Amlodipine

Amlodipine belongs to the dihydropyridine class of calcium channel blockers, drugs that lower blood pressure by acting on the calcium channels of vascular smooth muscle. It blocks the entry of calcium through so-called L-type channels in the walls of arteries, causing them to relax and widen; this reduces the resistance the heart must pump against and lowers blood pressure ^[1]. Unlike some other calcium channel blockers, amlodipine acts far more on blood vessels than on the heart itself, so at usual doses it has little direct effect on heart rate or the force of contraction ^[1].

A defining property of amlodipine is its very long half-life, which sets it apart from earlier dihydropyridines. Because the drug is eliminated slowly, it can be taken once a day and produces a steady, gradual effect rather than an abrupt drop in blood pressure, which limits the reflex increase in heart rate seen with faster-acting agents ^[1]. It is broken down in the liver, and only one of its two mirror-image forms carries most of the activity.

Amlodipine is used chiefly to treat high blood pressure and to relieve and prevent angina, including both the common exertional form and the less common vasospastic (Prinzmetal) type. It is prescribed alone or in fixed combinations with other blood-pressure medicines such as ACE inhibitors and angiotensin-receptor blockers, and sometimes with a statin ^[1].

Its cardiovascular benefits have been examined in several large trials. In the ALLHAT study, an amlodipine-based regimen prevented heart attacks and death about as well as a diuretic, although the diuretic performed better at preventing heart failure ^[2]. In the ASCOT trial, a regimen built on amlodipine prevented more strokes and cardiovascular events, and led to fewer new cases of diabetes, than one based on an older beta-blocker and diuretic combination ^[3]. In the VALUE trial, amlodipine and the drug valsartan produced similar rates of cardiac events, with amlodipine lowering blood pressure more quickly early in treatment ^[4]. Together these studies established amlodipine as a well-validated option for hypertension.

The most common side effects reflect the drug's blood-vessel-widening action: swelling of the ankles and lower legs, flushing, headache, and occasional dizziness or palpitations; ankle swelling in particular becomes more likely at higher doses ^[1]. Amlodipine was approved in 1990, is included on the World Health Organization's list of essential medicines, and is available inexpensively as a generic in oral tablet form.

Amlodipine is prescription only and generally well tolerated. Its most common effect is ankle and leg swelling, which comes from widening small arteries and is dose-related rather than a sign of fluid overload. It can also cause flushing, headache, dizziness, palpitations and tiredness, and rarely gum overgrowth. It should be used carefully in severe aortic narrowing and in significant heart failure. It is broken down by CYP3A4, so strong inhibitors such as clarithromycin can raise its levels, and it in turn raises simvastatin levels, so that statin is capped at 20 mg.

Amlodipine is a CYP3A4 substrate with a long half-life, and most of its interactions follow from that. Strong inhibitors such as clarithromycin, itraconazole and ritonavir raise its concentrations and with them the risk of hypotension and ankle edema, an effect more pronounced in older people. Inducers such as rifampin and carbamazepine work the other way and can cost blood pressure control.

Amlodipine is a mild inhibitor itself, which matters for two groups of drugs. It raises simvastatin exposure by roughly three quarters at high statin doses, enough that the simvastatin labeling restricts how much can be given alongside it; myopathy is the consequence. In transplant recipients it lifts cyclosporine troughs by about 40 percent and, in CYP3A5 expressers, tacrolimus exposure several-fold, which risks calcineurin inhibitor nephrotoxicity.

Additive hypotension with other antihypertensives, nitrates and PDE5 inhibitors such as sildenafil is predictable; sildenafil does not change amlodipine levels, but the blood pressure effects sum.

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Amlodipine was discovered by chemists at Pfizer during the early 1980s as part of a search for a longer-acting dihydropyridine calcium channel blocker, and it was patented in 1982. It reached the market as Norvasc around 1990, formulated as the besylate salt to give a stable, well-absorbed once-daily tablet. Its defining advance over earlier dihydropyridines such as nifedipine was its very slow binding kinetics and long half-life, which produced a smooth, sustained fall in blood pressure without the reflex surges that had troubled shorter-acting agents. It went on to become one of the most prescribed medicines in the world and was validated in large outcome trials, including the landmark ALLHAT study of high-risk hypertensive patients.

Amlodipine is widely regarded as a workhorse of hypertension treatment, prized for its reliability, its forgiving once-daily dosing, and a mountain of outcome evidence supporting its use. Because its effect builds and fades gradually, a forgotten dose rarely causes trouble, and its selectivity for blood vessels over the heart means it lowers pressure without slowing the heart or weakening its pump. Clinicians appreciate that it combines cleanly with almost every other class of blood-pressure medicine. Its main honest drawback is dose-related ankle swelling, along with occasional flushing, but these are cosmetic rather than dangerous, and overall it is considered one of the best-tolerated antihypertensives available.