Amlodipine

Amlodipine is used in the management of hypertension (high blood pressure) and coronary artery disease in people with either stable angina (where chest pain occurs mostly after physical or emotional stress) 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. Calcium channel blockers, including amlodipine, may provide greater protection against stroke than beta blockers. Evidence from two meta-analyses has reported no significant difference between calcium channel blockers, ACE inhibitors, diuretics Combination therapy Amlodipine can be given as a combination therapy with a variety of medications: • Amlodipine/atorvastatin, where amlodipine is given for hypertension or CAD and atorvastatin prevents cardiovascular events, or if the person also has high cholesterol. • Amlodipine/aliskiren or amlodipine/aliskiren/hydrochlorothiazide if amlodipine alone cannot reduce blood pressure. Aliskiren is a renin inhibitor, which works to reduce primary hypertension (that with no known cause) by binding to renin and preventing it from initiating the renin–angiotensin system (RAAS) pathway to increase blood pressure. Hydrochlorothiazide is a diuretic and decreases overall blood volume. • Amlodipine/benazepril if either drug has failed individually, or amlodipine alone caused edema. Benazepril is an ACE inhibitor and blocks the conversion of angiotensin I to angiotensin II in the RAAS pathway. • Amlodipine/celecoxib • Amlodipine/lisinopril • Amlodipine/olmesartan or amlodipine/olmesartan/hydrochlorothiazide if amlodipine is insufficient in reducing blood pressure. Olmesartan is an angiotensin II receptor antagonist and blocks part of the RAAS pathway. • Amlodipine/perindopril if using amlodipine alone caused edema. Perindopril is a long-lasting ACE inhibitor. • Amlodipine/telmisartan, where telmisartan is an angiotensin II receptor antagonist. • Amlodipine/valsartan or amlodipine/valsartan/hydrochlorothiazide, where valsartan is an angiotensin II receptor antagonist. == Contraindications ==

The only absolute contraindication to amlodipine is an allergy to amlodipine or any other dihydropyridines. 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. 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. 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. 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. == Adverse effects ==

Some common dose-dependent adverse effects of amlodipine include vasodilatory effects, peripheral edema, dizziness, palpitations, and flushing. 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. Amlodipine-association edema can be avoided by adding ACE inhibitors or angiotensin II receptor antagonist. Amlodipine-associated gingival overgrowth is a relatively common side effect with exposure to amlodipine. 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. == Overdose ==

Although rare, amlodipine overdose toxicity can result in widening of blood vessels, severe low blood pressure, and fast heart rate. Vasopressors are also administered when low blood pressure is not alleviated by fluid resuscitation. == 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. When more than 20 mg of simvastatin, a lipid-lowering agent, are given with amlodipine, the risk of myopathy increases. 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. Giving amlodipine with Viagra increases the risk of hypotension. == Pharmacology ==

Amlodipine is a long-acting calcium channel antagonist that selectively inhibits calcium ion influx across cell membranes. 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. Amlodipine has an inhibitory effect on calcium influx in smooth muscle cells to inhibit contraction. In turn, following treatment lasting a month, with amlodipine, cardiac output is significantly enhanced. Amlodipine does not affect serum calcium concentration. It specifically inhibits the currents of L-type Cav1.3 channels in the zona glomerulosa of the adrenal gland. The mechanisms by which amlodipine relieves angina are: • 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. • Variant 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 additionally been found to act as an antagonist of the mineralocorticoid receptor, or as an antimineralocorticoid. Pharmacokinetics 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%; 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. 20-25% of the drug is excreted in the faeces. ==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 such as amlodipine besylate and amlodipine benzoate. The medical form comes as besilate, mesylate, or maleate. == Society and culture ==

Brand names In the US, Norvasc is marketed by Viatris after Upjohn was spun off from Pfizer. == Veterinary use ==

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