Alpha blockers + Calcium-channel blockers - Drug Interactions

Blood pressure may fall sharply when calcium-channel blockersare first given to patients already taking alpha blockers (particularly prazosin and terazosin),and vice versa. In a small study,tamsulosin did not have any clinically relevant effects on bloodpressure well controlled by nifedipine. Verapamil may increasethe AUC of prazosin and terazosin. Alpha blockers and calcium-channel blockers may be combined for additional blood pressurelowering in patients with hypertension.

1. Doxazosin. Although there was a tendency for first-dose hypotension no serious adverse events or postural symptoms were seen in 6 normotensive subjects given nifedipine 20mg twice daily for 20 days, with doxazosin 2mg once daily for last 10 days. The same results were noted in 6 other normotensive subjects given drugs in opposite order. No pharmacokinetic interactions were found.(See reference number 1) However, US manufacturers note a study in which slight (less than 20%) alterations were found in pharmacokinetics of nifedipine and doxazosin when they were given concurrently. As would be expected,blood pressures were lower when both drugs were given.(See reference number 2)

Prazosin. In a placebo-controlled,crossover study 12 hypertensive subjects were given nifedipine 20 mg and prazosin 2 mg, separated by one hour. Concurrent use reduced blood pressure more than either drug alone,but when prazosin was given after nifedipine its effects were delayed (See reference number 3). Two patients with severe hypertension given prazosin 4 or 5mg experienced a sharp fall in blood pressure shortly after being given nifedipine sublingually. One of them complained of dizziness and had a reduction in standing blood pressure from 232/124 to 88/48 mmHg about 20 minutes after taking nifedipine 10 mg. However, in a further 8 patients with hypertension taking prazosin, reduction in blood pressure 20 minutes after addition of sublingual nifedipine was smaller (mean reduction of 25/12 mmHg when lying and 24/17 mmHg when standing) (See reference number 4). It is not clear what contribution prazosin had to effect seen with sub-lingual nifedipine, since experiment was not repeated using a prazosin placebo, but blood pressure in these patients had earlier remained unchanged 1 hour after taking prazosin alone. Note that sublingual nifedipine alone may cause a dangerous drop in blood pressure.

Tamsulosin. In a placebo-controlled study in 8 hypertensive men with blood pressure well controlled by nifedipine, addition of tamsulosin 400 micrograms daily for 7 days then 800 micrograms daily for a further 7 days had no clinically relevant effect on blood pressure (assessed after 6 and 14 days of tamsulosin). In addition, no first-dose hypotension was seen on first day of tamsulosin, or when tamsulosin dose was increased (See reference number 5).

Terazosin. Retrospective analysis of a large multinational study in patients given terazosin 5 or 10mg daily found that terazosin only affected blood pressure of patients taking calcium-channel blockers (amlodipine, felodipine, flunarizine, isradipine and nifedipine) if blood pressure was uncontrolled. No change in blood pressure was seen in those with normal blood pressure (i.e. those without hypertension and those with hypertension controlled by calcium-channel blockers). The most common adverse effect in 10-week terazosin phase was dizziness, and incidence of this appeared to be lower in those taking antihypertensives (13 to 16%) than those not taking antihypertensives (21 to 25%) (See reference number 6).

The US manufacturers note that when diltiazem 240mg daily was given with alfuzosin 2.5mg three times daily maximum serum levels and AUC of alfuzosin were raised by 50 % and 30%, respectively, and maximum serum levels and AUC of diltiazem were raised by 40%. However,no changes in blood pressure were seen (See reference number 7).

Prazosin. A study in 8 normotensive subjects given a single 1mg dose of prazosin found that peak serum prazosin levels were raised by 85 % (from 5.2 to 9.6 nanograms/mL) and prazosin AUC was increased by 62 % when it was given with a single 160mg dose of verapamil. The standing blood pressure,which was unchanged after verapamil alone, fell from 114/82 to 99/81 mmHg with prazosin alone, and was further reduced to 89/68 mmHg when both drugs were given together (See reference number 8). A similar pharmacokinetic interaction was noted in another study in hypertensive patients (See reference number 9). In this study, first 1mg dose of prazosin alone caused a 23 mmHg fall in standing systolic blood pressure, and half patients (3 of 6) experienced symptomatic postural hypotension. A similar fall in blood pressure occurred when first 1mg dose of prazosin was given to 6 patients who had been taking verapamil for 5 days, and 2 patients experienced symptomatic postural hypotension (See reference number 9).

Tamsulosin. A study into safety of tamsulosin, with particular regard to use of other medications, found that concurrent use of verapamil increased risk of adverse events related to tamsulosin treatment by threefold. The use of other calcium-channel blockers (not specified) did not appear to increase adverse effects,although there was a trend towards an increase (See reference number 10).

Terazosin. When verapamil 120mg twice daily was added to terazosin 5mg daily in 12 hypertensive patients, peak plasma levels and AUC of terazosin were increased by about 25%. In contrast, in another 12 patients taking verapamil 120mg twice daily, addition of terazosin

(1 mg increased to 5mg daily) had no effect on verapamil pharmacokinetics (See reference number 11). Both groups of patients had significant falls in standing blood pressure when they first started taking both drugs. Symptomatic orthostatic hypotension (which lessened within about 3 weeks) occurred in 4 patients when verapamil was first added to terazosin,and in 2 patients when terazosin was first added to verapamil (See reference number 11).

Not fully understood. It would seem that vasodilatory effects of alpha blockers and calcium-channel blockers can be additive or synergistic, particularly after first dose (See reference number 1,12). The fall in blood pressure seen with prazosin and verapamil may, in part, result from a pharmacokinetic interaction,(See reference number 12)as does interaction between alfuzosin and diltiazem. Tamsulosin possibly has less effect on blood pressure since it has some selectivity for alpha receptors in prostate (see Alpha blockers,).

The interaction between calcium-channel blockers and alpha blockers would appear to be established and of clinical importance, although 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, . 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 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 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 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 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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