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]
Amlodipine/atorvastatin, where amlodipine is given for hypertension or CAD and atorvastatin prevents cardiovascular events, or if the person also has high cholesterol.
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.[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
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]
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]
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-typeCav1.3 channels in the
zona glomerulosa of the
adrenal gland.[45][46]
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.[47]
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]
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]
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