Pharmacology Scribe: Amber W./Allison R.
Dr. Syapin, 11am Hire: Trey M.
Wed, 10/18/2000
Contraceptives
Special thanks to Melissa Chan for recording the lecture and Joel George and Michael Findley for proofing the scribe.
§ several methods of contraception, but we’re only going to talk about those that involve drugs.
§ One of the most commonly used pharmaceutical agents is nonoxynol-9, a surfactant that has spermicidal and perhaps STD-preventing properties.
§ Hormonally, the most important contraceptive agents are the progestins and estrogens.
§ There are 2 classes of progestins in use: derivatives of 17-alpha-hydroxyprogesterone, and derivatives of 19-nortestosterone.
§ The 17-alpha-hydroxyprogesterone metabolites include hydroxyprogesterone caproate, medroxyprogesterone acetate (MPA), and megestrolacetate. These compounds are relatively selective for progesterone-like activity.
§ The 19-nortestosterone derivatives are more progesterone-like than androgenic but do show significant cross-over. These include norethindrone, ethynodiol diacetate, norgestrel, desogestrel, and norgestimate.
§ Norgestrel is more potent as a progesterone but less selective than the 17-alpha derivatives.
§ The gonanes desogestrel and norgestimate are purportedly the least estrogenic of the class.
§ For estrogens, there’s basically only one that’s used. It is the most potent, though, and is called ethinyl estradiol. Some preparations contain mestranol, but this is converted in the body to ethinyl estradiol.
§ For the oral contraceptives, there are two basic types of preparations: monophasic and multiphasic.
§ Monophasic preparations are fixed doses of a progestin and an estrogen, so the woman will take the same dose throughout a 21 day regimen, and then take a 7 day break.
§ The adverse effects that come from the estrogen are dose-limiting, and the dose for any particular patient must take into account the minimal effective dose and the dose at which side effects are intolerable.
§ A new monophasic preparation of medroxyprogesterone acetate with estradiol (Lunelle) is available which is administered monthly by injection, allows monthly periods, and is as effective as oral contraceptives. This is particularly useful for patients who might forget to take pills, or where oral administration is contraindicated for some other reason.
§ Multiphasic preparations are also taken over a 21 day period, but early in the cycle there is a high estrogen/progestin ratio, and later in the cycle there is a low estrogen/progestin ratio. This mimics the normal hormone ratios during a menstrual cycle, and may reduce side effects, particularly those involving serum lipids.
§ For multiphasic preparations, the estrogen is usually held constant and the progestin is varied to create differing ratios. There are also progestin-only combinations called mini-pills.
§ In addition to tablets, contraceptives are available in injected and implanted forms.
§ Lunelle is the newest, and is given at only monthly intervals, whereas the older ones were much longer term.
§ Depo-provera is a MPA administered every three months. Unfortunately, because of its longer duration, it may take a year after therapy is discontinued before a woman is able to get pregnant. This is contrast to Lunelle, where pregnancy may result as soon as 4 or 5 months after therapy is withdrawn.
§ The Norplant system consists of capsules of a permeable silicon rubber that is implanted under the skin. It contains the progestin levonorgesterol, and is long term (up to 5 years). In overweight women, the efficacy may decline in the 4th or 5th year, so replacing the implant at 4 year intervals may be recommended.
§ What do contraceptives do? The most important thing for oral contraceptives is inhibition of ovulation. They also thicken cervical mucus, impeding the mobility of sperm; alter the endometrium, making it less favorable for implantation; decrease the mobility of fallopian tubes, making it harder for an egg and sperm to get together.
§ Progestin mini-pills do not inhibit ovulation, but do cause all the other changes and are just slightly less effective.
§ For combination oral contraceptives, there is a continuous feedback suppression of LH and FSH, which prevents a midcycle surge. Although the exact mechanism is not understood, the follicles rarely develop and the ovaries atrophy, but the endometrium is stimulated, so during the 7 day break menstrual bleeding will occur.
§ Oral contraceptives can have a number of non-reproductive effects. They increase plasma cortisol, renin, aldosterone, and thyroid hormone levels, changes in the liver production of steroid binding globulins, changes in the production of clotting factors (significant because of the increased risk of thromboemoblic disease), and increased HR and BP (monitor BP in patients on oral contraceptives). The increased cortisol levels can produce hyperglycemia.
§ Besides contraception, combination oral contraceptives can be used to treat gynecological problems (e.g., dysmenorrhea, endometriosis) that do not respond to individual therapy, or to postpone menses when indicated for a particular patient.
§ Contraindications to therapy: thromboembolic disease, women > 35, overweight, HTN, migraines, or smokers; existing liver disease; genital or breast cancers; young women (epiphyseal closure); pregnant women, or nursing women. The minipill is ok for nursing women, because estrogens will get in the milk and cause jaundice in the infant but progestins won’t.
§ Toxic effects of contraceptives were originally thought to be related to the estrogen component, but recent evidence indicates that the progestin used along with the estrogen may influence the adverse affects. However, it is still predominantly the estrogen component responsible for most of the effects we’ll see. Thromboembolic risk increases significantly, and may last for many years after termination of therapy. This includes heart attacks and strokes, and these risks (particularly strokes) are exacerbated by the risk factors of being over 35, obese, diabetic, or smoking.
§ Some of the adverse effects may persist for months or years after oral contraceptives are stopped. Amenorrhea is common, and may last a year or more. Exactly why this occurs is unclear (perhaps rebound GnRH secretion), but it can be treated successfully with clomiphene citrate.
§ Hepatic dysfunction is also common (up to 20%), hence liver disease is a contraindication.
§ The effects of oral contraceptives on cancer is controversial, but recent studies indicate there is no increased risk of breast cancer. However, many experts disagree and point to flaws in study design, etc.
§ Common first cycle effects include nausea, headaches, vomiting, fluid retention, muscle cramps, weight gain. Depression is a more serious side effect occuring in about 6% of women, and necessitates stopping the contraceptive.
§ For injected/implanted preparations there are some unique effects in addition to the common first cycle effects. Lunelle is too new to really appreciate the adverse effects associated with it, but for Depo-provera, there may be initial irregular bleeding followed by amenorrhea. The amenorrhea should not be considered an adverse effect but rather is a desired outcome of treatment. There may also be an increased risk for osteoporosis; women initially lose more bone mass than normal but level off after a certain period (perhaps a year or so). With the Norplant system, local anesthesia is required for its implant, and its implantation carries its own mechanical risks (suturing, cutting into the skin, infection, etc.). Early in the use of the system, there are frequent adverse effects, including dermatitis, breast discharge, weight gain, anorexia, hirsutism, and breakthrough bleeding.
§ There are forms of postcoital contraception. Large doses of ethinyl estradiol taken within 72 hours of intercourse are contraceptive. This form consists of 4 pill of 50ug ethinyl estradiol (highest dose available), and can be taken 2 pills twice a day, or 2 pills daily for 2 days. This prevents implantation in the case there was a fertilized ovum. High doses cause a large incidence of nausea and vomiting (about 50%), so an anti-emetic is commonly used at the same time.
§ The incidence of nausea and vomiting decreases significantly in the other types of post-coital contraceptives, but is still significant.
§ Breast tenderness, cramping, etc. are other side effects.
§ Regular oral contraceptives with the highest dose of ethinyl estradiol can also be used, and whether or not you have progestin does not affect the efficacy. This system was used for a long time “under the counter” before being marketed specifically for this purpose. Preven was the first kit to be marketed, and includes 4 tablets of ethinyl estradiol and levonorgestrel along with a pregnancy kit. The pregnancy kit is important because estrogen is teratogenic to embryos. Another kit called Plan B contains only high doses of levonorgestrel, and consists of two treatments. The first is taken as soon as possible, but within 72 hours of intercourse, and the second is taken 12 hours later.
§ Although it is known that estrogens are teratogenic to an existing embryo, should these methods fail it has not been demonstrated that there will be any problems with the recently fertilized embryo. In other words, only if an embryo is already implanted will the estrogens have a teratogenic effect. It is the estrogens, not the progestins, that are teratogenic.
Finally, Dr Syapin cleared up a question from his glucocorticoid lecture. Alternate day therapy revisited: There are apparently two different systems of classifying glucocorticoids, based on whether they’re used for endocrine or non-endocrine purposes. Essentially, the ones Dr. Syapin classified as “short-acting” in his powerpoints won’t be used, so the intermediate acting ones (prednisone et al.) were renamed “short-acting.” For alternate day therapy, you will use the “short-acting” drugs that are really “intermediate acting” like prednisone. This won’t show up on the block exam, but since Dr. Syapin doesn’t write the USMLE or NBME, we might want to go ahead and learn it anyway.