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Amlodipine

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Last Update: April 21, 2024.

Continuing Education Activity

Amlodipine, an oral dihydropyridine calcium channel blocker, demonstrates prolonged efficacy by inhibiting voltage-dependent L-type calcium channels. This action interrupts initial calcium influx, distinguishing it within its pharmacological class. With a half-life of 30 to 50 hours, amlodipine affords the convenience of once-daily dosing, contrasting with shorter-acting alternatives like nifedipine. Approved as amlodipine besylate by the FDA in 1987, this medication has since become a cornerstone in managing hypertension and related conditions. This activity discusses the indications, contraindications, and nuances of amlodipine therapy essential for interprofessional collaboration. By also discussing off-label uses, monitoring protocols, and pharmacokinetic intricacies, healthcare professionals can tailor treatment regimens to individual patient needs. Armed with a comprehensive understanding of amlodipine's pharmacology, healthcare providers are empowered to optimize therapeutic outcomes while mitigating adverse effects, thereby enhancing patient care and safety.

Objectives:

  • Identify the FDA-approved and off-label indications of amlodipine.
  • Evaluate the mechanism of action of amlodipine.
  • Assess the adverse drug reactions of amlodipine.
  • Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from amlodipine pharmacotherapy.
Access free multiple choice questions on this topic.

Indications

Amlodipine is an oral dihydropyridine calcium channel blocker. The FDA initially approved amlodipine besylate in 1987.

FDA-Approved Indications

  • Hypertension: Amlodipine is an excellent first-line choice among the multiple options of antihypertensive agents. It may be used alone or in combination with other antihypertensive agents.[1][2]
  • Chronic stable angina: Amlodipine is indicated for the symptomatic treatment of chronic stable angina. Amlodipine may be used alone or in combination with other antianginal agents.[3]  
  • Vasospastic angina (Prinzmetal or variant angina): Amlodipine is indicated to treat confirmed or suspected vasospastic angina.[4] 
  • Angiographically documented coronary artery disease (CAD): In patients with recently documented CAD by angiography and without heart failure or an ejection fraction <40%, amlodipine is indicated to reduce the risk of hospitalization from angina and reduce the risk of a coronary revascularization procedure.[5]

Off-Label Uses

  • Diabetic nephropathy [6]
  • Left ventricular hypertrophy [7]
  • Raynaud phenomenon [8]
  • Silent myocardial ischemia [9][10]
  • Group 1 pulmonary arterial hypertension (PAH): Use only in patients with idiopathic PAH and positive vasodilator testing.[11]
  • Microvascular angina: According to the 2023 AHA/ACC guideline for chronic coronary disease, amlodipine should be considered as a third-line therapy for microvascular angina (non-obstructive coronary artery disease and proven coronary microvascular dysfunction) in patients already on β-blockers.[12] 
  • Kidney transplant recipients: According to the Kidney Disease: Improving Global Outcomes (KDIGO) Management of Blood Pressure in Chronic Kidney Disease guidelines, a dihydropyridine calcium channel blocker such as amlodipine or an angiotensin receptor blocker is recommended as the first-line antihypertensive agent in adult kidney transplant recipients.[13]

Mechanism of Action

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

Amlodipine blocks the voltage-dependent L-type calcium channels, inhibiting the initial calcium influx. Reduced intracellular calcium causes decreased vascular smooth muscle contractility, increased smooth muscle relaxation, and resultant vasodilation. Additionally, amlodipine is associated with improved vascular endothelial function in patients with hypertension. Amlodipine reduces blood pressure by inducing smooth muscle relaxation and vasodilatation.[3]

Amlodipine's role in relieving stable angina involves the reduction of afterload secondary to its vasodilatory and antihypertensive properties. Reducing afterload lowers 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 spasms and restoring blood flow in the coronary arteries.[14]

Raynaud phenomenon (RP) is an excessive vascular response to cold temperature that manifests clinically by color changes of the distal skin of the digits and toes, nose, and earlobes. Amlodipine induces smooth muscle relaxation and is an effective short-term treatment for patients with Raynaud phenomenon.[15]

ACE inhibitors (ACE-Is)/angiotensin receptor blockers (ARBs) are the initial treatment of choice for diabetic nephropathy. However, clinical trials have shown that combined antihypertensive therapy with either amlodipine plus an ARBs/ACE-Is exerts a greater antiproteinuric effect in patients with type 2 diabetic nephropathy.[16][17]

ASCOT (Anglo-Scandinavian Outcome Trial) demonstrated that an amlodipine-based blood pressure regimen decreased the long-term incidence of stroke compared with atenolol, but further research is still required.[18]

Pharmacokinetics

Absorption: The absolute bioavailability of amlodipine is between 64% and 90%. Food does not alter the bioavailability of amlodipine. Peak plasma concentrations are achieved between 6 and 12 hours. Steady-state plasma levels are achieved after 7 to 8 days of daily dosing of amlodipine. Patients with hepatic dysfunction have decreased clearance of amlodipine. Accordingly, there is an increase in AUC of approximately 40% to 60% in patients with liver conditions.

Distribution: Amlodipine has high plasma protein binding (93%).

Metabolism: Amlodipine is extensively metabolized by the liver to inactive metabolites. CYP3A4 and CYP3A5 play an important role in the metabolism of amlodipine.[19][20][21]

Excretion: Amlodipine's plasma half-life is biphasic, with a terminal elimination half-life of about 30 to 50 hours, which is increased with hepatic dysfunction. Amlodipine is primarily excreted renally; 10% of the parent compound and 60% of the metabolites are excreted in the urine.

Administration

Available Dosage Forms and Strengths

Amlodipine is primarily administered orally and is available in 2.5, 5, and 10 mg tablets. Additionally, suspensions created from oral tablets are available for pediatric and older patients with difficulty swallowing. 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 having once-daily dosing.[22]

Recommended Dosages

Hypertension

  • Adults: Initial dose of 5 mg; maximum dose of 10 mg daily
  • Older and debilitated patients: Reduce initial dose to 2.5 mg; maximum dose of 10 mg daily
  • Adolescents and children aged 6 years or older: 2.5 to 5 mg once daily; maximum dose of 5 mg daily
  • Children aged 6 years old or younger: 0.05 to 0.2 mg/kg/d; maximum dose 0.3 to 0.6 mg/kg/d (up to 5 mg/d) [23]

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
  • Older and debilitated patients: The initial dose is 5 mg once daily; the maintenance dose is 10 mg once daily.[4]

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

  • Amlodipine/atorvastatin: Atorvastatin is a lipid-lowering agent that blocks cholesterol synthesis and is administered to reduce cardiovascular events.[24][25]
  • Amlodipine/aliskiren or amlodipine/aliskiren/hydrochlorothiazide: Aliskiren is a direct renin inhibitor that binds renin and prevents activating the renin-angiotensin-aldosterone system (RAAS). Hydrochlorothiazide is a thiazide diuretic that leads to a reduction in blood volume. Both combinations lower blood pressure.[26][27]
  • Amlodipine/benazepril or amlodipine/perindopril: Benazepril and perindopril are ACE inhibitors that block the conversion of angiotensin I to angiotensin II in the RAAS.[28]
  • 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.[29][30]
  • Amlodipine/valsartan/hydrochlorothiazide: A randomized controlled trial demonstrated the efficacy of triple therapy (amlodipine/valsartan/hydrochlorothiazide) for moderate or severe hypertension.[31][32]

Specific Patient Population

Hepatic impairment: Amlodipine is primarily metabolized by the liver, and the plasma elimination half-life is prolonged with impaired hepatic function; gradual titration of the dose is recommended. The initial dose is 2.5 mg once daily for hypertension or 5 mg once daily for angina. Adjust the dosage based on clinical response.[2]

Renal impairment: Renal impairment does not significantly influence the pharmacokinetics of amlodipine. Consequently, patients with renal impairment do not require dose adjustment.

Pregnancy considerations: Untreated hypertension in pregnancy increases the risk of preeclampsia, premature delivery, intrauterine growth restriction (IUGR), and intrauterine death. Chronic Hypertension and Pregnancy (CHAP) results indicate that in pregnant women with mild chronic hypertension, an approach of target blood pressure of less than 140/90 mm Hg was associated with better pregnancy outcomes than a strategy of reserving treatment only for severe hypertension.[33] Based on these findings, the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) guidelines suggest treatment with antihypertensive agents for mild chronic hypertension in pregnancy to a goal BP of <140/90 mm Hg.[34] Calcium channel blockers are widely used in pregnancy, and ACOG suggests other agents such as labetalol, nifedipine, and methyldopa.[35] However, amlodipine exposure in pregnancy does not appear to be associated with increased fetal malformations compared with other antihypertensive medications or maternal hypertension without treatment.[36] Based on a recent meta-analysis, amlodipine can also be used safely for hypertension during pregnancy.[37]

Breastfeeding considerations: Human milk levels of amlodipine are low, and plasma levels in breastfed infants are undetectable. Maternal use of amlodipine during breastfeeding has not caused any adverse effects in breastfed infants. Amlodipine is acceptable in nursing mothers.[36][38]

Pediatric patients: The efficacy and safety of amlodipine in children younger than 6 years old remain uncertain. Per the guidelines from the American Heart Association and American Thoracic Society for pediatric pulmonary hypertension, amlodipine doses should always be titrated up from a lower dose. A trial of amlodipine should be performed only in those patients who have positive acute vasoreactivity testing with nitric oxide or epoprostenol. In children with a previous history of high-altitude pulmonary edema (HAPE), amlodipine may be deemed a reasonable option for prophylaxis.[39]

Older patients: When prescribing amlodipine for older individuals, it's advisable to exercise caution, typically initiating treatment at the lower end of the dosage spectrum. This approach acknowledges the higher likelihood of impaired hepatic or cardiac function, as well as the increased incidence of accompanying diseases or concurrent medication usage. Older patients may have decreased clearance, leading to increased AUC, necessitating a lower initial dose.[2]

Adverse Effects

The significant adverse effects of amlodipine include peripheral edema, heart failure, pulmonary edema, flushing, dizziness, headache, drowsiness, skin rash, nausea, abdominal pain, and constipation. Researchers observed edema, dizziness, flushing, and palpitations in controlled clinical trials in a dose-dependent manner. For example, 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 headaches, fatigue, nausea, and abdominal pain was 7.3%, 4.5%, 2.9%, and 1.6%, respectively.[40] 

Calcium channel blockers, including amlodipine, have been linked to rare instances of idiosyncratic drug-induced liver disease. A mixed hepatocellular-cholestatic pattern is typical of amlodipine-induced liver injury.[41] Patients have complete recovery 4 to 8 weeks after stopping the drug.[42] Amlodipine-induced gingival hyperplasia is a common adverse effect. Maintaining good oral hygiene practices is beneficial for prevention. In cases where gingival hyperplasia persists despite these measures, surgical intervention may be necessary.[43]

Drug-Drug Interactions

Coadministration of amlodipine and clarithromycin or erythromycin has reportedly increased the risk of hypotension and acute kidney injury due to decreased metabolism by CYP3A4.[44] Additionally, when amlodipine is used with high doses of statins, there is an increased risk for myopathy and rhabdomyolysis.[45] The interaction with tacrolimus is described in the monitoring section.

Prescribing Cascade

It is important to note that amlodipine can cause peripheral edema. A prescribing cascade occurs when the edema is mistaken as a new medical condition, and a diuretic is consequently prescribed to treat the edema.[46]

Contraindications

Amlodipine is contraindicated in patients with known hypersensitivity to amlodipine or its dosage form components. Lymphocyte transformation test (LTT) can be used to diagnose drug allergy.[47]

Warning and Precautions

Amlodipine is contraindicated in patients with cardiogenic shock, severe aortic stenosis, unstable angina, severe hypotension, heart failure, and hepatic impairment. According to the manufacturer's labeling, patients with severe coronary artery disease may have worsening angina after initiating amlodipine therapy. In cardiogenic shock, the heart cannot pump effectively, exacerbated by inhibiting the influx of calcium ions into cardiac cells. In severe aortic stenosis, amlodipine can cause ventricular collapse and dysfunction. Amlodipine causes a reflexive increase in cardiac contractility in unstable angina, increasing myocardial oxygen demand and worsening ischemia. Amlodipine can further reduce blood pressure, causing hypoperfusion to vital organs and syncope in patients with severe hypotension.[48] Patients with heart failure may experience pulmonary edema, shortness of breath, and dyspnea with amlodipine.[49] Patients with hepatic impairment may not metabolize amlodipine effectively, leading to a longer half-life with possible increases in plasma concentrations.[50]

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 per the 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guidelines. Furthermore, the healthcare team should monitor patients for adverse effects such as peripheral edema, dizziness, and flushing.[51]

Amlodipine may increase the AUC of tacrolimus. In one study, amlodipine decreased the tacrolimus clearance by 2.2 to 3.8 fold, increasing AUC and systemic exposure in CYP3A5 expressers. Monitoring of trough blood levels of tacrolimus is recommended.[52]

Toxicity

Signs and Symptoms of Overdose

Amlodipine overdose and toxicity can lead to massive vasodilation, hypotension, and reflex tachycardia as compensatory mechanisms. Prolonged systemic hypotension can progress to shock and even death.

Management of Overdose

Activated charcoal (AC) should be administered to patients with amlodipine overdose. The hypotension usually remits intravenous (IV) fluid resuscitation, IV calcium gluconate, and vasopressor therapy with norepinephrine or dopamine. High-dose insulin is also sometimes administered as research has shown it lowers mortality and improves hemodynamics. Electrocardiographic results, vital signs, kidney function, urine output, and electrolytes require continual monitoring during an overdose.[48][53] As amlodipine has high plasma protein binding, hemodialysis is not likely to be beneficial. A recent case report describes successful resin hemadsorption/hemoperfusion treatment for amlodipine overdose, demonstrating its efficacy in resolving severe toxicity and hemodynamic instability.[54]

Enhancing Healthcare Team Outcomes

Amlodipine is a first-line choice among the myriad options of antihypertensive agents. Amlodipine has also shown robust reductions in cardiovascular endpoints (especially stroke). In addition, 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 having once-daily dosing. Therefore, healthcare providers, including physicians, nurse practitioners, physician assistants, and pharmacists, should be familiar with the indications and contraindications of amlodipine. However, the drug can cause severe hypotension in overdose; it is recommended to titrate the dose with an initial low dose gradually. In addition, long-term patient monitoring is necessary for optimal blood pressure control. The PERSONAL-CovidBP trial demonstrated that smartphone-enabled remote precision dosing of amlodipine effectively lowered blood pressure in individuals with primary hypertension during the COVID-19 pandemic.[55]

Amlodipine therapy requires the participation of the entire interprofessional healthcare team. Clinicians (MDs, DOs, NPs, PAs) and specialists will typically initiate treatment. The pharmacist should report to the clinician for potential drug interactions (eg, simvastatin or erythromycin). In addition, pharmacists should verify dosing and educate the patient about the common adverse drug reactions. The nurse should assess patient adherence and offer to counsel on medication administration. Both nursing and pharmacy staff should alert the prescriber if they encounter any issues. In an acute overdose of amlodipine, emergency physicians and triage nurses should stabilize the patient with a primary focus on circulation. In a massive overdose of amlodipine, it is important to obtain an emergency consultation with a medical toxicologist. Critical care physician supervision is necessary for patients requiring vasopressor therapy in MICU.

The interprofessional team approach can improve patient outcomes related to amlodipine therapy by maximizing efficacy and minimizing the risk of adverse drug reactions. In addition, a pragmatic randomized controlled trial indicated that team-based care (TBC) involving community pharmacists and nurses working in an interprofessional manner with clinicians could accomplish long-term blood pressure control related to antihypertensive therapy, including calcium channel blockers.[56]

Review Questions

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Disclosure: Kishen Bulsara declares no relevant financial relationships with ineligible companies.

Disclosure: Preeti Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Manouchkathe Cassagnol declares no relevant financial relationships with ineligible companies.

Copyright © 2024, StatPearls Publishing LLC.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Bookshelf ID: NBK519508PMID: 30137793

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