There is no doubt that the aforementioned glycosides are the most satisfactory inotropic compounds. However, digitalis drugs can be counter productive in some patients for a number of reasons. Theophylline has been intensively studied as an inotropic agent; however, it turned out to be unfit for long-term use.
Derivatives of the bipiridine series, such as amrinone and minrinone, have recently been found useful as inotropic agents.
The mechanism of action of these drugs is not completely understood. However, it is very likely that they inhibit cellular phosphodiesterase of the myocardium, which leads to an elevation in the cellular level of cyclic AMP, which in turn facilitates contraction of myocardial cells. It is clear that these drugs are not /¡-adrenoreceptor antagonists, and that their effect is not mediated by inhibition of (Na+-K+) ATPase. They simultaneously increase the flow of calcium ions into the cell. They are used for short-term control of patients that inadequately react to cardiac glycosides, diuretics, and coronary vasodilating agents.
Amrinone: Amrinone, 3-amino-5-(4-piridinyl)-2(1#)-pyridinone (17.2.4), can be synthesized from piridine-4-acetic acid, the reaction of which with a mixture of diemthylfor-mamide—phosphorous oxychloride gives 2-(4-piridyl)-3-dimethylaminoacrolein (17.2.1). Reacting this with cyanoacetamide gives 3-cyano-5-(4-piridyl)-2(1#)-pyidinone (17.2.2). Hydrolysis of the cyano group of this product gives 3-carbamyl-5-(4-piridyl)-2(1#)-pyidi-none (17.2.3). A Hofmann rearrangement of this product (using bromine in sodium hydroxide) gives amrinone (17.2.4).
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