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Timolol: antihypertensive & antiglaucoma

Figure 16.15 • Nonselective ^-blockers.

jS ^blockers are drugs that have a greater affinity for the ^-receptors of the heart than for ^-receptors in other tissues. Such cardioselective agents should provide two important therapeutic advantages. The first advantage should be the lack of a blocking effect on the ^-receptors in the bronchi. Theoretically, this would make ^1-blockers safe for use in patients who have bronchitis or bronchial asthma. The second advantage should be the absence of blockade of the vascular ^-receptors, which mediate vasodilation. This would be expected to reduce or eliminate the increase in peripheral resistance that sometimes occurs after the administration of nonse-lective ^-blockers. Unfortunately, cardioselectivity is usually observed with ^-blockers at only relatively low doses. At normal therapeutic doses, much of the selectivity is lost.

At present, the following ^-selective blockers are used therapeutically: acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone, Betoptic), bisoprolol (Zebeta), esmolol (Brevibloc), and metoprolol (Lopressor). Structures of these agents are depicted in Figure 16.16. All of these agents except esmolol are indicated for the treatment of hypertension. Atenolol and metoprolol are also approved for use in treating angina pectoris and in therapy following myocardial infarction. Betaxolol is the only ^-selective blocker indicated for the treatment of glaucoma.

Esmolol was designed specifically to possess a very short DOA; it has an elimination half-life of 9 minutes. Its effects disappear within 20 to 30 minutes after the infusion is discontinued. Esmolol must be diluted with an injection


oh o ^ "nhch(ch3)2 oh nhcoch2ch2ch3

Acebutolol: antihypertensive ch2conh2 Atenolol: antihypertensive o ^r ^nhch(ch3)2 oh o nhch(ch3)2

oh ch2ch2och2—<^j ch2och2ch2och(ch3)2

Betaxolol: antihypertensive & antiglaucoma Bisoprolol: antihypertensive o "y" ^nhch(ch3)2

oh o ^ ^nhch(ch3)2 oh ch2ch2c02ch3

Esmolol: short-acting antihypertensive ch2ch2och3

Metoprolol: antihypertensive

solution before administration; it is incompatible with sodium bicarbonate. The short DOA of esmolol is the result of rapid hydrolysis of its ester functionality by esterases present in erythrocytes (Fig. 16.17). The resultant carboxylic acid is an extremely weak jS-blocker that does not appear to exhibit clinically significant effects. The acid metabolite has an elimination half-life of 3 to 4 hours and is excreted primarily by the kidneys. This agent is administered by continuous intravenous infusion for control of ventricular rate in patients with atrial flutter, atrial fibrillation, or sinus tachycardia. Its rapid onset and short DOA render it useful during surgery, after an operation, or during emergencies for short-term control of heart rates. Esmolol and acebutolol are also indicated for treating certain cardiac arrhythmias.

In the class of ^-selective blockers, only acebutolol possesses ISA. However, this activity is very weak. Acebutolol and betaxolol possess membrane-stabilizing activity, but the activity is much weaker than that seen with propranolol.

The half-life values of acebutolol and metoprolol are comparable to that seen with propranolol, and those of atenolol and bisoprolol are about twice that of propranolol. Betaxolol, with a half-life ranging between 14 and 22 hours, has the longest DOA of the ^-selective blockers. Like pro pranolol, metoprolol has low bioavailability because of significant first-pass metabolism. Although the bioavailability of betaxolol is very high, it is metabolized extensively by the liver, with very little unchanged drug excreted in the urine. Atenolol (log P = 0.10), like nadolol (log P = 1.29), has low lipid solubility and does not readily cross the BBB. It is absorbed incompletely from the gastrointestinal tract, the oral bioavailability being approximately 50%. Little of the absorbed portion of the dose is metabolized; most of it is excreted unchanged in the urine. In the case of bisoprolol, about 50% of a dose undergoes hepatic metabolism, whereas the remaining 50% is excreted in the urine unchanged.

Acebutolol is one of the very few ^-blockers whose metabolite plays a significant role in its pharmacological actions. This drug is absorbed well from the gastrointestinal tract, but it undergoes extensive first-pass metabolic conversion to diacetolol by hydrolytic conversion of the amide group to the amine, followed by acetylation of the amine (Fig. 16.18). After oral administration, plasma levels of diace-tolol are higher than those of acebutolol. Diacetolol is also a selective ^-blocker with partial agonistic activity; it has little membrane-stabilizing activity. It has a longer half-life (8-12 hours) than the parent drug and is excreted by the kidneys.

Metabolism Labetolol

CH2CH2CO2H Figure 16.17 • Metabolism of esmolol.


Several drugs have been developed that possess both ß- and a-receptor-blocking activities within the same molecule. Two examples of such molecules are labetalol (Normodyne) and carvedilol (Coreg). As in the case of dobutamine, the arylalkyl group with nearby methyl group in these molecules is responsible for its a1-blocking activity. The bulky n-substituents and another substituted aromatic ring are responsible for its ß-blocking activity.

Labetalol (Normodyne, Trandate, others), a phenylethanolamine derivative, is representative of a class of drugs that act as competitive blockers at a1-, ß1-, and ß2-receptors. It is a more potent ß-blocker than a-blocker. Because it has two asymmetric carbon atoms (1 and 1'), it exists as a mixture of four isomers. It is this mixture that is used clinically in treating hypertension. The different isomers, however, possess different a- and ß-blocking activities. The ß-blocking activity resides solely in the (1r,1'r) isomer, whereas the a1-blocking activity is seen in the (1S,1'R) and (1s,1's) isomers, with the (1s,1'r) isomer possessing the greater therapeutic activity.63 Labetalol is a clinically useful antihypertensive agent. The rationale for its use in the management of hypertension is that its a-receptor-blocking effects produce vasodilation and its ß-receptor-blocking effects prevent the reflex tachycardia usually associated with vasodilation. Although labetalol is very well absorbed, it undergoes extensive first-pass metabolism.

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