Amlodipine

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Amlodipine
Amlodipine.svg
Amlodipine 3D ball.png
Clinical data
Pronunciation /æmˈloʊdɪˌpiːn/ [1]
Trade names Norvasc, Istin, Norliqva, others
AHFS/Drugs.com Monograph
MedlinePlus a692044
License data
Pregnancy
category
Routes of
administration 		Oral
Drug class Calcium channel blocker
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 64–90%
Protein binding 93% [7]
Metabolism Liver
Metabolites Various inactive pyrimidine metabolites
Onset of action Highest availability 6–12 hours after oral dose [10]
Elimination half-life 30–50 hours
Duration of action At least 24 hours [10]
Excretion Urine [10]
Identifiers
  • (RS)-3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.102.428 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C20H25ClN2O5
Molar mass 408.88 g·mol−1
3D model (JSmol)
Chirality Racemic mixture
  • Clc1ccccc1C2/C(C(=O)OC)=C(/C)N/C(COCCN)=C2/C(=O)OCC
  • InChI=1S/C20H25ClN2O5/c1-4-28-20(25)18-15(11-27-10-9-22)23-12(2)16(19(24)26-3)17(18)13-7-5-6-8-14(13)21/h5-8,17,23H,4,9-11,22H2,1-3H3 Yes check.svgY
  • Key:HTIQEAQVCYTUBX-UHFFFAOYSA-N Yes check.svgY
   (verify)

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) [10] and variant angina (also called Prinzmetal angina or coronary artery vasospasm, among other names). [11] It is taken orally (swallowed by mouth). [10]

Contents

Common side effects include swelling, feeling tired, abdominal pain, and nausea. [10] Serious side effects may include low blood pressure or heart attack. [10] Whether use is safe during pregnancy or breastfeeding is unclear. [2] [10] When used by people with liver problems, and in elderly individuals, doses should be reduced. [10] Amlodipine works partly by vasodilation (relaxing the arteries and increasing their diameter). [10] It is a long-acting calcium channel blocker of the dihydropyridine type. [10]

Amlodipine was patented in 1982, and approved for medical use in 1990. [12] It is on the World Health Organization's List of Essential Medicines. [13] It is available as a generic medication. [10] [14] In 2021, it was the fifth most commonly prescribed medication in the United States, with more than 73 million prescriptions. [15] [16]

Medical uses

Amlodipine is used in the management of hypertension (high blood pressure) [17] and coronary artery disease in people with either stable angina (where chest pain occurs mostly after physical or emotional stress) [18] 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. [7] Calcium channel blockers, including amlodipine, may provide greater protection against stroke than beta blockers. [19] [20] Evidence from two meta-analyses has reported no significant difference between calcium channel blockers, ACE inhibitors, diuretics [21] [19] and angiotensin receptor blockers [21] in stroke protection while one 2015 meta-analysis has suggested that calcium channel blockers offer greater protection against stroke than other classes of antihypertensive. [20]

Amlodipine along with other calcium channel blockers are considered the first choice in the pharmacological management of Raynaud's phenomenon. [22]

Combination therapy

Amlodipine can be given as a combination therapy with a variety of medications: [10] [23]

Contraindications

The only absolute contraindication to amlodipine is an allergy to amlodipine or any other dihydropyridines. [7]

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. [24] 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. [25] 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. [26] 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. [7] [6]

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. [7] [6]

Those who have heart failure, or recently had a heart attack, should take amlodipine with caution. [27]

Adverse effects

Amlodipin Sandoz, bottle and pills in Sweden 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. [7] [28] 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. [7] 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. [29] Amlodipine-association edema can be avoided by adding ACE inhibitors or angiotensin II receptor antagonist. [10] 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. [7]

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%). [7] Side effects occurring less than 1% of the time include: blood disorders, impotence, depression, peripheral neuropathy, insomnia, tachycardia, gingival enlargement, hepatitis, and jaundice. [7] [30] [31]

Amlodipine-associated gingival overgrowth is a relatively common side effect with exposure to amlodipine. [32] Poor dental health and buildup of dental plaque are risk factors. [32]

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. [10]

Amlodipine and other dihydropyridine calcium channel blockers are associated with primary open angle glaucoma. [33]

Overdose

Although rare, [34] amlodipine overdose toxicity can result in widening of blood vessels, severe low blood pressure, and fast heart rate. [35] Toxicity is generally managed with fluid replacement [36] 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. [7] [35]

Interactions

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. [7] 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). [37] When more than 20 mg of simvastatin, a lipid-lowering agent, are given with amlodipine, the risk of myopathy increases. [38] 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. [39] Giving amlodipine with Viagra increases the risk of hypotension. [7] [10]

Pharmacology

Amlodipine is a long-acting calcium channel antagonist that selectively inhibits calcium ion influx across cell membranes. [40] 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. [41] [42] Amlodipine has an inhibitory effect on calcium influx in smooth muscle cells to inhibit contraction.[ citation needed ]

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. [43] In turn, following treatment lasting a month, with amlodipine, cardiac output is significantly enhanced. [43] 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. [43]

Mechanism of action

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. [10]

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. [44] 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. [45] [46]

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. [49]

Pharmacokinetics

Amlodipine and one of its major metabolites: The nitrogen-containing ring is oxidized, and two of the side chains are hydrolyzed. 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.

Amlodipine has been studied in healthy volunteers following oral administration of 14C-labelled drug. [51] 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. In the blood it has high plasma protein binding of 97.5%. [41] 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. [7] 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. [52] 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. [53] 20-25% of the drug is excreted in the faeces. [54]

History

Pfizer's patent protection on Norvasc lasted until 2007; total patent expiration occurred later in 2007. [55] 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. Fixed-dose combination of amlodipine and perindopril, an angiotensin converting enzyme inhibitor are also available. [56]

The medical form comes as besilate, mesylate or maleate. [57]

Veterinary use

Amlodipine is most often used to treat systemic hypertension in both cats and dogs. [58] In cats, it is the first line of treatment due to its efficacy and few side effects. [59] 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. [60] 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. [61] By decreasing resistance to forward flow in the systemic circulation it results in a decrease in regurgitant flow into the left atrium. [62] 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. [63]

Related Research Articles

An antianginal is a drug used in the treatment of angina pectoris, a symptom of ischaemic heart disease.

<span class="mw-page-title-main">Angina</span> Chest discomfort that is generally brought on by inadequate blood flow to the cardiac muscle

Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease.

Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as medications to decrease blood pressure in patients with hypertension. CCBs are particularly effective against large vessel stiffness, one of the common causes of elevated systolic blood pressure in elderly patients. Calcium channel blockers are also frequently used to alter heart rate, to prevent peripheral and cerebral vasospasm, and to reduce chest pain caused by angina pectoris.

<span class="mw-page-title-main">Vasodilation</span> Widening of blood vessels

Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel walls are composed of endothelial tissue and a basal membrane lining the lumen of the vessel, concentric smooth muscle layers on top of endothelial tissue, and an adventitia over the smooth muscle layers. Relaxation of the smooth muscle layer allows the blood vessel to dilate, as it is held in a semi-constricted state by sympathetic nervous system activity. Vasodilation is the opposite of vasoconstriction, which is the narrowing of blood vessels.

Antihypertensives are a class of drugs that are used to treat hypertension. Antihypertensive therapy seeks to prevent the complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34% and of ischaemic heart disease by 21%, and can reduce the likelihood of dementia, heart failure, and mortality from cardiovascular disease. There are many classes of antihypertensives, which lower blood pressure by different means. Among the most important and most widely used medications are thiazide diuretics, calcium channel blockers, ACE inhibitors, angiotensin II receptor antagonists (ARBs), and beta blockers.

<span class="mw-page-title-main">Nifedipine</span> Calcium channel blocker medication

Nifedipine, sold under the brand name Procardia among others, is a calcium channel blocker medication used to manage angina, high blood pressure, Raynaud's phenomenon, and premature labor. It is one of the treatments of choice for Prinzmetal angina. It may be used to treat severe high blood pressure in pregnancy. Its use in preterm labor may allow more time for steroids to improve the baby's lung function and provide time for transfer of the mother to a well qualified medical facility before delivery. It is a calcium channel blocker of the dihydropyridine type. Nifedipine is taken by mouth and comes in fast- and slow-release formulations.

<span class="mw-page-title-main">Felodipine</span> Medication of the calcium channel blocker type

Felodipine is a medication of the calcium channel blocker type that is used to treat high blood pressure.

<span class="mw-page-title-main">Valsartan</span> Angiotensin II receptor antagonist

Valsartan, sold under the brand name Diovan among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It belongs to a class of medications referred to as angiotensin II receptor blockers (ARBs). It is a reasonable initial treatment for high blood pressure. It is taken by mouth.

<span class="mw-page-title-main">Hydralazine</span> Anti-hypertension medication

Hydralazine, sold under the brand name Apresoline among others, is a medication used to treat high blood pressure and heart failure. This includes high blood pressure in pregnancy and very high blood pressure resulting in symptoms. It has been found to be particularly useful in heart failure, together with isosorbide dinitrate, for treatment of people of African descent. It is given by mouth or by injection into a vein. Effects usually begin around 15 minutes and last up to six hours.

<span class="mw-page-title-main">Variant angina</span> Medical condition

Variant angina, also known as Prinzmetal angina,vasospastic angina, angina inversa, coronary vessel spasm, or coronary artery vasospasm, is a syndrome typically consisting of angina. Variant angina differs from stable angina in that it commonly occurs in individuals who are at rest or even asleep, whereas stable angina is generally triggered by exertion or intense exercise. Variant angina is caused by vasospasm, a narrowing of the coronary arteries due to contraction of the heart's smooth muscle tissue in the vessel walls. In comparison, stable angina is caused by the permanent occlusion of these vessels by atherosclerosis, which is the buildup of fatty plaque and hardening of the arteries.

<span class="mw-page-title-main">Amlodipine/benazepril</span> Antihypertensive medication

Amlodipine/benazepril, sold under the brand name Lotrel among others, is a fixed-dose combination medication used to treat high blood pressure. It is a combination of amlodipine, as the besilate, a calcium channel blocker, and benazepril, an angiotensin converting enzyme inhibitor. It may be used if a single agent is not sufficient. It is taken by mouth.

<span class="mw-page-title-main">Nicardipine</span> Antihypertensive drug of the calcium channel blocker class

Nicardipine (Cardene) is a medication used to treat high blood pressure and angina. It belongs to the dihydropyridine class of calcium channel blockers (CCBs). It is also used for Raynaud's phenomenon. It is available in by mouth and intravenous formulations. It has been used in percutaneous coronary intervention.

<span class="mw-page-title-main">Perindopril</span> High blood pressure medication

Perindopril is a medication used to treat high blood pressure, heart failure, or stable coronary artery disease.

<span class="mw-page-title-main">Lercanidipine</span> Antihypertensive drug of the calcium channel blocker class

Lercanidipine is an antihypertensive drug. It belongs to the dihydropyridine class of calcium channel blockers, which work by relaxing and opening the blood vessels allowing the blood to circulate more freely around the body. This lowers the blood pressure and allows the heart to work more efficiently.

Amlodipine/olmesartan, sold under the brand name Azor, among others is a fixed-dose combination medication used to treat high blood pressure. It contains amlodipine, as the besilate, a dihydropyridine calcium channel blocker, and olmesartan medoxomil, an angiotensin II receptor blocker.

<span class="mw-page-title-main">Clevidipine</span> Antihypertensive drug of the calcium channel blocker class

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Levamlodipine (INN), also known as levoamlodipine or S-amlodipine is a pharmacologically active enantiomer of amlodipine. Amlodipine belongs to the dihydropyridine group of calcium channel blocker used as an antihypertensive and antianginal agent. It was approved by the U.S. FDA in December 2019 and is currently marketed under the brand name Conjupri.

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<span class="mw-page-title-main">Lisinopril/amlodipine</span> Combination drug used to treat high blood pressure

Lisinopril/amlodipine, sold under the brand name Lisonorm among others, is a medication used to treat high blood pressure. It is a combination of lisinopril an ACE inhibitor with amlodipine a calcium channel blocker. It may be used when blood pressure is not well controlled with each of the two agents alone. It is taken by mouth.

References

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