Amlodipine is a long-acting dihydropyridine calcium channel blocker used mainly to treat high blood pressure and some forms of chest pain. It was initially approved by the FDA in 1987 according to one database, although other sources give different dates (see History and regulation). It was developed at Pfizer, which first patented it in 1982 and sold it under the brand name Norvasc.
Chemistry and stereochemistry
Patent literature describes amlodipine as a 1,4-dihydropyridine bearing a 2-chlorophenyl group and an aminoethoxymethyl side chain. Racemic amlodipine contains (R)- and (S)-isomers in a 1:1 ratio, but the (S)-isomer is the only one with calcium channel blocking activity. Pharmacological data are consistent with this: the (−) isomer has been reported to be more active than the (+) isomer. Single-enantiomer products have therefore been developed, including levamlodipine and an (S)-amlodipine formulation, which is discussed under enantiomers and Adverse effects.
The salt form also changed during development. Patents indicate that the maleate was initially preferred, but amlodipine maleate suffered from tabletting and stability problems, and the commercial product uses the besylate salt instead.
Pharmacology
Mechanism of action
Amlodipine acts as a dihydropyridine calcium antagonist, reducing calcium entry into membrane-bound ion channels in vascular smooth muscle and cardiac muscle. Laboratory data suggest it occupies both dihydropyridine and non-dihydropyridine binding sites on cell membranes. Contraction in both tissue types depends on extracellular calcium passing through ion channels, so blocking this flow reduces contractile activity.
The drug is more selective for blood vessels than for the heart. Its effect on vascular smooth muscle is greater than its effect on cardiac muscle, which explains why its main clinical effect is on arterial tone. Reduced peripheral resistance lowers both systolic and diastolic pressure, through blockade of calcium channels in smooth muscle that produces peripheral vasodilation.
Its kinetics are also distinctive. At physiological pH it is partly ionized, and it associates with and dissociates from its receptor slowly, which produces a gradual onset of action. Compared with nifedipine, its onset is generally slower and its duration longer.
Mechanism in angina
The mechanisms underlying its antianginal effect are not fully worked out. One explanation is that in exertional angina, amlodipine reduces total peripheral resistance against which the heart works, lowering myocardial oxygen demand at a given level of exercise. Amlodipine has also been reported to release nitric oxide in animal coronary microvessels, but this is a preclinical finding.
Pharmacokinetics and metabolism
Amlodipine's long half-life supports once-daily dosing. Reported values vary: one source gives a biological half-life of some 35-40 hours, while another gives 35–50 hours. Its metabolites are generally considered to have little calcium-blocking activity. It is metabolized by CYP3A4 and CYP3A5, so interactions with other drugs are a recognized concern. Calcium channel blockers as a class may have additive effects with other drugs such as beta blockers and other antihypertensives.
Clinical uses
Hypertension
Amlodipine is indicated to lower blood pressure, alone or with other antihypertensive drugs. Lower arterial pressure is linked to fewer strokes and heart attacks, the main cardiovascular events that treatment aims to prevent. A review article in PMC describes amlodipine as a first-line antihypertensive agent, with particular emphasis on stroke prevention. This classification is an interpretation by one review and is not a universal position.
Angina and coronary artery disease
Labeled angina uses include the symptomatic treatment of chronic stable angina and vasospastic angina (Prinzmetal's or variant angina). The drug is used in coronary artery disease management, and its use is often combined with other antianginal agents.
Other uses
Patent documents mention possible roles in congestive heart failure and migraine. These are not core labeled indications and reflect speculative or preclinical claims rather than established clinical practice.
Dosing
The usual starting dose is 5 mg and the maximum daily dose is 10 mg. A lower starting dose is used in the elderly and in patients with hepatic failure.
Adverse effects
Peripheral edema
Peripheral edema is the most frequently reported adverse effect and a common reason for changing therapy. It usually starts in the ankles and feet. In one pooled analysis, edema occurred in 16.6% of patients given amlodipine versus 6.2% given placebo. Edema is dose-related: low and medium doses (2.5–5 mg) resulted in lower rates of edema than the 10 mg dose. Rates also differ by sex, with one dataset reporting that edema occurred in 14.6% of female patients compared to 5.6% of male patients.
The same meta-analysis estimated that the placebo-adjusted rate was 63%, indicating that 37% of edema cases were unrelated to amlodipine. Its authors concluded that up to one-third of edema cases on amlodipine might not be induced by amlodipine. A consumer-health source proposes that the drug relaxes arteries more than veins, allowing fluid to shift into surrounding tissues; this is a proposed mechanism, not an established finding.
Other effects
Common effects include headache, edema, rash, fatigue, and dizziness, along with flushing and palpitations. In the meta-analysis, the incidence of headache was lower on amlodipine than on placebo, mainly at low and medium doses. Serious reactions are rare: erythema multiforme, Stevens-Johnson syndrome, and similar severe skin reactions are listed as very rare. Both weight gain and weight loss have been reported, but the incidence of either is less than one percent.
Formulations and enantiomer studies
Single-enantiomer products aim to retain the therapeutic effect with fewer side effects. In a randomized, double-blind trial in Sri Lanka, addition of (S)-amlodipine besylate at half the dose of conventional amlodipine provided better tolerability with reduced incidence of peripheral edema, and equal antihypertensive efficacy. The trial was limited in size and its findings have not been established as a general conclusion. Levamlodipine, the (S)-enantiomer, has also been studied: controlled clinical trials showed that levamlodipine is rarely associated with these side effects.
Combination products include amlodipine with telmisartan and perindopril, and brand names such as Azor, Caduet, and Exforge.
History and regulation
Amlodipine emerged from pharmacological work on calcium channel blockers, which began with the screening of coronary dilators. Pfizer developed amlodipine, followed by other dihydropyridines, and the compound was studied in the late 1980s. Patent literature notes that it was approved as a prescription drug in 1990 under the brand name Norvasc.
Sources give different approval dates. DrugBank lists first approvals in Canada in 2006, the United States in 1992, and the European Union in 2016, while another database cites 1987 for FDA approval. These discrepancies likely reflect differences in what each source counts as approval, and the earlier dates in the list above are more consistent with patent records.
Amlodipine is widely prescribed. One patent review notes that its efficacy and long half-life have made it one of the most broadly prescribed anti-hypertensive drugs worldwide. Its patent history includes many formulation and process patents, and such patents have been linked to novel preparation processes to achieve higher yields, reduced costs, and improved purity.
Open questions
Several aspects remain debated or incompletely characterized. The mechanism of its antianginal action is not fully elucidated, and the attribution of edema to amlodipine itself is contested, as the meta-analysis above suggests. The comparative benefit of single-enantiomer formulations rests on limited trials. Evidence for uses beyond hypertension and angina is mostly preclinical or drawn from patent documents rather than controlled clinical studies.
References
- Amlodipine: Uses, Interactions, Mechanism of Actiongo.drugbank.com
- (PDF) The Review: The Discovery and Development of Amlodipine Drugresearchgate.net
- Leg edema with (S)-amlodipine vs conventional amlodipine given in triple therapy for hypertension: a randomized double blind controlled clinical trialncbi.nlm.nih.gov
- Methods of pharmacological treatment using S(−) amlodipineimage-ppubs.uspto.gov
- Amide derivative of amlodipineimage-ppubs.uspto.gov
- Methods for treating hypertension and angina using salts of optically pure (−) amplodipineimage-ppubs.uspto.gov
- amlodipine [TUSOMtmedweb.tulane.edu
- Amlodipine in hypertension: a first-line agent with efficacy for improving blood pressure and patient outcomes - PMCpmc.ncbi.nlm.nih.gov
- Amlodipine: Package Insert / Prescribing Information / MOAdrugs.com
- Amlodipine Side Effects: Common, Severe, Long Termdrugs.com
- Peripheral edema and headache associated with amlodipine treatment: a meta-analysis of randomized, placebo-controlled trials - PubMedpubmed.ncbi.nlm.nih.gov
- Amlodipine Besylate Side Effects: Why You Swell & Urgent Next Stepsubiehealth.com
- Amlodipine side effects and how to avoid themsinglecare.com
- Levamlodipineen.wikipedia.org
- Calcium Channel Blockersfrontiersin.org
- The patent landscape of Amlodipinesynapse.patsnap.com
- Amlodipine (Norvasc): Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMDwebmd.com
- REVIEW published: 29 May 2017 doi: 10.3389/fphar.2017.00286frontiersin.org
- 14 Amlodipine Side Effects You Should Know About - GoodRxgoodrx.com