Heart failure sympathomimetics

Cardiostimulation. By stimulating Pi-receptors, hence activation of ade-nylatcyclase (Ad-cyclase) and cAMP production, catecholamines augment all heart functions, including systolic force (positive inotropism), velocity of shortening (p. clinotropism), sinoatrial rate (p. chronotropism), conduction velocity (p. dromotropism), and excitability (p. bathmotropism). In pacemaker fibers, diastolic depolarization is hastened, so that the firing threshold for the action potential is reached sooner (positive chronotropic effect, B). The cardiostim-ulant effect of p-sympathomimetics such as epinephrine is exploited in the treatment of cardiac arrest Use of p-sympathomimetics in heart failure carries the risk of cardiac arrhythmias. 

Due to the numerous indications for these type of drugs a large number of compounds have been introduced into therapy. Differences between these drugs concern their affinity profile towards the Pi-and j82-adrenoceptors, the lipophilicity and the ability to partially activate the receptor (intrinsic sympathomimetic activity, ISA). One isomer of the racemic mixture of labetalol and carvedilol are a-blocker as well. Although this might be therapeutically useful in the treatment of conditions like hypertension and heart failure, there is no real evidence for a contribution of this property to the overall beneficial effect of these compounds. 

Dobutamine Betai-selective agonist t increases cAMP synthesis Increases cardiac contractility, output Acute decompensated heart failure intermittent therapy in chronic failure reduces symptoms IV only duration a few minutes Toxicity Arrhythmias. Interactions Additive with other sympathomimetics... 

Dopamine Dopamine receptor agonist higher doses activate 13 and a adrenoceptors Increases renal blood flow higher doses increase cardiac force and blood pressure Acute decompensated heart failure shock IV only duration a few minutes Toxicity Arrhythmias Interactions Additive with sympathomimetics... 

SYMPATHOMIMETICS MOST COMMONLY USED IN CONGESTIVE HEART FAILURE... 

Sympathomimetics Most Commonly Used in Congestive Heart Failure... 

Beta-blockers with intrinsic sympathomimetic (ISA) properties are not pure antagonists. These agents partially stimulate the beta-receptors as well. Theoretically, these agents are less likely to cause bradycardia and bronchospasm, increase lipids, decrease cardiac output, and cause peripheral vasoconstriction. However, these agents can still cause bronchospasm or exacerbate heart failure. 

Most of these sympathomimetic drugs tend to be reserved for acute emergencies, including cardiogenic shock, septic shock, in heart surgery and in cardiac infarction or cardiac arrest. Xamoterol is a partial agonist at -adrenoceptors, and is used in mild heart failure only (see P-Adrenoceptor agonists). 

An important issue regarding use of /3-blockers in heart failure is whether the benefits seen represent a class effect, and if not, which drug(s) should be used. The evidence that benefits of /8-blockers in heart failure should not be viewed as a class effect is fairly strong. Specifically, a study powered for mortahty reduction showed that bucindolol was no different from placebo. There has been much debate since publication of this trial about why this particular /8-blocker failed to show benefit, but most practitioners now beheve it relates to ancillary properties of the drug that were counterproductive in heart failure, namely, intrinsic sympathomimetic activity or... 

Bipyridines, sympathomimetics, diuretics, beta blockers, and calcium channel blockers also have uses in treating heart failure. Rationales for their use are indicated. A newer drug, nesiritide, is a recombinant form of natriuretic peptide,... 

It would also appear that additional receptor subtypes remain to be targeted. Even if the ,l adrenoceptor is not a discrete protein, but rather an affinity state of the adrenoceptor, it appears that its selective blockade is possible (Hieble and Ruffolo, 1997). There is evidence that the intrinsic sympathomimetic activity of some /8-adrenocep-tor antagonists may be deleterious under some conditions (Willette et al., 1998). Since the adrenoceptor appears to be involved in this action it is possible that blockade may be beneficial, especially if the receptor is activated in heart failure patients. 

Esmolol (Brevibloc, others) is a Pi-selective antagonist with a very short duration of action. It has little if any intrinsic sympathomimetic activity, and it lacks membrane-stabilizing actions. Esmolol is administered intravenonsly and is nsed when P-blockade of short dnration is desired, or in critically ill patients in whom adverse effects of bradycardia, heart failure, or hypotension may necessitate rapid withdrawal of the drug. 

ADHD, attention-deficit/hyperactivity disorder AV, atrioventricular BPH, benign prostatic hypertrophy CAD, coronary artery disease CHF, congestive heart failure COPD, chronic obstructive pulmonary disease CV, cardiovascular DA, dopamine Dl, subtype 1 dopamine receptor Epi, epinephrine FFA, free fatty acids 5-HT, serotonin ISA, intrinsic sympathomimetic activity MI, myocardial infarction NE, norepinephrine NO, nitric oxide PVR, peripheral vascular resistance. 

In the decompensated patient who presents with heart failure and normal systemic vascular resistance, afterload reduction may be contraindicated, and treatment with a parenteral agent such as dobutamine may be preferable. The risk attendant to treatment with sympathomimetic drugs is related to the increase in myocardial Oj consumption that may occur this is of particular concern in patients with left heart failure that occurs as a direct consequence of myocardial ischemia. This clinical quandary has become less common in the era of aggressive myocardial revascularization when it is encountered, coadministration of dobutamine with parenteral nitroglycerin should be considered. 

The Austrian pharmacologist Heribert Konzett (1912-2004) had discovered in 1940 isoprenaUne, which should become the prototype of p-selective sympathomimetics. Due to its bronchodilatory properties, but without causing hyper-tention, it was considered the drug of choice to treat asthmatic attacks. With almost equally strong effect on pj- and p2-receptors, it was of concern, that isoprenaline acts as a very potent cardiac stimulant. Further structural optimisation then led to more selective pj-sympathomimetics, like dobutamine, for the treatment of heart failure and cardiogenic shock, while selective p2-sympathomimetics were aimed at safer therapies of bronchial asthma. 

A major disadvantage in the use of 6-blockers is their negative inotropic and chronotropic effects on the heart. Therefore, their use in patients with incipient heart failure is contraindicated . Sotolol has less depressant effects and has a better therapeutic ratio when compared clinically with most 6-blocking agents . Oxyprenolol and alprenolol are also less depressant upon basal heart functions possibly due to their intrinsic 6-sympathomimetic effects . ... 

Intrinsic 3-sympathomimetic activity of some 3-blockers did not appear to prevent the onset of cardiac failure in hearts dependant upon sympathetic drive. It was suggested that 3-blockers with significant 3-sympathomimetic action, such as DCI, might be less likely to precipatate heart failure. The more depressant propranolol lacks 3-sympathomimetic activity. No difference was observed between DCI and propranolol when introduced during the sympathomimetic-dependant phase of experimental heart failure in guinea pigs. ... 

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