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]
Non-FDA-approved Indications
Amlodipine can be used as monotherapy or in combination with several different medications to manage hypertension or CAD in patients. Common combinations include:
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]
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
CAD, Chronic Stable Angina, Prinzmental Angina, CAD Documented by Angiography and Without Heart Failure or Ejection Fraction less than 40%
Patients with Hepatic Impairment
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]
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]
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]
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]
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]
[1] | Steffen HM, Use of calcium channel antagonists for the treatment of hypertension in the elderly. Drugs [PubMed PMID: 15260512] |
[2] | Mason RP, Mechanisms of plaque stabilization for the dihydropyridine calcium channel blocker amlodipine: review of the evidence. Atherosclerosis. 2002 Dec [PubMed PMID: 12417269] |
[3] | 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 PMID: 25050869] |
[4] | 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 PMID: 28290816] |
[5] | 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 PMID: 24352340] |
[6] | Perna GP,Valle G,Cianfrone N,Luca GD,Amico C,Coli C, Amlodipine in ischaemic left ventricular dysfunction with mild to moderate heart failure. Clinical drug investigation. 1998 [PubMed PMID: 18370550] |
[7] | Leonard L,Phillips WJ, Near-complete migraine prophylaxis with amlodipine: a case report. Journal of pain and symptom management. 2007 Dec [PubMed PMID: 18053876] |
[8] | Athyros VG,Katsiki N,Karagiannis A, Cardiovascular risk reduction with combination of anti-atherosclerotic medications in younger and older patients. Current medical research and opinion. 2013 Jul [PubMed PMID: 23672630] |
[9] | Teo KK,Pfeffer M,Mancia G,O'Donnell M,Dagenais G,Diaz R,Dans A,Liu L,Bosch J,Joseph P,Copland I,Jung H,Pogue J,Yusuf S, Aliskiren alone or with other antihypertensives in the elderly with borderline and stage 1 hypertension: the APOLLO trial. European heart journal. 2014 Jul [PubMed PMID: 24616335] |
[10] | Brook RD,Kaciroti N,Bakris G,Dahlöf B,Pitt B,Velazquez E,Weber M,Zappe DH,Hau T,Jamerson KA, Prior Medications and the Cardiovascular Benefits From Combination Angiotensin-Converting Enzyme Inhibition Plus Calcium Channel Blockade Among High-Risk Hypertensive Patients. Journal of the American Heart Association. 2018 Jan 4 [PubMed PMID: 29301757] |
[11] | 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 PMID: 26395174] |
[12] | 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 PMID: 27556947] |
[13] | 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 PMID: 24346990] |
[14] | 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 PMID: 28951665] |
[15] | 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 PMID: 29404362] |
[16] | 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 PMID: 10650289] |
[17] | Abernethy DR,Schwartz JB, Pharmacokinetics of calcium antagonists under development. Clinical pharmacokinetics. 1988 Jul [PubMed PMID: 3042243] |
[18] | 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 PMID: 26102977] |