Several dihydropyridine calcium antagonists have been introduced during the past 25 years. First degeneration dihydropyridines are the naturally short-acting agents that include felodipine, isradipine, nifedipine, and nitrendip-ine. These rapid-acting vasodilators are powerful anti-hypertensive agents, but their fast onset of action results in marked vasodilation that causes reflex stimulation of the sympathetic nervous system and hemodynamic adverse effects that include increased heart rate, increased cardiac workload, and an increased incidence of heart failure in patients with left ventricular dysfunction. These adverse effects have become controversial and the short-acting formulations of dihydropyridines such as verapamil and diltiazem are no longer recommended. They have largely been removed from the marketplace.
Second generation agents such as verapamil SR, nifedipine XL, felodipine ER, and diltiazem SR and CD were developed with modified release properties to slow their onset of action. Adverse effects are still high, partic¬ularly edema and constipation, and heart failure is pre¬cipitated, albeit rarely.
Third generation agents include amlodipine. These agents have a naturally occurring long plasma half-life (over 24 h) but are washed out from the receptor relatively fast. Equilibrium is essentially between the plasma protein-bound drug and the calcium L channel. Amlodipine moves quickly onto the calcium channel to provide a quick onset of action and thus vasodilatation, which results in modest sympathetic stimulation and unwanted mild tachycardia or an increase in heart rate of about 10 beats per minute from baseline. These agents may precipitate pulmonary edema in patients with left ventricular dysfunction.

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