious Adverse Reactions:

    • Acute myocardial infarction (with immediate-release forms in patients with unstable angina)

    • Severe hypotension or shock

    • Severe skin reactions (e.g., erythema, blistering)

10. Drug Interactions

  • Major Drug Interactions:

    • CYP3A4 Inhibitors (e.g., ketoconazole, ritonavir): These can increase nifedipine levels by inhibiting its metabolism. Dose adjustment may be necessary.

    • CYP3A4 Inducers (e.g., rifampin): These can reduce nifedipine efficacy by increasing its metabolism.

    • Beta-blockers: The use of beta-blockers with nifedipine may exacerbate bradycardia and hypotension.

    • Digoxin: Nifedipine can increase digoxin levels, leading to potential toxicity.

  • Food-Drug Interactions:

    • Grapefruit juice can inhibit the metabolism of nifedipine through CYP3A4 inhibition, leading to increased plasma concentrations and a higher risk of adverse effects.

11. Clinical Pharmacology

  • Pharmacodynamics: Nifedipine decreases systemic vascular resistance (afterload) and improves coronary artery perfusion. It lowers blood pressure primarily by vasodilation and reduces the myocardial oxygen demand in conditions like angina.

  • Additional Effects: It may also improve blood flow in microcirculatory areas, such as the skin or lungs, making it useful for certain microvascular conditions.

12. Special Populations

  • Pregnancy: Category C. Nifedipine should only be used during pregnancy when the benefits outweigh the risks, particularly in the second and third trimesters. It has been used for the treatment of preterm labor under medical supervision.

  • Lactation: Nifedipine is excreted in breast milk, but in small amounts. The risk to the infant is considered minimal, but caution is recommended for long-term use.

  • Pediatrics: Nifedipine has been used off-label for the management of hypertension in children, particularly in adolescents, with doses adjusted based on weight and clinical response.

  • Geriatrics: Older adults are more prone to hypotension, especially after the first dose. Close monitoring of blood pressure is necessary in geriatric patients.

13. Therapeutic Uses

  • Hypertension: As a first-line agent or in combination with other antihypertensive medications.

  • Angina: In the prevention and treatment of stable and vasospastic angina.

  • Raynaud’s Phenomenon: To relieve symptoms by dilating blood vessels in the fingers and toes.

14. Monitoring and Follow-Up

  • Blood pressure and heart rate should be regularly monitored, especially during dose initiation and adjustments.

  • Monitor for signs of peripheral edema, a common side effect, and adjust the dose if necessary.

15. Overdose Management

  • Symptoms: Severe hypotension, bradycardia, reflex tachycardia, dizziness, and headache.

  • Treatment:

    • Activated charcoal may be considered if within 1-2 hours.

    • Vasopressors (e.g., norepinephrine) and intravenous fluids to manage hypotension.

    • Atropine for bradycardia.

16. Patient Counseling Information

  • Key Points:

    • Take nifedipine exactly as prescribed. Do not stop the medication abruptly.

    • Monitor blood pressure regularly to ensure that it is adequately controlled.

    • Report any signs of unusual swelling in the ankles or legs, dizziness, or palpitations.

  • Immediate Medical Attention:

    • Seek emergency medical help if you experience chest pain, difficulty breathing, or severe dizziness.

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