Continuing Education Activity

Amlodipine is an oral dihydropyridine calcium channel blocker. Compared to nifedipine and other medications in the dihydropyridine class, amlodipine has the longest half-life at 30 to 50 hours. The benefit of such a long half-life is the ability to have once-daily dosing. Amlodipine is available as amlodipine besylate, which was initially approved in 1987 by the FDA. This activity reviews the indications, contraindications, activity, adverse events, and other key elements of amlodipine in the clinical setting as relates to the essential points needed by members of an interprofessional team managing the care of patients that can benefit from amlodipine therapy.

Objectives:

• Identify the uses and indications of amlodipine, both approved and off-label.
• Describe the mechanism of action of amlodipine.
• Summarize the adverse event profile, toxicities, and contraindications for amlodipine.
• Outline interprofessional team strategies for improving care coordination and communication to advance the knowledge on amlodipine and improve outcomes.

Indications

Amlodipine is an oral dihydropyridine calcium channel blocker. Compared to nifedipine and other medications in the dihydropyridine class, amlodipine has the longest half-life at 30 to 50 hours. The benefit of such a long half-life is the ability to have once-daily dosing. Amlodipine is available as amlodipine besylate, which was initially approved in 1987 by the Food and Drug Administration (FDA).

FDA-approved Indications

Hypertension[1]

Double-blind, placebo-controlled, randomized studies have shown statistically significant placebo-corrected reductions in supine and standing blood pressures 24 hours after the administration of amlodipine

Coronary Artery Disease[2]

• Chronic stable angina
• Prinzmental angina (variant or vasospastic angina)
• CAD determined by angiography in patients without heart failure or ejection fraction less than 40%
• As shown by the results of the “Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis" (CAMELOT) trial, the use of amlodipine in patients with CAD resulted in reduced coronary revascularizations and hospital visits secondary to anginal symptoms

Non-FDA-approved Indications

• Diabetic nephropathy[3]
• Left ventricular hypertrophy[4]
• Raynaud phenomenon[5]
• Silent myocardial ischemia[6][7]

Amlodipine can be used as monotherapy or in combination with several different medications to manage hypertension or CAD in patients. Common combinations include:

• Amlodipine/atorvastatin: Atorvastatin is a lipid-lowering agent that blocks the synthesis of cholesterol and is administered to reduce cardiovascular events.[8]
• Amlodipine/aliskiren or amlodipine/aliskiren/hydrochlorothiazide: Aliskiren is a direct renin inhibitor that binds renin and prevents the activation of the renin-angiotensin-aldosterone system (RAAS). Hydrochlorothiazide is a thiazide diuretic that leads to a reduction in blood volume. Both combinations lower blood pressure.[9]
• Amlodipine/benazepril or amlodipine/perindopril: Benazepril and perindopril are ACE-inhibitors that block the conversion of angiotensin I to angiotensin II in the RAAS.[10]
• Amlodipine/olmesartan or amlodipine/telmisartan or amlodipine/valsartan: Olmesartan, telmisartan, and valsartan are angiotensin-II receptor blockers (ARBs) that inhibit the activity of angiotensin II in the RAAS.[11]

Mechanism of Action

Normally, vascular smooth muscle contraction initiates when calcium enters the cell via voltage-dependent L-type calcium channels. The calcium binds to intracellular calmodulin, which subsequently binds to and activates myosin light-chain kinase (MLCK). MLCK is responsible for the phosphorylation of myosin light-chain, ultimately leading to muscle contraction and vasoconstriction. The vascular smooth muscle contraction becomes further amplified by calcium-induced calcium release from the sarcoplasmic reticulum. This sequence of events leads to a decreased vascular cross-sectional area, increased vascular resistance, and increased blood pressure.

Amlodipine works by blocking the voltage-dependent L-type calcium channels, thereby inhibiting the initial influx of calcium. Reduced intracellular calcium leads to decreased vascular smooth muscle contractility, increased smooth muscle relaxation, and resultant vasodilation. Ultimately, this causes a decrease in blood pressure.

Amlodipine’s role in relieving stable angina is due to the lowering of afterload secondary to its vasodilatory and antihypertensive properties. Reducing afterload leads to a lowering of myocardial oxygen demand at any level of exertion as the heart does not need to work as hard to pump blood into the systemic circulation.

Amlodipine also alleviates Prinzmetal or variant angina by blocking coronary spasm and restoring blood flow in the coronary arteries.[12]

Administration

Amlodipine is primarily administered orally and is available as 2.5 mg, 5 mg, and 10 mg tablets. For pediatric patients and elderly patients with difficulty swallowing, suspensions created from oral tablets are available.

Recommended Dosages

Hypertension

• Adults: initial dose 5 mg once daily; maximum dose of 10 mg per day
• Geriatric and Debilitated Patients: reduce initial dose to 2.5 mg once daily; maximum dose of 10 mg per day
• Adolescents and Children 6 years of age or older: 2.5 to 5 mg once daily; maximum dose of 5 mg per day
• Children 6 years of age or younger: 0.05 to 0.2 mg/kg per day; maximum dose 0.3 to 0.6 mg/kg per day (up to 5 mg per day)

CAD, Chronic Stable Angina, Prinzmental Angina, CAD Documented by Angiography and Without Heart Failure or Ejection Fraction less than 40%

• Adults: initial dose 5 to 10 mg once daily
• Elderly and debilitated patients: initial dose 5 mg once daily; usual dose is 10 mg once daily

Patients with Hepatic Impairment

• Adults: initial dose of 2.5 mg once daily for hypertension or 5 mg once daily for angina. Adjust the dosage based on clinical response.

Adverse Effects

The significant adverse effects of amlodipine include peripheral edema, heart failure, pulmonary edema, flushing, dizziness, headache, drowsiness, skin rash, nausea, and abdominal pain. In controlled clinical trials, researchers observed edema, dizziness, flushing, and palpitations in a dose-dependent manner. At a dose of 10 mg, the incidence of edema, dizziness, flushing, and palpitations was 10.8%, 3.4%, 2.6%, and 4.5%, respectively. The incidence of a headache, fatigue, nausea, and abdominal pain was 7.3%, 4.5%, 2.9%, and 1.6%, respectively.

Coadministration of amlodipine and clarithromycin or erythromycin has reportedly increased the risk of hypotension and acute kidney injury due to decreased metabolism by CYP3A4.[13] Additionally, when amlodipine is used together with high doses of statins, there is an increased risk for myopathy and rhabdomyolysis.[14]

Contraindications

Amlodipine is contraindicated in patients with known hypersensitivity to amlodipine or its dosage form components. Amlodipine is relatively contraindicated, and its use requires caution in patients with cardiogenic shock, severe aortic stenosis, unstable angina, severe hypotension, heart failure, and hepatic impairment. In cardiogenic shock, the heart cannot pump effectively, and this situation is exacerbated by inhibiting the influx of calcium ions into cardiac cells.[15] In severe aortic stenosis, amlodipine can cause ventricular collapse and dysfunction. In unstable angina, amlodipine causes a reflexive increase in cardiac contractility, which increases myocardial oxygen demand and worsens the ischemia. In patients with severe hypotension, amlodipine can result in a further drop in blood pressure, hypoperfusion to vital organs, and syncope.[15] Patients who have heart failure may experience pulmonary edema, shortness of breath, and dyspnea with amlodipine.[16] Lastly, patients with hepatic impairment may not be able to metabolize amlodipine effectively, leading to a longer half-life with possible increases in plasma concentrations.[17]

Monitoring

In general, laboratory monitoring is not necessary for patients taking amlodipine. Since amlodipine is an antihypertensive medication, clinicians and patients should regularly measure blood pressure to achieve target levels as per the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guidelines. Furthermore, the healthcare team should monitor patients for adverse side effects such as peripheral edema, dizziness, flushing, among others.[18]

Toxicity

Amlodipine overdose and toxicity can lead to massive vasodilation, hypotension, and reflexive tachycardia to compensate. Prolonged systemic hypotension can progress to shock and even death. The hypotension usually remits intravenous (IV) fluid resuscitation, calcium salts, and vasopressor therapy with dopamine or norepinephrine. High-dose insulin is also sometimes administered as research has shown it to lower mortality and improve hemodynamics. Electrocardiographic results, vital signs, kidney function, urine output, and electrolytes require continual monitoring during an overdose.[15]

Enhancing Healthcare Team Outcomes

Healthcare workers, e.g., physicians, pharmacists, nurse practitioners, etc., should be familiar with the indications and contraindications of amlodipine. Compared to nifedipine and other medications in the dihydropyridine class, amlodipine has the longest half-life at 30 to 50 hours. The benefit of such a long half-life is the ability to have once-daily dosing.  The drug can cause severe hypotension, and thus, the recommendation is to dose gradually titrate the dose with an initial low dose. Long-term patient monitoring is necessary to determine its effectiveness.

Amlodipine therapy requires the participation of the entire interprofessional healthcare team. Clinicians (MD, DO, NP, PA, PharmD) and specialists will typically initiate treatment, but the pharmacist should have input regarding drug interactions (e.g., statins like simvastatin and erythromycin) and verify dosing and patient adherence. The nurse should be aware of signs of toxicity, assess patient adherence, and offer to counsel on medication administration. Both nursing and pharmacy should alert the prescriber if they encounter any issues. These are but a few examples of how a properly functioning interprofessional team can improve amlodipine therapy. [Level 5]