JS-Blockers

Note The dipping reagent is to be preferred because of the strongly irritating effects of formaldehyde on the respiratory tract. Detection limits of ca. 10—40 ng have been reported for alkaloids [4] and 50 ng—1 pg for jS-blockers [2, 3]. 

In one study, researchers from Vanderbilt University in Nashville, Tennessee (USA), compared responses to a jS-blocker called atenolol among 34 patients. All patients had genetic variations affecting one of the building blocks of the receptor that binds to jS-blocker drugs, which affected the way the receptor responded to the binding of the drug. 

In turn, a- and )3-adrenoblockers are subdivided into selective and nonselective groups. Nonselective 8-adrenoblockers exhibit affinity for both and Sj-adrenoreceptors. Included in this category are propranolol, nadolol, timolol, and labetalol (a combined a- and )3-adrenoblocker). Selective jS -blockers are acebutol, atenolol, esmolol, and meto-prolol, which in therapeutic doses predominantly binds to jS -adrenoreceptor regions. 

Pindolol, oxprenolol, acebutolol and alprenolol are /3-blocker ISA. A weak sympathomimetic effect can be seen in the heart if almost all /3-adrenoceptors are occupied by these compounds. The advantage of ISA might be that a basal /3-adrenergic stimulus is left. In some vessel beds a reduction of the vascular activity and thereby a reduction in resistance has been observed with pindolol which might be beneficial in the therapy of hypertension. The pharmacodynamic and -kinetic properties of some frequently used jS-blocker are shown in Table 2. 

Beside the cardiac indications /3-blockers can be used in the therapy of glaucoma. Systemic but also the local application of these compounds can reduce intraocular pressure. The mechanism of this action is a reduced production of aqueous humor by the ciliary body. Although applied locally, jS-blockers might be absorbed in sufficient amounts to induce systemic side effects in susceptible individuals. 

Hyperthyroidism is characterized by an enhanced sympathetic activity, especially in the heart. The salutary inhibition of jS-adrenoceptors under these conditions can be achieved by all jS-blocker alike. Some of the clinically used compounds are able to reduce the conversion (de-iodination) of thyroxine (T4) to the active 3,5,3 -Triiodothyronine (T3)... 

There are various neurologic disorders which can be treated with jS-blockers like migraine, certain forms of tremor and alcohol withdrawal syndrome. Somatic manifestations of anxiety respond well to /3-adrenoceptor blockade. jS-Blockers with a selectivity for the jSi-subtype might be useful to avoid extracardial side effects. 

Since the bronchial tonus is under the relaxant influence of 62-adrenoceptor stimulation, especially unselective jS-blockers increase the respiratory resistance. In susceptible patients this might induce airway obstruction or even acute asthma. The blockade of jS2-adrenoceptors inhibits the mobilization of free fatty acids and glucose. This might result in hypoglycemia in diabetic patients. Furthermore, these patients will be not aware of the danger since most of the sympathetically mediated alerting symptoms like tachycardia are suppressed by the jS-blockers as well. jSi-Selective blockers show this type of side-effect less pronounced than unselective compounds. 

Adrenoceptors of the /3-subtype are important mediators of the sympathetic activation of the heart, kidney, and bronchi. /3-Adrenoceptors are also found in other organs and tissues such as blood vessels and the central nervous system. Accordingly, /3-adrenoceptor antagonists or jS-blockers inhibit the stimulating influence of the endogenous catecholamines (noradrenaline, adrenaline) on the various organs and tissues which are subject to sympathetic innervation. In cardiovascular medicine the /3-blockers are used in particular to blunt the sympathetic activation of the heart and kidneys. These effects are mediated by the /3i-subtype of the /3-adrenoceptors. The currently used /3-blockers are all competitive antagonists of the /3i-adrenoceptor, which is the basis of their therapeutic application. 

The jS-blockers used in ophthalmology (treatment of open-angle glaucoma) are not discussed here. 

The therapeutic efficacy of ATi-receptor blockers in hypertensive disease is well documented. The ATi-blockers are assumed to be as effective as various classes of well-known antihypertensives, such as jS-blockers, diuretics, ACE-inhibitors and calcium antagonists. A major advantage of the ATi-blockers may be their favourable pattern of side-effects, which so far does not appear to differ from the use of placebo. In particular the fact that ATi-blockers do not cause cough (in contrast to the ACE-inhibitors) appears to be an advantage. 

The six main drug classes used, worldwide, for blood pressure lowering treatment are diuretics, jS-blockers, calcium channel blockers (CCB), ACE inhibitors, angiotensin II (All) receptor blockers and a-adrenergic blockers. In some parts of the world, reserpine and methyldopa are also frequently used. 

Highly recommended are jS-blockers for those who have a prior MI event. They showed a significant effect on death. Recent studies suggest that patients who have coronary artery disease without acute myocardial infarction and/or congestive heart failure have approximately the same protective benefit against death. 

Nitroglycerin will be effective for on-going chest pain relief. Ca channel antagonists and long-acting Nitrates can be used when jS-blockers are contraindicated. These drugs may be also used for the initial therapy, additional to -blockers or when jS-blockers treatment failed. However, for the effectiveness of vasodilatation itself is relatively weaker evidence. 

Prompt administration of Aspirin 162 mg and a jS-blocker is strongly recommended. 

The use of inotropic support will be acceptable only in low-cardiac-output status. Eor pulmonary congestion, ACE-inhibitor therapy and aldosterone blockade will be best recommended, especially for long term use. It will be good to start with a jS-blockers before discharge for secondary prevention. 

Administration of one of the jS-blockers and an ACE-I is mandatory for all patients with a recent MI, regardless of the ejection fraction (EE). If the LVEE is reduced in patients without a history of MI, yS-blockers and/or ACE-I should be administrated as long as the patients do not have heart failure symptoms. If an ACE-I is contraindicated, it has to be substituted by an ARB, if the patient is post-MI with low EE, but no manifest HF. This may also be true without a history of MI. ACE-I and ARB are beneficiary for those with hypertension and left ventricular hypertrophy (LVH), without HF symptoms. 

The cornerstone of therapy for ventricular fibrillation is electrical deflbrillation. In the acute setting, defibrination is first-line therapy. Intravenous bretylium can occasionally contribute to conversion, but this is infrequent. In the management of out-of-hospital cardiac arrest, high-dose epinephrine (5 mg intravenously) improves the rate of successful resuscitation in patients with asystole, but not in those with ventricular fibrillation, when compared with the standard dose of 1 mg. Vasopressin (40 U intravenously) may more effective than 1 mg intravenous epinephrine in out-of-hospital patients with ventricular fibrillation that is resistant to electrical defibrillation. The OPTIC smdy (see Connolly et al., 2006) showed that amiodarone plus jS-blocker is superior than sotalol or jS-blocker alone for reducing ICD shocks in patients with reduced left ventricular function and history of sustained VT, VF, or cardiac arrest. 

Norbomene was functionalized with cyclodextrins and surface grafted onto silica-based supports using ROMP (44). The CSP are suitable for the enantioselective separation various amino acids, including jS-blockers and other compounds, such as chiral ferrocene derivates. 

Q4 Beta-adrenoceptor (/3-adrenoreceptors) antagonists were originally introduced as anti-anginal agents. It was then noted that patients BP decreased over a period of weeks these agents have now been used to treat hypertension for many years. The beta-blockers (jS-blockers) are the agents of choice for young hypertensive patients. Their mechanism of action is unclear, but there are several components ... 

Alkylamincs have a variety of applications in the chemical industry as starting materials for the preparation of insecticides and pharmaceuticals. Labetalol for instance, a so-called jS-blocker used for the treatment of high blood pressure, is prepared by Sisr2 reaction of an epoxide with a jirimary amine. The substance marketed for drug use is a mixture of all four possible stereoisomers, but the biological activity derives primarily from the R.R) isomer. 

The paucity of QSAR studies in whole animals is understandable in terms of the costs, the heterogeneity of the biological data, and the complexity of the results. Nevertheless, in the few studies that have been done, excellent QSAR have been obtained, despite the small number of subjects in the data set (164). One particular example is insightful. The renal and nonrenal clearance rates of a series of 11 jS-blockers, including bufuralol, tolamolol, propranolol, alprenolol, oxprenolol, acebutol, timolol, metoprolol, prindolol, atenolol, and nadolol were measured (230). The following QSAR were formulated using those data (164). 

Similar adsorption data have also been reported for the adsorption isotherms of many compounds in various systems. For example, the adsorption data of several jS-blockers, particularly those of propranolol acquired in a 1 to 7000 relative concentration range, on an immobilized cellulase. Cel 7A, fit very well to the bi-Langmuir model, as illustrated in Figure 3.13 [47,55]). The enantioselective site was identified as a pair of amino acid residues in the tunnel formed by the main chain of the protein. The parameters of the isotherm depend on the pH as illustrated in Figure 3.14. A bi-Langmuir model was also found to accoimt well for the separation of pairs of enantiomers on polymers molecularly imprinted with one of the enantiomers [56]. Note, however, that there are also many systems in which the adsorption isotherms of enantiomers are not accounted for by a bi-Langmuir model showing that enantioselectivity is often achieved by a complex... 

This isotherm model has been used successfully to accoimt for the adsorption behavior of numerous compounds, particularly (but not only) pairs of enantiomers on different chiral stationary phases. For example, Zhou et ah [28] foimd that the competitive isotherms of two homologous peptides, kallidin and bradyki-nine are well described by the bi-Langmuir model (see Figure 4.3). However, most examples of applications of the bi-Langmuir isotherm are found with enantiomers. lire N-benzoyl derivatives of several amino acids were separated on bovine serum albumin immobilized on silica [26]. Figure 4.25c compares the competitive isotherms measured by frontal analysis with the racemic (1 1) mixture of N-benzoyl-D and L-alanine, and with the single-component isotherms of these compounds determined by ECP [29]. Charton et al. foimd that the competitive adsorption isotherms of the enantiomers of ketoprofen on cellulose tris-(4-methyl benzoate) are well accounted for by a bi-Langmuir isotherm [30]. Fornstedt et al. obtained the same results for several jS-blockers (amino-alcohols) on immobilized Cel-7A, a protein [31,32]. 

FIGURE 17-6. Algorithm for the treatment of atrial fibrillation and atrial flutter. Sx = symptoms AVN = AV node DCC = direct-current cardioversion CCB = calcium channel antagonist (verapamil or diltiazem) BB = jS-blocker ASA = aspirin OHD = organic heart disease AADs = antiarrhythmic drugs INR = international normalized ratio MVD = mitral valve disease CHF = congestive heart failure HTN = hypertension DM = diabetes mellitus. 

Aspirin, NSAIDs (cyclooxygenase inhibitors), sulfites, benzalkonium chloride, jS-blockers Occupational stimuli... 

Adaprolol. If membrane transport (lipophilicity)and relative stability are important for pharmacological activity, then the R group of (8)should be relatively lipophilic and impart ester stability. From the various soft jS-blockers developed in our laboratory (n = 1),... 

Adverse effects associated with practolol have been collectively described as the oculomucocutaneous syndrome. The incidence of the syndrome is small but the seriousness of the tissue damage has tended to overshadow this incidence. Practolol was marketed in 1970, and by the end of 1975 the drug had been used for some 300,000 patient years in the UK, and around one million worldwide. By October 1974, 164 cases were known, and in November 1977, the total had reached 915 (Nicholls 1978). The drug was withdrawn in 1976. It is now reasonably certain that none of the other jS-blockers in clinical use has so far induced an oculomuco-cutaneous-type syndrome. 

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