Negative inotropism

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. 

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. 

Ryanodine leads to contracture of mammalian skeletal muscle, whereas it causes negative inotropism in cardiac muscle. This apparent opposite effects are due to difference in the Ca2+ extruding activity the released Ca2+ remains within cytoplasm in skeletal muscle because of low Ca2+ extruding activity, whereas the increased cytoplasmic Ca2+ is rapidly excluded out of the cytoplasm in cardiac muscle via Na+ -Ca2+ -exchange. 

Hattori Y, Levi R Effect of PGDj on cardiac con- 43 tractihty a negative inotropism secondary to coronary vasoconstriction conceals a primary positive inotropic action. J Pharmacol Exp Ther 1986 237 ... 

Cardiac function (i.e., can the patient tolerate negative inotropic medications)... 

Inflammatory cytokines have been implicated in the pathophysiology of HF.9 Several proinflammatory (e.g., tumor necrosis factor-a [TNF-a], interleukin-1, interleukin-6, and interferon-y) and anti-inflammatory cytokines (e.g., interleukin-10) are overexpressed in the failing heart. The most is known about TNF-a, a pleiotrophic cytokine that acts as a negative inotrope, stimulates cardiac cell apoptosis, uncouples 3-adrenergic receptors from adenylyl cyclase, and is related to cardiac cachexia. The exact role of cytokines and inflammation in HF pathophysiology continues to be studied. 

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. 

In patients who have failed initial therapy (i.e., salvage), liposomal amphotericin products, itraconazole, or the echinocandin caspofungin can be used. Itraconazole has a response rate of approximately 40%.100 Oral itraconazole exhibits erratic absorption the IV formulation is suspended in cyclodextrin, which is eliminated renally, and thus IV itraconazole should be avoided in patients with a creatinine clearance of less than 30 mL/minute (0.29 mL/s m2).103 Itraconazole also has negative inotropic cardiac effects and increases the serum concentrations of medications (e.g., cyclophosphamide, etopo-side, calcineurin inhibitors, and sirolimus). 

Bradycardia, decreased conduction (atrioventricular block at high doses), small negative inotropic action... 

Drugs may precipitate or exacerbate HF because of their negative inotropic, cardiotoxic, or sodium- and water-retaining properties. 

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. 

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