Amlodipine - Drug Monograph

Introduction

Amlodipine is a widely prescribed dihydropyridine calcium channel blocker used primarily in the management of hypertension and chronic stable angina. As a third-generation calcium channel antagonist, it offers several advantages over earlier agents, including once-daily dosing, excellent oral bioavailability, and a favorable side effect profile. First approved by the FDA in 1992, amlodipine has become one of the most commonly prescribed antihypertensive medications worldwide due to its efficacy, safety profile, and convenient dosing regimen.

Mechanism of Action

Amlodipine exerts its therapeutic effects by selectively inhibiting the transmembrane influx of calcium ions through L-type voltage-gated calcium channels in vascular smooth muscle and cardiac muscle. This inhibition produces:

• Peripheral arterial vasodilation resulting in reduced peripheral vascular resistance
• Coronary artery vasodilation increasing myocardial oxygen delivery
• Reduced afterload without significantly affecting cardiac contractility or conduction

Unlike non-dihydropyridine calcium channel blockers (verapamil, diltiazem), amlodipine has minimal effects on cardiac conduction and contractility at therapeutic doses, making it primarily a vasodilator.

Indications

• Hypertension (alone or in combination with other antihypertensive agents)
• Chronic stable angina
• Vasospastic angina (Prinzmetal's or variant angina)

• Raynaud's phenomenon
• Diabetic nephropathy (as part of antihypertensive regimen)
• Heart failure with preserved ejection fraction (selected patients)

Dosage and Administration

• Initial dose: 2.5-5 mg orally once daily
• Maintenance dose: 5-10 mg once daily
• Maximum dose: 10 mg daily

• Initial dose: 5-10 mg orally once daily
• Elderly or hepatic impaired: Start with 5 mg daily

• Geriatric patients: Initiate with 2.5 mg daily
• Hepatic impairment: Start with 2.5 mg daily, titrate cautiously
• Renal impairment: No dosage adjustment required
• Pediatric patients (6-17 years): 2.5-5 mg once daily

• May be taken with or without food
• Tablets should be swallowed whole
• Consistent timing daily recommended

Pharmacokinetics

• Oral bioavailability: 64-90%
• Peak plasma concentration: 6-12 hours post-dose
• Food does not significantly affect absorption

• Volume of distribution: 21 L/kg
• Protein binding: ~93%
• Steady-state achieved: 7-8 days of continuous dosing

• Extensive hepatic metabolism via CYP3A4
• Inactive metabolites produced

• Half-life: 30-50 hours (prolonged in elderly)
• Excretion: primarily urine (60%), feces (20-25%)
• Dialysis: Not removed by hemodialysis

Contraindications

• Hypersensitivity to amlodipine or any component of the formulation
• Severe hypotension (systolic BP <90 mmHg)
• Cardiogenic shock
• Concomitant use with strong CYP3A4 inhibitors in patients with hepatic impairment

Warnings and Precautions

Drug Interactions

• Strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin): ↑ amlodipine levels
• Cyclosporine: ↑ cyclosporine levels
• Simvastatin: ↑ simvastatin exposure

• Other antihypertensives: Additive hypotensive effects
• Sildenafil and other PDE5 inhibitors: Enhanced hypotensive effects
• Grapefruit juice: May increase amlodipine bioavailability

Adverse Effects

• Peripheral edema (5-10%)
• Headache (7%)
• Fatigue (4%)
• Dizziness (3%)
• Flushing (2%)
• Palpitations (2%)

• Severe hypotension
• Myocardial infarction
• Arrhythmias
• Allergic reactions including angioedema
• Hepatitis
• Gingival hyperplasia (long-term use)

Monitoring Parameters

• Blood pressure (standing and supine)
• Heart rate
• Liver function tests
• Renal function
• ECG (if cardiac disease suspected)

• Blood pressure at 2-4 week intervals during titration
• Signs/symptoms of peripheral edema
• Liver function (periodically)
• Heart rate and rhythm
• Signs of hypotension (dizziness, syncope)

• Angina patients: Frequency of angina attacks
• Elderly patients: Orthostatic blood pressure changes

Patient Education

• Take medication at the same time each day
• Do not stop abruptly without medical supervision
• Rise slowly from sitting/lying position to prevent dizziness
• Report swelling in ankles/feet, unexplained weight gain, or shortness of breath
• Avoid grapefruit and grapefruit juice during therapy
• Use caution when driving or operating machinery until effects known
• Inform all healthcare providers about amlodipine use
• Store at room temperature away from moisture

• Continue dietary sodium restriction
• Maintain regular physical activity as tolerated
• Avoid excessive alcohol consumption
• Follow prescribed diet and weight management plans

References

1. FDA Prescribing Information: Norvasc (amlodipine besylate). 2021 2. Williams B, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021-3104 3. Chrysant SG. Amlodipine: an effective and well-tolerated antihypertensive agent regardless of age or gender. J Hum Hypertens. 2018;32(6):395-403 4. Messerli FH, et al. Dihydropyridine calcium channel blockers: a class of drugs with a potentially positive impact on the natural history of hypertension. J Clin Hypertens. 2018;20(5):871-879 5. National Institute for Health and Care Excellence (NICE). Hypertension in adults: diagnosis and management. NICE guideline [NG136]. 2019 6. Epstein BJ, Vogel K, Palmer BF. Dihydropyridine calcium channel antagonists in the management of hypertension. Drugs. 2007;67(9):1309-1327 7. Abernethy DR. The pharmacokinetic profile of amlodipine. Am Heart J. 1989;118(5 Pt 2):1100-1103 8. Mason RP, et al. Vascular and cardiac benefits of amlodipine alone and in combination. J Hum Hypertens. 2019;33(1):10-19