Selective P, blockers

Two different types of P-adrenoceptors have been characterized and categorized as P - and P2-subtypes. The P -receptors are associated primarily with the cardiac muscle, whereas the P2-subtype is located peripherally. Selective P -blockers include practolol (121) and (122), atenolol (123) and (124), and betaxolol (125) and (126). 

Non-selective P-blockers are first-line treatment for preventing variceal bleeding they vasoconstrict the splanchnic bed through multiple mechanisms. 

Only non-selective p-blockers reduce bleeding complications in patients with known varices. Blockade of P, receptors reduces cardiac output and splanchnic blood flow. 02-Adrenergic blockade prevents p2-receptor-mediated splanchnic vasodilation while allowing unopposed a-adrenergic effects this enhances vasoconstriction of both the systemic and splanchnic vascular beds. The combination of P, and P2 effects makes the non-selective p-blockers preferable to car-dioselective agents in treating portal hypertension.1,36,41... 

Nitrates have been suggested in patients who do not achieve therapeutic goals (heart rate reduction) with P-blocker therapy alone. Trials to evaluate the effects of nitrates (e.g., isosorbide mononitrate) on portal pressure, both alone and in combination with P-blockers, show enhanced reduction of portal pressure however, there is an increase in mortality when nitrates are used alone. Adverse effects are significantly higher in patients treated with the combination of non-selective P-blockers and nitrates as opposed to P-blocker monotherapy.42,43 Unfortunately,... 

It is recognized that many patients treated for glaucoma require a second concomitant medication to lower lOP. The appeal of a combination product stems from the belief that adherence to complex multiple medical regimens is improved with simplified dosing schedules. The two most common ocular hypotensive medications are in the prostaglandin and P-blocker classes. Several combination products are presently available worldwide that combine various prostaglandin analogues with a non-selective P-blocker.These products include a combination of latanoprost or travoprost with timolol. Studies have demonstrated comparable efficacy and in the case of the travoprost-timolol combination, a favorable lOP reduction between the combination product and the separate compounds administered concomitantly. At the present time, neither combination product is available in the United States. 

Labetalol is a racemic mixture, one isomer is a P-adrenoceptor blocker (nonselective), another blocks a-adrenoceptors its dual effect on blood vessels minimises the vasoconstriction characteristic of nonselective P-blockade so that for practical purposes the outcome is similar to using a p -selective P-blocker (see Table 23.1). It is less effective than drugs like atenolol or bisoprolol for the routine treatment of h3q>ertension, but is useful for some specific indications. 

However, there is usually a price to pay for extensive alteration in autonomic processes in the body. For instance, adverse effects include precipitation of asthma attacks. Similarly, the blood flow in the extremities will often be reduced, so patients may well complain of cold feet or hands. It may be possible to gain some selectivity of drug action, with consequent minimization of side-effects, by using receptor-subtype-selective p-blockers. Thus, Pi-adrenoceptor antagonists have a higher affinity for the pj-adrenoceptor of the heart, and thus they may have some preferential action there, since P2-adrenoceptors are found at most other sites in the body, including the airways and blood vessels. 

Other p antagonists have been evaluated to varying extents. Oxprenolol (no longer marketed in the U.S.) and penbutolol (levatol) are non-subtype-selective p blockers with intrinsic sympathomimetic activity. Medroxalol is a nonselective p blocker with receptor—blocking activ-... 

Dysfunction of beta-adrenoceptors has been implicated in essential tremor, and management usually involves administration of propranolol. However, the more selective P, blocker meto-prolol is equally effective and may be more suitable in a patient with pulmonary disease. The answer is (C). 

Isosteric replacement of the ethereal linkage (—O—) with such moieties as CH2, S or NCH3 is formd to be more or less detrimental however, a tissue-selective P-blocker has been synthesized by replacing NH for O. 

Figure 3.14 Structures of selected P-blockers dichloroisoprenaline (1), propranolol (2), atenolol (3), bisoprolol (4), metoprolol (5), and bupranolol (6).

TABLE 3.6 Characteristic Fragment Ions of Selected P-blockers after Derivatization Using EI°... 

TABLE 4.7 Characteristic Product Ions of Selected P-blockers Generated by Positive ESI and CID... 

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