Danazol Anti-androgen Drug

INTRODUCTION

Danazol (INN, USAN, BAN, JAN) (brand names Danocrine, Danol, Danazol, Danatrol, Danoval, Cyclomen, many others), also known as 17α-ethinyl-17β-hydroxy-4-androsten-[2,3-d]isoxazole, is a synthetic steroid that is used primarily in the treatment of endometriosis and is marketed widely throughout the world.[2][3][4][1] It is the derivative of ethisterone (17α-ethynyltestosterone) where the 3-ketone is replaced with a 2,3-isoxazole moiety.[5][6] Danazol was approved by the US Food and Drug Administration as the first drug to specifically treat endometriosis in 1971.[5][7] Although effective for endometriosis, its use is limited by its masculinizing side effects.[8] Since their introduction, danazol has largely been replaced by gonadotropin-releasing hormone (GnRH) agonists in the treatment of the condition

THERAPEUTIC USES:

Danazol is used to treat a number of different medical problems. These include:

Endometriosis.

Fibrocystic breast disease (cysts in the breasts).

Hereditary angioedema (swelling of the different parts of the body, such as abdomen or stomach, arms, legs, throat, skin, or sexual organs.

This medicine is available only with your doctor's prescription.

Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses may not be included in product labeling, danazol is used in certain patients with the following medical conditions:

Gynecomastia (breast development in males).

Menorrhagia (abnormally heavy and prolonged menstrual periods).

SIDE EFFECT

Androgenic side effects are of concern, as some women taking danazol may experience unwanted hair growth (hirsutism), acne, irreversible deepening of the voice,[9] or adverse blood lipid profiles.[15] In addition, breast atrophy and decreased breast size may occur.[9] The drug may also cause hot flashes, elevation of liver enzymes, and mood changes.[15] Some patients who use danazol experience weight gain and fluid retention. Due to its side effects, danazol is seldom prescribed continuously beyond six months.

The use of danazol for endometriosis has been linked to an increased risk of ovarian cancer.[16] Patients with endometriosis have specific risk factors for ovarian cancer, so this may not apply for other uses.

Danazol, like most other androgenic drugs, has been linked with an increased risk of liver tumors. These are generally benign.[17]

Unlike GnRH agonists, danazol appear to significantly increase the risk of osteoporosis.[citation needed] Also, symptoms of hot flushes tend to be less common or severe

PRECAUTIONS:

Before taking danazol, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: heart/blood vessel disease (such as coronary artery disease, stroke), high blood pressure (hypertension), diabetes, high cholesterol levels, breast cancer, liver disease, kidney disease, seizures, migraine headaches, unusual vaginal bleeding, certain blood disorders (porphyria, polycythemia), prostate cancer.

Before having surgery, tell your doctor or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

This medication may affect the sperm. 

PHARMACOKINETICS

Danazol has an elimination half-life of 3–6 hours after a single dose and 24–26 hours with repeated administration.[1] Its major metabolites are 2-hydroxymethylethisterone (formed by CYP3A4 and described as inactive) and ethisterone, and other, minor metabolites include ∆2-hydroxymethylethisterone, 6β-hydroxy-2-hydroxymethylethisterone, and ∆1-6β-hydroxy-2-hydroxymethylethisterone.

PHARMACODYNAMIC

Danazol suppresses the pituitary-ovarian axis. This suppression is probably a combination of depressed hypothalamic-pituitary response to lowered estrogen production, the alteration of sex steroid metabolism, and interaction of danazol with sex hormone receptors. The only other demonstrable hormonal effect is weak androgenic activity. Danazol depresses the output of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH).

MECHANISM OF ACTION:

Antigonadotropic activity

Via its weak progestogenic and androgenic activity, through activation of the PR and AR in the pituitary gland, danazol produces antigonadotropic effects.[18] Although its does not significantly affect basal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in premenopausal women (and hence does not profoundly suppress gonadotropin or sex hormone levels like other, stronger antigonadotropins do), the drug prevents the mid-cycle surge in the levels of these hormones during the menstrual cycle. By doing this, it suppresses increases in estrogen and progesterone levels at this time and prevents ovulation.

Mechanism of action in endometriosis

Because danazol reduces estrogen production and levels,[25] it has functional antiestrogenic properties.[28] The combination of its antiestrogenic, androgenic, and progestogenic or antiprogestogenic actions cause atrophy of the endometrium, which alleviates the symptoms of endometriosis

CONTRAINDICATIONS

Danazol should not be administered to patients with: 

1. Undiagnosed abnormal genital bleeding.

2. Markedly impaired hepatic, renal, or cardiac function.

3. Pregnancy. 

4. Breastfeeding.

5. Porphyria - Danazol can induce ALA synthetase activity and hence porphyrin metabolism.

6.Androgen-dependent tumor. 

7.Active thrombosis or thromboembolic disease and history of such events. 

8.Hypersensitivity to danazol.

DRUG-DRUG INTERACTION:

• Carbamazepine + Danazol = increase your risk for serious side effects.

• Danazol+ cyclosporine= leading to an increase of the renal toxicity of these drugs.

• Danazol + tacrolimus= leading to an increase of the renal toxicity of these drugs.

• Danazol can increase the calcemic response to synthetic vitamin D analogs in primary hypoparathyroidism.

REFERENCE: Tripathi K.D; "Essentials of medical pharmacology"; Page no-301