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Amlodipine

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Amlodipine
Clinical data
Pronunciation/æmˈloʊdɪˌpiːn/[1]
Trade namesNorvasc, others
AHFS/DrugsMonograph
MedlinePlusa692044
License data
Pregnancy
category
Routes of
administration		Oral
Drug classCalcium channel blocker
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability64–90%
Protein binding93%[7]
MetabolismLiver
MetabolitesVarious inactive pyrimidine metabolites
Onset of actionHighest availability 6–12 hours after oral dose[10]
Eliminationhalf-life30–50 hours
Duration of actionAt least 24 hours[10]
ExcretionUrine[10]
Identifiers
  • (RS)-3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard(EPA)
ECHA InfoCard100.102.428Edit this at Wikidata
Chemical and physical data
FormulaC20H25ClN2O5
Molar mass408.88g·mol−1
3D model (JSmol)
ChiralityRacemic 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,4,9-11,22H2,1-3H3checkY
  • Key:HTIQEAQVCYTUBX-UHFFFAOYSA-NcheckY
(verify)

Amlodipine,sold under the brand nameNorvascamong others, is acalcium channel blockermedication used to treathigh blood pressure,coronary artery disease(CAD)[10]andvariant angina(also called Prinzmetal angina or coronary artery vasospasm, among other names).[11]It is takenorally(swallowed by mouth).[10]

Common side effects includeswelling,feeling tired,abdominal pain,andnausea.[10]Serious side effects may includelow blood pressureorheart attack.[10]Whether use is safe duringpregnancyorbreastfeedingis unclear.[2][10]When used by people withliver problems,and in elderly individuals, doses should be reduced.[10]Amlodipine works partly byvasodilation(rela xing the arteries and increasing their diameter).[10]It is a long-actingcalcium channel blockerof thedihydropyridinetype.[10]

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

Medical uses[edit]

Amlodipine is used in the management of hypertension (high blood pressure)[17]and coronary artery disease in people with either stableangina(where chest pain occurs mostly after physical or emotional stress)[18]orvasospastic angina(where it occurs in cycles) and withoutheart failure.It can be used as either monotherapy orcombination therapyfor 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 againststrokethanbeta blockers.[19][20]Evidence from two meta-analyses has reported no significant difference between calcium channel blockers,ACE inhibitors,diuretics[21][19]andangiotensin 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 ofantihypertensive.[20]

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

Combination therapy[edit]

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

Contraindications[edit]

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

Other situations occur, however, where amlodipine generally should not be used. In patients withcardiogenic 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 withaortic stenosis(narrowing of theaortawhere it meets theleft ventricle) since it does not inhibit the ventricle's function is generally safe, it can still cause collapse in cases of severe stenosis.[25]Inunstable angina(excludingvariant angina), amlodipine can cause areflexincrease incardiac contractility (how hard the ventricles squeeze)andheart rate,which together increase the demand for oxygen by the heart itself.[26]Patients with severehypotensioncan have their low blood pressure exacerbated, and patients inheart failurecan getpulmonary edema.Those with impairedliver functionare unable to metabolize amlodipine to its full extent, giving it a longer half-life than typical.[7][6]

Amlodipine's safety inpregnancyhas 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[edit]

Amlodipin Sandoz, bottle and pills in Sweden

Some common dose-dependent adverse effects of amlodipine include vasodilatory effects,peripheral edema,dizziness,palpitations,andflushing.[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 thearteriolesand 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 theinterstitial 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 arefatigue(4.5% vs. 2.8% with a placebo),nausea(2.9% vs. 1.9%),abdominal pain(1.6% vs. 0.3%), anddrowsiness(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,andjaundice.[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 worseninganginaor acute myocardial infarction, especially in those with severeobstructive 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 onvascular smooth muscle,causing a reduction in peripheralvascular resistanceand a consequent reduction in blood pressure.[10]

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

Overdose[edit]

See also:Calcium channel blocker toxicity

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 withfluid replacement[36]monitoringECGresults, vital signs, respiratory system function, glucose levels, kidney function, electrolyte levels, and urine output.Vasopressorsare also administered when low blood pressure is not alleviated by fluid resuscitation.[7][35]

Interactions[edit]

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 blockerdiltiazem,the antibioticclarithromycin,and possibly some antifungals.[7]Amlodipine causes several drugs to increase in levels, includingcyclosporine,simvastatin,andtacrolimus(the increase in the last one being more likely in people with CYP3A5*3 genetic polymorphisms).[37]When more than 20 mg of simvastatin, alipid-lowering agent,are given with amlodipine, the risk ofmyopathyincreases.[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 withViagraincreases the risk of hypotension.[7][10]

Pharmacology[edit]

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 decreasingcardiac outputexpressed by pressure-rate product and cardiac contractability in comparison withverapamil,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[edit]

Amlodipine is an angioselectivecalcium channel blockerand inhibits the movement of calcium ions intovascular smooth musclecells andcardiac muscle cellswhich 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 inperipheral vascular resistance,thus lowering blood pressure. Its effects on cardiac muscle also prevent excessive constriction in thecoronary arteries.[10]

Negativeinotropiceffects can be detectedin vitro,but such effects have not been seen in intact animals at therapeutic doses. Among the twostereoisomers[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 ofL-typeCav1.3channels in thezona glomerulosaof theadrenal gland.[45][46]

The mechanisms by which amlodipine relieves angina are:

Amlodipine has additionally been found to act as anantagonistof themineralocorticoid receptor,or as anantimineralocorticoid.[49]

Pharmacokinetics[edit]

Amlodipine and one of its major metabolites: The nitrogen-containing ring is oxidized, and two of the side chains are hydrolyzed.[50]

Amlodipine has been studied in healthy volunteers following oral administration of14C-labelled drug.[51]Amlodipine is well absorbed by the oral route with a mean oralbioavailabilityaround 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 byCYP3A4,with itsamine groupbeing oxidized and its sideesterchain beinghydrolyzed,resulting in an inactivepyridinemetabolite.[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[edit]

Pfizer'spatentprotection 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 andperindopril,anangiotensin converting enzymeinhibitor are also available.[56]

The medical form comes asbesilate,mesylate,ormaleate.[57]

Society and culture[edit]

Brand names[edit]

In the US, Norvasc is marketed byViatrisafter Upjohn was spun off from Pfizer.[58][59]

Veterinary use[edit]

Amlodipine is most often used to treat systemichypertensionin both cats and dogs.[60]In cats, it is the first line of treatment due to its efficacy and few side effects.[61]Systemichypertensionin cats is usually secondary to another abnormality, such aschronic kidney disease,and so amlodipine is most often administered to cats withkidney disease.[62]While amlodipine is used in dogs with systemic hypertension, it is not as efficacious. Amlodipine is also used to treatcongestive heart failuredue tomitral valve regurgitationin dogs.[63]By decreasing resistance to forward flow in the systemic circulation it results in a decrease in regurgitant flow into theleft atrium.[64]Similarly, it can be used on dogs and cats with left-to-right shunting lesions such asventricular septal defectto reduce the shunt. Side effects are rare in cats. In dogs, the primary side effect isgingival hyperplasia.[65]

References[edit]

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