Tolazoline Phentolamine

Figure 16.14 • Mechanism of inactivation of «-adrenergic receptors by S-haloalkylamines.

Figure 16.14 • Mechanism of inactivation of «-adrenergic receptors by S-haloalkylamines.

Phenoxybenzamine Mechanism Action

responses of smooth muscle and of the heart muscle. Although phenoxybenzamine is capable of blocking acetylcholine, histamine, and serotonin receptors, its primary pharmacological effects, especially that of vaso-dilation, may be attributed to its «-adrenergic blocking capability. As would be expected of a drug that produces such a profound «-blockade, administration is frequently associated with reflex tachycardia, increased cardiac output, and postural hypotension. There is also evidence indicating that blockade of presynaptic «2-receptors contribute to the increased heart rate produced by phenoxybenzamine.

The onset of action of phenoxybenzamine is slow, but the effects of a single dose of drug may last 3 to 4 days, because essentially new receptors must be made to replace those that have been inhibited irreversibly. The principal peripheral effects following its administration are an increase in systemic blood flow, an increase in skin temperature, and a lowering of blood pressure. It has no effect on the parasympathetic system and little effect on the gastrointestinal tract. The most common side effects are mio-sis, tachycardia, nasal stuffiness, and postural hypotension, all of which are related to the production of adrenergic blockade.

Oral phenoxybenzamine is used for the preoperative management of patients with pheochromocytoma and in the chronic management of patients whose tumors are not amenable to surgery. Only about 20% to 30% of an oral dose is absorbed.


Prazosin (Minipress), terazosin (Hytrin), and doxazosin (Cardura) are quinazoline «rblockers. As a result, in part, of its greater «^receptor selectivity, the quinazoline class of «-blockers exhibits greater clinical utility and has largely replaced the nonselective haloalkylamine and imidazoline «-blockers. Structurally, these agents consist of three components: the quinazoline ring, the piperazine ring, and the acyl moiety. The 4-amino group on the quinazoline ring is very important for «^receptor affinity. Although they possess a piperazine moiety attached to the quinazoline ring, this group can be replaced with other heterocyclic moieties (e.g., piperidine moiety) without loss of affinity. The nature of the acyl group has a significant effect on the pharmacokinetic properties.55

Prazocin Terazocin Doxazocinstructure

These drugs dilate both arterioles and veins and are thus used in the treatment of hypertension. They offer distinct advantages over the other a-blockers, because they produce peripheral vasodilation without an increase in heart rate or cardiac output. This advantage is attributed, at least in part, to the fact that prazosin blocks postjunctional a1-receptors selectively without blocking presynaptic a2-receptors. Contraction of the smooth muscle of prostate gland, prostatic urethra, and bladder neck is also mediated by a1-adrenoceptors, with a1A being predominant, and blockade of these receptors relaxes the tissue. For this reason, these agents are also used in the treatment of BPH, where they help improve urination flow rates.

Although the adverse effects of these drugs are usually minimal, the most frequent one, known as the first-dose phenomenon, is sometimes severe. This is a dose-dependent effect characterized by marked excessive postural hypotension and syncope, and can be minimized by giving an initial low dose at bedtime.

The main difference between prazosin, terazosin, and doxazosin lies in their pharmacokinetic properties. As mentioned previously, these differences are dictated by the nature of the acyl moiety attached to the piperazine ring. These drugs are metabolized extensively with the metabolites excreted in the bile. The fact that a single a1A-adreno-ceptor subtype is found in the prostatic and urethral smooth muscle cells led to the design of drugs with urose-lectivity for this receptor subtype. Thus, alfuzosin and tamsulosin are uroselective a1-blockers and first-line drugs for treatment of BPH without utility in treating hypertension.

Alfuzosin (Uroxatral) is also a quinazoline a1-blocker but differs from terazosin in replacing the piperazine ring in terazosin with an open piperazine ring (a rotatable propy-lenediamine group). Alfuzosin is more selective for the subtype of a1A-receptor in the prostate gland than those in vascular tissue. Thus, it has been used extensively in treating BPH as a first-line drug with fewer cardiovascular side effects than terazosin and doxazosin.

Tamsulosin (Flomax), a nonquinazoline benzensulfon-amide, is the first in the class of subtype selective a1A-blocker. It is many folds more selective for a iA-receptors than for the other a1-receptors. This selectivity may favor blockade of a1A-receptors found in the prostate gland over those found in vascular tissue. Tamsulosin is efficacious in the treatment of BPH with little effect on blood pressure. Orthostatic hypotension is not as great with this agent as with the nonselective quinazolines.


Yohimbine and Corynanthine. Yohimbine (Yocon) is a competitive and selective a2-blocker. The compound is an indolealkylamine alkaloid and is found in the bark of the tree Pausinystalia yohimbe and in Rauwolfia root; its structure resembles that of reserpine. These isomeric indole alkaloids known as the yohimbanes exhibit different degrees of selectivity toward the a1- and a2-receptors, depending on their stereochemistry. For example, yohimbine is a

Phentolamine Examples

selective a2-blocker, whereas corynanthine is a selective a1-blocker. The only difference between these two compounds is the relative stereochemistry of the carbon containing the carbomethoxy substituent. In yohimbine, this group lies in the plane of the alkaloid ring system, whereas in corynanthine, it lies in an axial position and thus is out of the plane of the rings.56

Yohimbine increases heart rate and blood pressure as a result of its blockade of a2-receptors in the CNS. It has been used experimentally to treat male erectile impotence.

Mirtazapine (Remeron) is another example of tetracyclic a2-blockers that shows selectivity for a2-receptors versus a1-receptors.57 Blockade of central a2-receptors results in an increased release of NE and serotonin. This has prompted its use as an antidepressant. This agent also has activity at nonadrenergic receptors. It is a potent blocker of 5-HT2 and 5-HT3 serotonin receptors and at histamine H1-receptors.


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