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HY points followed by a quiz at the end
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GnRH receptor agonists
- Be familiar with a few of the names –> goserelin, nafarelin, leuprolide
MOA of GnRH receptor agonists?
- By agonizing the GnRH receptors continuously, despite leading to a transient increase in LH and FSH production, the net result is a desensitization of the receptors and suppression of LH and FSH. This means these drugs act as antagonists despite technically being agonists at the GnRH receptor –> ultimately leads to decreased LH + FSH –> decreased androgen production by the gonads.
When are they used?
- Classically for prostate cancer (after flutamide).
- Prostate cancer is normally stimulated by androgens, so by giving a continuous GnRH receptor agonist (usually leuprolide), the net result is decreased androgen production. However, during the first couple days of therapy, since it takes time for the desensitization of the GnRH receptors to occur, there will be a transient rise in LH + FSH –> increased androgens. Therefore, we co-administer leuprolide with flutamide, an androgen receptor blocker, which prevents the transient rise in androgens from having an agonistic effect.
- Can be used for uterine fibroids, adenomyosis, and endometriosis. However it should be noted they are not first-line therapies. You should just be peripherally aware that they can be used in theory.
Flutamide
MOA of flutamide?
- Androgen receptor blocker
When is it used?
- Given simultaneous to (or before) GnRH receptor agonists (e.g., leuprolide) in the treatment of prostate cancer.
- Since leuprolide will cause a transient increase in androgens, flutamide will block this effect.
Degarelix
MOA of degarelix?
- GnRH receptor antagonist
When is it used?
- Prostate cancer
- Unlike GnRH receptor agonists, it does not cause a transient rise in androgens. Therefore flutamide need not be co-administered.
Clomiphene
MOA of clomiphene?
- Technically a selective estrogen receptor modulators (SERM), which means it has different effects at different tissues, but for USMLE purposes, memorize it as an estrogen receptor partial agonist at the hypothalamus.
- The partial agonist effect is akin to being an antagonist because it does not induce as much efficacy at the receptor compared to estrogen (i.e., the hypothalamus interprets the binding of clomiphene as insufficient estrogen binding).
- Result is increased GnRH secretion –> increased LH + FSH –> induction of ovulation.
When is it used?
- Induces ovulation in those with abnormal cycles (i.e, enables women to time copulation for fertilization) and subfertility.
- Can be used in women with subfertility.
Adverse effects?
- Hot flashes
- Multiple gestation pregnancies (e.g., quadruplets due to release of multiple ova; although some argue this isn’t actually a bad thing).
Tamoxifen vs raloxifene
MOA of tamoxifen and raloxifene?
- Selective estrogen receptor modulators (SERMs)
- Bind to estrogen receptors with varying degrees of antagonism and agonism depending on the tissue the receptors are located in.
- Both are antagonists are breast tissue and agonists at bone.
- Tamoxifen is a partial agonist at endometrium; raloxifene is an antagonist at endometrium.
When are they used?
- Estrogen receptor positive (ER+) breast cancer.
If they are agonists at bone, does that mean they’re used to preserve bone density?
- No. Whilst in theory they could be used to preserve bone density, they are not used for this purpose because they increase risk of thromboembolic events (i.e., DVT, stroke, MI). This is because estrogen upregulates fibrinogen and factors V and VIII.
What’s the highest yield point for USMLE regarding these drugs?
- Because tamoxifen is a partial agonist at endometrium, there is increased risk of endometrial cancer with its use. The only time tamoxifen should ever be considered in a patient who has breast cancer is if the patient has history of hysterectomy.
- 54F with ER(+) breast cancer + long paragraph of a vignette including surgical history + commenced on tamoxifen; Q asks what aspect of the patient’s history makes her a good candidate for tamoxifen –> answer = “history of hysterectomy,” or “surgical history.”
Aromatase inhibitors
- Be familiar with a few names –> anastrozole, exemestane
MOA of anastrazole and exemestane?
- Aromatase converts androgens to estrogens. Therefore aromatase inhibitors decrease estrogen synthesis.
When are they used?
- Estrogen receptor + (ER+) breast cancer.
- Usually used in postmenopausal women (but USMLE won’t assess you on this detail; you just need to know the drug names + MOA).
Hormone replacement therapy (HRT)
- Estrogen and progestin (any number of progesterone compounds) given cyclically.
- If the woman does not have a uterus, just give continuous estrogen (only reason progesterone is normally given is to prevent unopposed estrogen increasing the risk of endometrial cancer, but if the woman has history of hysterectomy, give estrogen alone).
When is it used?
- Only approved indication is severe vasomotor symptoms (i.e., hot flashes, urge incontinence).
- Is not used to preserve bone density. This is because estrogen increases risk of thromboembolic events (i.e., DVT, stroke, MI), since estrogen upregulates fibrinogen and factors V and VIII. It also increases risk of breast cancer. The risk of breast cancer is related to the estrogen exposure; it has nothing to do with whether progesterone is added or not; progesterone is only added for women without Hx of hysterectomy in order to prevent endometrial cancer.
- If a peri- or postmenopausal woman has vaginal dryness alone (atrophic vaginitis) resulting in dyspareunia (painful sex), topical non-hormonal lubricants are used first, followed by topical estrogen. That is, oral HRT is not needed for mere atrophic vaginitis. But it’s HY for USMLE 2CK obgyn component to know topical estrogen is for atrophic vaginitis.
Mifepristone
MOA of mifepristone?
- Progesterone receptor antagonist used as an abortifacient (i.e., to induce abortion in early first trimester).
- Do not confuse with misoprostol, which is a prostaglandin E1 analogue.
- The combination of mifepristone, followed by misoprostol, is used to induce abortion.
Ulipristal
MOA of ulipristal?
- Selective progesterone receptor modulator (SPRM) that acts as an antagonist at progesterone receptor.
- Used for emergency contraception.
- Most effective pharmacologic agent for emergency contraception. Most effective emergency contraception overall is copper IUD.
Danazol
MOA of danazol?
- Androgen receptor partial agonist
When is it used?
- Treatment for hereditary angioedema (deficiency of C1 esterase inhibitor). Weird, but it causes the the liver to produce more C1 esterase inhibitor.
- Can be used for endometriosis (won’t be an answer on the USMLE, but just be peripherally aware of this).
Side-effects?
- Danazol is known to cause pseudotumor cerebri (increased intracranial pressure; ICP).
- When are you asked what can cause increased ICP, things that should come to mind are: obesity, combined oral contraceptive pills, danazol, high-dose vitamin A (bear liver, or isotretinoin).
- Can cause hirsutism. Despite being a partial agonist (i.e., does not achieve full efficacy at the androgen receptor), it still causes hirsutism and this will show up in vignettes.
Finasteride
MOA of finasteride?
- 5α-reductase inhibitor.
- 5α-reductase normally converts testosterone into dihydrotestosterone (DHT), so finasteride decreases production of DHT.
When is it used?
- Treats benign prostatic hyperplasia (BPH).
- Prostatic tissue growth is stimulated by DHT, so decreased DHT production –> treatment for BPH.
- Can be used as monotherapy, or in combo with tamsulosin or terazosin.
Tamsulosin, terazosin
MOA of tamsulosin and terazosin?
- α1 receptor antagonists, with greater binding to the receptors on the internal sphincter of the bladder.
- α1 agonism normally causes constriction of the sphincter, so antagonism causes decreased tone of the sphincter –> better ability to void the bladder. This does not cause incontinence since the external sphincter is under somatic (voluntary) control; in contrast, the internal sphincter is under sympathetic (autonomic; involuntary) control.
When are they used?
- BPH, same as finasteride. Can be used as monotherapy, or in combo with finasteride.
- Can lower blood pressure slightly, so if the Q gives HTN in a guy with BPH, and finasteride and the α1 blocker are both listed, choose the latter.
Sildenafil
MOA of sildenafil?
- Phosphodiesterase-5 inhibitor –> prevents breakdown of cGMP.
- cGMP normally activates protein kinase G –> leads to relaxation of smooth muscle in the corpus cavernosum –> increased blood flow –> tumescence (erection).
When is it used?
- To achieve penile tumescence (erection).
Minoxidil
- Opens potassium channels on vascular smooth muscle –> hyperpolarization of the cell (potassium flows out) –> relaxation of smooth muscle –> decreases blood pressure (can be used for hypertension).
- Can be used topically for androgenic alopecia (male pattern balding).
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