Amlodipine

Amlodipine

1 : 1 mixture (racemate)
Systematic (IUPAC) name
(RS)-3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
Clinical data
Trade names	Norvasc
AHFS/Drugs.com	monograph
MedlinePlus	a692044
Licence data	US FDA:link
Pregnancy category	AU: C US: C (Risk not ruled out)
Legal status	UK: POM (Prescription only) US: ℞-only
Routes of administration	Oral (tablets)
Pharmacokinetic data
Bioavailability	64 to 90%
Metabolism	Hepatic
Biological half-life	30 to 50 hours
Excretion	Renal
Identifiers
CAS Number	88150-42-9 Y
ATC code	C08CA01 (WHO)
PubChem	CID: 2162
IUPHAR/BPS	6981
DrugBank	DB00381 Y
ChemSpider	2077 Y
UNII	1J444QC288 Y
KEGG	D07450 Y
ChEBI	CHEBI:2668 Y
ChEMBL	CHEMBL1491 Y
Chemical data
Formula	C20H25ClN2O5
Molecular mass	408.879 g/mol
SMILES Clc1ccccc1C2C(=C(/N/C(=C2/C(=O)OCC)COCCN)C)\C(=O)OC
InChI 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 Y Key:HTIQEAQVCYTUBX-UHFFFAOYSA-N Y
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Amlodipine (as besylate, mesylate or maleate) is a medication used to lower blood pressure and prevent chest pain. It belongs to a group of medications known as dihydropyridine-type calcium channel blockers. By widening of blood vessels it lowers blood pressure. In angina, amlodipine increases blood flow to the heart muscle to relieve pain due to angina.

It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.

Medical uses

Amlodipine is used in the management of hypertension and coronary artery disease (chronic stable angina, vasospastic angina, and angiographically documented CAD without heart failure or ejection fraction < 40%.) 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 children 6–17 years of age.

Contraindications

Absolute

• Allergy to amlodipine

Relative

• Cardiogenic shock
• Unstable angina
• Systolic and diastolic blood pressure below 90/60 mmHg
• Aortic stenosis
• Breastfeeding
• Pregnancy

Adverse effects

Adverse side effects of the use of amlodipine may include:

• Common and dose-related: peripheral edema (5.1%), dizziness (2.6%), palpitations (2.1%), flushing (1.5%)
• Common, not dose-related: fatigue (4.5%), nausea (2.9%), abdominal pain (1.6%), somnolence (1.4%)
• Rare (less than 1% incidence): blood disorders, impotence, depression, insomnia, tachycardia, or gingival enlargement, hepatitis, jaundice

Overdosage

See also: Calcium channel blocker toxicity

Although rare, amlodipine overdose toxicity can result in widening of blood vessels, severe low blood pressure, and fast heart rate.

Amlodipine toxicity is generally managed with the following measures:

• Fluid replacement
• Monitoring of ECG, vitals, respiratory system, glucose, kidney function, electrolytes, and urine output
• Vasopressor administration (for low blood pressure unresponsive to fluid resuscitation)

Mechanism

Amlodipine inhibits the movement of calcium ions into vascular smooth muscle cells and cardiac muscle cells. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells. Negative inotropic effects can be detected in vitro, but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure. As a calcium channel blocker, amlodipine is expected to inhibit the currents of L-type Cav1.3 channels in the zona glomerulosa.

The mechanisms by which amlodipine relieves angina include:

• Stable angina: amlodipine reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, thereby lowering myocardial oxygen demand, at any given level of exercise.
• Prinzmetal's angina: amlodipine blocks spasm of the coronary arteries and restores blood flow in coronary arteries and arterioles in response to calcium, potassium, epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro.

Metabolism

Amlodipine has been studied in healthy volunteers following oral administration of ¹⁴C-labelled drug. amlodipine is well absorbed by the oral route with a mean oral bioavailability around 60%. It is metabolized in the liver to inactive metabolites via CYP3A4. The half-life of amlodipine is about 30–50 hours, and steady-state plasma concentrations are achieved after 7 to 8 days of daily dosing. 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.

Interactions

• CYP3A inhibitors: Co-administration of moderate to strong inhibitors of the cytochrome p450 enzyme CYP3A4 (such as itraconazole, clarithromycin) that metabolizes amlodipine in the liver may increase the plasma concentrations of amlodipine.
• CYP3A inducers: No data is currently available for co-administration of CYP3A4 inducers with amlodipine.
• Simvastatin: Co-administration of simvastatin at doses greater than 20 mg can lead to an increase in simvastatin plasma concentrations and increase risk of myopathy.
• Sildenafil: Co-administration of sildenafil can lead to an increased risk of hypotension.
• Tacrolimus: Co-administration of tacrolimus in patients with the CYP3A5*3 genetic polymorphism may increase tacrolimus plasma concentrations.

Combination therapy

If monotherapy with amlodipine or candesartan is not sufficient to reach the reducing blood pressure target, a combination of amlodipine 5 mg and candesartan 8 mg can be effective, lowering blood pressure after 12 weeks in patients not adequately controlled by monotherapy. People suffering from high blood pressure and high cholesterol can also benefit from using a combination of amlodipine with atorvastatin.

History

Pfizer's patent protection on Norvasc lasted until 2007; total patent expiration occurred later in 2007. 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.The efficacy and tolerability of a fixed-dose combination of amlodipine 5 mg and perindopril 4 mg, an angiotensin converting enzyme inhibitor, have recently been confirmed in a prospective, observational, multicentre trial of 1250 hypertensive patients.

See also

• Aliskiren/amlodipine
• Amlodipine/valsartan

External links

• U.S. National Library of Medicine: Drug Information Portal - Amlodipine