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Dutasteride

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Covid-19
Trade names  Avodart
MedlinePlus  a603001
ATC code  G04CB02 (WHO)
Molar mass  528.53 g/mol
Bioavailability  60%
AHFS/Drugs.com  Monograph
Routes of administration  By mouth
CAS ID  164656-23-9
Protein binding  99%
Dutasteride
Pregnancy category  US: X (Contraindicated) Not to be handled by pregnant women

Dutasteride and tamsulosin treat enlarged prostates overview


Dutasteride, sold under the brand name Avodart among others, is a medication used to treat benign prostatic hyperplasia (enlarged prostate) and androgenetic alopecia (pattern hair loss).

Contents

It was developed by GlaxoSmithKline and is a 5α-reductase inhibitor which prevents the conversion of the androgen sex hormone testosterone into the more potent dihydrotestosterone (DHT). The drug has been licensed for the treatment of androgenetic alopecia in South Korea since 2009, but has not been approved for this specific indication in the United States, though it is commonly used off-label.

How to pronounce dutasteride avodart memorizing pharmacology flashcard


Prostate enlargement

Dutasteride is useful for treating benign prostatic hyperplasia (BPH); colloquially known as an "enlarged prostate". It is approved by the Food and Drug Administration (FDA) in the U.S. for this indication.

Prostate cancer

In those who are being regularly screened, 5α-reductase inhibitors such as finasteride and dutasteride reduce the overall risk of being diagnosed with prostate cancer; however, there is insufficient data to determine if they have an effect on the risk of death and may increase the chance of more serious cases.

Pattern hair loss

Dutasteride is approved for the treatment of male androgenetic alopecia in South Korea at a dosage of 0.5 mg per day. It has been found in several studies to improve hair growth in men more rapidly and to a greater extent than 2.5 mg/day finasteride. Dutasteride has also been used off-label in the treatment of female pattern hair loss.

Excessive hair growth

Although no reports specific to dutasteride currently exist, 5α-reductase inhibitors like finasteride have been found to be effective in the treatment of hirsutism (excessive facial and/or body hair growth) in women. In a study of 89 women with hyperandrogenism due to persistent adrenarche syndrome, finasteride produced a 93% reduction in facial hirsutism and a 73% reduction in bodily hirsutism after 2 years of treatment. Other studies using finasteride for hirsutism have also found it to be clearly effective. Dutasteride may be more effective than finasteride for this indication due to the fact that its inhibition of the 5α-reductase enzyme is comparatively more complete.

Adverse effects

Dutasteride has been found to be well-tolerated in clinical studies in both men and women, producing minimal side effects. Sexual dysfunction, including erectile dysfunction, loss of libido, and reduced ejaculate may occur in 3.4 to 15.8% of men treated with the drug. Several small studies have reported an association between 5α-reductase inhibitors and depression. However, most studies have not observed this side effect, and a direct link has yet been established. There have also been reports in a subset of men of long-lasting sexual dysfunction and depression persisting even after discontinuation of dutasteride. Other general side effects include headache and gastrointestinal discomfort. Isolated reports of menstrual changes, acne, and dizziness also exist. There is a very small risk of gynecomastia (breast enlargement) in men. In pregnant women, dutasteride can cause birth defects in male fetuses, namely ambiguous genitalia, and for this reason, should never be given to them.

Sexual dysfunction

This class of medications increases rates of erectile dysfunction (with between 3.4 and 15.8% developing problems after starting their use). This is linked to lower quality of life and can cause stress in relationships. There is also an association with lowered sexual desire. It has been reported that these adverse sexual side effects may persist even after discontinuation of the drug in a subset of men.

Prostate cancer

The FDA has added a warning to dutasteride about an increased risk of high-grade prostate cancer. While the potential for positive, negative or neutral changes to the potential risk of developing prostate cancer with dutasteride has not been established, evidence has suggested it may temporarily reduce the growth and prevalence of benign prostate tumors, but could also mask the early detection of prostate cancer. The primary area for concern is for patients who may develop prostate cancer whilst taking dutasteride for benign prostatic hyperplasia, which in turn could delay diagnosis and early treatment of the prostate cancer, thereby potentially increasing the risk of these patients developing high-grade prostate cancer.

Contraindications

Children, women who are or who may become pregnant, and people with known significant hypersensitivity (e.g., serious skin reactions, angioedema) to dutasteride or finasteride should not take dutasteride. Exposure to dutasteride and other 5α-reductase inhibitors during pregnancy can cause birth defects. Since these medications are readily absorbed through the skin, women who are or may become pregnant should not handle them and if they come into contact with leaking capsules, the contact area should be washed immediately in soapy water. People taking dutasteride should not donate blood and, due to its long half-life, should also not donate blood for at least 6 months after the cessation of treatment.

Pharmacology

Dutasteride belongs to a class of drugs called 5α-reductase inhibitors, which block the action of the 5α-reductase enzymes that convert testosterone into DHT. It is an irreversible inhibitor of all three isoforms of 5α-reductase, types I, II, and III. This is in contrast to finasteride, which is similarly an irreversible inhibitor of 5α-reductase but only inhibits the type II and III isoenzymes. As a result of this difference, dutasteride is able to achieve a reduction in circulating DHT levels of as much as 98%, whereas finasteride is only able to achieve a reduction of 65 to 70%. In spite of the differential reduction in circulating DHT levels, the two drugs decrease levels of DHT to a similar extent of approximately 85 to 90% in the prostate gland, where the type II isoform of 5α-reductase predominates.

In addition to DHT, dutasteride prevents the 5α-reductase-mediated formation of neurosteroids such as allopregnanolone, THDOC, and 3α-androstanediol (see also neurosteroidogenesis inhibitor). These neurosteroids are potent positive allosteric modulators of the GABAA receptor and have been found to possess antidepressant, anxiolytic, and pro-sexual effects in animal research. For this reason, prevention of neurosteroid formation may be involved in the sexual dysfunction and depression that has been associated with 5α-reductase inhibitors like dutasteride.

Pharmacokinetics

Dutasteride has an extremely long terminal half-life of four or five weeks. For this reason, it takes months for dutasteride to be eliminated from the body after discontinuation. In contrast to dutasteride, the terminal half-life of finasteride is short, at only 6 to 8 hours.

Chemistry

Dutasteride is a 4-azasteroid. It is an analogue of finasteride in which the t-butyl amide moiety has been replaced with a 2,5-bis(trifluoromethyl)phenyl group.

History

Dutasteride was patented in 1996 and was first described in the scientific literature in 1997. It was approved by the FDA for the treatment of BPH in November 2001 and was introduced into the U.S. market the following year under the brand name Avodart. Dutasteride has subsequently been introduced in many other countries as well, including throughout Europe and South America. The patent protection of dutasteride expired in November 2015 and the drug has since become available in the U.S. in a variety of low-cost generic formulations.

Premenstrual symptoms

A study found that dutasteride, which blocks the formation of the neurosteroid allopregnanolone from progesterone, is effective in reducing symptoms in women with premenstrual dysphoric disorder.

References

Dutasteride Wikipedia


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