Amlodipine


Article Author:
Kishen Bulsara


Article Editor:
Manouchkathe Cassagnol


Editors In Chief:
James Beauchamp
Mark Pellegrini
Nicole Hale-Crutch


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
5/15/2019 9:10:32 PM

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 is initiated 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 is 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 systemic circulation.

Amlodipine also alleviates prinzmental 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 20 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 2.5 mg once daily for hypertension or 5 mg once daily for angina. Adjust the dosage based on clinical response.

Adverse Effects

The major 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, edema, dizziness, flushing, and palpitations were observed 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 been reported to increase 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 absolutely contraindicated in patients with known hypersensitivity to amlodipine or its components. Amlodipine is relatively contraindicated and should be used with 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, leading to a longer half-life adequately [17]

Monitoring

In general, laboratory monitoring is not required 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, patients should be monitored 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 is usually alleviated by intravenous (IV) fluid resuscitation, calcium salts, and vasopressor therapy with dopamine or norepinephrine. High-dose insulin is also sometimes administered as it has been shown to lower mortality and improve hemodynamics. Electrocardiographic results, vital signs, kidney function, urine output, and electrolytes are continually monitored during an overdose.[15]

Enhancing Healthcare Team Outcomes

Healthcare workers including nurse practitioners 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 it is recommended that the patient be gradually titrated with an initial low dose. Long-term patient monitoring is necessary to determine its effectiveness.


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Amlodipine - Questions

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A 65-year old man visits his primary care provider for a routine checkup. On physical examination, his blood pressure is measured to be 149/88 mmHg. The provider decides to prescribe him amlodipine besylate, to be taken once daily. Which of the following should be discussed with the patient during medication counseling?



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To which of the following classes of medication does amlodipine belong?



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A 65-year-old woman visits her primary care provider for her annual checkup. The nurse measures her blood pressure, which comes out to be 152/89 mmHg. She has no previous history of high blood pressure, diabetes, or dyslipidemia. The provider decides to start the patient on amlodipine besylate, 5 mg once daily. How should the patient be counseled about the mechanism of action of this medication?



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At a therapeutic dose, which of the following medications has the least effect on myocardial contractility and is least useful for the management of atrial fibrillation or flutter?



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A man with a history of smoking, chronic bronchitis, and high blood pressure presents to the emergency room with a high-grade fever, rapid breathing, and a productive cough. A chest x-ray reveals a left upper lobe pneumonia. The patient currently takes amlodipine for his hypertension and was started on erythromycin to treat his pneumonia. Which of the following is true?



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A 48-year-old man with hypertension and a 30-pack-year history of smoking complains of increasing muscle pain, fatigue, weakness, and dark urine for the past two months. Labs showed markedly elevated serum creatine kinase. The patient has been regularly taking amlodipine besylate to control his blood pressure. Which of the following medications, if taken concurrently with amlodipine, may explain the patient's symptoms?



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A 44-year-old patient has been diagnosed with hypertension and has been prescribed amlodipine. The patient denies alcohol use and his liver enzymes are within normal limits. Which of the following is an appropriate dosing regimen for this patient?



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A 73-year-old male presents with a history of hypertension and chronic stable angina. He has been told in the past that he has an arrhythmia but does not know the type of arrhythmia. He recently was given a new medication to try for his hypertension and angina but cannot recall the name of the drug. A physical examination demonstrates new onset, 2+ pitting edema in the lower leg bilaterally. The mechanism of the medication he was most likely prescribed will decrease the activity of which of the following?



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A 59-year-old Indian man with a history of type 2 diabetes comes into the provider's office complaining of blurry vision, nosebleeds, and exertional chest pain for the past six months. The blood pressure is measured to be 160/94 mmHg. A CT angiogram is performed, which reveals partially occlusive coronary artery plaques. Which of the following medication regimens would be most appropriate for this patient?



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To which drug class does amlodipine belong?



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Amlodipine - References

References

Steffen HM, Use of calcium channel antagonists for the treatment of hypertension in the elderly. Drugs     [PubMed]
Mason RP, Mechanisms of plaque stabilization for the dihydropyridine calcium channel blocker amlodipine: review of the evidence. Atherosclerosis. 2002 Dec     [PubMed]
Tabur S,Oğuz E,Sabuncu T,Korkmaz H,Çelik H, The effects of calcium channel blockers on nephropathy and pigment epithelium-derived factor in the treatment of hypertensive patients with type 2 diabetes mellitus. Clinical and experimental hypertension (New York, N.Y. : 1993). 2015     [PubMed]
Lee EY,Park JK,Lee W,Kim YK,Park CS,Giles JT,Park JW,Shin K,Lee JS,Song YW,Lee EB, Head-to-head comparison of udenafil vs amlodipine in the treatment of secondary Raynaud's phenomenon: a double-blind, randomized, cross-over study. Rheumatology (Oxford, England). 2014 Apr     [PubMed]
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Ruilope LM, Fixed-Combination Olmesartan/Amlodipine Was Superior to Perindopril Amlodipine in Reducing Central Systolic Blood Pressure in Hypertensive Patients With Diabetes. Journal of clinical hypertension (Greenwich, Conn.). 2016 Jun     [PubMed]
Tang L,Gamal El-Din TM,Swanson TM,Pryde DC,Scheuer T,Zheng N,Catterall WA, Structural basis for inhibition of a voltage-gated Ca{sup}2 {/sup} channel by Ca{sup}2 {/sup} antagonist drugs. Nature. 2016 Sep 1     [PubMed]
Agarwal MA,Flatt D,Khouzam RN, The potential detrimental effects of calcium channel blockers' overdose and current available management. Annals of translational medicine. 2018 Jan     [PubMed]
Siriangkhawut M,Tansakul P,Uchaipichat V, Prevalence of potential drug interactions in Thai patients receiving simvastatin: The causality assessment of musculoskeletal adverse events induced by statin interaction. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society. 2017 Sep     [PubMed]
Gandhi S,Fleet JL,Bailey DG,McArthur E,Wald R,Rehman F,Garg AX, Calcium-channel blocker-clarithromycin drug interactions and acute kidney injury. JAMA. 2013 Dec 18     [PubMed]
Huang Q,Li Y,Sheng C,Dou Y,Zheng M,Zhu Z,Wang J, 7B.09: BLOOD PRESSURE LOWERING EFFICACY OF AMLODIPINE AND NIFEDIPINE-GITS IN AMBULATORY HYPERTENSION. Journal of hypertension. 2015 Jun     [PubMed]
de Vries RJ,van Veldhuisen DJ,Dunselman PH, Efficacy and safety of calcium channel blockers in heart failure: focus on recent trials with second-generation dihydropyridines. American heart journal. 2000 Feb     [PubMed]
Abernethy DR,Schwartz JB, Pharmacokinetics of calcium antagonists under development. Clinical pharmacokinetics. 1988 Jul     [PubMed]
Ostroumova OD,Kochetkov AI, [Effects of Amlodipine/Lisinopril Fixed-Dose Combination on Severity of Left Ventricular Hypertrophy and Parameters of Myocardial Stiffness in Patients With Hypertension]. Kardiologiia. 2016 Dec     [PubMed]

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