Terazosin

Summary

Synopsis

Terazosin ¹ is a post-synaptic α ₁ -adrenoceptor antagonist with a similar pharmacodynamic profile to prazosin. It differs from prazosin in having a longer duration of action, with an elimination half-life some 2 to 3 times that of prazosin, allowing the convenience of once daily administration. Moreover, its absorption from the gastrointestinal tract is more complete and predictable than that of prazosin which may facilitate dose titration.

Terazosin therapy results in a significant reduction in blood pressure in patients with mild to moderate essential hypertension, with little influence on heart rate. The drug is an effective antihypertensive when administered as monotherapy or in combination with a range of antihypertensive agents including β-blockers, diuretics and combinations of the two. In the few patients with congestive heart failure studied, terazosin produced an increase in cardiac output with a reduction in ventricular filling pressure and systemic vascular resistance, but no studies have been performed to assess the therapeutic potential of terazosin in this indication. Reductions in total plasma cholesterol and low density plus very low density lipoprotein cholesterol fractions have been reported after terazosin therapy, while high density lipoprotein cholesterol concentrations have tended to increase. Should such beneficial changes be confirmed in long term clinical studies they would suggest a therapeutic advantage of terazosin over some other antihypertensive drugs, particularly diuretics, which have been reported to adversely affect the plasma lipid profile.

The most common side effects associated with terazosin treatment are dizziness, headache, asthenia and nasal congestion, but these are usually mild and do not require treatment discontinuation. Terazosin is normally administered once daily, starting at a dose of 1 mg/day and gradually titrating upwards as the blood pressure stabilises at each new dose, until blood pressure is adequately controlled or to a maximum dose of 20mg daily. First-dose syncope occurs rarely after terazosin, and can largely be avoided by giving the first dose at bedtime. Thus, terazosin offers a useful alternative to the drugs currently available for the management of mild to moderate essential hypertension either as monotherapy or in combination with other antihypertensive drugs.

Pharmacodynamic Studies

Terazosin is structurally related to prazosin, and like prazosin exerts a blood pressure lowering effect primarily by blocking post-synaptic α₁-adrenoceptors. Radioligand binding studies in animals showed terazosin to bind selectively to α₁-adrenoceptors with low affinity for pre-synaptic α₂-adrenoceptors. Terazosin had an equivalent blood pressure lowering effect to prazosin in animal studies, although the latter was more potent on a weight-for-weight basis.

In patients with mild to moderate hypertension, terazosin significantly reduced blood pressure with only a small increase in heart rate, while in patients with heart failure it increased cardiac output and lowered ventricular filling pressure and systemic vascular resistance. Some beneficial changes in the plasma lipid profile were reported in patients given terazosin: total plasma cholesterol and the low density plus very low density cholesterol fractions were reduced and high density lipoprotein cholesterol tended to be increased.

Pharmacokinetic Studies

Terazosin is well absorbed from the gastrointestinal tract; bioavailability was reported at about 90%, compared with a mean of 57% for prazosin. Plasma drug concentration increased proportionately with oral doses up to 5mg, and the peak plasma concentration occurred 1 to 2 hours after administration. Food had no significant effect on absorption.

Terazosin is thought to be metabolised extensively by the liver, with the biliary tract the major route of excretion. Elimination half-life is approximately 12 hours, some 2 to 3 times longer than that of prazosin. The pharmacokinetics of terazosin were not significantly altered in patients with mild to moderate hypertension compared with values in healthy subjects, except plasma clearance which was significantly reduced. The plasma half-life of terazosin was increased to a small extent in elderly subjects and plasma clearance was reduced. Terazosin’s pharmacokinetics were not significantly altered in patients with moderate to severe renal insufficiency.

Therapeutic Trials

Oral administration of terazosin, at a dosage of 1 to 40mg daily reduced blood pressure to a significantly greater extent than placebo in patients with mild to moderate hypertension without, in most cases, causing a significant increase in heart rate. The drug has been studied in trials as monotherapy and in combination with other antihypertensive drugs. As monotherapy, administered at a dosage of up to 20mg once daily, it had a similar antihypertensive efficacy to prazosin up to 10mg twice daily, reducing mean supine systolic and diastolic blood pressures by 5 to 10mm Hg. However, terazosin at a dosage of up to 10mg twice daily was significantly less effective than hydrochlorothiazide 25 to 50mg twice daily in reducing supine diastolic blood pressure.

Addition of terazosin to existing therapy with a β-blocker, diuretic, β-blocker plus diuretic or ‘other’ antihypertensive drug resulted in a significantly greater reduction in blood pressure than placebo added to such therapy.

Patients withdrawn from terazosin treatment showed significant increases in blood pressure, often to hypertensive levels. However, withdrawal symptoms such as rebound hypertension have not been reported.

Side Effects

During both short and long term studies terazosin was generally well tolerated. The most common adverse effects (> 10% incidence) reported during terazosin treatment were dizziness, headache, asthenia and nasal congestion. Symptoms were usually mild and transient. Among 567 patients treated with terazosin in placebo-controlled clinical trials, 60 (10.6%) withdrew because of side effects (combined with inadequate blood pressure control in 8), compared with 18 out of 309 (5.8%) who received placebo.

Dosage and Administration

Oral doses employed for monotherapy in patients with mild to moderate hypertension have ranged from 1 to 40mg once daily or 0.5 to 20mg twice daily. In combination therapy terazosin has been given in doses of 1 to 20mg daily. It is recommended that therapy be started at a dose of 1mg daily, titrating upwards thereafter as the blood pressure stabilises at each new dose, to achieve the required blood pressure or to a maximum dose of 20mg daily. The risk of first-dose fainting can be reduced by giving the initial dose at bedtime.