Doxazosin
Selective alpha 1 blocker for hypertension and benign prostatic hyperplasia
Doxazosin is a long acting selective α1 adrenoceptor blocker launched by Pfizer in 1988 under the brand name Cardura. In Germany it is available under the name Diblocin and as generics. The substance is approved for treatment of arterial hypertension and for symptomatic treatment of benign prostatic hyperplasia (BPH). Its long half life allows once daily dosing, and extended release formulations (XL, GITS) further smooth the plasma level.
In hypertension guidelines in recent years, α1 blockers have lost their first line role to ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers and thiazide diuretics. The ALLHAT trial showed a higher rate of heart failure on doxazosin compared with chlorthalidone, so the drug is now mainly used as adjunctive therapy in treatment resistant hypertension and in men who also have prostate symptoms, where both indications can be addressed simultaneously.
Mechanism of Action
Doxazosin competitively blocks the postsynaptic α1 adrenoceptor on the smooth muscle of arterioles, veins and the trigonum vesicae, internal sphincter and prostate capsule. Sympathetically mediated vasoconstriction is reduced, peripheral vascular resistance falls, blood pressure drops. Unlike non selective α blockers such as phenoxybenzamine, doxazosin binds α1 selectively and hardly affects α2 receptors, so reflex noradrenaline release with tachycardia does not occur.
In the lower urinary tract doxazosin relaxes the smooth muscle of the prostate, the prostate capsule and the bladder neck. Urinary flow improves, post void residual volume decreases, and lower urinary tract symptoms (LUTS) such as frequency, nocturia, weak stream and post void dribbling diminish. The prostate itself is not shrunk; that is the role of 5 α reductase inhibitors such as finasteride or dutasteride.
Selectivity among the three α1 subtypes (α1A, α1B, α1D) is low for doxazosin, which is why blood pressure is also affected. Newer α1A selective blockers such as tamsulosin or silodosin act more strongly at the prostate and less on the vasculature, reducing cardiovascular side effects but causing other effects such as intraoperative floppy iris syndrome more frequently.
Indications
- Essential arterial hypertension as adjunct therapy when first line drugs are insufficient
- Treatment resistant hypertension in combination with ACE inhibitor, calcium channel blocker and diuretic
- Symptomatic benign prostatic hyperplasia with moderate to severe lower urinary tract symptoms
- Combination of hypertension and BPH as an elegant dual effect in older men
- Pheochromocytoma as preoperative preparation, even though phenoxybenzamine is standard here
Dosage and Administration
Immediate release form (hypertension): start with 1 mg once daily in the evening, titrated every 1 to 2 weeks to 2, 4 or 8 mg, maximum 16 mg. BPH: start 1 mg, increase according to response to 4 or 8 mg. Extended release tablet (Cardura XL, GITS): 4 mg once daily, titrate to 8 mg; better tolerated because of smoother plasma levels.
Take the drug at the same time each day, preferably in the evening, to shift initial hypotension into the sleep phase. Swallow extended release tablets whole with liquid; the non absorbed tablet shell may be visible in the stool and is harmless. After a therapy interruption of more than one week, restart with the starting dose to avoid first dose phenomena.
Renal impairment: no dose adjustment, doxazosin is eliminated predominantly by the liver. Hepatic impairment: caution in severe impairment, keep the dose low, monitor closely. Older patients: increased orthostatic risk, careful titration, measure blood pressure in lying and standing positions.
Side Effects
Common (1 to 10 percent): dizziness, headache, fatigue, orthostatic hypotension, oedema, palpitations, nausea, nasal congestion, respiratory tract infections.
Uncommon (0.1 to 1 percent): syncope (especially after first dose), rhinitis, weight gain, tachycardia, dry mouth, erectile dysfunction, urinary incontinence in women.
Rare: hepatic dysfunction, rash, alopecia, priapism (urological emergency requiring immediate attention), thrombocytopenia, intraoperative floppy iris syndrome during cataract surgery.
First dose phenomenon: with the first dose, particularly in patients already on antihypertensives, there is a risk of pronounced orthostasis with syncope. Start with the lowest dose in the evening and counsel patients about the phenomenon. After a pause of several days, restart titration.
Interactions
- Other antihypertensives: additive blood pressure lowering, intended but orthostatic risk rises
- Phosphodiesterase 5 inhibitors (sildenafil, tadalafil, vardenafil): marked hypotension possible, minimum 4 hour gap, cautious titration
- Nitrates: strongly potentiated hypotension up to syncope, combination only under medical supervision
- NSAIDs: can blunt the antihypertensive effect
- Strong CYP3A4 inhibitors (clarithromycin, itraconazole, ritonavir): theoretically higher doxazosin plasma levels, clinical consequences are usually minor
- Alcohol: enhanced vasodilation, increased fall risk
Special Notes
Floppy iris syndrome: patients on doxazosin should always inform the surgeon before cataract or other eye surgery. The intraoperative floppy iris syndrome can complicate surgery and special measures are required. Preoperative discontinuation is not recommended.
Contraindications: known hypersensitivity, orthostatic dysregulation, urinary flow obstruction, chronic urinary tract infections, bladder stones, severe hepatic dysfunction.
Pregnancy: insufficient data, use only when other options are unavailable. Breastfeeding: passage into breast milk is not fully quantified, breastfeeding is not recommended.
Monitoring: blood pressure in lying and standing positions; for BPH use symptom questionnaires (IPSS) and uroflowmetry. In men, post void residual measurement and a baseline PSA are useful, since doxazosin does not alter PSA but prostate work up before therapy is reasonable.
Tapering at discontinuation? Unlike β blockers and clonidine, gradual withdrawal is not mandatory; no rebound effect is described. When restarting after a break, however, titration must begin again.
You might also be interested in
- Dutasteride, 5 α reductase inhibitor in BPH
- Mirabegron, β3 agonist in overactive bladder
- Chlorthalidone, thiazide diuretic in hypertension
- Enalapril, ACE inhibitor as first line agent
- Lowering blood pressure, an overview of all measures
Frequently Asked Questions
Why is doxazosin no longer first line in hypertension?
The ALLHAT trial showed a higher rate of heart failure on doxazosin than on chlorthalidone. The reduction of hard cardiovascular endpoints was also less convincing than with ACE inhibitors or diuretics. Current guidelines therefore recommend α blockers only as adjunct therapy in treatment resistant hypertension.
When will I notice an effect on prostate symptoms?
An improvement in urinary flow and bladder emptying is often noticed in the second to fourth week. Maximum effect develops after about 8 weeks. Without improvement, reconsider therapy and discuss alternatives such as a 5 α reductase inhibitor or surgical treatment.
Why take it in the evening?
Evening dosing shifts the strongest blood pressure drop into the sleep phase and reduces the risk of syncope from orthostatic hypotension. The first dose in particular is taken shortly before bedtime. If dizziness still occurs, rise slowly from lying or sitting.
Do I need to inform my eye surgeon?
Yes, before any eye surgery, especially cataract surgery. Intraoperative floppy iris syndrome can complicate the procedure. The surgeon can then use special surgical techniques or iris expanding devices. Preoperative discontinuation is not recommended, since the phenomenon can persist after prolonged pauses.
Sources
- EMA, European Medicines Agency
- AWMF, S2e Guideline on Benign Prostatic Hyperplasia and Hypertension
- Gelbe Liste, Doxazosin active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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