Download Week 9 Pharmacology Notes and more Lecture notes Pharmacology in PDF only on Docsity!
Welcome to Pharmacology by Lecturio. 00: I'm Dr. Pravine Shukle. 00: We're going to be covering some reproductive pharmacology today. 00: Listen, this is a huge topic. 00: You can see all the different subtypes and categories on the screen beside me. 00: The gonadal hormone antagonists and agonists sometimes do the same thing and sometimes they do the opposite thing of what you expect. 00: We're going to spend a lot of time in each section and we're going to go over them in detail, so that you understand them and you feel confident answering questions on exams. 00: We're going to be talking about estrogens and anti-estrogens. 00: We’ll be talking about progestins and anti-progestins and we're going to be talking about androgens and anti-androgens. 00: With respect to the anti-estrogen medications, there's a whole bunch of subtypes there. 00: There are the receptor antagonists. 00: There are aromatase inhibitors and then there are GnRH agonists, like danazol, and antagonists, which interestingly enough do the same thing. 01: Underneath the receptor antagonist section – this is estrogen receptor antagonists – we have full antagonists and we have selective antagonists.
With respect to the progestins, we have actual progestin that we administer and we have an anti-progestin called mifepristone. 01: With respect to the androgens, we have a whole list of medications. 01: We have anti-androgens that are receptor antagonists. 01: We have 5-α-reductase inhibitors. 01: We have synthesis inhibitors. 01: And we have other ones such as the GnRH agonists and antagonists. 01: When we take a look at reproductive pharmacology, just have a look at this diagram. 01: I won't go over it in detail now because each section of this diagram will be placed beside the specific area that we’re talking about. 01: This just gives us an overview. 01: So, have a look at it on your own time. 01: It's a very good diagram to understand how all of the drugs fit in. Esrogen and Progestin when you take these medications in uterine tubes and in the endometrium We’re going to start off with estrogens. 00: This is a huge topic. And I'll go over in detail for you because it's going to be very relevant when you're out in practice.
We know that estradiols will increase your triglyceride levels. 01: It may reduce your LDL levels and it may increase your HDL levels. 01: And finally, there are issues surrounding coagulation. 01: We know that estradiols will increase coagulability of most patients. 01: So, that becomes problematic when you're giving estradiols to women who are at risk for stroke, for example. 01: And so, sometimes, we actually withdraw estradiols from patients who are at risk for stroke for that very same reason. 01: We also withdraw medications in patients who are hypertensive because we’re worried about risk of stroke. 02: I want to mention diethylstilbestrol. 02: Now, diethylstilbestrol is important not because we use it, but because we don't use it. 02: It was used unsuccessfully in trying to prevent miscarriages in the 1970s. 02: It caused severe toxicity, causes ectopic pregnancies, infertility and vaginal adenocarcinomas. 02: Now, we are starting to enter into multi-generation issues. 02: So, we start talking about DES daughters. 02:
So, these are the daughters of women who were on diethylstilbestrol in the 1970s and 1960s. 02: There's a 40 times increased risk of vaginal clear cell adenocarcinoma in the daughters of women who had taken this medication. 02: And we believe that there may also be an increased risk of breast cancer and cervical cancer. 02: And we’re unsure if obesity rates are higher in these women and we’re unsure if obesity plays a role in the development of these diseases. 03: What about sons? Well, we believe that there may also be an increased risk of cryptorchidism and hypospadias and there may also be a risk of transgenderism and gender dysphoria. 03: The last one shouldn't really be called a risk per se, but we have noticed that there may be increased rates of these conditions as DES sons. 03: Once again, we’re unsure of the role of obesity in these patients. 03: Now, we talk about the third generation. 03: So, we’re starting to see third-generation patients. 03: Now, if you start to have third-generation effects from a medication, we start worrying about epigenetic abnormalities that were induced by the DES. 03: We have seen an increased association with irregular menses. 03: Now, the girls who are third-generation are often in their teens at this point in time. 03: We’ll have to see what happens to them as they get older.
These morning-after pills prevent pregnancy if given within 24 to 72 hours after coitus. 05: Combinations of estrogens and progestins dominate the landscape, but progestin-only products have fewer side effects and are replacing the older pills. 05: In terms of how they work, they work by inhibiting ovulation. 05: Now, of course, ovulation inhibition is only relevant if these medications are administered in the first half of the cycle before the luteinizing hormone surge. 05: There is also a decreased receptivity of a zygote in uterine tubes and in the endometrium when you take these medications and there is altered cervical mucus gland formation that also reduces receptivity. 06: Here is a summary of the major characteristics of the common emergency contraceptive methods available in the United States. 06: t’s important to note that EC is used to prevent pregnancy after unprotected intercourse by inhibiting ovulation or interfering with the fertilization of an ovulated egg. 06: ECs are not designed to terminate an established pregnancy and are not abortion-inducing drugs Among the most efficacious EC methods are intrauterine devices (IUDs). The Copper IUD, known as Paragard, and the LNG IUD, sold as Mirena, demonstrate pregnancy rates of less than 1% but require clinician insertion. 06: When considering oral medications, there is Ulipristal acetate, also known as UPA, sold under the brand name Ella, and oral LNG, commercially known as Plan B One-Step, among others. 07: These oral options have pregnancy rates of approximately 1 to 3%. Notably, Plan B One-Step is available over the counter, which allows for accessibility without the need for a prescription. 07:
Here's an example of oral contraceptives. 07: Oral contraceptives are progestins only or can be combinations with estrogen. 07: They are monophasic, which is the same dose every day, or they can be multiphasic, which means that they get variable doses each day. 07: There is sometimes a placebo week. 07: So, you can see in this particular example, There is sometimes a placebo week. 07: So, you can see in this particular example, we have the bottom row of seven tablets which are a placebo week. 07: This is usually the week that the patient is allowed to have the actual period. 07: Oral estrogens also can be used for non-contraceptive needs. 08: Sometimes, we treat hypogonadism in young females with oral estrogens. 08: Sometimes we treat older women with hormone replacement therapy, particularly if they've had surgical removal of their ovaries or if they’ve had premature ovarian failure. 08: Finally, in postmenopausal women, we sometimes use hormone replacement therapy, although that type of treatment is falling out of favor over the past five years. 08: In terms of side effects from the oral contraceptive agents or oral estrogens, there is an increased risk of endometrial cancer. 08: Now, we can reduce or mitigate that risk by combining this medication with a progestin.
It induces secretion of endometrium and also maintains a healthy endometrium for pregnancy. 10: Medroxyprogesterone is the prototypical oral synthetic progestin. 10: That is the one that you need to remember. 10: There are other ones as well that are older, more androgenic forms. 10: These agents are also being replaced by newer agents that are actually much better in efficacy. 10: Now, the synthetic progesterones support endometrium, but they don't support the endometrium for pregnancy, which is why, in some cases, they can be used in women who don't want to get pregnant. 10: In terms of the synthetic progestins, they do inhibit ovulation. 10: And in hormone replacement therapy, they are used as an adjunct to estrogen. 10: And they do that because it helps reduce endometrial cancer risk. 10: So, what are the side effects of the progestins? First of all, they do alter carbohydrate metabolism and they may stimulate fat deposition as well. 11: We do know that it decreases the HDL level. 11: We sometimes see a reduction in bone density in the long term in people who are on progestins only and we believe that it may be due to suppressed estrogen levels. 11: We know that there is delayed ovulation after you stop progestins.
So, sometimes, patients may take as long as three months to have ovulation start up again. 11: And high doses of progestins will suppress gonadotrophic releasing hormone and luteinizing hormone and follicular stimulating hormone secretion from the hypothalamus and pituitary. Anti-estrogen and antiprogestin I'm Dr. Shukle. 00: We're going to cover a topic called Selective Estrogen Receptor Modulators. 00: This is a difficult concept for a lot of medical students. 00: So, we're going to take our time going over it, and try and get the understanding really up to a high level. 00: When we take a look at the overall armamentarium that we use in Gonadal hormone agonists and antagonists, you can see that the SERMs or Selective Estrogen Receptor Modulators fall under the receptor antagonists. 00: Why is that? Well, because from a pharmacological point of view, this is what we're using it for. 00: We're using it for its antagonistic action, not for its agonistic action. 00: Now have a look at this diagram. It's a really nice diagram. 00: After this lecture is over, I want you to pause the video and study it so that you can see where all of the drugs fit in. 00: The first of these SERMs that I want to talk about is probably the most famous of them, and it's used most commonly in breast cancer, and that is Tamoxifen. 01:
So it's a very nice drug that's come along and starting to be picked up more and more in terms of use. 02: Another drug in this drug classes Bazedoxifene, which is also a cousin of Tamoxifen. 02: You can see that these agents all end in F-E-N-E except for tamoxifen, which the E was dropped for some reason that I can't explain. 03: But generally speaking, when you have that suffix, that's the class of drugs we're talking about. 03: This also is used for menopausal symptoms, and it's also used for osteoporosis prevention with estrogens. 03: Clomiphene is another example of a drug in this drug class. 03: It reduces the negative feedback loop in the pituitary. 03: What you end up having when you give this medication is you have an increase in the luteinizing hormone and follicular stimulating hormone. 03: Why would we ever want to do that? Well in patients who don't have ovulation or an ambulatory patients, it actually can induce ovulation. 03: Now let's move on to the full antagonists. 03: An example of the full antagonists include drugs like Fulvestrant. 03: It is a pure estrogen antagonist in all tissues, whether you're talking about breast or endometrium.
So it is used in breast cancer, in patients who are resistant to Tamoxifen. 04: And it is also used in patients who have breast cancer who also have high risk for endometrial cancer. 04: So although it isn't used as much as Tamoxifen, it is a very good drug. 04: And you can see where it fits on our pathway here it's right next to the Tamoxifens. 04: The next category of our drugs are the aromatase inhibitors. 04: They're also called synthesis inhibitors. 04: Why do we call them synthesis inhibitors? Because if you take a look at our diagram here, you'll see that aromatase is really responsible for the one of the last steps in the production of estrogen. 04: Now, these drugs are nonsteroidal competitive aromatase inhibitors. 04: They are used in the treatment of breast cancer for obvious reasons because we want to reduce the effects of estrogen on the breast cancer. 04: Another agent in this class is Exemestane. 04: which is an irreversible aromatase inhibitor. 04: Now, I put it in a slightly different category because it is irreversible. 05: It is also used in the treatment of breast cancer.
These are the gonadotropin-releasing hormone analogues, which means that they simulate the activity of gonadotropin releasing hormone. 06: The first of this that I'm going to talk about is Leuprolide. 06: Now, we have discussed this in a previous lecture, but I'll just mention it here for completeness sake. 06: This provides continuous stimulation of GnRH receptors, which actually end up suppressing secretion in the long run. 06: Why does that happen? Well think about teasing your little brother or your little sister, continuous teasing of your little brother or little sister eventually results in that sibling ignoring you. 06: It's kind of the same thing with the brain and with the body. 06: If you have continuous stimulation of certain types of receptors, eventually, the effect of that stimulation becomes less and less. 07: That happens through a process called Receptor-mediated endocytosis, also called downregulation. 07: So you end up taking in those receptors And you destroy them at a higher rate than you're producing them. 07: Eventually, you have fewer receptors to respond to your stimulus and you have less of an effect. 07: Now, the end result of using a drug like this is that it inhibits ovarian production of estrogen and progesterone. 07:
So it is an anti estrogen and anti progesterone medication. 07: We use this in the treatment of precocious puberty in girls. 07: So if patients have high levels of estrogen and progesterone at a very young age, and they start to have early puberty, we can use this agent to delay puberty. 07: We also use this short term for the treatment of endometriosis. 07: We don't want to use it long term for obvious reasons. 07: And we can use it short term for the treatment of fibroids as well, which is kind of the same process as the endometriosis. 08: Let's move on now to the Gonadotropin-releasing hormone antagonists. 08: So Ganirelix is one of the first examples that we'll use. 08: And sometimes this is used for controlled ovarian hyperstimulation in patients who are anovulatory. 08: We can also use certain agents in prostate cancer in men, because again, you're antagonizing the effects of gonadotropin releasing hormone so it can be used in males. 08: Now, we can use it in females as well. 08: It is used in the first week of therapy with leuprolide in those patients. 08: We are less likely to cause a tumor flare with this combination. 08:
In plasma, it is bound to sex hormone binding globulin or SHBG. 00: It is converted to dihydrotestosterone, which is going to be the active compound in this system. 00: Now, obviously, testosterone is going to give masculinizing characteristics. 00: You will have an increased hematocrit, positive nitrogen balance, normalizing your increasing bone density, more virilization which includes facial hair. 00: It is often used in men for replacement therapy. 00: We’re starting to diagnose low testosterone levels more and more often in men and we’re starting to see that they have significant biomedical issues with low testosterone and we’re starting to treat them quite effectively. 00: Rapid hepatic metabolism can sometimes occur with these medications and that's why oral medications aren't terribly effective. 01: So, we tend to use injections and patches. 01: The use of testosterone patches has resulted in a significant reduction in male – elderly male depression as well, as it seems that testosterone seems to keep men happy for some reason. 01: In terms of toxicity, the worst of the issues is really cholestatic jaundice. 01: We see that actually quite a bit. 01: Transaminitis is going to be an issue and hepatocellular carcinoma is the most feared of the potential problems.
Now, in women, who are on testosterone therapy, we see some virilization. 01: We see hirsutism, which is increased facial hair; we see enlargement of the clitoris; and we see a deepening of the voice. 01: We also see in women menstrual irregularities, more aggression, and rare episodes of hypersexuality. 01: In terms of pregnant women, we will see virilization of the female fetus. 02: In males, we can sometimes get a paradoxical feminization of the patient, and that's because of feedback inhibition. 02: We started to see this first in weightlifters because they figured that – well, I'm taking a little bit of testosterone and that's helping me build muscle mass; if I take a lot, I'll probably get a lot of muscle mass if I take a lot, I'll probably get a lot of muscle mass and there they started growing breasts and looking more female. 02: And so, that – we've looked into these patients and tried to figure out why that happened and we discovered that excess testosterone, especially exogenous testosterone, seems to lead to feedback inhibition at the pituitary and hypothalamus. 02: Other androgens are often referred to as anabolic steroids. 02: The prototypical anabolic steroid is stanozolol. 02: In the lab, there was a high anabolic to androgen activity ratio. 03: In the real world, the androgen effects are actually still quite significant. 03:
