Alfadil XL Mechanism of Action

Pharmacological Category: Alpha-1 Adrenoreceptor Antagonist.
Pharmacology: Pharmacodynamics: Benign Prostatic Hyperplasia: Administration of Doxazosin, as mesilate (Alfadil XL) 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 mesilate, as (Alfadil XL) has demonstrated sustained efficacy and safety in the long-term treatment of BPH.
Doxazosin mesilate, as (Alfadil XL) 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: After oral administration of therapeutic doses, Doxazosin, as mesilate (Alfadil XL) 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, as mesilate (Alfadil XL) will lead to a smoother plasma profile.
Peak/trough ratio of Doxazosin, as mesilate (Alfadil XL) 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, as mesilate (Alfadil XL) 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.