A. ß-Sympatholytics: effect on cardiac function

A. ß-Sympatholytics: effect on cardiac function

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B. ß-Sympatholytics: effect on bronchial and vascular tone
C. "Anxiolytic" effect of ß-sympatholytics

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Types of P-Blockers

The basic structure shared by most p-sympatholytics is the side chain of P-sympathomimetics (cf. isoproterenol with the P-blockers propranolol, pindo-lol, atenolol). As a rule, this basic structure is linked to an aromatic nucleus by a methylene and oxygen bridge. The side chain C-atom bearing the hydroxyl group forms the chiral center. With some exceptions (e.g., timolol, penbuto-lol), all P-sympatholytics are brought as racemates into the market (p. 62).

Compared with the dextrorotatory form, the levorotatory enantiomer possesses a greater than 100-fold higher affinity for the p-receptor and is, therefore, practically alone in contributing to the P-blocking effect of the racemate. The side chain and substituents on the amino group critically affect affinity for P-receptors, whereas the aromatic nucleus determines whether the compound possess intrinsic sympathomi-metic activity (ISA), that is, acts as a partial agonist (p. 60) or partial antagonist. In the presence of a partial agonist (e.g., pindolol), the ability of a full agonist (e.g., isoprenaline) to elicit a maximal effect would be attenuated, because binding of the full agonist is impeded. However, the P-receptor at which such partial agonism can be shown appears to be atypical (p3 or p4 subtype). Whether ISA confers a therapeutic advantage on a P-blocker remains an open question.

As cationic amphiphilic drugs, P-blockers can exert a membrane-stabilizing effect, as evidenced by the ability of the more lipophilic congeners to inhibit Na+-channel function and impulse conduction in cardiac tissues. At the usual therapeutic dosage, the high concentration required for these effects will not be reached.

Some P-sympatholytics possess higher affinity for cardiac P1-receptors than for P2-receptors and thus display cardioselectivity (e.g., metoprolol, ace-butolol, bisoprolol). None of these blockers is sufficiently selective to per mit its use in patients with bronchial asthma or diabetes mellitus (p. 92).

The chemical structure of P-block-ers also determines their pharmacoki-netic properties. Except for hydrophilic representatives (atenolol), P-sympatho-lytics are completely absorbed from the intestines and subsequently undergo presystemic elimination to a major extent (A).

All the above differences are of little clinical importance. The abundance of commercially available congeners would thus appear all the more curious (B). Propranolol was the first P-blocker to be introduced into therapy in 1965. Thirty-five years later, about 20 different congeners are being marketed in different countries. This questionable development unfortunately is typical of any drug group that has major therapeutic relevance, in addition to a relatively fixed active structure. Variation of the molecule will create a new patentable chemical, not necessarily a drug with a novel action. Moreover, a drug no longer protected by patent is offered as a generic by different manufacturers under dozens of different proprietary names. Propranolol alone has been marketed by 13 manufacturers under 11 different names.




Atenolol o II

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