1. Monophasic combination tablets

HORMONAL CONTRACEPTION(Oral, Parenteral, & Implanted Contraceptives) Downloaded from: www.pharmaju-lib.com

1. Monophasic combination tablets • Doses of estrogens & progestins are constant for 21 days • Estrogen: Ethinyl estradiol • Progestins: • Ethynodiol diacetate (+) • Norethindrone (+) • D,L-Norgestrel (+)

2. Biphasic combination tablets • Estrogen: Ethinyl estradiol in constant dose • Progestin: Norethindrone days 1-10 low dose; days 11-21 high dose

3. Triphasic combination pills • Estrogen: Ethinyl estradiol in constant dose • Progestin: L-Norgestrel or Norethindrone days 1-7: low dose days 8-14: medium dose days 15-21: high dose

4. Daily progestin tablets • Norethindrone • D,L-Norgestrel 5. Implantable progestin preparation • Etonorgestrel 6. injecting 150 mg of depot medroxyprogesterone acetate (DMPA) every 3 months

Mechanism of Action • Combination agents: 1.selective inhibition of pituitary function →inhibition of ovulation 2. change cervical mucus, 3. - “ - endometrium 4. - “ - motility & secretion in uterine tubes →↓ likelihood of conception & implantation. • Progestins alone does not always inhibit ovulation →other factors mentioned play a major role in the prevention of pregnancy

Pharmacological Effects 1. On the Ovary: depress ovarian function. ~ 2% of patients remain amenorrheic for periods of up to several years after administration is stopped. 2. On the Uterus: • cervix may show some hypertrophy & polyp formation • cervical mucus is made thicker & less copious • Agents containing "19-nor" progestins tend to produce > glandular atrophy & usually < bleeding

3. On the Breast: Stimulation, some enlargement is generally noted. • estrogens & combinations of estrogens & progestins tends to suppress lactation (minimal with small doses) • only small amounts of these compounds are found in milk (not been of importance) 4. On the CNS: Estrogens ↑ excitability in brain, progesterone ↓ it. - Thermogenic action of progesterone occur in the CNS - Estrogens are employed in therapy of premenstrual tension syndrome, postpartum depression, & climacteric depression.

5. On endocrine function: (-) gonadotropin secretion • ↑plasma renin activity & aldosterone secretion • estrogens ↑ plasma level of SHBG & ↓free androgens by ↑ their binding; • large amounts of estrogen may ↓ androgens by gonadotropin suppression. 6. On blood: similar to those reported in pregnancy- ↑ factors VII, VIII, IX, & X, ↓ antithrombin III • A number of patients developed folic acid deficiency anemias

7. On liver- • Estrogens ↓ flow of bile → may cause ↑ in cholelithiasis 8. On lipid metabolism- • Estrogens: ↑triglycerides & free & esterified cholesterol. • Phospholipids & HDL ↑ • LDL ↓ • doses of 50 μg or < of ethinylestradiol have minimal effects • progestins (particularly the 19-nortestosterone derivatives) antagonize these effects of estrogen • Preparations containing small amounts of estrogen &progestin may slightly ↓ triglycerides & HDL

9. On carbohydrate metabolism: alterations in carbohydrate metabolism similar to those observed in pregnancy • ↓ rate of absorption of carbohydrates from GIT • progesterone ↑ basal insulin level. Preparations with more potent progestins such as norgestrel may cause progressive ↓ in carbohydrate tolerance over the years (reversible) 10.On CV system- small ↑ in cardiac output →↑ systolic & diastolic BP & heart rate. It is important that blood pressure be followed in each patient. 11. On skin- ↑ pigmentation of skin (chloasma) • androgen-like progestins may ↑ production of sebum → acne in some patients. But, since ovarian androgen is↓, many patients note ↓ sebum production, acne, & terminal hair growth

Clinical Uses 1. The most important use of combined oral contraceptives (OCs): contraception • Specially packaged for ease of administration. • Pregnancy rate with combination agents is estimated to be about 0.5-1 per 100 woman years at risk • Phenytoin, antibiotics (Why?) & skipping a pill may result in failure→pregnancy 2. Treatment of endometriosis

Adverse Effects • Mild ADRs: 1. Nausea 2. mastalgia 3. breakthrough bleeding 4. edema • can be ↓by shift to a preparation containing less estrogen or containing progestins with more androgenic effects 5. Changes in serum proteins & ↑ sedimentation rate (WHY IS THAT?)

6. Headache is mild & transient • Migraine ↑ & is associated with ↑ frequency of cerebrovascular accidents • When this occurs or when migraine has its onset during therapy, treatment should be discontinued. 7. Withdrawal bleeding sometimes fails to occur—most often with combination OC—& may cause confusion with regard to pregnancy

B. Moderate Adverse Effects: Any of the following may require discontinuance of OCs: • Breakthrough bleeding: the most common problem with progestational agents alone - occurs in 25% of patients • Biphasic & triphasic OC ↓ breakthrough bleeding without ↑ total hormone content 2. Weight gain: more common with combination agents containing androgen-like progestins - can be controlled by shifting to preparations with less progestin effect or by dieting

3. ↑ skin pigmentation 4. Acne may be ↑ by agents containing androgen-like progestins (agents containing large amounts of estrogen usually cause improvement in acne) 5. Hirsutism may also be ↑ by "19-nortestosterone" derivatives, & combinations containing nonandrogenic progestins are preferred 6. Ureteral dilation (like in pregnancy), & bacteriuria is more frequent 7. Vaginal infections are more common 8. Amenorrhea, in many patients also galactorrhea. Prolactin levels should be measured, since this may be due to prolactinomas

C. Severe Adverse Effects: • Vascular disorders- • Venous thromboembolic disease (deep vein thrombosis, pulmonary embolism):incidence is related to estrogen b.Myocardial infarction (MI)- ↑ riskin women who are obese, have a history of preeclampsia or HTN or have hyperlipoproteinemia or diabetes or smokers. • The association is thought to involve acceleration of atherogenesis because of ↓ glucose tolerance, ↓ HDL, ↑ LDL, ↑ platelet aggregation, facilitation of coronary spasm • Progestational component of OCs ↓ HDL, in proportion to androgenic activity of progestin

c. Cerebrovascular disease-The risk of strokes is ↑ in women > age 35 who are heavy smokers. 2. GI disorders- cholestatic jaundice in patients taking progestin-containing drugs • incidence of hepatic adenomas may be ↑ • ischemic bowel disease secondary to thrombosis of arteries & veins 3. Depression- requires cessation of therapy in ~ 6% of patients 4. Cancer- ↓ risk of endometrial & ovarian c-r. • Some studies: ↑risk of breast c-r in younger women. • Relation of risk of cervical cancer to OC is still controversial

Contraindications Contraindications: • thrombophlebitis • thromboembolic phenomena • cardiovascular & cerebrovascular disorders • past history of these conditions • vaginal bleeding when the cause is unknown • adolescents in whom epiphysial closure has not yet been completed

Avoid in: • patients with known or suspected tumor of breast • liver disease • asthma • eczema • migraine • diabetes • hypertension • optic neuritis, retrobulbar neuritis • convulsive disorders

Cautions • congestive failure or other conditions with edema • fibroids: agents with the smallest amounts of estrogen, the most androgenic progestins or progestational agents alone should be selected • interaction with antimicrobial drugs: normal GI flora ↑ enterohepatic cycling (& bioavailability) of estrogens, antimicrobial drugs may ↓ efficacy of OCs. • Potent inducers of hepatic microsomal enzymes, such as rifampin or phenytoin, ↑ liver catabolism of estrogens or progestins & ↓ efficacy of OCs

Contraception With Progestins Alone • small doses of progestins administered: • Orally, • by implantation under the skin every 5 years • by injecting 150 mg of depot medroxyprogesterone acetate (DMPA) every 3 months • The latter is not desirable for women planning a pregnancy soon after cessation of therapy (ovulation suppression ~ 18 months after last injection) • particularly suited for patients for whom estrogen administration is undesirable • ↑ incidence of abnormal bleeding (spotting) esp first year of use

hepatic disease, hypertension, psychosis or mental retardation, prior thromboembolism. ADRs: - headache, dizziness, bloating weight gain of 1–2 kg, reversible reduction of glucose tolerance. Contraception with progestins is useful in patients with:

Long term DMPA use ↓menstrual blood loss & ↓ risk of endometrial cancer • May cause reversible ↓ bone density • changes in plasma lipids →↑ risk of atherosclerosis • ADRs: headache, dizziness, bloating, weight gain of 1-2 kg, reversible ↓ glucose tolerance

Progestin Implant • utilizes the subcutaneous implantation of capsules containing a progestin (Etonorgestrel) • These capsules release one-fifth to one-third as much steroid as oral agents, are extremely effective, and last for 5-6 years • The low levels of hormone have little effect on lipoprotein and carbohydrate metabolism or blood pressure. • Disadvantages? • patients experiencing headache or visual disturbances should be checked for papilledema.

Postcoital Contraceptives • Pregnancy can be prevented following coitus by administration of estrogens alone or in combination with progestins ("morning after" contraception) • when treatment is begun within 72 hours, it is effective 99% of the time • often administered with antiemetics, since 40% of patients have N or V • other ADRs: headache, dizziness, breast tenderness, abdominal & leg cramps

Mifepristone: • an antagonist at progesterone receptors, • has luteolytic effect & • is effective as postcoital contraceptive when combined with a prostaglandin • Its inhibition of progesteron induces bleeding during the luteal phase and in early pregnancy by releasing endogenous prostaglandins from the endometrium • It is used in the termination of pregnancies less than sixty-four days from conception.

↓ risk (incidence) of: ovarian cysts ovarian & endometrial cancer benign breast disease ectopic pregnancy iron deficiency rheumatoid arthritis Conditions ameliorated with use of OCs: premenstrual symptoms dysmenorrhea endometriosis acne hirsutism Beneficial effects of oral contraceptives unrelated to contraception

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1. Monophasic combination tablets