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Amlodipine, sold under the brand name Norvasc among others, is a calcium channel blocker medication used to treat high blood pressure, coronary artery disease (CAD)<ref name=ASHP2016/> and variant angina (also called Prinzmetal angina or coronary artery vasospasm, among other names).<ref name="Goldmancecil">Template:Cite book</ref> It is taken orally (swallowed by mouth).<ref name=ASHP2016/>

Common side effects include swelling, feeling tired, abdominal pain, and nausea.<ref name=ASHP2016/> Serious side effects may include low blood pressure or heart attack.<ref name=ASHP2016/> Whether use is safe during pregnancy or breastfeeding is unclear.<ref name="Drugs.com pregnancy" /><ref name=ASHP2016/> When used by people with liver problems, and in elderly individuals, doses should be reduced.<ref name=ASHP2016/> Amlodipine works partly by vasodilation (relaxing the arteries and increasing their diameter).<ref name=ASHP2016/> It is a long-acting calcium channel blocker of the dihydropyridine type.<ref name=ASHP2016/>

Amlodipine was patented in 1982, and approved for medical use in 1990.<ref>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO23rd">Template:Cite book</ref> It is available as a generic medication.<ref name="ASHP2016">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In 2022, it was the fifth most commonly prescribed medication in the United States, with more than 70Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In Australia, it was one of the top 10 most prescribed medications between 2017 and 2023.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Medical usesEdit

Amlodipine is used in the management of hypertension (high blood pressure)<ref>Template:Cite journal</ref> and coronary artery disease in people with either stable angina (where chest pain occurs mostly after physical or emotional stress)<ref>Template:MedlinePlusEncyclopedia</ref> or vasospastic angina (where it occurs in cycles) and without heart failure. It can be used as either monotherapy or combination therapy for the management of hypertension or coronary artery disease. Amlodipine can be administered to adults and to children 6–17 years of age.<ref name="Norvasc FDA label">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Calcium channel blockers, including amlodipine, may provide greater protection against stroke than beta blockers.<ref name="Chen_2013">Template:Cite journal</ref><ref name="Mukete_2015">Template:Cite journal</ref> Evidence from two meta-analyses has reported no significant difference between calcium channel blockers, ACE inhibitors, diuretics <ref name="Iyengar_2021">Template:Cite journal</ref><ref name="Chen_2013" /> and angiotensin receptor blockers<ref name="Iyengar_2021" /> in stroke protection while one 2015 meta-analysis has suggested that calcium channel blockers offer greater protection against stroke than other classes of antihypertensive.<ref name="Mukete_2015" />

Amlodipine along with other calcium channel blockers are considered the first choice in the pharmacological management of Raynaud's phenomenon.<ref name="Baumhäkel Böhm pp. 207–214">Template:Cite journal</ref><ref name="n686">Template:Cite book</ref>

Combination therapyEdit

Amlodipine can be given as a combination therapy with a variety of medications:<ref name="ASHP2016" /><ref>Template:Cite journalTemplate:Closed access</ref>

ContraindicationsEdit

The only absolute contraindication to amlodipine is an allergy to amlodipine or any other dihydropyridines.<ref name="Norvasc FDA label" />

Other situations occur, however, where amlodipine generally should not be used. In patients with cardiogenic shock, where the heart's ventricles are not able to pump enough blood, calcium channel blockers exacerbate the situation by preventing the flow of calcium ions into cardiac cells, which is required for the heart to pump.<ref name="diseaseinter">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> While use in patients with aortic stenosis (narrowing of the aorta where it meets the left ventricle) since it does not inhibit the ventricle's function is generally safe, it can still cause collapse in cases of severe stenosis.<ref>Template:Cite journal</ref> In unstable angina (excluding variant angina), amlodipine can cause a reflex increase in cardiac contractility (how hard the ventricles squeeze) and heart rate, which together increase the demand for oxygen by the heart itself.<ref name="hitchings">Template:Cite book</ref> Patients with severe hypotension can have their low blood pressure exacerbated, and patients in heart failure can get pulmonary edema. Those with impaired liver function are unable to metabolize amlodipine to its full extent, giving it a longer half-life than typical.<ref name="Norvasc FDA label" /><ref name="Istin SmPC">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Amlodipine's safety in pregnancy has not been established, although reproductive toxicity at high doses is known. Whether amlodipine enters the milk of breastfeeding mothers is also unknown.<ref name="Norvasc FDA label" /><ref name="Istin SmPC" />

Those who have heart failure, or recently had a heart attack, should take amlodipine with caution.<ref name="amlodipine nhs.uk 2018">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Adverse effectsEdit

File:Amlodipin Sandoz bottle.jpg
Amlodipin Sandoz, bottle and pills in Sweden

Some common dose-dependent adverse effects of amlodipine include vasodilatory effects, peripheral edema, dizziness, palpitations, and flushing.<ref name="Norvasc FDA label" /><ref>Template:Cite journal</ref> Peripheral edema (fluid accumulation in the tissues) occurs at rate of 10.8% at a 10-mg dose (versus 0.6% for placebos), and is three times more likely in women than in men.<ref name="Norvasc FDA label" /> It causes more dilation in the arterioles and precapillary vessels than the postcapillary vessels and venules. The increased dilation allows for more blood, which is unable to push through to the relatively constricted postcapillary venules and vessels; the pressure causes much of the plasma to move into the interstitial space.<ref>Template:Cite journal</ref> Amlodipine-association edema can be avoided by adding ACE inhibitors or angiotensin II receptor antagonist.<ref name="ASHP2016" /> Of the other dose-dependent side effects, palpitations (4.5% at 10 mg vs. 0.6% in placebos) and flushing (2.6% vs. 0%) occurred more often in women; dizziness (3.4% vs. 1.5%) had no sex bias.<ref name="Norvasc FDA label" />

Common but not dose-related adverse effects are fatigue (4.5% vs. 2.8% with a placebo), nausea (2.9% vs. 1.9%), abdominal pain (1.6% vs. 0.3%), and drowsiness (1.4% vs. 0.6%).<ref name="Norvasc FDA label" /> Side effects occurring less than 1% of the time include: blood disorders, impotence, depression, peripheral neuropathy, insomnia, tachycardia, gingival enlargement, hepatitis, and jaundice.<ref name="Norvasc FDA label" /><ref>Template:Cite book</ref><ref>Template:Cite journal</ref>

Amlodipine-associated gingival overgrowth is a relatively common side effect with exposure to amlodipine.<ref name=Ga2018/> Poor dental health and buildup of dental plaque are risk factors.<ref name="Ga2018">Template:Cite journal</ref>

Amlodipine may increase the risk of worsening angina or acute myocardial infarction, especially in those with severe obstructive coronary artery disease, upon dosage initiation or increase. However, depending on the situation, amlodipine inhibits constriction and restores blood flow in coronary arteries as a result of its acting directly on vascular smooth muscle, causing a reduction in peripheral vascular resistance and a consequent reduction in blood pressure.<ref name=ASHP2016/>

Amlodipine and other dihydropyridine calcium channel blockers are associated with primary open angle glaucoma.<ref>Template:Cite journal</ref>

OverdoseEdit

Template:See also Although rare,<ref>Template:Cite book</ref> amlodipine overdose toxicity can result in widening of blood vessels, severe low blood pressure, and fast heart rate.<ref name="Pillay_2013">Template:Cite book</ref> Toxicity is generally managed with fluid replacement<ref>Template:Cite book</ref> monitoring ECG results, vital signs, respiratory system function, glucose levels, kidney function, electrolyte levels, and urine output. Vasopressors are also administered when low blood pressure is not alleviated by fluid resuscitation.<ref name="Norvasc FDA label" /><ref name="Pillay_2013" />

InteractionsEdit

Several drugs interact with amlodipine to increase its levels in the body. CYP3A inhibitors, by nature of inhibiting the enzyme that metabolizes amlodipine, CYP3A4, are one such class of drugs. Others include the calcium-channel blocker diltiazem, the antibiotic clarithromycin, and possibly some antifungals.<ref name="Norvasc FDA label" /> Amlodipine causes several drugs to increase in levels, including cyclosporine, simvastatin, and tacrolimus (the increase in the last one being more likely in people with CYP3A5*3 genetic polymorphisms).<ref>Template:Cite journal</ref> When more than 20 mg of simvastatin, a lipid-lowering agent, are given with amlodipine, the risk of myopathy increases.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The FDA issued a warning to limit simvastatin to a maximum dose of 20 mg if taken with amlodipine based on evidence from the SEARCH trial.<ref>Template:Cite journal</ref> Giving amlodipine with Viagra increases the risk of hypotension.<ref name="Norvasc FDA label" /><ref name="ASHP2016" />

PharmacologyEdit

Amlodipine is a long-acting calcium channel antagonist that selectively inhibits calcium ion influx across cell membranes.<ref>Template:Cite book</ref> It targets L-type calcium channels in muscle cells and N-type calcium channels in the central nervous system which are involved in nociceptive signalling and pain perception.<ref name="Amlodipine">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite book</ref> Amlodipine has an inhibitory effect on calcium influx in smooth muscle cells to inhibit contraction.<ref name="Norvasc FDA label" />

Amlodipine ends up significantly reducing total vascular resistance without decreasing cardiac output expressed by pressure-rate product and cardiac contractability in comparison with verapamil, a non-dihydropyridine.<ref name="Nazzaro_1995">Template:Cite journal</ref> In turn, following treatment lasting a month, with amlodipine, cardiac output is significantly enhanced.<ref name="Nazzaro_1995" /> Unlike verapamil which has efficacy in moderation of emotional arousal and reduces cardiac load without lowering cardiac output demands, amlodipine increases the cardiac output response concomitantly with increased functional cardiac load.<ref name="Nazzaro_1995" />

Mechanism of actionEdit

Amlodipine is an angioselective calcium channel blocker and inhibits the movement of calcium ions into vascular smooth muscle cells and cardiac muscle cells which inhibits the contraction of cardiac muscle and vascular smooth muscle cells. Amlodipine inhibits calcium ion influx across cell membranes, with a greater effect on vascular smooth muscle cells. This causes vasodilation and a reduction in peripheral vascular resistance, thus lowering blood pressure. Its effects on cardiac muscle also prevent excessive constriction in the coronary arteries.<ref name=ASHP2016/>

Negative inotropic effects can be detected in vitro, but such effects have not been seen in intact animals at therapeutic doses. Among the two stereoisomers [R(+), S(–)], the (–) isomer has been reported to be more active than the (+) isomer.<ref name="J.R. Karmokeretal.2016">Template:Cite journal</ref> Serum calcium concentration is not affected by amlodipine. And it specifically inhibits the currents of L-type Cav1.3 channels in the zona glomerulosa of the adrenal gland.<ref>Template:Cite book</ref><ref>Template:Cite book</ref>

The mechanisms by which amlodipine relieves angina are:

Amlodipine has additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid.<ref name="Luther2014">Template:Cite journal</ref>

PharmacokineticsEdit

File:Amlodipine and major metabolite.svg
Amlodipine and one of its major metabolites: The nitrogen-containing ring is oxidized, and two of the side chains are hydrolyzed.<ref>Template:Cite journal</ref>

Amlodipine has been studied in healthy volunteers following oral administration of 14C-labelled drug.<ref name="pmid2967593">Template:Cite journalTemplate:Closed access</ref> Amlodipine is well absorbed by the oral route with a mean oral bioavailability around 60%; the half-life of amlodipine is about 30 h to 50 h, and steady-state plasma concentrations are achieved after 7 to 8 days of daily dosing.<ref name="Norvasc FDA label" /> In the blood it has high plasma protein binding of 97.5%.<ref name="Amlodipine" /> Its long half-life and high bioavailability are largely in part of its high pKa (8.6); it is ionized at physiological pH, and thus can strongly attract proteins.<ref name="Norvasc FDA label" /> It is slowly metabolized in the liver by CYP3A4, with its amine group being oxidized and its side ester chain being hydrolyzed, resulting in an inactive pyridine metabolite.<ref>Template:Cite book</ref> Renal elimination is the major route of excretion with about 60% of an administered dose recovered in urine, largely as inactive pyridine metabolites. However, renal impairment does not significantly influence amlodipine elimination.<ref>Template:Cite book</ref> 20-25% of the drug is excreted in the faeces.<ref>Template:Cite journal</ref>

HistoryEdit

Pfizer's patent protection on Norvasc lasted until 2007; total patent expiration occurred later in 2007.<ref>Template:Cite news</ref> A number of generic versions are available. In the United Kingdom, tablets of amlodipine from different suppliers may contain different salts. The strength of the tablets is expressed in terms of amlodipine base, i.e., without the salts. Tablets containing different salts are therefore considered interchangeable. A fixed-dose combination of amlodipine and perindopril, an angiotensin converting enzyme inhibitor is also available.<ref>Template:Drugs.com on amlodipine and perindopril. Accessed 28 February 2020.</ref>

The medical form comes as besilate, mesylate, or maleate.<ref>Template:Cite book</ref>

Society and cultureEdit

Brand namesEdit

In the US, Norvasc is marketed by Viatris after Upjohn was spun off from Pfizer.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Veterinary useEdit

Amlodipine is most often used to treat systemic hypertension in both cats and dogs.<ref name=papich>Template:Cite book</ref> In cats, it is the first line of treatment due to its efficacy and few side effects.<ref>Template:Cite journal</ref> Systemic hypertension in cats is usually secondary to another abnormality, such as chronic kidney disease, and so amlodipine is most often administered to cats with kidney disease.<ref name="diamondback">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> While amlodipine is used in dogs with systemic hypertension, it is not as efficacious. Amlodipine is also used to treat congestive heart failure due to mitral valve regurgitation in dogs.<ref>Template:Cite journal</ref> By decreasing resistance to forward flow in the systemic circulation it results in a decrease in regurgitant flow into the left atrium.<ref>Template:Cite journal</ref> Similarly, it can be used on dogs and cats with left-to-right shunting lesions such as ventricular septal defect to reduce the shunt. Side effects are rare in cats. In dogs, the primary side effect is gingival hyperplasia.<ref name="wedgewood">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

ReferencesEdit

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