Prazosin Hydrochloride
(British Approved Name Modified, US Adopted Name, rINNM)
Drug Nomenclature
INNs in main languages (French, Latin, Russian, and Spanish):
Pharmacopoeias. In China, Europe, and US.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Prazosin Hydrochloride). A white or almost white powder. Very slightly soluble in water; slightly soluble in alcohol and in methyl alcohol; practically insoluble in acetone. Protect from light.
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Prazosin Hydrochloride). A white to tan powder. Slightly soluble in water, in dimethylacetamide, in dimethylfor-mamide, and in methyl alcohol; very slightly soluble in alcohol; practically insoluble in acetone and in chloroform. Store in airtight containers. Protect from light.
Adverse Effects
Prazosin hydrochloride can cause orthostatic hypotension which may be severe and produce syncope after the initial dose; it may be preceded by tachycardia. This reaction can be avoided by starting treatment with a low dose, preferably at night (see Uses and Administration, below). The hypotensive effects may be exaggerated by exercise, heat, or alcohol ingestion. The more common adverse effects include dizziness, drowsiness, headache, lack of energy, nausea, and palpitations, and may diminish with continued prazosin therapy or with a reduction in dosage. Other adverse effects include oedema, chest pain, dyspnoea, constipation, diarrhoea, vomiting, depression and nervousness, sleep disturbances, vertigo, hallucinations, par-aesthesia, nasal congestion, epistaxis, dry mouth, urinary frequency and incontinence, reddened sclera, blurred vision, tinnitus, abnormal liver enzyme values, pancreatitis, arthralgia, alopecia, lichen planus, skin rashes, pruritus, and diaphoresis. Impotence and pria-pism have also been reported.
Effects on the cardiovascular system. Orthostatic hypotension, preceded by tachycardia and sometimes producing syncope, is an established adverse effect of the initial dose of prazosin.
Sinus bradycardia was associated with prazosin in a patient who had light headedness after each daily dose.
Effects on the gastrointestinal tract. Faecal incontinence in a 52-year-old man receiving prazosin was exacerbated by haem-orrhoidectomy and appeared to be due to diminished resting anal tone, presumably because of smooth muscle relaxation secondary to alpha-adrenoceptor blockade. Symptoms ceased almost immediately on stopping the drug.
Effects on mental function. Psychiatric symptoms including confusion, paranoia, and hallucinations developed in 3 patients associated with prazosin treatment. Two of the patients had chronic renal failure and the other had mild renal impairment. Acute psychosis has also been reported with doxazosin.
Hypersensitivity. Urticaria and angioedema were attributed to prazosin in a 70-year-old woman.
Lupus erythematosus. One study has reported the formation of antinuclear antibodies in patients receiving prazosin, but this is not in agreement with other reports, and commentators consider the association unproven. There is no evidence of the development of lupus erythematosus.
Urinary incontinence. There have been reports of urinary incontinence developing in patients receiving prazosin. Analysis of 56 cases reported to the Australian Adverse Drug Reactions Advisory Committee indicated that typically symptoms appeared within 1 or 2 days of the start of therapy and persisted until the drug was withdrawn or the dose reduced. Both stress and urge incontinence occurred, sometimes in the same patient. Of the 56 patients, 51 were women and most were elderly. In a study in women attending a hypertension clinic urinary incontinence was reported in 40.8% of 49 women receiving alpha blockers (prazosin, terazosin, or doxazosin) and in 16.3% of controls. Incontinence might be due to a reduction in urethral pressure induced by alpha-adrenoceptor blockade. Interestingly, faecal incontinence has also been reported with prazosin — see Effects on the Gastrointestinal Tract, above.
Treatment of Adverse Effects
If overdosage with prazosin occurs activated charcoal should be given if the patient presents within 1 hour of ingestion. Severe hypotension may occur and treatment includes support of the circulation by postural measures and parenteral fluid volume replacement, and if necessary cautious intravenous infusion of a vasopressor. Prazosin is not removed by dialysis.
Precautions
Treatment with prazosin should be introduced cautiously because of the risk of sudden collapse following the initial dose. Extra caution is necessary in patients with hepatic or renal impairment and in the elderly.
Prazosin is not recommended for the treatment of heart failure caused by mechanical obstruction, for example aortic or mitral valve stenosis, pulmonary embolism, and restrictive pericardial disease. It should be used with caution in patients with angina pectoris. Prazosin may cause drowsiness or dizziness; patients so affected should not drive or operate machinery.
Cataract surgery. For a warning about intraoperative floppy iris syndrome during cataract surgery in patients taking alpha blockers, see Surgical Procedures under Precautions for Tamsu-losin Hydrochloride.
Cerebral haemorrhage. Hypotension with disturbance of consciousness occurred in 3 patients with recent cerebral haemorrhage after an initial dose of prazosin 500 micrograms.
Tolerance. Although prazosin may be of initial benefit in patients with chronic heart failure, some studies have reported the development of tolerance to its haemodynamic effects on prolonged therapy. This may be partly due to upregulation of alpha: adrenoceptors.
Interactions
The hypotensive effects of prazosin may be enhanced by use with diuretics and other antihypertensives, and by alcohol and other drugs that cause hypotension. The risk of first-dose hypotension may be particularly increased in patients receiving beta blockers or calcium-channel blockers.
Analgesics. Indometacin reduced prazosin-induced hypotension in 4 of 9 subjects.
Antidepressants and antipsychotics. A patient who was taking amitriptyline and chlorpromazine developed acute agitation on receiving prazosin. The symptoms settled rapidly when prazosin was discontinued. Antidepressants and antipsychotics may enhance the hypotensive effect of prazosin and other alpha blockers.
Calcium-channel blockers. An enhanced hypotensive effect has been reported in normotensive subjects given prazosin and verapamil concurrently; the effect may be due in part to enhanced bioavailability of prazosin. Markedly increased hypotensive responses have also been reported with combined use of prazosin and nifedipine, although the validity of such reports has been questioned.
Digoxin. For reference to the effect of prazosin on serum-digox-in concentrations, see under Digoxin.
Pharmacokinetics
Prazosin is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring 1 to 3 hours after an oral dose. The bioavailability is variable and a range of 43 to 85% has been reported. Prazosin is highly bound to plasma proteins. It is extensively metabolised in the liver and some of the metabolites are reported to have hypotensive activity. It is excreted as the metabolites and 5 to 11% as unchanged prazosin mainly in the faeces via the bile. Less than 10% is excreted in the urine. Small amounts are distributed into breast milk. Its duration of action is longer than would be predicted from its relatively short plasma half-life of about 2 to 4 hours. Half-life is reported to be increased to about 7 hours in patients with heart failure.
The elderly. The bioavailability of prazosin was significantly reduced in the elderly, about 40% less unchanged drug reaching the systemic circulation compared with the young. This was attributed to a reduction in the absorption from the gastrointestinal tract. The half-life was also prolonged in the elderly and this was associated with an increase in the volume of distribution at steady state. However, it was considered unlikely that these effects would have major clinical significance.
Protein binding. Although a study found that prazosin was about 80 to 85% bound to serum albumin and only about 10 to 30%) bound to α1-acid glycoprotein in vitro, potential interactions between the binding proteins in vivo were not taken into account; binding to α1-acid glycoprotein might be more significant in clinical practice. A subsequent study indicated that variations in prazosin protein binding pre- and post-operatively were related to variations in concentration of the glycoprotein.
Uses and Administration
Prazosin is an alpha Mocker that acts by selective blockade of alpharadrenoceptors. It is used in the management of hypertension, in Raynaud’s syndrome (see Peripheral Vascular Disease, below), and to relieve symptoms of urinary obstruction in benign prostatic hyperplasia. It has also been used in heart failure.
Prazosin produces peripheral dilatation of both arterioles and veins and reduction of peripheral resistance, usually without reflex tachycardia. It reduces both standing and supine blood pressure with a greater effect on the diastolic pressure. It is reported to have no effect on renal blood flow or glomerular filtration rate, and has little effect on cardiac output in hypertensive patients. In patients with heart failure, prazosin reduces both preload and afterload and produces an improvement in cardiac output, although tolerance may develop. In benign prostatic hyperplasia, prazosin may relieve the symptoms of urinary obstruction by reducing smooth muscle tone in the prostate and bladder neck.
Prazosin is given orally as the hydrochloride, but doses are usually expressed in terms of the base. Prazosin hydrochloride 1.1 mg is equivalent to about 1 mg of prazosin. After oral dosage the hypotensive effect is seen within 2 to 4 hours and persists for several hours. Full effects are seen after 4 to 6 weeks.
A low starting dose is given in the evening to lessen the risk of collapse which may occur in some patients after the first dose (see Adverse Effects, above). Doses may need to be reduced in the elderly and in patients with hepatic or renal impairment.
In hypertension, the usual initial dose in the UK is 500 micrograms two or three times daily for 3 to 7 days; if tolerated the dose may then be increased to 1 mg two or three times daily for a further 3 to 7 days, and thereafter gradually increased, according to the patient’s response, to a usual maximum of 20 mg daily in divided doses. In the US the recommended starting dose is 1 mg two or three times daily and up to 40 mg daily in divided doses has been given; however, the usual maintenance dose is between 6 and 15 mg daily. Smaller doses may be required in patients also taking other antihypertensives. Modified-release preparations may allow once daily dosing.
In Raynaud’s syndrome and in benign prostatic hyperplasia an initial dose of 500 micrograms twice daily may be given, increasing to a maintenance dose not exceeding 2 mg twice daily.
In heart failure, treatment has been started with 500 micrograms two to four times daily and increased gradually according to response; the usual maintenance dose has been 4 to 20 mg daily.
Erectile dysfunction. Prazosin has been given transurethrally with alprostadil in the management of erectile dysfunction.
Familial Mediterranean fever. Familial Mediterranean fever is usually treated with prophylactic colchicine, but its use may be limited by adverse effects. A Japanese man who had suffered from attacks for 16 years was treated with prazosin 3 mg daily. There were no further attacks for more than a year after starting treatment, but stopping prazosin resulted in a recurrence.
Muscle cramp. Skeletal muscle cramp may occur during haemodialysis, possibly due to activation of the sympathetic nervous system. Prazosin was reported to reduce the incidence of cramp in 4 of 5 patients with frequent haemodialysis-associated muscle cramp. However, the increased incidence of hypotension reported might limit its use for this indication.
Peripheral vascular disease. Alpha blockers, including prazosin, may be used in the management of Raynaud’s syndrome (see Vasospastic Arterial Disorders). Studies of the benefits of prazosin have produced varying results. A short-term reduction in number and duration of attacks was reported in 5 of 7 patients given prazosin 2 mg daily but only 1 patient had complete relief from attacks and few could tolerate doses higher than 6 mg daily. Improvements were not maintained during continued treatment for 2 months. Others have reported benefit from prazosin 1 mgtwo or three times daily in the majority of patients, with one study suggesting greater benefit in Raynaud’s disease (the primary, idiopathic form) than in secondary Raynaud’s syndrome. In a subsequent study, higher doses of prazosin (2 or 4 mg three times daily) were no more effective than 1 mg three times daily, and were associated with a significantly greater incidence of adverse effects. A systematic review concluded that prazosin was modestly effective in the treatment of Raynaud’s syndrome secondary to scleroderma.
Post-traumatic stress disorder. Post-traumatic stress disorder is usually treated with psychotherapy or drugs such as SSRIs. Increased alpharadrenergic receptor activity may be a contributory factor, and several small studies have reported that treatment with prazosin improves nightmares and sleep disturbances in patients with this condition. A reduction in nightmares occurred in 5 patients taking part in a small 6-week open-label study; doses ranged from 1 mg at night to 2 mg night and morning. A similar improvement was found in a retrospective study of combat veterans with chronic treatment-resistant symptoms, where doses of prazosin were increased gradually from 1 mg at night up to a maximum daily dose of 20 mg if required, and in a placebo-controlled study in similar patients given doses of up to 15 mg at night. Another small study and a case report have also reported benefit; doses varied from 1 mg at night to 10 mg daily in 2 divided doses.
Renal calculi. For the potential use of alpha blockers to aid the passage of renal calculi, see under Uses of Tamsulosin Hydrochloride.
Scorpion stings. Stings from the Indian red scorpion (Mesobuthus tamulus) are potentially fatal. The scorpion venom is a potent sympathetic stimulator resulting in high circulating catecholamines, hypertension, arrhythmias, pulmonary oedema, and circulatory failure. The efficacy of antivenom is questionable and treatment for cardiotoxicity is supportive. Prazosin, given orally, appears to be beneficial and has been suggested as first-line treatment, except in cases of severe pulmonary oedema. Prazosin has also been used in other countries to treat stings by dangerous scorpion species.
Preparations
British Pharmacopoeia, 2008: Prazosin Tablets;
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2: Prazosin Hydrochloride Capsules.
Single-ingredient Preparations
The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed
Argentina: Decliten; Minipres; Australia: Minipress; Mipraz¤; Prasig¤; Pratsiol; Prazohexal¤; Pressin; Austria: Minipress; Belgium: Minipress; Brazil: Minipress; Canada: Apo-Prazo; Minipress; Novo-Prazin; Nu-Prazo; Czech Republic: Deprazolin; Denmark: Hexapress; Peripress¤; Prazac; Finland: Patsolin¤; Peripress; Pratsiol; Prazocor¤; France: Alpress; Minipress; Germany: Adversuten; duramipress; Eurex¤; Minipress; Hong Kong: Apo-Prazo; CP-Prazo; Minipress; Mizosin; Pratsiol¤; Hungary: Huma-Prazin; Minipress; India: Minipress; Prazocip; Ireland: Hypovase; Israel: Hypotens; Italy: Minipress¤; Japan: Minipress; Malaysia: Atodel; Minipress; Minison; Mexico: Anapres; Ensibest; Europrazosin¤; Minipres; Prabioquim¤; Sinozzard; Netherlands: Minipress¤; Norway: Peripress¤; New Zealand: Apo-Prazo; Hyprosin; Pratsiol; South Africa: Minipress; Pratsiol; Singapore: Minipress; Spain: Minipres; Sweden: Peripress¤; Switzerland: Minipress; Thailand: Atodel; Lopress; Minima¤; Minipress; Mysial¤; Parabowl; Polypress; Pratsiol¤; Pressin; United Kingdom: Alphavase¤; Hypovase; Kentovase¤; United States: Minipress; Venezuela: Minpres
Multi-ingredient Preparations
Germany: Polypress¤; United States: Minizide
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