Prazosin pharmacokinetics

Pharmacokinetics Prazosin is extensively metabolized. The metabolites of prazosin are active. Duration of antihypertensive effect is 10 hours. 

Doxazosin, also a selective a i-blocker, resembles prazosin in most aspects, but it has a better pharmacokinetic profile, at least for long-term use as in essential hypertension. Owing to its slow onset of action, doxazosin causes far less orthostatic hypotension and reflex tachycardia than prazosin. As a result of its long duration of action, it can be administered once daily in the long-term treatment of essential hypertension. 

Pharmacokinetic characteristics of prazosin are listed in Table 11-2. Terazosin is also extensively metabolized but undergoes very little first-pass metabolism and has a half-life of 12 hours. Doxazosin has an intermediate bioavailability and a half-life of 22 hours. 

The characteristics of individual alpha blockers are discussed in Chapter 20. Basically, these drugs can be differentiated according to their relative alpha-1 selectivity, their duration of action, and other pharmacokinetic properties. Prazosin (Minipress) has been the primary alpha blocker used in the past, but newer agents such as doxazosin and terazosin (Hytrin) are gaining acceptance in treating hypertension. Prazosin and other alpha blockers approved as antihypertensives are listed in Table 21-4. 

Pasanisi F, Meredith PA, Elliott HL, Reid JL. Verapamil and prazosin pharmacodynamic and pharmacokinetic interactions in normal man. Br J Clin Pharmacol 1984 18 290P. 

The main difference between prazosin, terazosin, and doxazosin lies in their pharmacokinetic properties. As men-lloncd above, these differences are dictated by the nature of the acyl moiety attached to the piperazine ring. A comparison of these three agents with respect to their oral bioavailability, half-life, and duration of action is shown in Table 16-2. These drugs are metabolized extensively, with the me-taNiies excreted in the bile. 

The newer selective alphaj-adrenoreceptor-blocking agents, such as trimazosin, doxasozin, and terazosin, display a pharmacologic profile virtually identical to that of prazosin, but pharmacokinetic differences between the various alpha,-blockers exist. 

B. Pharmacokinetics These drugs are all active by the oral as well as the parenteral route, though phentolamine and tolazoline are rarely given orally. Phenoxybenzamine has a short elimination half-life but a long duration of action—about 48 hours—because it binds covalently to its receptor. Phentolamine and tolazoline have durations of action of 2-4 hours when used orally and 20-40 minutes when given parenterally. Prazosin acts for 8-10 hours. 

The structures for the available ai-receptor blockers are shown in Figure 29.5. These include prazosin, doxazosin, and temazosin, the structure-activity relationships of which were previously discussed in Chapter 13, along with their pharmacokinetics and metabolism. 

The interaction between calcium-channel blockers and alpha blockers would appear to be established and of clinical importance, although the documentation is limited. Marked additive hypotensive effects can occur when concurrent use is first started, particularly with alfuzosin, bunazosin, prazosin and terazosin but see also Alpha blockers , (p.83). It is recommended that patients already taking calcium-channel blockers should have their dose of calcium-channel blocker reduced and begin with a low-dose of alpha blocker, with the first dose taken just before going to bed. Caution should also be exercised when calcium-channel blockers are added to established treatment with an alpha blocker. Patients should be warned about the possibilities of exaggerated hypotension, and told what to do if they feel faint and dizzy. There is limited evidence that terazosin and tamsulosin may not cause an additional hypotensive effect in the longer term in patients with BPH who have hypertension already well-controlled with calcium-channel blockers. Nevertheless, caution should be exercised in this situation, and a dose reduction of the calcium-channel blocker may be required. It seems likely that any pharmacokinetic interaction will be accounted for by this dose titration. 

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