P-adrenergic agents

Dopamine is a a- and P-adrenergic agent with dopaminergic activity Low doses of dopamine (1 to 5 mcg/kg per minute) maintain renal perfusion, higher doses (greater than 5 mcg/kg per minute) exhibit a- and P-adrenergic activity and are frequently utilized to support blood pressure and to improve cardiac function. Low doses of dopamine should not be used for renal protection as part of the treatment of severe sepsis.24,27-28... 

Dunn III, W.J., Wold, S. and Martin, Y.C (1978). Structure-Activity Study of p-Adrenergic Agents Using the SIMCA Method of Pattern Recognition. J.Med.Chem., 21,922-930. 

The p-hydroxy and p-amino acid structural motif occurs commonly in compounds of pharmaceutical importance [1]. Examples include the p-substituted P-adrenergic agents, used in the treatment of cardiovascular and psychiatric disorders [2-4], and the biologically active molecules cispentacin [5], sitagliptin [6] (Figure 14.1), taxol [7], and otamixaban [8]. 

The other main p-adrenergic agents authorised for carcass quality improvement are ractopamine and zilpaterol (Figure 13.13). These are approved in a number of countries including the USA where they are permitted in cattle, pigs and turkeys (ractopamine) or cattle (zilpaterol), but they are not permitted in the EU. 

RNHCH.CH(OHlCH— R R P Adrenergic receptor blocking agents 473... 

Synthetic Derivatives of Indoles as Pharmaceuticals. Thousands of indole derivatives have been prepared and evaluated as potential pharmaceuticals (32). Of those which have been put into use perhaps the most important are the nonsteroidal antiinflammatory agent indomethacin [53-86-1] (10) (33) and the p-adrenergic blocker pindolol [13823-86-9] (11) (34). 

Aerosol adniinistration of isoproterenol produces a prompt (2—5 minutes) intense bronchodilatation of relatively short (1 h) duration. The lack of P2-selectivity leads, in many cases, to tachycardia and blood pressure elevation. Also, use of isoproterenol, like all other known P-agonists, results in a down-regulation, or desensitization, of P-adrenergic receptors. This desensitization is only partial, and after time (depending on dose, patient, and agent), a stable, less responsive state is achieved in which P-agonists remain effective. Isoproterenol has been widely used for many years. 

Intravenous or oral doses of a P-blocker should be administered early in the care of a patient with STE ACS, and then oral agents should be continued indefinitely. Early administration of a P-blocker to patients lacking a contraindication within the first 24 hours of hospitalization is a quality care indicator.2,3 In ACS the benefit of P-blockers mainly results from the competitive blockade of P,-adrenergic receptors located on the myocardium. Pi-Blockade produces a reduction in heart rate, myocardial contractility, and blood pressure, decreasing myocardial oxygen demand. As a result of these effects, P-blockers reduce the risk for recurrent ischemia, increase in infarct size and risk of reinfarction, and occurrence of ventricular arrhythmias in the hours and days following MI.39... 

Norepinephrine is a potent a-adrenergic agent with less pronounced P-adrenergic activity. Doses of 0.01 to 3 mcg/kg per minute can reliably increase blood pressure with small changes in heart rate or cardiac index. Norepinephrine is a more potent agent than dopamine in refractory septic shock.24,27-28... 

Dobutamine is a P-adrenergic inotropic agent that can be utilized for improvement of cardiac output and oxygen delivery. Doses of 2 to 20 mcg/kg per minute increase cardiac index however, heart rate increases significantly. Dobutamine should be considered in septic patients with adequate filling... 

Thiadiazoles have proven of some utility as aromatic nuclei for medicinal agents. For example, the previous volume detailed the preparation of a series of "azolamide" diuretic agents based on this class of heterocycle. It is thus of note that the 1,2,5-thiadiazole ring provides the nucleus for a clinically useful agent for treatment of hypertension which operates by an entirely different mechanism, p-adrenergic blockade. In its preparation, reaction of the amide-nitrile 211 with sulfur monochloride leads directly to the substituted thiadiazole 212. ... 

Vasodilators. Hydralazine causes direct relaxation of arteriolar smooth muscle. An important consequence of this vasodilation, however, is reflex tachycardia (T CO). It may also cause sodium retention (T plasma volume). The resulting increase in CO tends to offset effects of the vasodilator. Therefore, these drugs are most effective when administered along with sympathetic agents such as P-adrenergic receptor antagonists, which prevent unwanted compensatory responses by the heart. 

The answer is c. (Hardman, pp 233—235.) The chief danger of therapy with p-adrenergie blocking agents, such as nadolol and propranolol, is associated with the blockade itself, p-adrenergic blockade results in an increase in airway resistance that can be fatal in asthmatic patients. Hypersensitivity reactions such as rash, fever, and purpura are rare and necessitate discontinuation of therapy... 

Other protein kinases may indirectly influence the activation of NF-kappap. For example, in contrast to the pro-inflammatory effects typically observed with activation of kinases, the elevation ofcAMP activates PKA and blocks transcription of iNOS mRNA [51,178, 229, 230]. Astrocytes contain a variety of NT receptors that are coupled to Gs-adenylate cyclase [231] and, either activation of P-adrenergic/dopamine receptors or employing agents that increase cAMP, such as forskolin (adenylate cyclase activator), PDE inhibitors [i.e. pentoxifylline], dibutyrl cAMP, or 8-bromo cAMP can attenuate lipopolysaccharide (LPS)/cytokine activated iNOS mRNA in microglia, astrocytes and a number of other cell types [51,176,177,178, 232-237]. In contrast, agents that suppress the intracellular concentration of cAM P such as H-89 and Rp-cAM P are pro-... 

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