|Systematic (IUPAC) name|
(RS)-3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
|Trade names||Norvasc, others|
|By mouth (tablets)|
|Bioavailability||64 to 90%|
|Biological half-life||30 h to 50 h|
|ATC code||C08CA01 (WHO)|
|PDB ligand ID||6UB (PDBe, RCSB PDB)|
|Molar mass||408.879 g/mol|
Amlodipine, sold under the brand name Norvasc among others, is a medication used to treat high blood pressure and coronary artery disease. While calcium channel blockers are not typically recommended in heart failure, amlodipine may be used if other medications are not sufficient for high blood pressure or heart related chest pain. Amlodipine is taken by mouth and has an effect for at least a day.
Common side effects include: swelling, feeling tired, abdominal pain, and nausea. Serious side effects may include low blood pressure or a heart attack. It is unclear if use is safe during pregnancy or breastfeeding. Doses should be decreased in people with liver problems and those who are old. Amlodipine is a long acting calcium channel blocker of the dihydropyridine type. It works partly by increasing the size of arteries.
Amlodipine was first patented in 1986 with commercial sale beginning in 1990. It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system. It is available as a generic medication. Wholesale cost in the developing world is 0.003 to 0.040 USD per day for a typical dose as of 2014. In the United States a months supply costs less than 25 USD.
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.
- Cardiogenic shock
- Unstable angina
- Systolic and diastolic blood pressure below 90/60 mmHg
- Aortic stenosis
- 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
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 of action
Amlodipine is an angioselective calcium channel blocker. Calcium stimulates the actions of cells. Calcium channels are found on heart muscles, blood vessels, and other cells. When the channels open, calcium flows into the cell, causing them to contract. Calcium channel blockers interfere with this stimulation. This relaxes blood vessels widening them. This lowers blood pressure and reduces the stress on the heart. In those with heart related chest pain, amlodipine may increase blood flow to the heart muscle.
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. Among two sterioisomers [R(+), S(-)], the (-) isomer has been reported to be more active than the (+) isomer.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.
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 h to 50 h, 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.
- CYP3A inhibitors: giving with 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: giving with simvastatin at doses greater than 20 mg can lead to an increase in simvastatin plasma concentrations and increase risk of myopathy.
- Sildenafil: giving with sildenafil can lead to an increased risk of hypotension.
- Tacrolimus: giving with tacrolimus in patients with the CYP3A5*3 genetic polymorphism may increase tacrolimus plasma concentrations.
If monotherapy with amlodipine or candesartan is not sufficient to reach the reducing blood pressure target, a combination of amlodipine and candesartan can be effective, lowering blood pressure after 12 weeks in people 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.
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 and perindopril, an angiotensin converting enzyme inhibitor, have recently been confirmed in a prospective, observational, multicentre trial of 1250 hypertensive patients.
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