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Amlodipine

Amlodipine: A Cornerstone in Cardiovascular Therapy

Introduction

Amlodipine is a long-acting calcium channel blocker (CCB) commonly prescribed for hypertension, angina, and other cardiovascular conditions. It belongs to the dihydropyridine class and has gained wide popularity due to its efficacy, once-daily dosing, and favorable side effect profile. Since its approval in the late 1980s, Amlodipine has been a first-line agent in hypertension guidelines globally.

1. Chemical and Pharmacological Overview

  • IUPAC Name: 3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate

  • Molecular Formula: C20H25ClN2O5

  • Molecular Weight: 408.88 g/mol

  • Drug Class: Dihydropyridine calcium channel blocker (CCB)

  • Brand Names: Norvasc®, Istin®, Amlip®, among others

2. Mechanism of Action

Amlodipine selectively inhibits L-type calcium channels in vascular smooth muscle, resulting in vasodilation and reduced peripheral vascular resistance. It does not significantly affect the heart rate or myocardial contractility at therapeutic doses, making it distinct from non-dihydropyridine CCBs like verapamil or diltiazem.

Key Effects

  • Reduces afterload: Decreases systemic vascular resistance

  • Improves coronary blood flow: Beneficial in angina

  • Minimal reflex tachycardia: Due to its slow onset of action

3. Pharmacokinetics

Parameter Value
Bioavailability ~60–65%
Peak Plasma Time 6–12 hours
Half-life 30–50 hours (long-acting)
Protein Binding 93–98%
Metabolism Liver (CYP3A4)
Excretion Urine (90% as metabolites)

The long half-life allows for once-daily dosing, promoting better adherence.

4. Therapeutic Indications

1. Hypertension (High Blood Pressure)

  • Amlodipine is a first-line agent in many national and international guidelines.

  • Effective as monotherapy or in combination with ACE inhibitors, ARBs, or diuretics.

2. Chronic Stable Angina

  • Reduces myocardial oxygen demand by lowering blood pressure and afterload.

  • Improves exercise tolerance and reduces frequency of angina attacks.

3. Vasospastic (Prinzmetal's) Angina

  • Relieves coronary artery spasm due to its potent vasodilatory effect.

4. Coronary Artery Disease (CAD)

  • Used for symptomatic relief and BP control in patients with CAD.

5. Raynaud’s Phenomenon

  • Off-label use to reduce vasospastic episodes.

5. Dosage and Administrations

Patient Group Initial Dose Max Dose
Adults 5 mg daily 10 mg daily
Elderly 2.5–5 mg 10 mg daily
Children (6–17) 2.5 mg daily 5 mg daily

Administration Tips:

  • Take with or without food.

  • Can be taken in the morning or evening.

  • Avoid grapefruit juice (CYP3A4 interaction).

6. Combination Therapies

1. Amlodipine + Valsartan

  • Dual BP control via vasodilation and RAAS inhibition.

2. Amlodipine + Telmisartan or Olmesartan

  • Popular fixed-dose combinations for better compliance.

3. Amlodipine + Hydrochlorothiazide

  • Synergistic effects in resistant hypertension.

4. Amlodipine + Atorvastatin

  • For hypertensive patients with dyslipidemia or cardiovascular risk.

7. Side Effects and Safety Profile

Common Side Effects

  • Peripheral edema (ankle swelling)

  • Headache

  • Dizziness

  • Flushing

  • Fatigue

Serious Adverse Effects (Rare)

  • Hypotension

  • Gingival hyperplasia

  • Palpitations

  • Hepatic enzyme elevation

  • Allergic reactions

Peripheral Edema

  • Most common reason for discontinuation.

  • Can be managed by reducing dose or combining with ACE inhibitors.

8. Contraindications and Cautions

Contraindications

  • Known hypersensitivity to Amlodipine

  • Severe hypotension (SBP < 90 mmHg)

  • Cardiogenic shock

Caution In

  • Severe hepatic impairment

  • Aortic stenosis

  • Heart failure (preserved EF—use caution)

Amlodipine is generally safe in patients with renal impairment, requiring no dose adjustment.

9. Drug Interactions

Major Interactions

  • CYP3A4 inhibitors (e.g., ketoconazole, erythromycin): May increase plasma levels.

  • CYP3A4 inducers (e.g., rifampin, carbamazepine): May reduce efficacy.

  • Simvastatin: Limit simvastatin dose to 20 mg/day when co-administered.

Minimal Interaction With

  • Diuretics

  • Beta-blockers

  • Anticoagulants

10. Use in Special Populations

Pregnancy

  • Category C

  • Use only if clearly needed

  • Not considered teratogenic but lacks sufficient data

Lactation

  • Excreted in small amounts in breast milk

  • Generally considered safe by some guidelines

Elderly

  • Increased sensitivity to antihypertensive effects

  • Start at lower doses (2.5 mg)

Pediatrics

  • Approved for children 6 years and older

11. Clinical Monitoring

Parameter Frequency
Blood pressure Regularly
Heart rate At each visit
Liver enzymes (if needed) Periodically
Peripheral edema Ongoing

12. Clinical Trials and Evidence

ASCOT-BPLA Trial

  • Compared Amlodipine-based regimen vs atenolol-based.

  • Amlodipine reduced the risk of stroke and all-cause mortality.

VALUE Trial

  • Amlodipine vs valsartan in hypertensive patients.

  • Amlodipine more effective in early BP control.

ALLHAT Trial

  • Compared different classes of antihypertensives.

  • Amlodipine was non-inferior to thiazides and ACE inhibitors.

These studies highlight amlodipine's effectiveness and cardiovascular safety profile.

13. Advantages Over Other Antihypertensives

Feature Amlodipine Beta-blockers ACE Inhibitors
Dosing Frequency Once daily 1–2 times daily Once/twice daily
Onset of Action Gradual Moderate Gradual
Edema Risk Higher Low Low
Heart Rate Effects Minimal ↓ HR Minimal
Bronchospasm Risk None Present None

14. Generic Availability and Cost-Effectiveness

Amlodipine is off-patent, widely available, and inexpensive. It is on the WHO Model List of Essential Medicines, making it accessible in both developing and developed nations.

15. Future Prospects and Research

  • Nanoparticle formulations for improved bioavailability

  • Amlodipine in fixed-dose polypills for better cardiovascular prevention

  • Ongoing research into antioxidant and anti-inflammatory properties

Its role may extend beyond blood pressure control into areas like endothelial function and microvascular protection.

Conclusion

Amlodipine is a cornerstone drug in modern cardiovascular therapy. Its combination of efficacy, safety, affordability, and simplicity of use makes it one of the most prescribed antihypertensives worldwide. Whether used alone or in combination, it continues to demonstrate excellent outcomes in blood pressure control, angina relief, and cardiovascular risk reduction. Its favorable profile across various patient populations—from young hypertensives to elderly with comorbidities—ensures its relevance well into the future.