Mechanism of action
Amlodipine selectively inhibits L-type voltage-gated calcium channels located primarily in vascular smooth muscle cells. By blocking calcium influx, it prevents smooth muscle contraction and produces sustained arterial vasodilation. This reduces systemic vascular resistance and lowers blood pressure without significantly affecting cardiac contractility or conduction.
Unlike non-dihydropyridines (verapamil, diltiazem), amlodipine has high vascular selectivity and minimal direct cardiac effects. It does not suppress sinoatrial or atrioventricular node function at therapeutic doses. The drug reduces myocardial oxygen demand by decreasing afterload and also dilates coronary arteries, making it effective for both hypertension and angina.
Amlodipine has a very long half-life (30-50 hours), allowing once-daily dosing and producing gradual onset of action that minimizes reflex tachycardia. Its slow onset distinguishes it from short-acting dihydropyridines like immediate-release nifedipine.
- Amlodipine peripheral edema is from arteriolar dilation increasing capillary pressure, not fluid retention; diuretics are ineffective
- Short-acting dihydropyridines (immediate-release nifedipine) cause reflex tachycardia; amlodipine's long half-life minimizes this. Non-dihydropyridines (diltiazem, verapamil) slow heart rate and suppress AV conduction
- Unlike non-dihydropyridines, amlodipine does not cause bradycardia, AV block, or negative inotropy
- Long half-life (30-50 hours) allows once-daily dosing and prevents reflex tachycardia
- Limit simvastatin to 20 mg daily when combined with amlodipine to avoid rhabdomyolysis
- CYP3A4 inhibitors (grapefruit juice, azoles, macrolides) significantly increase amlodipine levels
- Safe in systolic heart failure (PRAISE, ALLHAT trials) unlike verapamil and diltiazem
- Effective for vasospastic (Prinzmetal) angina due to coronary artery dilation
- Contraindicated in severe aortic stenosis due to risk of hypotension and coronary hypoperfusion
Indications
Hypertension: Amlodipine is a first-line agent for essential hypertension, effective as monotherapy or in combination with other antihypertensives. It is particularly useful in elderly patients and those with isolated systolic hypertension.
Chronic stable angina: Reduces frequency of anginal episodes and improves exercise tolerance by decreasing myocardial oxygen demand and increasing coronary blood flow.
Vasospastic angina (Prinzmetal angina): Effective due to its coronary vasodilatory properties, preventing coronary artery spasm.
Combination therapy: Frequently combined with ACE inhibitors, ARBs, or diuretics for better blood pressure control. The combination with an ACE inhibitor or ARB may reduce amlodipine-induced peripheral edema.
Amlodipine is not indicated for acute coronary syndromes or acute hypertensive emergencies due to its gradual onset of action.
Pharmacokinetics
Absorption: Well absorbed after oral administration with bioavailability of approximately 64-90%. Food does not significantly affect absorption. Peak plasma concentrations occur 6-12 hours after dosing.
Distribution: Highly protein-bound (97-98%), primarily to albumin. Large volume of distribution reflects extensive tissue penetration.
Metabolism: Extensively metabolized in the liver by CYP3A4 to inactive metabolites. No active metabolites contribute to pharmacologic effect.
Elimination: Very long elimination half-life of 30-50 hours enables once-daily dosing and provides smooth blood pressure control over 24 hours. Approximately 60% excreted in urine as metabolites, 10% as unchanged drug.
Special populations: Half-life is prolonged in elderly patients and those with hepatic impairment, requiring dose reduction. Renal impairment does not significantly alter pharmacokinetics, and dose adjustment is generally not necessary. Amlodipine is not removed by hemodialysis.
Adverse effects
Peripheral edema (5-30%): The most common adverse effect, dose-dependent and more frequent at higher doses. Results from preferential arteriolar dilation causing increased capillary hydrostatic pressure without corresponding venodilation. This is not due to fluid retention, so diuretics are typically ineffective. Edema is usually bilateral, non-pitting, and most prominent in ankles and feet.
Headache (7-10%): Due to cerebral vasodilation, usually transient and improves with continued therapy.
Flushing (2-3%): Sensation of warmth, particularly facial flushing, from cutaneous vasodilation.
Dizziness and fatigue (3-5%): Related to blood pressure reduction.
Palpitations (1-4%): May occur due to reflex sympathetic activation, though less common than with short-acting dihydropyridines.
Gingival hyperplasia (rare): Overgrowth of gum tissue, reversible with discontinuation. Mechanism involves altered calcium regulation in fibroblasts.
Hypotension: Excessive blood pressure lowering may occur, especially when combined with other antihypertensives.
Amlodipine does not cause negative inotropic effects, bradycardia, or AV block at therapeutic doses, distinguishing it from non-dihydropyridine calcium channel blockers.
Contraindications and warnings
Absolute contraindications:
- Known hypersensitivity to amlodipine or other dihydropyridines
- Severe aortic stenosis (vasodilation may precipitate hypotension and reduced coronary perfusion)
- Cardiogenic shock
- Severe hypotension
Use with caution in:
- Heart failure: While amlodipine is relatively safe in heart failure (neutral effect in PRAISE and ALLHAT trials), monitor for worsening symptoms. It does not have the negative inotropic effects of non-dihydropyridines.
- Hepatic impairment: Reduced clearance requires lower initial doses and slower titration.
- Severe coronary artery disease: Rarely, acute hypotension may precipitate myocardial ischemia.
Pregnancy: Category C. Animal studies show adverse fetal effects at high doses. Use only if potential benefit justifies potential risk. Limited human data available.
Breastfeeding: Excreted in breast milk. Consider risks and benefits.
Elderly: Increased bioavailability and longer half-life may necessitate lower starting doses.
Amlodipine does not have a black box warning.
Drug interactions
CYP3A4 inhibitors: Strong inhibitors (ketoconazole, itraconazole, ritonavir, clarithromycin, grapefruit juice) increase amlodipine levels significantly, increasing risk of hypotension and edema. Monitor blood pressure and consider dose reduction.
CYP3A4 inducers: Rifampin, carbamazepine, phenytoin may decrease amlodipine levels and reduce efficacy.
Simvastatin: Amlodipine inhibits CYP3A4-mediated metabolism of simvastatin. Limit simvastatin dose to 20 mg daily when used with amlodipine to reduce risk of myopathy and rhabdomyolysis.
Other antihypertensives: Additive blood pressure-lowering effects with ACE inhibitors, ARBs, beta-blockers, and diuretics. This is often therapeutic but monitor for excessive hypotension.
Sildenafil and other PDE-5 inhibitors: Additive vasodilatory effects may cause significant hypotension. Use caution and consider dose reduction of PDE-5 inhibitor.
Cyclosporine and tacrolimus: Amlodipine may increase levels of these immunosuppressants. Monitor drug levels closely.
Amlodipine does not significantly interact with digoxin, warfarin, or cimetidine. It does not affect heart rate or conduction, so it can be safely combined with beta-blockers without risk of bradycardia or heart block.
Clinical pearls
- Peripheral edema mechanism: Remember that amlodipine edema is due to increased capillary hydrostatic pressure from arteriolar dilation without venodilation. Diuretics are ineffective; adding an ACE inhibitor or ARB helps by promoting venodilation.
- No myocardial depression: Unlike verapamil and diltiazem, amlodipine does not cause negative inotropy, making it safe in systolic heart failure (PRAISE and ALLHAT trials).
- Slow onset: The long half-life means full therapeutic effect takes 5-7 days. Do not escalate doses too quickly. This also means missed doses have minimal impact on blood pressure control.
- No reflex tachycardia: The slow onset prevents the significant reflex tachycardia seen with immediate-release nifedipine.
- Simvastatin interaction: Always remember to limit simvastatin to 20 mg daily when prescribing with amlodipine.
- Combination therapy: Amlodipine is frequently combined with ACE inhibitors or ARBs (renin-angiotensin system blockers) for synergistic blood pressure control and potential reduction in peripheral edema.
- Not for acute situations: Never use for hypertensive emergency or acute MI due to gradual onset.
- Grapefruit juice: Advise patients to avoid grapefruit juice, which inhibits CYP3A4 and increases amlodipine levels.
Practice questions
1. A 62-year-old man with hypertension is started on amlodipine 10 mg daily. Four weeks later, he returns complaining of bilateral ankle swelling that worsens by the end of the day. Physical examination reveals non-pitting edema of both ankles. Blood pressure is well controlled at 128/78 mmHg. Serum creatinine, BUN, and urinalysis are normal. Which of the following best explains this patient's edema?
2. A 58-year-old woman with stable angina is being treated with amlodipine 5 mg daily and atorvastatin 40 mg daily. Her physician wants to switch her statin to simvastatin for cost reasons. Which of the following is the most appropriate simvastatin dose?
3. A 70-year-old man with hypertension and heart failure with reduced ejection fraction (HFrEF, EF 35%) comes for medication review. His current regimen includes lisinopril, carvedilol, spironolactone, and furosemide, but his blood pressure remains elevated at 152/88 mmHg. Which of the following calcium channel blockers would be most appropriate to add?
Frequently asked questions
How does amlodipine work?
Amlodipine works by blocking L-type calcium channels in vascular smooth muscle, preventing calcium influx and causing relaxation of arterial walls. This selective arterial vasodilation reduces systemic vascular resistance and blood pressure without significantly affecting heart rate or cardiac contractility. The drug has high vascular selectivity compared to non-dihydropyridine calcium channel blockers like verapamil, which also affect the heart.
What are the side effects of amlodipine?
The most common side effect is peripheral edema, occurring in 5-30% of patients and caused by increased capillary pressure from arteriolar dilation. Other frequent effects include headache, flushing, dizziness, and fatigue. Rare but notable side effects include gingival hyperplasia (gum overgrowth) and palpitations. Unlike non-dihydropyridine calcium channel blockers, amlodipine does not cause bradycardia or heart block.
Why does amlodipine cause swelling in legs and ankles?
Amlodipine causes leg and ankle swelling through a mechanism unrelated to fluid retention. It dilates arterioles but not veins, increasing hydrostatic pressure in capillaries and forcing fluid into interstitial tissues. This is why diuretics do not effectively treat amlodipine-induced edema. Adding an ACE inhibitor or ARB may help by promoting balanced venodilation. The edema is typically bilateral, non-pitting, and dose-dependent.
Can amlodipine be taken with beta-blockers?
Yes, amlodipine can be safely combined with beta-blockers without risk of excessive bradycardia or heart block. Unlike non-dihydropyridine calcium channel blockers (verapamil, diltiazem), amlodipine does not suppress sinoatrial or atrioventricular node function. This combination is often used in hypertension management and provides complementary mechanisms: beta-blockers reduce cardiac output and renin release, while amlodipine reduces systemic vascular resistance.
What is the difference between amlodipine and lisinopril?
Amlodipine is a calcium channel blocker that works by dilating arteries through blocking calcium channels, while lisinopril is an ACE inhibitor that blocks angiotensin II formation and reduces vasoconstriction. Amlodipine commonly causes peripheral edema and flushing, whereas lisinopril characteristically causes dry cough and hyperkalemia. Both are first-line agents for hypertension and are often combined for synergistic effect. Lisinopril provides additional renoprotection in diabetic nephropathy.
Conditions it is used for
Related drugs
Sources and further reading
DailyMed (FDA labels)StatPearls (NCBI Bookshelf)MedlinePlusWHO ATC/DDD index: C08CA01
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.