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Pharmacology: Pharmacodynamics: Hypertension: Cardura: Administration of doxazosin to hypertensive patients causes a clinically significant reduction in blood pressure as a result of a reduction in systemic vascular resistance. This effect is thought to result from selective blockade of the alpha-1-adrenoceptors located in the vasculature. With once-daily dosing, clinically significant reductions in blood pressure are present throughout the day and at 24 hours post-dose. A gradual reduction in blood pressure occurs, with maximum reductions usually occurring 2 to 6 hours after dosing. In patients with hypertension, blood pressures during treatment with doxazosin were similar in both the supine and standing positions. Unlike non-selective alpha-adrenoceptor blocking agents, tolerance has not been observed in long-term therapy with doxazosin. Elevations of plasma renin activity and tachycardia were seen infrequently in sustained therapy.
Doxazosin produces favorable effects on blood lipids, with a significant increase in the high-density lipoprotein (HDL)/total cholesterol ratio and significant reductions in total triglycerides and total cholesterol. It therefore confers an advantage over diuretics and beta-adrenoceptor blocking agents, which adversely affect these parameters. Based on the established association of hypertension and blood lipids with coronary heart disease, the favorable effects of doxazosin therapy on both blood pressure and lipids indicate a reduction in the risk of developing coronary heart disease.
Treatment with doxazosin has been shown to result in regression of left ventricular hypertrophy, inhibition of platelet aggregation, and enhanced tissue plasminogen activator capacity. Additionally, doxazosin improves insulin sensitivity in patients who have impairment.
Doxazosin has been shown to be free of adverse metabolic effects and is suitable for use in patients with asthma, diabetes, left ventricular dysfunction, and gout.
An in vitro study has demonstrated the antioxidant properties of the 6'- and 7'-hydroxy metabolites of doxazosin at concentrations of 5 μm.
In a controlled clinical trial in hypertensive patients, treatment with doxazosin was associated with improvement of erectile dysfunction. In addition, the patients who received doxazosin reported fewer new cases of erectile dysfunction than those who received other antihypertensive agents.
Cardura XL: Administration of doxazosin GITS to hypertensive patients causes a clinically significant reduction in blood pressure as a result of a reduction in systemic vascular resistance. This effect is thought to result from selective blockade of the alpha-1-adrenoceptors located in the vasculature. With once-daily dosing, clinically significant reductions in blood pressure are present throughout the day and at 24 hours post dose. The majority of patients are controlled on the initial 4 mg dose of doxazosin GITS. In patients with hypertension, blood pressure reductions during treatment with doxazosin GITS were similar in both the sitting and standing positions.
Subjects treated with standard doxazosin for hypertension can be transferred to doxazosin GITS and titrated upwards, as needed, while maintaining efficacy and tolerability.
Unlike non-selective alpha-adrenoceptor blocking agents, tolerance has not been observed in long-term therapy with doxazosin GITS. Elevations of plasma renin activity and tachycardia were seen infrequently in sustained doxazosin therapy.
Doxazosin produces favorable effects on blood lipids, with a significant increase in the high-density lipoprotein (HDL)/total cholesterol ratio and significant reductions in total triglycerides and total cholesterol. It, therefore, confers an advantage over diuretics and beta-adrenoceptor blocking agents, which adversely affect these parameters. Based on the established association of hypertension and blood lipids with coronary heart disease, the favorable effects of doxazosin therapy on both blood pressure and lipids indicate a reduction in risk of developing coronary heart disease.
Treatment with doxazosin has been shown to result in regression of left ventricular hypertrophy, inhibition of platelet aggregation, and enhanced tissue plasminogen activator capacity. Additionally, doxazosin improves insulin sensitivity in patients who have impairment.
Doxazosin has been shown to be free of adverse metabolic effects and is suitable for use in patients with asthma, diabetes, left ventricular dysfunction, and gout.
An in vitro study has demonstrated the antioxidant properties of the 6'- and 7'-hydroxy metabolites of doxazosin at concentrations of 5 micromolar.
Benign Prostatic Hyperplasia: Administration of doxazosin GITS to patients with symptomatic BPH results in a significant improvement in urodynamics and symptoms. The effect in BPH is thought to result from selective blockade of the alpha-adrenoceptors located in the muscular stroma and capsule of the prostate and in the bladder neck.
Doxazosin has been shown to be an effective blocker of the 1A subtype of the alpha-1- adrenoceptor, which accounts for over 70% of the subtypes in the prostate. This accounts for the action in BPH patients.
Doxazosin GITS has demonstrated sustained efficacy and safety in the long term-treatment of BPH.
Doxazosin GITS given in the recommended dosage regimen has little or no effect on blood pressure in normotensive patients.
In a controlled clinical BPH trial, treatment with doxazosin in patients with sexual dysfunction was associated with improvement in sexual function.
Pharmacokinetics: Absorption: Cardura: After oral administration of therapeutic doses, doxazosin is well absorbed with peak blood levels occurring at about 2 hours.
Cardura XL: After oral administration of therapeutic doses, doxazosin GITS is well absorbed with peak blood levels gradually reached at 8 to 9 hours after dosing. Peak plasma levels are approximately one-third of those of the same dose of standard doxazosin tablets. Trough levels at 24 hours are, however, similar.
The pharmacokinetic characteristics of doxazosin GITS will lead to a smoother plasma profile.
Peak/trough ratio of doxazosin GITS is less than half that of standard doxazosin tablets.
At steady state, the relative bioavailability of doxazosin from doxazosin GITS compared to the standard form was 54% at the 4 mg dose and 59% at the 8 mg dose.
Pharmacokinetic studies with doxazosin GITS in the elderly have shown no significant alterations compared to younger patients.
Biotransformation/Elimination: The plasma elimination is biphasic, with the terminal elimination half-life being 22 hours. This provides the basis for once-daily dosing. Doxazosin is extensively metabolized, with <5% excreted as unchanged drug.
Pharmacokinetic studies with standard doxazosin in patients with renal impairment have shown no significant alterations compared to patients with normal renal function.
There are only limited data in patients with liver impairment and on the effects of drugs known to influence hepatic metabolism (e.g., cimetidine). In a clinical study in 12 subjects with moderate hepatic impairment, single-dose administration of doxazosin resulted in an increase in AUC of 43% and a decrease in apparent oral clearance of 40%. As with any drug wholly metabolized by the liver, use of doxazosin in patients with altered liver function should be undertaken with caution (see Precautions).
Approximately 98% of doxazosin is protein-bound in plasma.
Doxazosin is primarily metabolized by O-demethylation and hydroxylation.
Doxazosin is extensively metabolized in the liver. In vitro studies suggest that the primary pathway for elimination is via CYP 3A4; however, CYP 2D6 and CYP 2C9 metabolic pathways are also involved for elimination, but to a lesser extent.
Toxicology: Preclinical Safety Data: Carcinogenesis: Chronic dietary administration (up to 24 months) of doxazosin at maximally tolerated doses of 40 mg/kg/day in rats and 120 mg/kg/day in mice revealed no evidence of carcinogenic potential. The highest doses evaluated in the rat and mouse studies are associated with AUCs (a measure of systemic exposure) that are 8 times and 4 times the human AUC at a dose of 16 mg/day, respectively.
Mutagenesis: Mutagenicity studies revealed no drug- or metabolite-related effects at either chromosomal or subchromosomal levels.
Impairment of Fertility: Studies in rats showed reduced fertility in males treated with doxazosin at oral doses of 20 mg/kg/day (but not 5 or 10 mg/kg/day), about 4 times the human AUC at a dose of 12 mg/day. This effect was reversible within 2 weeks of drug withdrawal. There have been no reports of any effects of doxazosin on male fertility in humans.
Lactation: Studies in lactating rats given a single oral dose of 1 mg/kg of [2-14C]-doxazosin indicate that doxazosin accumulates in rat breast milk with a maximum of concentration about 20 times greater than the maternal plasma concentration.
