Drugs affecting uterine tone & infertility

Drugs Affecting Uterine Tone & Contraception

By

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science

M.H.FarjooM.H.Farjoo

Drugs Affecting Uterine Tone & Infertility

Drugs Affecting Uterine Tone: Abortifacients Tocolytics Drugs For Labor & Delivery

Drugs Affecting Contraception: Hormonal Contraception Contraception in Men Drug Pictures

Abortifacients

Abortion is the termination of pregnancy before 20 weeks.

Prostaglandins may be used to terminate pregnancy.

Drug preparations of prostaglandins are capable of inducing labor at any time during pregnancy.

Medical abortion may be induced by prostaglandins and an antiprogestin.

Abortifacients (Cont’d)

PGE is used for first & second trimester abortion and for ripening the cervix before abortion.

Dinoprostone, (PGE2 with vaginal oxytocic effect): It is used for abortion in the second trimester. The mean time to abortion is 17 hours, in >25% of cases

the abortion is incomplete.

Misoprostol, (PGE1 with oral oxytocic effect) Combined with antiprogestins (mifepristone) to produce

early abortion.


Mifepristone (RU 486) is a progesterone antagonist terminating pregnancy during the first trimester.

It has luteolytic properties in 80% of women.

Useful in the treatment of endometriosis, cushing's syndrome and breast cancer.

Its mechanism of action is not known.


It terminates pregnancy in > 85% of cases during the first 7 weeks of conception.

The major adverse effect was prolonged bleeding that often did not require treatment.

Mifepristone with a vaginal PGE1 or its oral type (misoprostol) terminates pregnancy in >95% of patients.


The prostaglandin is given 48 hrs. after the mifepristone to augment uterine contractions and ensure expulsion of the conceptus.

Prostaglandin analogs are absorbed through the skin.

Nurses who are pregnant should be careful in handling them.

If accidental contact occurs, the exposed area should be washed immediately with soap and water.


Adverse Effects of PGs (Related to the vasomotor and vasovagal effects of PGE2): Vomiting & Diarrhea Fever Bronchoconstriction Hypotension and Syncope Hypertension Flushing

Tocolytics

Tocolytics inhibit labor and maintain the pregnancy.

Uterine contractions with cervical changes between 20 and 37 weeks of gestation are considered premature. labor.

Drug therapy is most effective when the cervix is dilated <4 Cm and membranes are intact.

Ritodrine and terbutaline (Beta2-Agonists), magnesium sulfate and nifedipine are used as tocolytics.

Tocolytics (Cont’d)

Ritodrine and terbutaline directly relax pregnant uterus.

They suppress premature labor and can delay labor for several days.

They may cause: Tremors, anxiety, insomnia, headache

Tachycardia, Hypertension

Vomiting

Hyperglycemia

Tocolytics (Cont’d)

Magnesium sulfate Inhibits Ach release in NMJ.

It may cause hypermagnesemia (decreased respiratory rate and hypotonia).

Other adverse effects include: Hypotension, fatigue Higher doses: Hypothermia, paralytic ileus

Contraindications: Myasthenia gravis Renal failure

Drugs For Labor & Delivery

Drugs used during labor, delivery, and the immediate postpartum period include: Oxytocics

Oxytocin Ergot alkaloids Prostaglandins

Opioids Local Anesthetics General Anesthetics

Oxytocin

Oxytocin (Pitocin) is used to induce labor at full-term and to augment labor when uterine contractions are ineffective.

It also can be used to prevent or control uterine bleeding after delivery or to complete an incomplete abortion.

It is contraindicated in the presence of fetal distress, CPD, preterm labor, placenta previa, previous uterine surgery & severe preeclampsia.

Amine alkaloids Peptide alkaloids

Ergot alkaloids

Alkaloid’s Chemistry

Produced by a fungus that infects grain especially rye.

Ergot poisoning signs & symptoms (ergotism): Dementia with hallucinations

Prolonged vasospasm, which may result in gangrene Stimulation of uterine smooth muscle, which in pregnancy

may result in abortion

Lysergic acid diethylamide (LSD)

Ergot alkaloids (Cont’d)

In very small dose, they evoke rhythmic contraction and relaxation of the womb.

At higher concentrations, induces powerful and prolonged contracture.

Vomiting and diarrhea is induced by low doses (Activation of CTZ and GI serotonin receptors).

Their use at delivery to accelerate labor, caused a dramatic increase in fetal and maternal mortality rates.

Introduction of Ergot Alkaloids (Cont,d)

Peptide alkaloidsAmine alkaloids


Hyperprolactinemia Postpartum hemorrhage (if oxytocin fails) :

Uterus at term is very sensitive to ergot alkaloids Induce powerful and prolonged contracture of uterus. Should never be given before delivery. Only for control of late uterine bleeding Methylergonovine (Methergine) 0.2 mg is the agent of

choice. It is usually effective within 1–5 minutes

Bromocriptine


Ergot alkaloids are contraindicated in: Severe hypertension During pregnancy Peripheral vascular disease Coronary artery disease Renal or hepatic disease Severe infections

Prostaglandins

PGF2α has potent oxytocic actions.

PGF2α and oxytocin have similar success rates and comparable induction-to-delivery intervals.

In some cases of postpartum bleeding, PGF2α controls hemorrhage when methylergonovine or oxytocin fail.

Opioids

Parenteral opioid analgesics are used to control discomfort and pain during labor and delivery.

They may prolong labor and cause sedation and respiratory depression in the mother and neonate.

Meperidine (pethidine) may cause less neonatal depression than other opioid analgesics.

If neonatal respiratory depression occurs, it can be reversed by naloxone.

Local Anesthetics

Local anesthetics are used to control pain.

They are injected for regional anesthesia.

Epidural blocks involve injection into the epidural space of the spinal cord.

With regional anesthesia, the mother is usually conscious and the neonate is rarely depressed.

Fentanyl may be combined with an anesthetic for both analgesia and anesthesia.

General Anesthetics The halogenated gases are potent uterine muscle

relaxants. They Consist of :

Halothane Enflurane Isoflurane Desflurane Sevoflurane

They are useful for intrauterine fetal manipulation or manual extraction of a retained placenta.

M.H.Farjoo

Hormonal Contraception Classification Mechanism of Action Pharmacologic Effects Clinical Uses Adverse Effects: Mild, Moderate, Severe Contraindications Contraception With Progestins Alone Postcoital (Emergency) Contraceptives Beneficial Effects

M.H.Farjoo

Classification

Two types of preparations are used for oral contraception: Combinations of estrogens and progestins

Monophasic LD: Low Dose HD: High Dose

Biphasic, Triphasic, 4 phasic

Progestin therapy alone.

Constant dosage of both components during the cycle.

Dosage of one or both components is changed once the cycle

M.H.Farjoo

Mechanism of Action The combination pills selectively inhibit pituitary

function that results in inhibition of ovulation.

The combination agents also change the cervical mucus, the endometrium, and motility and secretion of the uterine tubes.

The continuous use of progestins alone does not always inhibit ovulation but inhibits pregnancy.

The other factors mentioned, therefore, play a major role in the prevention of pregnancy.

M.H.Farjoo

Pharmacologic Effects, Ovary & breast

75% of women will ovulate in the first post treatment cycle and 97% by the third post treatment cycle.

About 2% remain amenorrheic for up to several years after administration is stopped.

Estrogens alone or in combinations tend to suppress lactation.

When the doses are small, the effects on breast feeding are not appreciable.

Only small amounts of these compounds cross into the milk which is not important.

M.H.Farjoo

Pharmacologic Effects, CNS

Estrogens tend to increase excitability in the brain, whereas progesterone decreases it.

The thermogenic action of progesterone has central origin.

Estrogens can relieve premenstrual tension syndrome, postpartum depression, and climacteric depression.

M.H.Farjoo

Pharmacologic Effects, Endocrine

Estrogens given orally or at high doses increase the concentration of the cortisol.

Cortisol concentrations may be more than double the levels in untreated individuals.

Large amounts of estrogen may decrease androgens by gonadotropin suppression.

M.H.Farjoo

Pharmacologic Effects, Blood

OCPs do not alter bleeding or clotting times.

There is an increase in factors VII, VIII, IX, and X and a decrease in antithrombin III.

Increased amounts of coumarin may be required to prolong PT in patients taking OCPs.

M.H.Farjoo

Pharmacologic Effects, Liver

The proportion of cholic acid is increased while the proportion of chenodeoxycholic acid is decreased.

So cholelithiasis is increased with the use of these agents.

M.H.Farjoo

Pharmacologic Effects, Lipid & Carbohydrate

Lipid metabolism: Estrogens increase serum triglycerides,

cholesterol, Phospholipids and HDL but decrease LDL.

Carbohydrate metabolism: Potent progestins such as norgestrel may reversibly

decrease carbohydrate tolerance over several years.

M.H.Farjoo

Pharmacologic Effects, Skin

The OCPs increase pigmentation of the skin (chloasma).

This effect is enhanced in women with dark complexions and by exposure to UV light.

Sebum production, acne, and terminal hair growth is decreased in many patients.

M.H.Farjoo

Clinical Uses The most important use of combined estrogens

and progestins is for oral contraception. The pregnancy rate with combination agents is

0.5–1 per 100 woman years Contraceptive failure occurs when:

One or more doses are missed. Antibiotics (especially broad spectrum) are taken. Use of enzyme inducing drugs (Phenytoin,

rifampin).Normal gastrointestinal flora increases the bioavailability of estrogens.

A poster printed in 1975 to encourage male participation in family planning programs.

M.H.Farjoo

Clinical Uses Cont’d

Progestins and estrogens are also useful in the treatment of endometriosis.

In severe dysmenorrhea the suppression of ovulation with estrogen alone may be followed by painless periods.

The long-term use of large doses of progestins (single or with estrogens) prevents the periodic breakdown of the endometrium.

This may lead to endometrial fibrosis and prevent the reactivation of implants for prolonged periods.

M.H.Farjoo

Mild Adverse Effects Nausea, mastalgia Headache which is mild and often transient Migraine is often made worse and has been

associated with an increased frequency of CVAs.

failure of Withdrawal bleeding, most often with combination preparations.

If disturbing, a different preparation may be tried or other methods of contraception used.Confusion with pregnancy

In this case or when migraine begins during therapy, treatment should be discontinued

M.H.Farjoo

Moderate Adverse Effects Weight gain. Breakthrough bleeding: is the most common

problem in using progestational agents alone. It occurs in up to 25% of patients It is more frequent in low-dose preparations

than high levels of progestin and estrogen. The biphasic and triphasic pills decrease

breakthrough bleeding without increasing the total hormone content.

Any of them may require stopping the drug!

M.H.Farjoo

Moderate Adverse Effects Cont’d

Increased skin pigmentation especially in dark-skinned women.

The incidence being about 5% at the end of the first year and about 40% after 8 years.

It is exacerbated by vitamin B deficiency and is often reversible (though may be very slowly) upon discontinuance of drug.

Acne is exacerbated by androgen-like progestins whereas agents containing large amounts of estrogen improve it.

M.H.Farjoo

Moderate Adverse Effects Cont’d

Hirsutism.

Ureteral dilation & more frequent bacteriuria.

Vaginal infections are more common.

Amenorrhea especially in patients who have had menstrual irregularities before.

Many of these patients have prolactinomas and galactorrhea so prolactin should be measured.

M.H.Farjoo

Severe Adverse Effects The incidence of thromboembolic disease in patients

taking low-dose OCPs is threefold higher.

Its incidence is related to the estrogen.

Antithrombin III, is substantially decreased during OCP use.

The risk is increased in stasis, increased levels of homocysteine, diminished antithrombin III, or injury.

It is not related to age, parity, mild obesity or cigarette smoking.

M.H.Farjoo

Severe Adverse Effects Cont’d

Myocardial infarction: Women 30–40 years who do not smoke, 4 / 100,000

per year. Women 40–44 years who smoke heavily, 185 / 100,000

per year.

CVA: prevalent in women > 35 years old. Risk of MI and CVA is not increased in past users. Subarachnoid hemorrhages is increased among

both current and past users and may increase with time.

M.H.Farjoo

Severe Adverse Effects Cont’d

In general, OCPs increase cardiovascular disorders at all ages and among both smokers and non smokers.

This risk is concentrated in women 35 years or older who are heavy smokers.

M.H.Farjoo

Severe Adverse Effects Cont,d

Cholestatic jaundice which disappears 1-8 weeks after the drug is discontinued.

The incidence of cholangitis and cholecystitis is increased.

Increased incidence of hepatic adenomas.

Depression in 6% of patients.

M.H.Farjoo

Contraindications Thrombophlebitis, thromboemboli. Cardiovascular and cerebrovascular disorders or a

past history of these conditions. Vaginal bleeding with unknown cause. Breast tumor or estrogen-dependent neoplasm. Liver disease, asthma, eczema, migraine, diabetes,

hypertension, or convulsion. Heart failure or when edema is dangerous. In adolescents in whom epiphysial closure has not yet

been completed.

M.H.Farjoo

Contraception with Progestins Alone

Injecting depot medroxyprogesterone acetate (DMPA, Depo-provera) every 3 months achieves effective contraception.

After a 150 mg dose, ovulation is inhibited for at least 14 weeks.

All users have unpredictable spotting and bleeding.

Ovulation suppression can persist for 18 months after the last injection.

M.H.Farjoo

Contraception with Progestins Alone Cont,d

Norgestrel, also used in combined OCPs and minipill, is available in the SC implant form (in USA).

Progestins alone are about as effective as IUDs or LD combination pills.

Norgestrel is used in nursing mothers as “minipill”.

Minipill has also used in women over 40, in whom fertility may be decreased.

Progestins alone reduce the risk of endometrial cancer but increase the risk of atherosclerosis.

M.H.Farjoo

Contraception with Progestins Alone Cont,d

The progestin implant method (Norplant) lasts 5 – 6 years.

Patients with headache or visual disturbances should be checked for papilledema.

Useful in patients with: Hepatic disease Hypertension Psychosis or mental retardation Prior thromboembolism.

M.H.Farjoo

Postcoital (Emergency) Contraceptives

Estrogens alone or in combination with progestins are used (morning after pills).

When treatment is begun within 72 hours, it is effective 99% of the time.

Antiemetics are often administered, since 40% of the patients have nausea or vomiting.

M.H.Farjoo

Postcoital (Emergency) Contraceptives Cont,d

Other adverse effects include headache, dizziness, breast tenderness, and abdominal and leg cramps.

Mifepristone (RU 486), has a luteolytic effect and is effective as a postcoital contraceptive.

When combined with a prostaglandin it is also an effective abortifacient.

Conjugated estrogens: 10 mg three times daily for 5 days

Ethinyl estradiol: 2.5 mg twice daily for 5 days

Diethylstilbestrol: 50 mg daily for 5 days

Mifepristone, 600 mg once with misoprostol, 400 mcg once1

L-Norgestrel: 0.75 mg twice daily for 1 day (eg, Plan B2)

Norgestrel, 0.5 mg, with ethinyl estradiol, 0.05 mg (HD OCP) Two tablets and then two in 12 hours

1Mifepristone given on day 1, misoprostol on day 3.

Postcoital Contraceptives

M.H.Farjoo

Beneficial Effects of OCPs

Reduces the risk of: Ovarian cysts, ovarian and endometrial

cancer, and benign breast disease.

Ectopic pregnancy, iron deficiency and rheumatoid arthritis.

Premenstrual symptoms, dysmenorrhea, endometriosis.

M.H.Farjoo

Contraception in Men

Gossypol Destroys seminiferous epithelium but does not

alter the endocrine function of the testis.

Hypokalemia is the major adverse effect and may lead to transient paralysis.

Ethinyloestradiol (0.035 mg) and Cyproterone Acetate (2 mg)

Ethinyloestradiol and Cyproterone Acetate

Ethinyl Estradiol, Desogestrel

Yaz & Yasmin: Ethinyl Estradiol and DrospirenoneYaz, Yasmin pills suspected in 23 deaths: At least 23 Canadian women who were taking two of the most commonly prescribed birth control pills in the world have died (CBC news, Canada, January 2013)

Approved by FDA on May 7, 2010

4 phasic, Generic product in Iran:• 2 Tab: (Estradiol Valerate 3mg)• 5 Tab: (Estradiol Valerate 2mg+ Dienogest 2mg)• 17 Tab: (Estradiol Valerate 2mg+ Dienogest 3mg)• 2 Tab: (Estradiol Valerate 1mg)• 2 Tab: non hormonal

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Drugs affecting uterine tone & infertility