Continuing Education Activity

Amlodipine is an oral dihydropyridine calcium channel blocker. Amlodipine works by blocking the voltage-dependent L-type calcium channels, thereby inhibiting the initial influx of calcium. 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 who 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 drug reactions of amlodipine.
• Outline inter-professional 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. Amlodipine is available as amlodipine besylate, initially approved in 1987 by the Food and Drug Administration (FDA).

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]

Non-FDA-approved Indications

• Diabetic nephropathy[6]
• Left ventricular hypertrophy[7]
• Raynaud phenomenon[8]
• Silent myocardial ischemia[9][10]
• Group 1 pulmonary arterial hypertension(PAH)- Use only in idiopathic PAH patients with positive vasodilator testing.[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 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. 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. Additionally, amlodipine has improved vascular endothelial function in hypertensive patients. Amlodipine decreases blood pressure by inducing smooth muscle relaxation and vasodilatation.[3]

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 lowering 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.[12]

Raynaud phenomenon (RP) is an excessive vascular response to cold temperature, manifested 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's phenomenon.[13]

ACE inhibitors(ACE-I)/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-I plus exerts a greater antiproteinuric effect in patients with type 2 diabetic nephropathy[14][15]

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.[16]

Pharmacokinetics

Absorption:  The absolute bioavailability of amlodipine is between 64% and 90%. Food doesn't 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%.

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

Metabolism: Amlodipine is extensively metabolized by the liver to inactive metabolites.

Excretion: The plasma half-life of amlodipine is biphasic with a terminal elimination half-life of about 30 to 50 hours which is increased with hepatic dysfunction. The primary route of excretion is renal; 10% of the parent compound and 60% of the metabolites are excreted in the urine.

Administration

Amlodipine is primarily administered orally and is available in 2.5 mg, 5 mg, and 10 mg tablets. In addition, suspensions created from oral tablets are available for pediatric and elderly 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 the ability to have once-daily dosing.[17]

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)[18]

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[4]

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 cholesterol synthesis and is administered to reduce cardiovascular events.[19][20]
• 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.[21][22]
• Amlodipine/benazepril or amlodipine/perindopril: Benazepril and perindopril are ACE inhibitors that block the conversion of angiotensin I to angiotensin II in the RAAS.[23]
• 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.[24][25]

Use in Specific Patient Population

Patients with 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]

Patients with Renal Impairment: The pharmacokinetics of amlodipine is not significantly influenced by renal impairment. Consequently, patients with renal impairment don't require dose adjustment.

Pregnancy Considerations: Untreated hypertension in pregnancy increases the risk for pre-eclampsia, 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.[26] 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.[27] Calcium channel blockers are widely used in pregnancy, and ACOG suggests other agents such as labetalol, nifedipine, and methyldopa.[28] 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.[29] Based on a recent meta-analysis, amlodipine can also be used safely for hypertension during pregnancy.[30]

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. Consequently, amlodipine is acceptable in nursing mothers.[29][31]

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. In addition, the incidence of headaches, fatigue, nausea, and abdominal pain was 7.3%, 4.5%, 2.9%, and 1.6%, respectively.[32] 

Calcium channel blockers, including amlodipine, have been linked to rare instances of idiosyncratic drug-induced liver disease. A mixed hepatocellular-cholestatic pattern is a typical feature of amlodipine-induced liver injury.[33] Complete recovery is anticipated after stopping the drug within 4 to 8 weeks.[34] Coadministration of amlodipine and clarithromycin or erythromycin has reportedly increased the risk of hypotension and acute kidney injury due to decreased metabolism by CYP3A4.[35] Additionally, when amlodipine is used with high doses of statins, there is an increased risk for myopathy and rhabdomyolysis.[36]

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.[37]

Contraindications

Amlodipine is contraindicated in patients with known hypersensitivity to amlodipine or its dosage form components. In addition, amlodipine is relatively 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, which is 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, hypoperfusion to vital organs, and syncope in patients with severe hypotension.[38] Heart failure patients may experience pulmonary edema, shortness of breath, and dyspnea with amlodipine.[39] 

Patients with hepatic impairment may not metabolize amlodipine effectively, leading to a longer half-life with possible increases in plasma concentrations.[40]

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 side effects such as peripheral edema, dizziness, and flushing.[41]

Amlodipine may increase the AUC of tacrolimus. In one study,  amlodipine decreased the tacrolimus clearance by 2.2 to 3.8 folds, increasing AUC and systemic exposure in CYP3A5 expressers. Consequently, monitoring of trough blood levels of tacrolimus is suggested.[42]

Toxicity

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. 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 to lower mortality and improve hemodynamics. Electrocardiographic results, vital signs, kidney function, urine output, and electrolytes require continual monitoring during an overdose.[38][43] As amlodipine has high plasma protein binding, hemodialysis is not likely to be of benefit.

Enhancing Healthcare Team Outcomes

Amlodipine is an excellent 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 the ability to have once-daily dosing. Therefore, healthcare providers, including clinicians, pharmacists, nurse practitioners, etc., should be familiar with the indications and contraindications of amlodipine. However, the drug can cause severe hypotension in overdose; thus, the recommendation is to gradually titrate the dose with an initial low dose. In addition, long-term patient monitoring is necessary for optimal blood pressure control. 

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 (e.g., 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.[44] [Level 1]