Products
Amlodipine is commercially available in tablet form (Norvasc, generic). It has been approved in many countries since 1990. Amlodipine is also combined fixed with the following agents: Aliskiren, atorvastatin, perindopril, telmisartan, valsartan, olmesartan, hydrochlorothiazide, and indapamide.
Structure and properties
Amlodipine (C20H25ClN2O5, Mr = 408.9 g/mol) has a chiral center and is a racemate. It is present in the original Norvasc in the form of the salt amlodipine besylate, a white powder that is sparingly soluble in water. Besilates are the salts of benzenesulfonic acid. In generics, it is present either as amlodipine besilate as in the original or as amlodipine mesilate (salt of methanesulfonic acid). Drugs containing amlodipine maleate are no longer commercially available in many countries; they are controversial because of potential stability problems. When the generics were introduced, there was heated debate about whether the different salts were interchangeable. While regulators assume they are, the manufacturer has made various arguments against it (e.g., Meredith, 2009).
Effects
Amlodipine (ATC C08CA01) has antihypertensive, vasorelaxant, and antiischemic properties. It lowers total peripheral resistance (afterload), unloads the heart, and improves oxygen delivery to the myocardium. The effects are due to inhibition of calcium influx via L-type calcium channels into cardiac muscle cells and vascular smooth muscle cells.
Indications
Amlodipine is indicated as a monopreparation for the treatment of arterial hypertension and for seizure prophylaxis in stable and in vasospastic angina.
Dosage
According to the drug label. The usual dose in adults is 5 mg to a maximum of 10 mg. Adverse effects are increased at higher doses. The dose is taken independently of meals. Because of the long half-life of 35 to 50 hours, once-daily administration is sufficient.
Contraindications
Amlodipine is contraindicated in hypersensitivity. The German label additionally lists severe hypotension, shock, aortic stenosis, unstable angina, acute myocardial infarction, and severe hepatic impairment as contraindications. Full precautions can be found in the drug label.
Interactions
Other antihypertensive agents may cause increased lowering of blood pressure. This may be desirable in the context of combination therapy. Drug-drug interactions with theophylline and ergotamine cannot be ruled out. Grapefruit juice may slightly increase the plasma concentration and AUC of amlodipine. Consumption of small amounts should result in few complications. However, consumption of more than one liter per day is discouraged. Amlodipine is extensively biotransformed to inactive metabolites in the liver and has a high first-pass metabolism. The Swiss Pharmacopoeia makes no statement about the enzymes involved. According to Flockhart, Katoh et al. (2000) and the German SmPC, CYP3A4 is relevantly involved. According to the German and U.S. expert information, strong CYP3A4 inhibitors such as azole antifungals can lead to a significant increase in plasma concentrations. CYP inducers could decrease levels.
Adverse effects
The most common adverse effect is oedema (water retention). Due to vasodilatation and lowering of blood pressure, dizziness, headache, palpable heartbeats, drowsiness, fatigue, and redness of the face are common. Occasionally, blood pressure drops too low. Lower abdominal pain and nausea are two other common side effects. Numerous other side effects are possible, including the rare gingival proliferation. Very rarely, serious cardiovascular events and liver inflammation have been reported. However, the extent to which these cases are related to the use of amlodipine is not precisely known.
