Pharmacology of reproduction. ORAL CONTRACEPTION

Pharmacology of reproduction

ORAL CONTRACEPTION

ORAL STEROID CONTRACEPTION

• COMBINED(COC) x only PROGESTIN (POP) x POSTCOITAL (PCC)

• efficacy- Pearl index 0,5 - 1 (COC), 0,5 - 4 (POP)

• ONE PHASE – stable estrogen (ethinylestradiol ) + stable progestin (derivát 19-

nortestosteronu )

• TWO PHASES – stable estrogen + 2 doses of progestin

• THREE PHASES - 2-3 doses of estrogen + 3 rising doses of progestin

ORAL CONTRACEPTION - II

• ethinylestradiol - 20 - 50g (+progestin: levonorgestrel, norgestimat …)

• 1 tbl 21 days – 7-days break - pseudomenstruation bleeding• MECHANISM OF ACTION• inhibition of ovulation (progestin),

estrogen cycle frequency + cervical mucous changes (pentr. of spermia). + disturbed indometrial quality ( nidation) + motility of ovarian tubes

• OTHEr EFFECTS:• ovaria (function,), uterus (changes in cervical mucus, atrophy,

bleeding), breast (stimulation of proliferation, enlargment),CNS (excitability:E-,P-), endocrine fcion (GnRH, ACTH), hemocoagulation (f.VII, VIII, IX, X), liver (syntetic fction), lipid metabolism (LDL,HDL), glucose met. (insulin),

ORAL CONTRACEPTION - III

• EFFECTS - BENEFITS• profylaxis of ectopic. gravidity, PID, anemia,

PMS, dysmenorhea, endometrial and ovarial ca, benign mastopathy, bone mass

• RISKS• KI: pregnancy, lactation, thromboembolic dis.,

liver dis, hypertension, smoking35 let,breast ca, gynekol. bleeding of unknown etiology, migrena

• AE: tension in breast, depresion, libido disorders, headache, TE events, GIT (nausea)

• DI: ! inductors of enzymes (carbamazepin, phenytoin, rifampicin)

Emergency Contraception

Definition: emergency contraceptives are methods a woman can use after intercourse to prevent pregnancy

Methods: • Plan B − the only dedicated product marketed

specifically for emergency contraception• Off-label use of progestin-only contraceptive pills• Off-label use of combination estrogen-progestin pills• Insertion of a copper-releasing IUD

Emergency ContraceptionIndications for use:

• contraceptive failure (condom broke, pills forgotten)• error in withdrawal or periodic abstinence• rape• any unintended “sperm exposure”

Contraindications:• pregnancyEC could prevent about ½ of unintended pregnancies −

1.5 million pregnancies in the U.S. every year.

Emergency Contraception: Plan B

Contents: 750 µg levonorgestrel per pill

Directions:Take the first tablet as soon as

possible within 72 hours after unprotected intercourse.

Take the second tablet 12 hours later.

The sooner Plan B is taken, the better. It can be taken up to 120 hours after intercourse.

If taken within 72 hours as directed, Plan B reduces the risk of pregnancy from a single act of intercourse by 89%.

≈ $35.00 per pack

Emergency Contraception: Plan B Mechanisms of Action

• Disruption of development and maturation of ovarian follicles

• Disruption of egg maturation and ovulation

• Interference with corpus luteum function

• Alteration of cervical mucus, blocking sperm transport

• Disruption of development of the zygote, morula, & blastocyst

• Impaired transport in the fallopian tube & uterine cavity

• Interference with development of the endometrium to impede implantation

When does pregnancy start???The American College of Obstetricians and Gynecologists (ACOG), the Food and Drug Administration (FDA), and the National Institutes of Health (NIH) have defined implantation as the beginning of pregnancy.

If fertilization has occurred, implantation starts about 7 days after ovulation.

Plan B disrupts the events leading up to implantation.

After implantation, it has no effect.

Emergency Contraception: Plan B

Is Plan B an “abortion pill?”

No. The oral abortifacient is RU-486 (mifepristone, Mifeprex) which is an antiprogestin that blocks the effects of progesterone by binding to its receptors. It is usually given in combination with misoprostol (Cytotec) to medically induce abortion in gestational ages up to 49 days after LMP.

If implantation has occurred, Plan B will do nothing.

Emergency Contraception

Alternatives to Plan B:20 tablets of a progestin-only pill (e.g., Micronor) x 2 doses, 12

hours apart

2 doses of a combined estrogen-progestin pill, 12 hours apartAlesse 5 pink pills (100 µg EE + 500 µg levonorgestrel)

Triphasil 4 yellow pills (120 µg EE + 500 µg levonorgestrel)

Ovral 2 white pills (100 µg EE + 500 µg levonorgestrel)

If you give estrogen, give an antiemetic also!

Emergency Contraception

Standards of care:• providing information• providing post-coital

treatment• providing advance Rx

www.NOT-2-LATE.com

1-888-NOT-2-LATE

“Every woman, every visit.”

− ACOG

Go get΄em!

MEN HORMONAL CONRACEPTION

• low doses of testosterone

• GnRH antagonists

• 17-methyl-19-nortestosteron (MENT)

TERATOGENITY of DRUGS

THALIDOMIDE

• Thalidomide (Contergan) - 1956 –morning nausea of pregnant women– in 28 countries 100 000 kg of thalidomide,

– malformed more than 10.000 children - phocomelie

– teratogenic dose in men very low ! (0,1 mg/kg)

– tested several animal species (instead of rabbitt) - 20-300 mg/kg

– only one dose is sufficient 50-100 mg in critical period (21.-36. after

conception)

7 wks pc

A teratogen is an agent that can produce a

permanent alteration of structure or function in an organism exposed

during embyronic or fetal life.

Many agents can produce a teratogenic

effect under some circumstances.

Nature of the agent

Factors That Influence Teratogenicity

Dose Route Frequency of exposure Duration of exposure

Gestational timing

Factors That Influence Teratogenicity

Concurrent exposures Concurrent illness Genetic susceptibility

– Mother– Fetus

Principal Mechanisms of Teratogenesis

Cell growth or proliferation Cell death Cell migration Cell and tissue interactions Disruptions

Mutagenesis

Principal mechanisms– Gene mutation– Chromosomal abnormalies

Before or after conception Males and females both

affected

Multifactorial42%

Unknown37% Chromosomal

3%

Monogenic8%

Teratogens10%

Baird et al. AJHG 42:677, 1988

Birth Defects in Childhood

Teratogens

Birth Defects in Childhood

Birth Defects Caused By Teratogenic Exposures Are

Preventable.

Prevention of Birth Defects Caused by

Teratogenic Exposures is an Important Public

Health Problem.

Prevention of known teratogenic exposures

Public Health Concerns

– Alcohol – Infectious diseases– Isotretinoin, thalidomide

Occupational exposures

Public Health Concerns

Environmental exposures Drugs of abuse Medications

Over-the-counter medicines

Medications

Herbals and dietary supplements

Prescription drugs

Frequently used by pregnant women

Medications

Biologically active Taken systemically Taken in high doses Information about

teratogenicity very limited

Teratogenic Risk of 468 Drugs Approved 1980-2000

0%

20%

40%

60%

80%

100%

0-4 5-9 10-14 15-20

Years Since FDA Approval

Undetermined None, Minimal or Unlikely Small, Moderate or High

Lo & Friedman, 2002

Teratogenic Risk of 468 Drugs Approved 1980-2000

Lo & Friedman, 2002

11 (2.4%) of treatments pose a “small”, “moderate” or “high” teratogenic risk

On average, 6.0 ± 4.1 years after FDA approval required to recognize risk in humans

Teratogenic Risk of 468 Drugs Approved 1980-2000

Lo & Friedman, 2002

30 (6.4%) of treatments unlikely to pose a risk in human pregnancy

On average, 9.1 ± 4.5 years after FDA approval required to show safety in humans

Animal teratology studies are valuable

Animal teratology studies are valuable

but false positives and false

negatives do occur.

Chlorpheniramine

Animal Teratology Studies: False Positives

Hydroxyzine Propoxyphene

Captopril, enalapril

Animal Teratology Studies: False Negatives

Carbimazole, methimazole Misoprostol

Pregnant women may not receive treatments that benefit their own health or that of the fetus

Lack of Knowledge Is a Problem

Exposures that really do pose a risk remain unrecognized

Women may be advised or choose to terminate pregnancy to avoid risk

Lack of Knowledge Is a Problem

Labeling tends to provoke anxiety, often unnecessarily

Characterizing teratogenic risks of important exposures

Public Health Priorities

Prevention of exposures that are known to be teratogenic

Recognition of pregnancies at high risk

categories of risk - FDA• A – controlled trials in pregnant women -

levothyroxin, liothironin, folic acid• B – animal studie negative and controlled clinical

trials not available - paracetamol• C - teratogenic in animals, no clinical trials or not

available in animals in women - teofylin, amlodipin• D – there are known risks, but you can not

substituten - beta-blockers, ACEi (III. trimestr)• X – risks overweights the benefits oral

contracetives, statins, finasterid, isotretinoin, warfarin, misoprostol, androgens

Teratogens in first trimester

• phenytoin, carbamazepine, valproate - neura tube defects (spina bifida)

• lithium – cardiac malformations• warfarin - bone deformation, chondrodysplasy, CNS

defects heparin (demineralization of bone in mother –

switch to LMW)• retinoids-def. CNS, heart, limbs, liver• danazol• oncologic drugs (fluorouracil, metotrexat,

cyclofosfamid, busulfan,…)

Teratogens in fetal period• ACEI –renal failure, oligohydramnion• tyreostatics (carbimazol, thiamazol, propylthiouracil)• benzodiazepins - dependency• barbiturátes - dependency• beta-blockers (atenolol)• NSA – constriction of ductus • tetracyklins – disturbances of bone mass, teeth • warfarin – intracranial hemorhagies• aspirin - bleeding• cytostatika

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