Inotropic agents heart failure

Friedel-Crafts acylation of 3,3-dimethyl-2-indolinone by succinic anhydride gives 3,3-dimethyl-5-(3-catboxyptopionyl)-2-indoline, which is used as an intermediate in the preparation of inotropic agents for treatment of heart failure (94). Antibacterial phlotophenone derivatives have been prepared by Friedel-Crafts acylation with ptopanoyl chlotide (95). 

Artificial Hearts. Congestive heart failure (CHF) is a common cause of disabiHty and death. It is estimated that three to four million Americans suffer from this condition. Medical therapy in the form of inotropic agents, diuretics (qv), and vasofilators is commonly used to treat this disorder (see Cardiovascularagents). Cardiac transplantation has become the treatment of choice for medically intractable CHF. Although the results of heart transplantation are impressive, the number of patients who might benefit far exceeds the number of potential donors. Long-term circulatory support systems may become an alternative to transplantation (5). 

The cardiac effects of the calcium antagonists, ie, slowed rate (negative chronotropy) and decreased contractile force (negative inotropy), are prominent in isolated cardiac preparations. However, in the intact circulation, these effects may be masked by reflex compensatory adjustments to the hypotension that these agents produce. The negative inotropic activity of the calcium antagonists may be a problem in patients having heart failure, where contractility is already depressed, or in patients on concomitant -adrenoceptor blockers where reflex compensatory mechanisms are reduced. 

Pyridyl-4-bromo-6-oxo-5,6,7,8-tetrahydrothiazolo[5,4-g]quinolones and analogues were prepared and tested as potential inotropic agents for treatment of heart failure. For example, the 2-(4-pyridyl) substituted thiazoloquinolone 38 gave a 122% increase in contractility of guinea pig papillary muscle (89EUP1). 

Dobutamine (76), on the other hand, is a dopamine derivative which does not act centrally, but is of interest because of its coronary vasodilator properties. Such drugs are potentially of value in treatment of angina pectoralis. Further, it is now undergoing extensive clinical trials as an inotropic agent for use in heart failure. Its synthesis is effected by Raney nickel catalyzed reduction of methyl p-methoxyvinylphenylketone (75) to its dihydro analog followed by reductive alkylation with p-(3,4-dimethoxyphenyl)ethylamine. The ether groups are cleaved with HBr to complete the synthesis of... 

The most salient pathophysiological features of congestive heart failure (CHF) are diminution of ventricular contractility and profound, sympathetically mediated vasoconstriction. Agents with both peripheral vasodilating [24] and positive inotropic [25] activities ameliorate the symptoms of CHF. 

The discovery of the positive inotropic and systemic vasodilator activities of bipyridine-derived compounds, like amrinone (7) and milrinone (8), has markedly stimulated research aimed at the development of structurally related non-steroidal, non-catecholamine cardiotonics. In this context, a wide variety of pyridazinone derivatives have been prepared and investigated in search for novel agents useful for the chronic management of congestive heart failure. 

H. G. Ramjit, M. M. Singh and A. B. Coddington, Gas chromatographic/mass spectro-metric analysis of methyl methanesulfonate and ethyl methanesulfonate in the bismesy-late salt of DPI 201-106, a positive inotropic agent for the treatment of heart failure. Journal of Mass Spectrometry, 31(8), 867-872.1996. 

Noradrenaline and adrenaline are the classic catecholamines and neurotransmitters in the sympathetic nervous system. Noradrenaline stimulates the following subtypes of adrenoceptors P, a, U2. It has positive inotropic and chronotropic activities as a result of /3i-receptor stimulation. In addition, it is a potent vasoconstrictor agent as a result of the stimulation of both subtypes (ai,a2) of a-adrenoceptors. After intravenous infusion, its effects develop within a few minutes, and these actions disappear within 1-2 minutes after stopping the infusion. It may be used in conditions of acute hypotension and shock, especially in patients with very low vascular resistance. It is also frequently used as a vasoconstrictor, added to local anaesthetics. Adrenaline stimulates the following subtypes of adrenoceptors /3i, P2, oil, 0L2. Its pharmacological profile greatly resembles that of noradrenaline (see above), as well as its potential applications in shock and hypotension. Like noradrenaline, its onset and duration of action are very short, as a result of rapid inactivation in vivo. Both noradrenaline and adrenaline may be used for cardiac stimulation. Their vasoconstrictor activity should be kept in mind. A problem associated with the use of /3-adrenoceptor stimulants is the tachyphylaxis of their effects, explained by the /3-adrenoceptor downregulation, which is characteristic for heart failure. 

Dopamine itself has long been used as an inotropic agent in acute treatment of congestive heart failure. Both that compound and a number of its analogues have a positive action on contractility as a consequence of their adrenergic agonist activity. 

The pharmacokinetic properties of these drugs are set forth in Table 12-5. The choice of a particular calcium channel-blocking agent should be made with knowledge of its specific potential adverse effects as well as its pharmacologic properties. Nifedipine does not decrease atrioventricular conduction and therefore can be used more safely than verapamil or diltiazem in the presence of atrioventricular conduction abnormalities. A combination of verapamil or diltiazem with 3 blockers may produce atrioventricular block and depression of ventricular function. In the presence of overt heart failure, all calcium channel blockers can cause further worsening of heart failure as a result of their negative inotropic effect. Amlodipine, however, does not increase the mortality of patients with heart failure due to nonischemic left ventricular systolic dysfunction and can be used safely in these patients. 

Toxic concentrations of disopyramide can precipitate all of the electrophysiologic disturbances described under quinidine. As a result of its negative inotropic effect, disopyramide may precipitate heart failure de novo or in patients with preexisting depression of left ventricular function. Because of this effect, disopyramide is not used as a first-line antiarrhythmic agent in the USA. It should not be used in patients with heart failure. 

Paradoxically, these agents—not positive inotropic drugs—are the first-line therapies for chronic heart failure. The drugs most commonly used are diuretics, ACE inhibitors, angiotensin receptor antagonists, aldosterone antagonists, and blockers (Table 13-1). In acute failure,... 

Packer M. The development of positive inotropic agents for chronic heart failure how have we gone astray J Am Coll Cardiol 1993 22(suppA) 119A-126A. 

Examples of specific drugs used in the treatment of chronic heart failure include digitalis glycosides (e.g., digoxin, positive inotropic agent), diuretics (hydrochlortiazide and furosemide), and vasodilators (nitrates such as nitroglycerin, ACE inhibitors, such as captopril, and hydralazine). 

Correct answer = D. It is important to increase the cardiac output to improve oxygen delivery and thus minimize anaerobic metabolism and improve CNS and renal perfusion. Since this patient apparently does not have a heart condition, such as congestive heart failure, she could benefit from fluid therapy. An inotropic agent, such as dopamine, would lead to an increased cardiac output and dilation of the renal vasculature. [Note At high doses, however, it may constrict the renal beds due to interaction on a receptors.] Antibiotic administration is also important but will not improve the patient s hemodynamics. 

Chronic heart failure is typically managed by reduction in physical activity, low dietary intake of sodium (less than 1500 mg sodium per day), and treatment with vasodilators, diuretics and inotropic agents. Drugs that may precipitate or exacerbate CHF—nonsteroidal antiinflammatory drugs (NSAIDs), alcohol, (3-blockers, calcium channel-blockers and some antiarrhythmic drugs—should be avoided if possible. Patients with CHF complain of dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, fatigue, and dependent edema. 

P-Adrenergic stimulation improves cardiac performance by positive inotropic effects and vasodilation. Dobutamine (see p. 66) is the most commonly used inotropic agent other than digitalis. Dobutamine leads to an increase in intracellular cAMP, which results in the activation of protein kinase. Slow calcium channels are one important site of phosphorylation by protein kinase. When phospho-rylated, the entry of calcium ion into the myocardial cells increases, thus enhancing contraction (Figure 16.11). Dobutamine must be given by intravenous infusion, and is primarily used in the treatment of acute heart failure in a hospital setting. 

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