ドキサゾシン

Pharmaceuticals -> Antihypertensives

Pharmaceuticals

2.1

3.38

0.8%

7.90e-01 g/L

275-277

289 - 290 °C

202.9 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

196.92 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Danger

H302 (20%): Harmful if swallowed [Warning Acute toxicity, oral]

P260, P264, P270, P273, P280, P301+P317, P301+P330+P331, P302+P361+P354, P304+P340, P305+P354+P338, P316, P319, P321, P330, P363, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 5 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Doxazosin has been associated with a low rate of serum aminotransferase elevations that in controlled trials was no higher than with placebo therapy. These elevations were transient and did not require dose modification. No instances of clinically apparent acute liver injury due to doxazosin have been published in the literature, but reports of cholestatic hepatitis have been received by the sponsor. Among the alpha adrenergic receptor antagonists, the most frequently implicated agent in causing liver injury has been alfuzosin with only single, and not well documented cases linked to other alpha blockers. Thus, acute symptomatic liver injury due to doxazosin is quite rare, and severe hepatotoxicity must be exceeding rare, if it occurs at all.

Reports with overdosage and toxicity with the alpha-1 antagonists, including doxazosin, remain very limited in the literature. There is a report of one case of acute doxazosin overdose in 2005. The study found that the patient presented to the emergency department (ED) with drowsiness, decreased blood pressure, and reflex tachycardia but did not have orthostatic hypotension or any other abnormalities. This patient was able to fully awaken with supportive therapy in 8 hours and was discharged 48 hours after admission to the ED. Although there are limited works of literature for the toxicity of doxazosin, it appears to have low acute toxicity.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

doxazosin

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

C - Cardiovascular system

QC - Cardiovascular system

Doxazosin decreases standing and supine blood pressure and relieves the symptoms of benign prostatic hypertrophy through the inhibition of alpha-1 receptors. Doxazosin may cause hypotension due to its pharmacological actions. This frequently occurs in the upright position, leading to a feeling of dizziness or lightheadedness. The first dose of doxazosin may lead to such effects, however, subsequent doses may also cause them. The risk of these effects is particularly high when dose adjustments occur or there are long intervals between doxazosin doses. Treatment should be started with the 1 mg dose of doxazosin, followed by slow titration to the appropriate dose. Patients must be advised of this risk and to avoid situations in which syncope and dizziness could be hazardous following the ingestion of doxazosin. Interestingly doxazosin exerts beneficial effects on plasma lipids. It reduces LDL (low-density lipoprotein) cholesterol and triglyceride levels and increases HDL (high-density lipoprotein) cholesterol levels. A note on priapism risk In rare cases, doxazosin and other alpha-1 blockers may cause priapism, a painful occurrence of persistent and unrelievable penile erection that can lead to impotence if medical attention is not sought as soon as possible. Patients must be advised of the priapism risk associated with doxazosin and to seek medical attention immediately if it is suspected.

Doxazosin selectively inhibits the postsynaptic alpha-1 receptors on vascular smooth muscle by nonselectively blocking the alpha-1a, alpha-1b, and alpha-1d subtypes. This action on blood vessels decreases systemic peripheral vascular resistance, reducing blood pressure, exerting minimal effects on the heart rate due to its receptor selectivity. Norepinephrine-activated alpha-1 receptors located on the prostate gland and bladder neck normally cause contraction of regional muscular tissue, obstructing urinary flow and contributing to the symptoms of benign prostatic hypertrophy. Alpha-1 antagonism causes smooth muscle relaxation in the prostate and bladder, effectively relieving urinary frequency, urgency, weak urinary stream, and other unpleasant effects of BPH. Recently, doxazosin was found to cause apoptosis of hERG potassium channels in an in vitro setting, possibly contributing to a risk of heart failure with doxazosin use.

Hepatic metabolism of doxazosin produces inactive O-demethylated and C-hydroxylated metabolites. Metabolism occurs via O-demethylation of the quinazoline nucleus of doxazosin or via hydroxylation of its benzodioxan portion. The enzymes involved in the metabolism of doxazosin include CYP2C19, CYP2D6, CYP2C19, and CYP3A4, which is the primary metabolizing enzyme. Doxazosin itself is considered to be mainly responsible for its pharmacological action, however, some active metabolites have been identified whose pharmacokinetics have not been adequately characterized.

NW1291F1W8

DOXAZOSIN

Mechanisms of Action [MoA] - Adrenergic alpha-Antagonists

Established Pharmacologic Class [EPC] - alpha-Adrenergic Blocker

Doxazosin is an alpha-Adrenergic Blocker. The mechanism of action of doxazosin is as an Adrenergic alpha-Antagonist.

DOXAZOSIN

Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS.

Drugs that bind to and block the activation of ADRENERGIC ALPHA-1 RECEPTORS.

Doxazosin is rapidly absorbed in the gastrointestinal tract and peak concentrations are achieved within 2-3 hours after administration. The bioavailability is about 60%-70%. The intake of food with doxazosin is not expected to cause clinically significant effects.

In a pharmacokinetic study using a 1 mg IV radiolabeled dose and a 2 mg oral dose, 63% of the ingested doxazosin was found to be excreted in the feces and about 9% of the dose was found to be excreted in the urine. Traces of radiolabeled unchanged drug were found in the urine and about 5% of the administered drug was found as unchanged drug excreted in the feces.

The volume of distribution of doxazosin is 1.0-1.9 L/kg. In a study of radiolabeled doxazosin administered to pregnant rats, doxazosin was found to cross the placenta.

The clearance of doxazosin is low and ranges from approximately 1-2 ml/min/kg.