P-adrenoceptor antagonists

Trausch, B., Oertel, R., Richter, K., Gramatte, T., Disposition and bioavailability of the P-adrenoceptor antagonist Talinolol in man, Biopharmaceut. Drug Disp. 1995, 16, 403-414. 

An SPE cartridge can be used multiple times, especially after the samples are pretreated with protein precipitation. Bourgogne et al. (2005) quantitated talinolol, a p -adrenoceptor antagonist used to treat arterial hypertension and coronary heart disease, in human plasma. The sample was first precipitated with perchloric acid and the supernatant was injected directly. An Xterra MS analytical column (50 x 4.6 mm, 3.5 [m, Waters) with a C18 recolumn filter (4x2 mm, 3.5 /.mi, Phenomenex) and a C8 EC cartridge were chosen. The cycle time was 4.8 min and linear range was 2.5 to 200 ng/mL. Protein precipitation allowed the SPE cartridge to be used for more than 90 injections. 

Nielsen HM, Rassing MR (2000b) TR146 cells grown on filters as a model of human buccal epithelium IV. Permeability of water, mannitol, testosterone and P-adrenoceptor antagonists. Comparison to human, monkey and porcine buccal mucosa. Int J Pharm 194 155-167... 

For simple molecules, like p-adrenoceptor antagonists octanol/water log D74 values are remarkably predictive of absorption potential. Compounds with log Dy 4 values below 0 are absorbed predominantly by the paracellular route and compounds with log Dy 4 values above 0 are absorbed by the transcellular route. 

Fig. 4.5 Central receptor occupancy after oral administration of p-adrenoceptor antagonists A, atenolol B, metoprolol C, pindolol D, propranolol. The high occupancy of pi receptors does not correlate with physicochemical properties (lipophilicity). The occupation of p2 receptors correlates with sleep disturbances and the intrinsic selectivity of the compounds.

Middlemiss, D.N. (1986) Blockade of the central 5-HT autoreceptor by P-adrenoceptor antagonists. Eur Pharmacol 120 51-56. 

P. A. van Zwieten (1993). An overview of the pharmacodynamic and therapeutic potential of combined a and P-adrenoceptor antagonists. Drugs 45 509. 

Traditional long-term anti-ischaemic triple therapy for coronary artery disease consists of a long-acting nitrate, p-adrenoceptor antagonist and a calcium-entry blocker. Most of these agents are also used for the treatment of hypertension. 

Table 8.4 Details of currently available P adrenoceptor antagonists, their relative degree of pi selectivity, the absence or presence of intrinsic sympathomimetic activity, and the availability of intravenous formulations...

Concomitant use with sympathomimetic drugs, p-adrenoceptor antagonists, calcium channel-entry blockers and other cardioactive drugs may result in bradyarrhythmias, bigemini, or tachyarrhythmias. Cardiac rhythm should be closely monitored and drug dosages carefully adjusted. Digoxin is mainly excreted by the kidneys and plasma levels should be closely monitored in patients with acute renal failure and in those whose renal function is compromised. 

Class II drugs are the p-adrenoceptor antagonists that suppress the sympathetic modulation of the heart action. They are used in the therapy of sinus tachycardia, supraventricular paroxysmal tachycardia and ventricular extra-systoles. Because of its rapid onset and short duration of action, esmolol is the preferred drug in this class for intra-operative use. 

Should it occur, treatment is largely symptomatic chlorpromazine 50-100 mg may control the central excitatory symptoms, and contribute to control of others, while more specific antihypertensive therapy may be required labetalol, a combined a- and p-adrenoceptor antagonist, has been used successfully. Arrhythmias may require 3 blockade. 

Combined therapy using calcium channel blockers with p-adrenoceptor antagonists is increasingly common, and is probably safest with the dihydropyridines. Synergy occurs that can lead to marked interference with... 

Liu, X., Callaerts-Vegh, Z., Evans, K.L., and Bond, R.A. 2002. Chronic infusion of p-adrenoceptor antagonist and inverse agonists decreases elevated protein kinase A activity in transgenic mice with cardiac-specific overexpression of human P2-adrenoceptor. J. Cardiovasc. Pharmacol. 40 448 155. 

Similar to the theoretical model of Palm et al. [54], based on dynamic surface properties for the prediction of drug absorption into human intestinal Caco-2 cell lines the authors used their molecular dynamics/GRID approach to correlate the absorption of the same set of six P-adrenoceptor antagonists with the coefficients obtained by the water probe at contour level -2 and -3 kcal/mol. 

A possible inhibitory effect of amfebutamone on CYP2D6 was used to explain an episode of severe bradycardia in a man taking the p-adrenoceptor antagonist, metoprolol (33). 

The potential ocular hypotensive effects of P-adrenoceptor antagonists (P-blockers) were first evaluated in the 1970s. This section highlights five agents currently marketed in the United States timolol, levobunolol, betaxolol, metipranolol, and carteolol (Table 10-1). 

More broadly, timolol therapy should be considered with caution in patients with any significant sign, symptom, or history for which systemic beta-blockade would be medically imwise.This includes disorders of cardiovascular or respiratory origin (e g., asthma, chronic bronchitis, and emphysema) as well as many other conditions. Spirometric evaluation after institution of timolol therapy may help to identify patients in whom bronchospasm develops after commencement of therapy. In general, however, patients with asthma and other obstructive pulmonary diseases should avoid this drug. Sympathetic stimulation may be essential to support the circulation in individuals with diminished myocardial contractility, and its inhibition by P-adrenoceptor antagonists may precipitate more severe cardiac feilure. 

Like levobimolol, metipranolol has an active metabo-Ute,des-acetyl-metiptanolol, which is an effective p-blocker. Metipranolol has been used in concentrations ranging from 0.1% to 0.6% and has ocular hypotensive efficacy within the range of other noncardioselective agents. As with other p-adrenoceptor antagonists, metipranolol decreases aqueous humor production. Retinal perfusion pressure and blood flow appear to increase during treatment with topical metipranolol. 

---