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Pharmacology in reproductive age and in post reproductive age Prof M aris Widodo Program pendidikan Dokter Universitas Islam Malang

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Page 1: Repro Farmakologiwomn2012

Pharmacology in reproductive age and in post reproductive age

Prof M aris Widodo Program pendidikan Dokter

Universitas Islam Malang

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MenstruasiKehamilan dan menyusuiKontrasepsi oralendometriosisMenopausePost menopause

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Obat pada kehamilan dan menyusui

perubahan farmakokinetik selama kehamilan penentuan dosis obat berbedabahaya efek teratogenikperubahan fisiologis selam kehamilan seperti

nausea vomitingkonstipasigastro oesophagial refluk

Thrombo embolismfarmakokinetik selama laktasi perlu diperhatikan

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Kontrasepsipria ;

spermicideinteruptusoperasi vasectomi

wanita :oral kontrasepsiIUDkalendertubectomi

yang sedang dikembangkan vaccine

kontrasepsi oral untuk wanita

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Kontrasepsi = pencegahan kehamilan setelah sexual intercourse dengan cara:

mencegah sperma hidup menuju oavummembuat barrier terhadap sperma menuju ovummencegah inplantasi ovum kedalam endometriummembuat lingkungan uterus tidak nyaman untuk inplantasi

Macam kontrasepsi yang irreversible oral, transdermal dan long acting contraseption

estrogen progestincondom, spermicide diafragma , with drawlintrauterin device

Kontrasepsi mantap / ireversibletubectomi wanitaVasectomi pria

herbal

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Progestin-only pills (minipills) tend to be less effective than combination OCs with typical use and are associated with irregular and unpredictable menstrual bleeding, as well as an increased frequency of functional ovarian cysts.

Irregular menstrual cycles indicate that ovulation has been inhibited; however, this is one of the most frequent reasons for the discontinuation of the minipill. Minipills are always begun on the first day of mensesand must be taken every day at approximately the same time to maintain contraceptive efficacy. Since minipills may not block ovulation (nearly 40% of women continue to ovulate normally), the risk of ectopic pregnancy is higher with their use than with the use of other hormonal contraceptives.

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Endometriosismultifactorial cyclic non cyclic paininfertility sub fertility

Ada jaringan endometrium diluar uterusMenyebabkan nyeri dan infertilitasTerapi utama menghilangkan nyeriMemperbaiki fertilitas

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TABLE 79–1. Clinical Presentation of EndometriosisSymptomsAsymptomaticDysmenorrheaDyspareuniaChronic pelvic pain (cyclic or acyclic)Premenstrual spottingGastrointestinal disturbancesUrinary disturbances (dysuria, hematuria)Low back painPainful defecation (dyschezia)SignsCul de sac or uterosacral ligament tendernessAdneal enlargement or tendernessPelvic massSubfertilityLaboratory TestsNoneOther Diagnostic ModalitiesRed “flame” lesions (early disease)Blue/brown/gray “powder burn” lesions“White lesions” (healed or inactive disease)“Chocolate cysts” (endometriomas containing blood)

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ART =Assited reproductive technology Danazol =steroid sintetic

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PERIMENOPAUSE AND MENOPAUSESYMPTOMS Vasomotor symptoms (hot flushes and night sweats) Sleep disturbances Mood changes Sexual dysfunction Problems with concentration and memory Vaginal dryness and dyspareunia

SIGNS Perimenopause: Dysfunctional uterine bleeding owing to anovulatory cycles (other gynecologic disorders should be excluded) Menopause: Signs of urogenital atrophy

LABORATORY TESTS Perimenopause: FSH on day 2 or 3 of the menstrual cyclegreater than 10–12 IU/L Menopause: FSH greater than 40 IU/LOTHER RELEVANT DIAGNOSTIC TESTS Thyroid function tests Iron stores

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Terapi Hormon pada wanitaEstrogen-based postmenopausal hormone therapy should

be used for the treatment of menopausal symptoms (i.e., vasomotor and urogenital symptoms) and, when specificallyindicated, for osteoporosis prevention.

A progestogen should be added for endometrial protectionwhen estrogen therapy is prescribed. Thus women with an intact uterus should not receive unopposed estrogen, whereas women who have undergone hysterectomy always should receive estrogen alone.

Lower doses of hormone therapy than previously usedshould be considered as standard initial therapy.

The major indication for estrogen-containing hormone Therapy is the relief of menopausal symptoms.

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Postmenopausal hormone treatment with oral combined estrogen plus progestogen has no benefit for cardiovascular disease prevention and increases the risk of breast cancer, coronary heart disease events, stroke, and venous thromboembolic events.

Hormone therapy improves mood and well-being primarily in women with hot flushes, night sweats, and sleep disturbance, but it does not improve gross quality-of-life measures in postmenopausal women who do not experience vasomotor symptoms.

Menopause is the permanent cessation of menses following the lossof ovarian follicular activity.1 By definition, it is a physiologic eventthat occurs after 12 consecutive months of amenorrhea—so the timeof the final menses is determined retrospectively.

Characteristics of the human menstrual cycle throughout reproductive life have been well described.7 Awoman is born with approximately two million primordial follicles in her ovaries. During a normal reproductive life span, she ovulates less than 500 times. The vast majorityof follicles undergo atresia.

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Estradiol-replacement therapy has been identifieda s a successful treatment for perimenopausal women with vasomotor and depressive symptoms.

Testosteronereplacement therapy has been reported to improve mood, well-being, and sexual functioning in perimenopausal women.

Assessment of the risks versus benefits of HRT should be done regularly during treatment.

Education, psychotherapy, well-balanced meals and snacks, regular exercise, dietary changes (e.g., limiting caffeine, alcohol, and salt), relaxation therapy, stress reduction,and sleep hygiene are first-line nonpharmacologic approaches for menstruation-related disorders.

Serotonin (5-hydroxytryptamine, 5-HT)–augmenting antidepressants are effective for treating premenstrual and perimenopausal mood and anxiety symptoms. Serotoninreuptake inhibitors (SRIs) may be given continuously or intermittently during the luteal phase of the menstrual cycle for PMDD.Nonsteroidal anti-inflammatory agents (NSAIDs) are the treatment of choice for dysmenorrhea, muscle aches, and headaches. Vitamin E supplementation may reduce fibrocystic breast changes if caffeine restriction is not helpful.Ovulation suppression (e.g., oral contraceptives, danazol, gonadotropin-releasing hormone agonists) should be used before resorting to surgical therapy in women with severe PMDD.

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PHYTOESTROGENSPhytoestrogens have physiologic effects in humans15; they are plant compounds with estrogen-like biologic activity and relatively weak estrogen-receptor-binding properties. Epidemiologic studies suggest that consumption of a phytoestrogen-rich diet, as seen in traditional Asiatic societies, is associated with a lower risk of breast cancer. HORMONAL REGIMENSApproved indications of hormone therapy include treatment of menopausal symptoms and osteoporosis prevention. Therapy directed at menopausal symptoms, such as hot flushes, is often short term. However, therapy directed at prevention of osteoporosis should be long term.In women with an intact uterus, hormone therapy consists of an estrogen plus a progestogen. Inwomen who have undergone hysterectomy, estrogen therapy is given unopposed by a progestogen.ESTROGEN AND PROGESTOGEN TREATMENT EstrogensThe primary accepted indication for estrogen-based hormonetherapy is the relief of vasomotor symptoms, and the initialdose should be the lowest effective dose for symptom control. Estrogensare naturally occurring hormones or synthetic steroidal or nonsteroidalcompounds with estrogenic activity.

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Methods of Estrogen and Progestogen Administration Continuous Cyclic Estrogen/Progestogen Treatment. Estrogen typically is administered continuously (daily).Aprogestogen is coadministered with the estrogen for at least 12 to 14 days of a 28-day Cycle.

Continuous-Combined Estrogen/Progestogen Treatment.Continuous-combined estrogen-progestogen administration results in endometrial atrophy and the absence of vaginal bleeding. However, initially it causes unpredictable spotting or bleeding, which usually resolves within 6 to 12 months.

continuous Long-Cycle Estrogen/Progestogen Treatment. To decrease the incidence of uterine bleeding, a modified sequential regimen has been developed. In the continuous long-cycle (or cyclicwithdrawal) estrogen-progestogen regimen, estrogen is given daily,and progestogen is given six times a year, every other month for 12 to 14 days, resulting in six periods a year.

Intermittent-Combined Estrogen/Progestogen Treatment. The intermittent combined estrogen-progestogen regimen, also called continuous-pulsed estrogen-progestogen or pulsed-progestogen, consists of 3 days of estrogen therapy alone, followed by 3 days ofcombined estrogen and progestogen, which is then repeated without Interruption.

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ANDROGENSThe therapeutic use of testosterone in women, although controversial, is becoming more widespread.39 Data to support this practice are limited; however, several randomized trials of transdermal testosterone therapy have been conducted and provide evidence for benefits in selected women. There is a cluster of symptoms that appears to characterize androgen insufficiency in women: loss of sexual desire, diminished well-being, loss of energy, and over time, decreased bone mass and reduced muscle strength.

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Estrogen alternative untuk hot flush

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Approximately 1% of women spontaneously develop ovarian failure before the age of 40 years.

Premature ovarian failure is not an early natural menopause. Most affected women produce estrogen intermittently and may ovulate despite the presence of high gonadotropin concentrations. However, these women sustain sex steroid deficiency formore years than do naturally menopausal women, resulting in a significantlyhigher risk for osteoporosis and cardiovascular disease.

Women with premature ovarian failure need exogenous sex steroids to compensate for the decreased production by their ovaries. Thus premenopausal hormone therapy is required at least until these women reach the age of “natural menopause.” The goal of therapy is to provide a hormone-replacement regimen that maintains sex steroid status as effectively as the normal, functioning ovary. This usually requires the administration of estrogen at a dose greater than the standard dose given to older women experiencing natural menopause.

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Synderoma terkait menstruasi premenstrual synderome PMSpre menopause syndrome and HRT

PMS 90 % psikis, cyclic, somatic pada saat late lutealKeluhan episodik dan meningkat pada premenopause

a complex interaction between genetic predisposition and cyclic changes in ovarian steroids, neurotransmitters, Neurohormones, and neuropeptides.

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Premenstrual and perimenopausal syndromes can manifest with a wide variety of symptoms, including depression, mood lability, irritability, anxiety, insomnia, fatigue, abdominal pain, breast tenderness, muscle aches, headaches, hot flashes, decreased libido, and concentration difficulties. Although some degree of these symptoms may be a normal phenomenon, up to 10% of women have significant impairment in social and/or occupational functioning and require treatment.

Tujuan terapi menghilangkan keluhan membuat lebih aktif dilingkunganya perubahan gaya hiduphormon replacement terapi

estradioltestosteroneinhibin gonadotrpin releasing hormon

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Drugs in Pregnancy-The issues

• Only half of all pregnancies are planned• Many women need medications for pregnancy

induced conditions (e.g. Morning Sickness), chronic conditions (e.g. Epilepsy), intercurrent conditions (Allergies)

• Women work with chemicals, exposed to radiation and use illicit drugs

• During embryogenesis-drugs &chemicals may adversely affect development

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Situational Analysis

• A) Anxiety of birth defects:• Leads women not to take medications during

pregnancy& lactation.• Leads pharmaceutical companies not to develop

drugs for pregnant &lactating women.• B) Women are not treated appropriately even after

first trimester, or for life threatening conditions

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Perception of Teratogenic Risk(1)

• Even when exposed to non teratogenic drugs-women assign 25% teratogenic risk (Am J Obstet Gynecol 1989)

• Evidence-based counseling can prevent unnecessary pregnancy terminations (Teratology 1990)

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Perception of Teratogenic Risk(2)

• Following the Chernobyl disaster-half of all pregnancies in Athens were terminated (Trichopolous, BMJ, 1985)

• Women exposed to diagnostic radiation assign major teratogenic risk (Bentur, Teratology, 1991)

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Glyburide• Fear:oral hypoglycemics cross placenta-neonatal

hypoglycemia

• Elliott (Am J Obstet Gynecol 1994):Glyburide does not cross the placenta in perfusion studies.

• Langer et al (NEJM 2001): Glyburide as effective and safe as insulinUndetectable umbilical cord levels with therapeutic maternal

levels(50-150ng/ml)

• Mechanisms: high protein binding(99.8%), short T1/2(2-6 hr), ABC transporter substrate.

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Fetal Safety of Oral Hypoglycemics

• Motherisk Meta analysis (Can J Clin Pharmacol 2003;10:179-83)

• 10 studies• 471 exposed;1,344 controls• Major malformations: OR 1.05 (.65-1.7)• Neonatal death: OR1.16(.67-2)

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Fetal Safety of Glyburide

• Meta analysis( Motherisk 2006)-glyburide vs insulin• Macrosomia- OR1.04(.74-1.45)• Birth weight: WMD 17g(-44-80)• Gestational age: WMD 0(-.28-.27)• Neonatal hypoglycemia OR 1.33(.99-1.79)• In Langer’s study:18/201 vs. 12/203• (OR 1.57(.73-3.34)

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Fetal Safety of Metformin

• Motherisk meta analysis• 1% malformation rate in metformin• 7% among disease matched controls(p<0.01)Potential protective effectPossibly because of improvement in insulin

resistance and in androgen status

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Major Medicinal Teratogens(1)

• Antiepileptics• Carbamazepine-NTD(1%)• Valproate-NTD(2%);other malformations (Holmes 2003)• Phenytoin: Fetal Hydantoin Syndrome(10-15%?)

• ACE inhibitors: renal insuffuciency, hypocalvaria

• Lithium-Ebstein’s anomaly(1/5000)

• Coumadin-Fetal Warfarin Sundrome

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History

• Thalidomide: probably the most notorious human teratogen

• Marketed as a sedative in late 1950’s– Associated with up to 12,000 birth defects,

primarily phocomelias– Other effects included:

• facial hemangiomata, oesophageal & duodenal atresia, teratology of Fallot, renal agenesis & anomalies of the external ear

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Thalidomide

• No malformations if taken before the 34th day after last menstruation & usually no malformations if taken after the 50th day

• Sensitive time period: day 35 to day 49– Day 35 – 37: absence of ears & deafness– Day 39 – 41: absence of arms– Day 43 – 44: phocomelia with three fingers– Day 46 – 48: thumbs with three joints

• If taken throughout the sensitive period: severe defects of the ears, arms & legs & internal malformations often leading to early death (40% died before their 1st birthday)

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Thalidomide• Association between thalidomide and human

teratogenicity suspected by Lenz (Germany) in November 1961 & endorsed by a letter by McBride to the Lancet in November 1961

• Withdrawn in Germany at the end of Nov 1961– end of malformation ‘epidemic’ seen in July 1962 (as predicted)

• Thalidomide continued to be sold for several months in some countries e.g. Belgium, Brazil, Canada, Italy & Japan

• Finally withdrawn in Japan in Sept 1962– peak in epidemic occurred in Japan at a time when epidemic

had ended in Germany

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Thalidomide

• 20% of pregnancies exposed during this period resulted in anomalies

• Administration to female rabbits did not show any adverse effects on fertility– There was an increase in early pregnancy loss

(equivalent to miscarriage)– There were no thalidomide-associated

malformations in surviving foetuses

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Overview• All drugs should be avoided in pregnancy unless they are

‘essential’• In practice, it may not be easy to know what treatment is

really necessary or whether a particular medicine is an appropriate choice

• Requires a balanced approach:– Being over-cautious may deny a beneficial therapy – Lack of due caution might harm babies as a consequence of drug exposure

• Benefits of treatment need to be weighed against the risks of giving no medication– Note: while the benefits of Tx may be clear, the risks may be largely unknown

or unquantifiable– For minor conditions, the risks almost always outweigh the (often trivial)

benefits

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The problem

• 80% of women use prescribed or OTC drugs during pregnancy– 3 – 8 different drugs (partly prescribed and partly

self-medication)• The risks of drug use in pregnancy has lagged

far behind advances in other areas of pharmacotherapy

• Main reasons: epidemiological difficulties in establishing causality and ethical barriers to prospective RCTs

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Teratogenicity and drugs

• In the UK, the spontaneous malformation rate at birth is 2-3% i.e. approximately 1 in 40 babies will be born with a malformation

• The incidence of malformations increases to approximately 5% by 4-5 years of age

• Drugs are thought to cause less than 1% of malformations

• Therapeutic drugs do not appear to be a significant cause of birth defects

• However, most birth defects have no known cause and exposure to drugs may play a part in some of these

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Causes of developmental disorders

• Unknown:- Spontaneous development disorders; multigenetic conditions; combination and interactions of exogenic and endogenic factors (65%)

• Genetic diseases:- (20%)

• Chromosomal disorders:- (5%)

• Anatomical factors:- Uterus anomalies; twin pregnancy; oligohydramy (2%)

• Maternal conditions:- Diabetes mellitus; hypothyroidism; phenylketonuria; cytomegaly; listeriosis; lues; rubella; toxoplasmosis; Varicella (4%)

• Chemical and physical agents:- Medicinal products; drugs of abuse (especially alcohol); ionizing radiation; hyperthermia; environmental chemicals (4%)

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Evaluating drug safety in pregnancy

• Most birth defects are rare & so an increased risk posed by a teratogen may not be easily identified

• Most suspected teratogens cause only a relatively small increase in baseline risk of malformations

• Epileptic women treated with anticonvulsant drugs have a 2-3 fold increased risk of malformations, i.e. a 10% risk of having an abnormal baby.– …or at least a 90% chance of having a normal baby

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Evaluating drug safety in pregnancy

• Epidemiological studies of drug exposure in pregnancy require large numbers of exposed infants to prove or disprove the teratogenic potential of a drug – few have the statistical power as they cannot include sufficient patients– e.g. 1,600 live births following 1st trimester exposure to

aciclovir would need to be monitored to detect a 5-fold increase in the risk of a specific defect which occurs as frequently as 1 per 1000 live births, with an 80% power

• For these reasons, no drug is safe beyond all doubt in early pregnancy

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Evaluating drug safety in pregnancy

• Animal studies are required before new drugs are licensed, but it is difficult to extrapolate findings to human pregnancy– Drugs which produce defects in animals can be

relatively safe in humans e.g. corticosteroids• Of over 2,000 drugs, chemicals &

environmental agents shown to be teratogenic in animals, less than 50 are proven human teratogens

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Some teratogenic drugs

ACE inhibitors Renal dysfunction and hypotension in the newborn, decreased skull ossification, hypocalvaria and renal tubular dysgenesis

Alcohol Fetal alcohol syndrome

Aminoglycosides Deafness, vestibular damage

Androgens (e.g. danazol) Masculinisation of female fetus

Anti-cancer drugs Multiple defects, abortion

Anti-thyroid drugs Fetal goitre

Carbamazepine Neural tube defects

Cocaine Cardiovascular, central nervous system defects

Diethylstilboestrol Vaginal carcinoma after in utero exposure

Lithium Cardiovascular defects (Ebstein’s anomaly)

Phenytoin Fetal hydantoin syndrome

Retinoids Craniofacial, cardiac, central nervous system defects

Sodium valproate Neural tube defects

Thalidomide Limb-shortening defects, renal malformations, congenital heart disease

Warfarin Fetal warfarin syndrome

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Embryo/fetotoxic risk assessment

• Generally accepted that the predictive value of animal studies for predicting safety in humans is less than adequate

• With the exception of androgens, several antimitotic drugs, sodium valproate and vitamin A derivatives, all human teratogens were discovered earlier in man than in animals– Most were case studies from alert clinicians rather

than epidemiological studies

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Drugs and the fetus• Nearly all drugs, except those with a very high molecular

weight e.g. insulin and heparin, cross the placenta to the fetus

• Lipid-soluble un-ionised drugs cross the placenta more rapidly than polar drugs

• In practice, all drugs should be regarded as having the potential to affect the unborn child

• The effect of drug exposure will depend upon:– Timing of exposure– Dosage– Concomitant maternal disease– Genetic susceptibility

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Drugs and the fetus

• However, it should be remembered that:– Teratogens do not cause defects in all fetuses

exposed at the critical period of gestation– A drug that harms a baby in one pregnancy may

have no effect in a subsequent pregnancy in the same woman

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Timing of drug exposure

• Exposure during the pre-embryonic period (until 14 days post-conception) the ‘all or nothing effect’

• Damage to all or most cells death• If only a few cells are injured normal development

– Women with a history of drug use in the month following their last menstrual period can often be reassured

– Limitations• Drug must be completely eliminated before this time (not useful

for drugs with long half-life)• Dates of conception uncertain

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Timing of drug exposure

• Fetus most vulnerable to teratogens from week 3 to week 8 after conception (embryonic phase) when major organ systems formed

• For some drugs there is a period of greatest risk– Exposure to sodium valproate at the time the neural tube

closes (between day 17 & 30 post-conception) may result in spina bifida

• Cleft palate develops at about 36 days post-conception & so a drug exposure outside this period is unlikely to be implicated in any a/e

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Timing of drug exposure

• During the fetal period (week 9 birth) the fetus is less susceptible to toxic insults, although some organs (cerebellum & urogenital structures) continue to be formed– Exposure is more likely to cause growth

retardation or interfere with functional development within specific organ systems

• Danazol can cause virilisation of a female fetus after 8 weeks gestation

• Warfarin may cause intracranial haemorrhage in the second & third trimesters

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Timing of drug exposure

• Drugs taken close to term cause predictable pharmacological effects– Beta-blockers can cause neonatal hypoglycaemia– SSRIs can cause withdrawal effects after regular in

utero exposure• Rarely, exposure can have delayed effects

– Diethylstilboestrol – synthetic oestrogen used for threatened spontaneous abortion

• Many female fetuses exposed before the 9th week developed vaginal or cervical cancer later in life

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Dose & polypharmacy

• In general teratogenicity is dose dependent– Neural tube defects & sodium valproate have

shown a correlation with:• Total daily dose• Dose per administration• Peak level achieved

– Dose is only a relative risk factor– Normal babies have been born to women who

have received high doses of valproate & vice versa

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Dose & polypharmacy

• Risk of malformations increases with exposure to multiple drugs – e.g. anti-epileptics

• 4% incidence of defects for 1 drug• 23% incidence for 4+ drugs

• Potential for confounding with disease severity can be discounted as epilepsy is not thought to be associated with an increase in malformation rate

• Avoid polypharmacy whenever possible

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Genetic factors

• Increasing evidence (mainly from anti-epileptic drugs) that genetic factors are important determinants of teratogenic effects

– Malformation rates may be correlated with high levels of epoxide metabolites of phenytoin in individuals with low activity of epoxide hydrolase

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Principles of prescribing in pregnancy

• Consider non-drug treatments• Avoid all drugs in 1st trimester if possible• Avoid drugs known to have harmful effects• Avoid new drugs where possible

– More experience with ‘older drugs’ – greater evidence of safety, but can’t assume they are necessarily safe

• Avoid polypharmacy • Use the lowest effective dose for the shortest duration

possible & review regularly• Consider the need for dosing changes & TDM due to the

effect of pregnancy on drug handling– Changes in serum albumin & total body water

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Hormone Replacement Therapy(HRT)

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Recent MHRA/CHM advice Drug Safety Update 2007; 1(2):2-4

• The decision to prescribe HRT should be based on a thorough evaluation of the potential benefits and potential risks of treatment.

• Healthcare professionals should assess every woman’s overall risk, including cardiovascular risk, particularly in those older than 60 years who have increased baseline risk of serious adverse events.

• Evidence for the risks of HRT in women who had premature menopause is limited. However, the baseline risk of adverse events in these younger women is low, and the balance of benefits and risks may be more favourable than in older women.

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Benefits from HRTDrug Safety Update 2007; 1(2):2-4

Menopausal symptoms• HRT effectively relieves vasomotor symptoms. • In most cases, 2–3 years’ therapy is sufficient, but some women may

need longer.• For all women, the lowest effective dose should be used for the

shortest time.

Osteoporosis• HRT is effective for prevention of osteoporosis, but its beneficial effect

on bone diminishes soon after stopping treatment.• Because of the risks associated with long-term use, HRT should be

used for prevention of osteoporosis only in women who are unable to use other medicines that are authorised for this purpose.

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Harms from HRT – cancersDrug Safety Update 2007; 1(2):2-4Breast cancer

• The risk of breast cancer is increased in women who take HRT for several years.

• Combined HRT has been associated with the highest risk.• For oestrogen-only HRT, risk is lower than with combined HRT. Some

studies have not shown an increased risk for oestrogen-only HRT.• Risk increases with duration of use and returns to baseline within a few

years of stopping treatment.• HRT, especially combined therapy, may increase mammographic density,

which may adversely affect radiological detection of breast cancer.

Ovarian cancer• Observational studies suggest that long-term use of oestrogen-only or

combined HRT may be associated with a small increased risk of ovarian cancer.

• Risk returns to baseline a few years after stopping treatment.

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Harms from HRT – CV disease (1)Drug Safety Update 2007; 1(2):2-4

Coronary heart disease (CHD)• RCTs found increased CHD risk in women who started combined HRT

more than 10 years after menopause. • Very few RCTs have assessed younger, newly menopausal women, and

some have suggested a lower relative risk in these women compared with older women.

• The low baseline risk of CHD in most younger women, and the very low attributable risk due to HRT, means that their overall CHD risk is likely to be low.

• No increased risk of CHD with use of oestrogen-only HRT has been identified to date.

• Importantly, there are no data from RCTs to suggest a cardiovascular benefit with oestrogen-only or combined HRT.

• Healthcare professionals should assess carefully every woman’s risk of CHD before prescribing HRT, irrespective of her age or time since menopause.

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Harms from HRT – CV disease (2)Drug Safety Update 2007; 1(2):2-4

Stroke• Increased risk of stroke (mostly ischaemic) with oestrogen-only and

combined HRT.• Increase in relative risk similar irrespective of age.• Baseline risk of stroke increases with age and therefore older women

have a greater absolute risk.• Limited observational data suggest that stroke risk may depend on

oestrogen dose.

Venous thromboembolism (VTE)• Oral HRT increases the risk of VTE (DVT or PE).• Events are more likely in the first year of use.• Risk appears higher with combined HRT than with oestrogen-only HRT.• Risk associated with other routes of administration not established, but

it may be lower with transdermal HRT.

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Alternatives to HRTCKS guidance. January 2008

• For many women, lifestyle adjustments, education, and reassurance may be sufficient.

• Vaginal lubricants and vaginal moisturizers can help ease vaginal dryness and related symptoms.

• Other potential treatments for menopausal symptoms include tibolone, clonidine, various antidepressants and testosterone.

• Complementary therapies are widely used, but are not recommended– few efficacy or safety data available– some herbs e.g. soy foods, gingseng, black cohosh and red clover have

oestrogenic properties– Black cohosh also possibly associated with hepatic impairment

• EMEA Committee on Herbal Medicinal Products (HMPC) www.emea.europa.eu/pdfs/human/hmpc/26925806en.pdf

Page 83: Repro Farmakologiwomn2012

Summary

• 80% of women experience menopausal symptoms and 45% find them distressing.

• For many women, lifestyle adjustments, education, and reassurance are sufficient.

• HRT is the main treatment– Tibolone is an alternative, but note risks and benefits.

• For individual women, need to weigh benefits of HRT against side-effects.

• Reassess appropriateness of treatment annually– Treatment longer than 5 years needs careful thought.

Page 84: Repro Farmakologiwomn2012

Waalaykum salam

assalamualaykum