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1997 Clinical pharmacology By Duy Thai

ORAL CONTRACEPTIVES Hypothalamus GnRH

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LH

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FSH

Anterior pituitary

Gonads Progesterone Ova Oestrogen Normal cycle of female hormones • The release of FSH indicates the start of a cycle • FSH causes the proliferation of cells (follicular cells) around an ovum • The follicular cells release oestrogen • Oestrogen is responsible for causing the proliferation of the endometrium, making it thicker and more vascular • Ovulation occurs midway through the cycle as a result of LH secretion • Once the ova is released, the follicle involutes to become the corpus luteum • The corpus luteum produces progesterone • Progesterone alters the endometrium into the secretory phase • In this phase, there is an increase in the number of glands and secretions. This prepares the uterus for implantation of a fertilised egg. • Progesterone also increases the body temperature so that at the time of ovulation, the woman often has an elevated temperature • If implantation does not occur, the hormones are shut off and the endometrial lining sloughs off • However, if implantation does occur, the hormones still shut off, but the developing placenta now takes over the role of producing oestrogen and progesterone. Pharmacological strategies to disrupt the normal cycle • The main hormones used are synthetic analogues of oestrogens and progestogens • The natural oestrogen is oestradiol • The synthetic oestrogen is ethinyloestradiol (no need to remember) • The natural progestogen is progesterone • The synthetic progestogen is norethisterone (no need to remember!) • These are given to keep the endometrium alive (prevent it from sloughing off) and thus prevent the next cycle from starting again. • There are 3 types of oral contraceptive pills 1. Combination preparations • A mixture of oestrogens and progestogens in fixed ratio of doses • If you take the drugs, you will stop bleeding • You should stop taking them at the end of 21 days. Therefore, the 7 days of drug free period will allow bleeding to occur. Then resume taking the drugs again. • ED preparations have the last 7 tablets as placebo so the woman does not have to worry about keeping track of how many days she has stopped taking the pill
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Testosterone Spermatozoa

1997 Clinical pharmacology By Duy Thai

2. Sequential preparations • Try to mimic normally what happens with the hormone levels • There are 2 types: • Biphasic (2 different types of pills with varying concentrations of oestrogens and progestogens in 21 days) • Triphasic (3 different pills in 21 days) • Start off with low progestogen, low oestrogen combination • Mid cycle - high oestrogen, slightly increased progestogen • End cycle - higher oestrogen, higher progestogen • Sometimes, during the cycle, there may be breakthrough bleeding 3. Progestogen only preparations (mini pill) • Least effective • Used if the women cannot take oestrogens • Used in lactating mothers • Need to be taken every single day Mechanisms of action • Progestogen inhibits LH secretion but not at every cycle (therefore, the mini pill is not very effective because some cycles, there might be ovulation occurring) • Oestrogen inhibits FSH - prevents maturation of an ovum • Why is the progestogen pill relatively effective, given that progestogen on its own is not really so? • Because, progestogens also have other effects apart from preventing ovulation • Modify the secretory activity of the cervical mucous, making it harder for the sperm to get through • When given exogenously, progestogens change the properties of the endometrium to make implantation unfavourable (recall that endogenous progestogens make the endometrium favourable for implantation) • Oral contraceptive pills must not be taken in conjunction with some antibiotics (e.g. Rifampicin). These antibiotics induce enzymes which enhance the breakdown of oral contraceptives • Oestrogens enter the enterohepatic circulation. • This means that they are conjugated in the liver and excreted in the bile • The normal flora of the gut separate the oestrogens from its conjugate, allowing it to be reabsorbed again. If antibiotics are taken and disrupt the normal flora, the oestrogens cannot be “un-conjugated” and so are excreted in the faeces. Cyproterone (need to know for exams!!) • Anti androgen • Blocks the effects of androgens in males and females • Used in the treatment of prostate cancers and precocious puberty in males • It is often part of the combination in oral contraceptive pills • It has similar effects to progestogens • Women who have acne and hirsuitism can take DIANE ® • This is a combination of oestrogen + cypropterone • The cycpropterone replaces progestogens (because it has similar actions) and is also beneficial because it blocks the effects of androgens (which are causing the acne and hirsuitism) • (Some progestogens have androgenic effects which actually cause acne and hirsuitism) Side effects of oral contraceptives • Side effects are commonly seen in the high dose preparations 1. Cardiovascular side effects: • Increased incidence of thromboembolic disorders (especially in older women and smokers) • Mild hypertension 2. Production of tumors: • In animal experiments at very high doses, oral contraceptives are thought to induce the formation of cancers. • High dose oestrogen may cause vaginal, uterine, and breast carcinomas
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1997 Clinical pharmacology By Duy Thai

3. Mild side effects: • Nausea, dizziness, vomiting, flushing, breast discomfort, headache, weight gain, decrease in libido • The weight gain is due to oestrogen causing Na+ and fluid retention. Oestrogens also have mild anabolic effects • Alteration in blood lipids: • Oestrogens: ↑ HDL, ↓ LDL • Progestogens: ↓ HDL, ↑ LDL • Mood: • Depression, irritability, fatigue Contraindications - must never give OCs to these people 1. Women with previous history of thromboemolic disorders 2. Previous history of cardio vascular disorders 3. If the person has had a CVA 4. If the person has uncontrolled hypertension (not responsive to drugs) 5. If the person has severely impaired liver function 6. If the person has a malignancy of the breast/genital tract 7. If the person suffers from focal migraine 8. If there is a history of breast cancers in the family Some beneficial effects of OCPs (apart from stopping pregnancy) • Progestogens reduces the possibility of endometrial carcinoma • If the woman has had a hysterectomy, only oestrogen can be taken • If the uterus is still present, oestrogens and progestogens is the way to go • Incidence of ovarian cancers is reduced • Benign tumors of the breast are protected by OCPs • However, if the tumors do become malignant, or there is already a malignancy, oestrogens will only enhance the growth of the tumor The morning after pill • Needs to be taken within 72 hours of sex • The pill contains a minimum of 100g of ethinyloestradiol • 2 pills need to be taken and then another 2 after 12 hours • Problems: • Severe nausea and vomiting • Therefore, give metaclopramide at the same time • Metaclopromide decreases the nausea • It also causes gastric emptying, which helps absorb the pill (since recall nausea stops gastric emptying)

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