Negative inotropic effect

In high concentrations it blocks calcium channels and, thus, exerts prominent negative inotropic effects. Its adverse effects include proarrhythmic effects, worsening of heart failure and (due to (3-adrenoceptor blockade) bradycardia and bronchospasm. 

Class II drugs are classical (3-adrenoceptor antagonists such as propranolol, atenolol, metoprolol or the short-acting substance esmolol. These drugs reduce sinus rate, exert negative inotropic effects and slow atrioventricular conduction. Automaticity, membrane responsiveness and effective refractory period of Purkinje fibres are also reduced. The typical extracardiac side effects are due to (3-adrenoceptor blockade in other organs and include bronchospasm, hypoglycemia, increase in peripheral vascular resistance, depressions, nausea and impotence. 

Class II antiarrhythmic drugs are (3-adrenoceptor antagonists such as propranolol, metoprolol or atenolol. (3-adrenoceptor antagonists slow sinus rate and atrioventricular conduction and exert negative inotropic effects. 

Class IV antiarrhythmic drugs are Ca2+ channel blockers, which predominantly slow sinus rate and atrioventricular conduction and thus are used in the treatment of supraventricular tachyarrhythmias. These drugs exert a pronounced negative inotropic effect. 

Hi-receptors in the adrenal medulla stimulates the release of the two catecholamines noradrenaline and adrenaline as well as enkephalins. In the heart, histamine produces negative inotropic effects via Hr receptor stimulation, but these are normally masked by the positive effects of H2-receptor stimulation on heart rate and force of contraction. Histamine Hi-receptors are widely distributed in human brain and highest densities are found in neocortex, hippocampus, nucleus accumbens, thalamus and posterior hypothalamus where they predominantly excite neuronal activity. Histamine Hrreceptor stimulation can also activate peripheral sensory nerve endings leading to itching and a surrounding vasodilatation ( flare ) due to an axonal reflex and the consequent release of peptide neurotransmitters from collateral nerve endings. 

Treatment with nondihydropyridine calcium channel blockers (diltiazem and verapamil) may worsen HF and increase the risk of death in patients with advanced LV dysfunction due to their negative inotropic effects. Conversely, dihydropyridine calcium channel blockers, although negative inotropes in vitro, do not appear to decrease contractility in vivo. Amlodipine and felodipine are the two most extensively studied dihydropyridine calcium channel blockers for systolic H F.39 4() These two agents have not been shown to affect patient survival, either positively or negatively. As such, they are not routinely recommended as part of a standard HF regimen however, amlodipine and felodipine can safely be used... 

Current data suggest little benefit on clinical outcomes beyond symptom relief for calcium channel blockers in the setting of ACS.43 Moreover, the use of first-generation shortacting dihydropyridines, such as nifedipine, should be avoided because they appear to worsen outcomes through their negative inotropic effects, induction of reflex sympathetic activation, tachycardia, and increased myocardial ischemia.43 Therefore, calcium channel blockers should be avoided in the acute management of MI unless there is a clear symptomatic need or a contraindication to p-blockers. 

Because of their negative inotropic effects, /J-blockers should be started in very low doses with slow upward dose titration to avoid symptomatic worsening or acute decompensation. Patients should be titrated to target doses when possible to provide maximal survival benefits. However, even lower doses have benefits over placebo, so any dose is likely to provide some benefit. 

Verapamil decreases heart rate, slows atrioventricular (AV) nodal conduction, and produces a negative inotropic effect that may precipitate heart failure in patients with borderline cardiac reserve. Diltiazem decreases AV conduction and heart rate to a lesser extent than verapamil. 

Q69 At therapeutic doses the occurrence of o negative inotropic effect v/ith omlodipine is rarely seen. Amlodipine has greater selectivity for vascular smooth muscle than for myocardium. 

Amlodipine is a calcium-channel blocker that blocks the intracellular movement of calcium ions and hence slows the contractility of the myocardium and relaxes the vascular smooth muscle. The negative inotropic effects are rarely seen at therapeutic doses since amlodipine has a greater selectivity for vascular smooth muscle than for the myocardium. 

Halothane exerts a pronounced hypotensive effect, to which a negative inotropic effect contributes. Enflurane and isoflurane cause less circulatory depression. Halothane sensitizes the myocardium to catecholamines (caution serious tachyarrhythmias or ventricular fibrillation may accompany use of catecholamines as antihypotensives or toco-lytics). This effect is much less pronounced with enflurane and isoflurane. Unlike halothane, enflurane and isoflurane have a muscle-relaxant effect that is additive with that of nondepolarizing neuromuscular blockers. 

Exposure to 50 ppm for 90 minutes may cause aggravation of angina pectoris exposed anginal patients may show a negative inotropic effect (weakened force of myocardial contraction) 50 ppm for 120 minutes may cause aggravation of intermittent claudication. ... 

Concomitant antiarrhythmic therapy Reserve concomitant use of disopyramide with other class lA antiarrhythmics or propranolol for life-threatening arrhythmias unresponsive to a single agent. Such use may produce serious negative inotropic effects or may excessively prolong conduction, particularly with cardiac decompensation. 

As propafenone exerts both beta blockade and a (dose-related) negative inotropic effect on cardiac muscle, fully compensate patients with CHF before receiving propafenone. If CHF worsens, discontinue propafenone unless CHF is due to the cardiac arrhythmia and, if indicated, restart at a lower dosage only after adequate cardiac compensation has been established. 

Hemodynamic effects - Small decreases in cardiac output and increases in systemic vascular resistance have occurred, with no significant negative inotropic effect. Blood pressure and pulse rate remain essentially unchanged. Mild depression of myocardial function has been observed following IV mexiletine (dosage form not available in the US) in patients with cardiac disease. 

CHF Do not administer itraconazole for the treatment of onychomycosis in patients with evidence of ventricular dysfunction, such as CHF or a history of CHF. Discontinue if signs and symptoms of CHF occur during treatment. If signs and symptoms of CHF occur during treatment, reassess the continued use of itraconazole. When itraconazole was administered IV to dogs and healthy human volunteers, negative inotropic effects were seen. 

Verapamil and diltiazem have negative inotropic effects. These calcium channel blockers may be harmful in asymptomatic patients with a low LVEF and in post-MI patients without HF symptoms. Digoxin will not be good to use in patients with low FF, with sinus rhythm and no history of HF symptoms, because the benefits will not exceed the risk. 

Disopyramide directly depresses myocardial contractility. The negative inotropic effect may be detrimental in patients with compromised cardiac function. Some patients develop overt congestive heart failure. At usual therapeutic doses, depression of myocardial function is not a problem in most patients with normal ventricular function. 

Flecainide produces modest negative inotropic effects that may become significant in the subset of patients with compromised left ventricular function. 

The common side effects seen in chronic therapy (Table 19.3) are mostly related to vasodilation—headaches, dizziness, facial flushing, hypotension, and so forth. High doses of verapamil in elderly patients are known to cause constipation. Serious side effects, especially following the intravenous use of verapamil, include marked negative inotropic effects and depression of preexisting sick sinus syndrome, A-V nodal disease, and... 

Mechanism of Action An antiarrhythmic that prolongs the refractory period of the cardiac cell by direct effect, decreasing myocardial excitability and conduction velocity. Therapeutic Effect Depresses myocardial contractility. Has anticholinergic and negative inotropic effects. 

Most of the haemodynamic effects of opioids are related to decreased central sympathetic outflow, specific vagal effects or, in the case of morphine and pethidine, histamine release. Fentanyl and its analogues do not cause histamine release. All opioids, with the exception of pethidine, produce bradycardia by actions on the afferent fibres of the vagus and the nucleus tractus solitarius and nucleus commissuralis, which have very high densities of opioid receptors. Pethidine often produces tachycardia, possibly due to its structural similarity to atropine. In isolated heart or heart-muscle preparations, opioids produce a dose-related negative inotropic effect, but only at concentrations 100 to several thousand times those found clinically. 

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