Antiestrogens
Antiestrogens
Antiestrogens bind to estrogen receptors and block estrogen action. The antiestrogens include tamoxifen citrate, toremifene citrate, and fulvestrant. Tamoxifen and toremifene are nonsteroidal estrogen agonist-antagonists, and fulvestrant is a pure estrogen antagonist.
Pharmacokinetics
After oral administration, tamoxifen is well absorbed and undergoes extensive metabolism in the liver before being excreted in stool. Serum levels of fulvestrant, when given I.M., peak in 7 to 9 days. Its half-life is 40 days. Toremifene is well absorbed, and absorption isn’t influencd by food.
Pharmacodynamics
The exact antineoplastic action of these agents isn’t known. However, they’re known to act as estrogen antagonists. Estrogen receptors, found in the cancer cells of one-half of premenopausal and three-fourths of postmenopausal women with breast cancer, respond to estrogen to induce tumor growth.
It’s bound to inhibit growth
The antiestrogens fulvestrant, tamoxifen, and toremifene bind to the estrogen receptors and inhibit estrogen-mediated tumor growth in breast tissue. Tamoxifen may be able to do this because it binds to receptors at the nuclear level or because the binding reduces the number of free receptors in the cytoplasm. Ultimately, DNA synthesis and cell growth are inhibited.
Yea or nay?
Who benefits from tamoxifen?
The current indication for the use of tamoxifen is based on the 1998 results of the “Breast Cancer Prevention Trial,” sponsored by the National Cancer Institute. Results indicated that tamoxifen reduced the rate of breast cancer in healthy high-risk women by one-half. However, tamoxifen has serious adverse effects that include potentially fatal blood clots and uterine cancer. The question is whether these risks are worth the benefits in healthy women.
The National Cancer Institute’s report
To help answer this question, the National Cancer Institute published a report in November of 1999. They concluded that most women older than age 60 would receive more harm than benefit from tamoxifen. Even though women younger than age 60 could benefit from taking tamoxifen, they were still at risk unless they had a hysterectomy, which eliminated the risk of uterine cancer or were in the very high-risk group for developing breast cancer.
Breaking it down further
The report also concluded that the risks of tamoxifen were greater than the benefits for black women older than age 60 and almost all other women older than age 60 who still had a uterus. But for older women without a uterus and with a 3.5% chance of developing breast cancer over the next 5 years, the benefits may outweigh the risks.
NSABP studies update
A report from the 2000 annual meeting of the American Society of Clinical Oncology, presented an analysis of data gathered from the National Surgical Adjuvant Breast and Bowel Project’s (NSABP’s) nine studies of adjuvant tamoxifen for breast cancer. The data analysis indicates that tamoxifen is as effective in Black women as in White women in reducing the occurrence of contralateral breast cancer (breast cancer that develops in the healthy breast after treatment in the opposite breast).
Future findings
The Study of Tamoxifen and Raloxifene (STAR), is a clinical trial that was conducted to determine whether raloxifene can prevent breast cancer better and with fewer adverse effects than tamoxifen. The study began in 1999 and recently concluded. The results showed that the raloxifem-treated group had a lower incidence of uterine cancer and clotting events than the tamoxifen group.
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Pharmacotherapeutics
Tamoxifen is used alone and as adjuvant treatment with radiation therapy and surgery in women with negative axillary lymph nodes and in postmenopausal women with positive axillary nodes. It’s used for advanced breast cancer involving estrogen receptor’positive tumors in postmenopausal women and may be used in palliative treatment of advanced or metastatic breast cancer that’s estrogen receptor’positive. Tumors in postmenopausal women are more responsive to tamoxifen than those in premenopausal women. Tamoxifen may also be used to reduce the incidence of breast cancer in women at high risk.
Toremifene is used to treat metastatic breast cancer in postmenopausal women with estrogen receptor’positive tumors.
Fulvestrant is used in postmenopausal women with receptor-positive metastatic breast cancer with disease progression after treatment with tamoxifen.
Drug interactions
There are no known drug interactions for fulvestrant. However, these reactions may occur with other antiestrogens:
- Tamoxifen and toremifene increase the effects of warfarin, increasing the risk of bleeding.
- Bromocriptine increases the effects of tamoxifen.
- Drugs that induce certain liver enzymes, such as phenytoin, rifampin, and carbamazepine, may increase tamoxifen metabolism, causing decreased serum levels. (See Adverse reactions to antiestrogens.)
Warning!
Adverse reactions to antiestrogens
The most common adverse reactions to antiestrogens, such as tamoxifen, toremifene, and fulvestrant, include:
- hot flashes
- nausea
- vomiting.
Tamoxifen
- Diarrhea
- Fluid retention
- Vaginal bleeding
Toremifene
- Vaginal discharge or bleeding
- Edema
Fulvestrant
- Diarrhea
- Constipation
- Abdominal pain
- Headache
- Backache
- Pharyngitis
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