OBAT PADA KEHAMILANOBAT PADA KEHAMILAN

Noor WijayahadiNoor Wijayahadi

Fokus Perhatian:Fokus Perhatian:1.1. Efek kehamilan terhadap obatEfek kehamilan terhadap obat2.2. Efek obat kepada janinEfek obat kepada janin3.3. Perlu Suplemen/Nutrisi Tambahan?Perlu Suplemen/Nutrisi Tambahan?

Wanita hamil rata-rata minum 4 jenis obat selama hamil40% pada masa rawan teratogen

– Retensi air meningkat (7-9Lt).Retensi air meningkat (7-9Lt).– Volume extracellular meningkat (4-6Lt).Volume extracellular meningkat (4-6Lt).– Cardiac output Cardiac output meningkatmeningkat..– Tekanan osmotik koloid menurun.Tekanan osmotik koloid menurun.– Renin meningkat selama kehamilanRenin meningkat selama kehamilan– Aldosterone meningkatAldosterone meningkat– Resistensi vaskuler perifer menurunResistensi vaskuler perifer menurun– Sekresi asam lambung tinggi pada Sekresi asam lambung tinggi pada Trimester 1 Trimester 1

dan 2dan 2– Pengosongan lambung lambat.Pengosongan lambung lambat.– Body fat meningkatBody fat meningkat

Perubahan selama kehamilanPerubahan selama kehamilan

– Konsentrasi serum albumin menurun Konsentrasi serum albumin menurun More free drug.More free drug.

– Progesterone merangsang enzyme hepar Progesterone merangsang enzyme hepar Increase clearance and shorter half-lifeIncrease clearance and shorter half-life..

– Simpanan lemak dan glycogen hepar Simpanan lemak dan glycogen hepar meningkat.meningkat.

– Renal blood flow and GFR meningkat pada Renal blood flow and GFR meningkat pada awal kehamilan dan menurun pada akhir awal kehamilan dan menurun pada akhir kehamilankehamilan

Perubahan selama kehamilanPerubahan selama kehamilan

GI absorption

Motilitas lambung menurunSekresi asam lambung menurun pH lambung meningkat

absorbsi obat menurun & konsentrasi obat di plasma menurun

AntiepilepticsKonsentrasi turun karena:– Peningkatan volume plasma– Penurunan ikatan protein– Peningkatan kliren renal and hepar

Carbamazapine, Dilantin, Valproic acid perlu monitoring kadar obat

Distribusi ObatVolume Plasma meningkat sampai 50%

konsentrasi obat di plasma menurun

Transfer Obat ke FetusTransfer Obat ke Fetus

Placental transfer :Placental transfer :–Passive diffusionPassive diffusion–Facilitated diffusionFacilitated diffusion–Active transportActive transportPlacental surface areaPlacental surface areaPlacental metabolismPlacental metabolism

Transfer ObatTransfer Obat

Across PlacentaAcross Placenta– Molecular weightMolecular weight– Lipid solubilityLipid solubility– IonizationIonization– Protein bindingProtein binding– Chemical Chemical

StructureStructure

Into Breast MilkInto Breast Milk– Molecular weightMolecular weight– Lipid solubilityLipid solubility– IonizationIonization– Protein bindingProtein binding– Drug Drug

concentrationconcentration– Drug equilibriumDrug equilibrium

Faktor LainFaktor Lain

Across PlacentaAcross Placenta– Size < 400 daltonsSize < 400 daltons– High blood High blood

concentrationconcentration– Similar Similar

configurationconfiguration

Into Breast MilkInto Breast Milk– Size < 200 daltonsSize < 200 daltons– Drug pKaDrug pKa– Equilibration speedEquilibration speed– High blood High blood

concentrationconcentration

I. Sifat Fisiko-kimiawi ObatI. Sifat Fisiko-kimiawi Obat

A. Lipid SolubilityA. Lipid Solubility• Obat larut lemak mudah masuk placenta Obat larut lemak mudah masuk placenta

thiopental, nicotine, salicylate thiopental, nicotine, salicylate

B. Derajat IonisasiB. Derajat Ionisasi- Obat Polar (ion) lambat tembus plasenta Obat Polar (ion) lambat tembus plasenta

i.e. succinylcholine and tubocurarinei.e. succinylcholine and tubocurarine

C. Protein binding.C. Protein binding.- Protein plasma fetus makin meningkat Protein plasma fetus makin meningkat

saat lahir albumin fetus > albumin ibu saat lahir albumin fetus > albumin ibu sulfonamides, barbiturates, phenytoin and sulfonamides, barbiturates, phenytoin and local anesthetic agents.local anesthetic agents.

D. Molecular SizeD. Molecular Size- cross the placenta readily (250-500), with cross the placenta readily (250-500), with

difficulty (500-1000), or poorly (>1000).difficulty (500-1000), or poorly (>1000).- Mayoritas obat mempunyai BM 100 - 500.Mayoritas obat mempunyai BM 100 - 500.

i.e. heparin vs warfarin.i.e. heparin vs warfarin.

I. Sifat Fisiko-kimiawi ObatI. Sifat Fisiko-kimiawi Obat

II. Jumlah Obat yang mencapai janin II. Jumlah Obat yang mencapai janin

III. Kecepatan PaparanIII. Kecepatan Paparan

IV. Lama PaparanIV. Lama Paparan

Eliminasi obat fetus via ginjal (urine) Eliminasi obat fetus via ginjal (urine) masuk cairan amniotic masuk cairan amniotic terserap oleh terserap oleh fetus lagifetus lagi

V. Tissue DistributionV. Tissue Distribution- Obat larut lemak disimpan di jaringan Obat larut lemak disimpan di jaringan

lemak (saat hamil meningkat) lemak (saat hamil meningkat) prolonged effect of the drug (slow prolonged effect of the drug (slow

release) release)

VI. Developmental StageVI. Developmental StageJanin paling rantan pada trimester I.Janin paling rantan pada trimester I.

From conception (0) to 14 days.From conception (0) to 14 days. morphologic differentiation.morphologic differentiation.

From 15 to 60 days after conception.From 15 to 60 days after conception. Time of organogenesis. Time of organogenesis.

Drug Affinity for Specific TissuesDrug Affinity for Specific Tissues

TetracyclineTetracyclineWarfarinWarfarinAminoglycosidesAminoglycosidesQuinineQuinineChlorpromazineChlorpromazineDiethylstilbestrolDiethylstilbestrol

CorticosteroidsCorticosteroidsPhenytoinPhenytoinIodidesIodidesPropylthiouracilPropylthiouracil

TeethTeeth

Middle earMiddle earRetinaRetina

Mullerian DuctMullerian DuctVaginaVaginaAdrenal GlandAdrenal Gland

Thyroid GlandThyroid Gland

Fetal TherapyFetal TherapyTherapy directed to the fetus.Therapy directed to the fetus.Corticosteroids Corticosteroids Rangsang maturasi paru Rangsang maturasi paru

pada prematurpada prematurPhenobarbital pada TM3 Phenobarbital pada TM3 Rangsang Rangsang

enzymes hepar fetus enzymes hepar fetus mengurangi mengurangi incidence of jaundice.incidence of jaundice.

Antiarrhythmic drugs.Antiarrhythmic drugs. For the treatment of For the treatment of fetal arrythmias.fetal arrythmias.

Drug ToxicityDrug Toxicity- Beberapa penyalahgunaan obat Beberapa penyalahgunaan obat

menembus placenta.menembus placenta.- Opioids Opioids dependence pada fetus dan dependence pada fetus dan

withdrawal pada neonatuswithdrawal pada neonatus..

TeratogensTeratogens

A substance, organism, physical agents A substance, organism, physical agents or deficiency state capable of inducing or deficiency state capable of inducing abnormal structure or function such as: abnormal structure or function such as: – Gross structural abnormalitiesGross structural abnormalities– Functional deficienciesFunctional deficiencies– Intrauterine growth restrictionIntrauterine growth restriction– Behavioral aberrationsBehavioral aberrations– DemiseDemise

Teratogenic FactorsTeratogenic Factors

Timing of exposureTiming of exposureDevelopmental stage during exposureDevelopmental stage during exposureMaternal dose and durationMaternal dose and durationMaternal pharmacokineticsMaternal pharmacokineticsGenetic factors/phenotypesGenetic factors/phenotypesInteractions between agentsInteractions between agents

Teratogenic agents1) Drugs and chemicals2) Infectious agents3) Radiation4) Other

TeratogenicityTeratogenicity

alcohol (FAS), Thalidomide (phocomelia), alcohol (FAS), Thalidomide (phocomelia), DES (uterine cancer), valproic acid (spina DES (uterine cancer), valproic acid (spina bifida).bifida).

Days from ovulation ?*< 15 days- All or nothing period

Result- spontaneous abortion*Day 15-60 (week 3-8)- Fetal susceptibility*>60 days (> week 9-10)- Functional defects and minor anomalies

Drugs that cause severe adverse effectsDrugs that cause severe adverse effects

ACE InhibitorsACE InhibitorsAminopterinAminopterinAmphetaminesAmphetaminesAndrogensAndrogensTCAsTCAsBARBsBARBsBusulfanBusulfanCarbamazepineCarbamazepineChlorpropamideChlorpropamideClomipramineClomipramineCocaineCocaineCyclofosfamideCyclofosfamideCytarabineCytarabine

DiazepamDiazepamDESDESEthanolEthanolEtretinateEtretinateHeroinHeroinIodideIodideIsotretinoinIsotretinoinLithiumLithiumMethadoneMethadoneMethotrexateMethotrexateMethylthiouracilMethylthiouracilMetronidazoleMetronidazoleOrganic solventsOrganic solvents

MisoprostolMisoprostolPenicillaminePenicillaminePhencyclidinePhencyclidinePhenytoinPhenytoinPropylthiouracilPropylthiouracilStreptoycinStreptoycinTamoxifenTamoxifenTetracyclineTetracyclineThalidomideThalidomideTrimethadioneTrimethadioneValproic acidValproic acidWarfarinWarfarin

B. Teratogenic MechanismsB. Teratogenic Mechanisms::1) Effects on 1) Effects on maternal tissuesmaternal tissues..2) Delivery of 2) Delivery of oxygen and nutrientsoxygen and nutrients..3) Alterations during 3) Alterations during differentiationdifferentiation..4) 4) DeficiencieDeficiencies.s.

1) Effects on maternal tissues.1) Effects on maternal tissues.Drugs may have a direct effect on maternal Drugs may have a direct effect on maternal

tissues with secondary or indirect tissues with secondary or indirect effects in the fetus.effects in the fetus.

e.g. Cocaine increases the risk for spontaneous e.g. Cocaine increases the risk for spontaneous abortions, placenta previa and permature abortions, placenta previa and permature labor; neonatal cerebral infarction, abnormal labor; neonatal cerebral infarction, abnormal development and decrease school development and decrease school performance. performance.

2) Delivery of oxygen.2) Delivery of oxygen.Interference of oxygen delivery to Interference of oxygen delivery to

the fetus may cause ischemia to the fetus may cause ischemia to tissues specially to brain, and tissues specially to brain, and cause severe damage or even cause severe damage or even death.death.

3) Food and Nutrient alterations 3) Food and Nutrient alterations Interference with nutrient delivery may Interference with nutrient delivery may

cause anemia and poor growth.cause anemia and poor growth.Alterations of certain factors such as Alterations of certain factors such as

vitamins or minerals may be teratogenic.vitamins or minerals may be teratogenic.e.g. Vitamin A (Retinol) has important e.g. Vitamin A (Retinol) has important

differentiation-directing actions in normal differentiation-directing actions in normal tissues. Excessive amounts may cause tissues. Excessive amounts may cause birth defects, bone abnormalities and liver birth defects, bone abnormalities and liver damage.damage.Excess niacin may cause ocular Excess niacin may cause ocular abnormalities.abnormalities.

4) Deficiencies.4) Deficiencies.Alterations of certain factors such as vitamins or Alterations of certain factors such as vitamins or

minerals may be teratogenic.minerals may be teratogenic.

e.g. Folic acid causes neural tube defects, e.g. Folic acid causes neural tube defects, supplementation reduces the incidence supplementation reduces the incidence of spina bifida.of spina bifida.

C. Teratogenic RiskC. Teratogenic Risk• It is recommended that all pregnant It is recommended that all pregnant

women be counseled with regard to women be counseled with regard to taking medications during pregnancy.taking medications during pregnancy.

• In reality, the risk of a neonatal In reality, the risk of a neonatal abnormality in the absence of any known abnormality in the absence of any known teratogen is teratogen is less than 3%.less than 3%.

• Up till know about Up till know about 30 compounds30 compounds have have been identified to be been identified to be teratogenic.teratogenic.

FDA Drug CategoriesFDA Drug CategoriesCategory ACategory A. Controlled Human Studies have not . Controlled Human Studies have not

demonstrated fetal risk.demonstrated fetal risk.Category BCategory B. Studies in animals have not demonstrated fetal . Studies in animals have not demonstrated fetal

risk. risk. No human studiesCategory CCategory C. . animal studies show adverse effect and no

human studiesOR no animal or human studies (benefit should outweigh risk)

Category DCategory D. There is positive evidence of human risk. . There is positive evidence of human risk. However, the benefits of use in pregnancy may be However, the benefits of use in pregnancy may be acceptable in spite of this risk.acceptable in spite of this risk.

Category XCategory X. Studies or experience in humans or animals has . Studies or experience in humans or animals has demonstrated fetal risk. The risk far outweighs any demonstrated fetal risk. The risk far outweighs any potential benefit. The drug is contraindicated in pregnant potential benefit. The drug is contraindicated in pregnant women or women who may become pregnant.women or women who may become pregnant.

FDA Pregnancy CategoriesFDA Pregnancy Categories

Category not required if:Category not required if:– Drug not absorbed systemicallyDrug not absorbed systemically

ANDAND– No potential for indirect fetal harmNo potential for indirect fetal harm

Otherwise, in addition to the pregnancy Otherwise, in addition to the pregnancy category, information on teratogenicity, category, information on teratogenicity, effects on reproduction, and when effects on reproduction, and when available, effects on later growth, available, effects on later growth, development and functional maturation of development and functional maturation of the child should be includedthe child should be included

FDA Pregnancy CategoriesFDA Pregnancy Categories

Major problems existMajor problems exist–Established in 1979Established in 1979–Lack of data in humansLack of data in humans–What does a “C” drug really meanWhat does a “C” drug really mean–Difficult to assign an “A” to any drugDifficult to assign an “A” to any drug–Does not address lactation safetyDoes not address lactation safety

FDA Labeling ChangesFDA Labeling Changes

3 categories – fertility, pregnancy, and 3 categories – fertility, pregnancy, and lactationlactationClinical considerations provides risks Clinical considerations provides risks and possible alternativesand possible alternativesSummary risk assessment evaluates Summary risk assessment evaluates human and animal datahuman and animal dataDiscussion of underlying data used to Discussion of underlying data used to formulate riskformulate risk

Dilantin- phenytoin syndrome

MicrocephalyNail dysplasiaDevelopmental delayCharacteristic facies

Risk for syndrome 10%Risk for some adverse effect (low IQ)- 30%

Dilantin- phenytoin syndrome

Valproic acid (Depakote)

1-2% risk of NTDNail and bone hypoplasiaValproic acid syndrome?

Recommendations for womenwith seizure disorders ?

Preferably a preconceptual consultation– Folate 4mg/day

Work with a neurologist to find the least teratogenic agent (monotherapy)Do not instruct a patient to d/c medication. A seizure is worse than effects of meds.– Status epi.-30% maternal mortality– 50% fetal mortality

Vitamin A derivative / Retinoic acidTiming is key- beyond 15 days postconceptionDose specific

Risk of syndrome- 10-30%Microcephaly/hydrocephalyCHDMicrotiaCleft lip/palate

Drug Trimester EffectACE inhibitors All, especially

second and thirdRenal damage

Aminopterin First Multiple gross anomaliesAmphetamines All Suspected abnormal

developmental patterns, decreased school performance

Androgens Second and third Masculinization of female fetus

Antidepressants, tricyclic

Third Neonatal withdrawal symptoms have been reported in a few cases with clomipramine, desipramine, and imipramine

AnticoagulantsWarfarin: D– Fetal warfarin syndrome: 10%– Exposure- 4-7 weeks– MR Stippled epiphysis– Hemorrhage Depressed nasal bridge– Normal: 65%– Spontaneous AB/ stillbirth- 25%

Heparin– Not teratogenic

Angiotensin-converting enzyme inhibitor D ?

Reduced fetal renal blood flowFetal anuriaIUGROligohydramnios

Alcohol D ?1-2% women of child-bearing age have an alcohol abuse problemFetal alcohol syndrome- most common cause of mental retardation in the US

TYPE EXAMPLES PROBLEMAntibiotics Chloramphenicol •Gray baby syndrome

•In G6PD deficiency breakdown of red blood cells

  Ciprofloxacin Possibility of joint abnormalities  Kanamycin Damage to the fetus's ear, resulting in

deafness   Nitrofurantoin In G6PD deficiency breakdown of red

blood cells   Streptomycin Damage to the fetus's ear, resulting in

deafness   Sulfonamides •Jaundice and possibly brain damage in

the newborn •In G6PD deficiency breakdown of red blood cells

  Tetracycline •Slowed bone growth, permanent yellowing of the teeth, and increased susceptibility to cavities in the baby •Occasionally, liver failure in the pregnant woman

TYPE EXAMPLES PROBLEMAntianxiety Diazepam late in pregnancy depression,

irritability, shaking, and exaggerated reflexes in the newborn

Anticoagulants

Heparin a long time osteoporosis & a decrease in the number of platelets in the pregnant woman

  Warfarin •Birth defects •Bleeding problems in the fetus and the pregnant woman

Anticonvulsants

•Carbamazepine •Phenobarbital •Phenytoin

•Some risk of birth defects •Bleeding problems in the newborn (need vitamin K) •Some risk of birth defects

  •Trimethadione •Valproate

•Increased risk of miscarriage •Increased risk of birth defects (cleft palate and abnormalities of the heart, face, skull, hands, or abdominal organ) 70% with trimethadione and 1% with valproate)

TYPE EXAMPLES PROBLEMAntihypertensives

ACE inhibitors late in pregnancy kidney damage, reduction in amniotic fluid, deformities of the face, limbs, and lungs

  Thiazide decrease in the levels of oxygen and potassium and the number of platelets in the fetus's blood

Chemoterapy •Busulfan •Chlorambucil •Cyclophosphamide •Mercaptopurine •Methotrexate

Birth defects such as less-than-expected growth before birth, underdevelopment of the lower jaw, cleft palate, abnormal development of the skull bones, spinal defects, ear defects, and clubfoot

Mood-stabilizing drug

Lithium Birth defects (mainly of the heart), lethargy, reduced muscle tone, poor feeding, underactivity of the thyroid gland, and nephrogenic diabetes insipidus in the newborn

TYPE EXAMPLES PROBLEMNSAIDs •Aspirin

•Other salicylates

•large doses delay in the start of labor, premature closing of ductus arteriosus, jaundice, and (occasionally) brain damage in the fetus and bleeding problems in the woman during and after delivery and in the newborn •late in pregnancy reduction in the amount of amnionic fluid

Oral hypoglycemic

•Chlorpropamide •Tolbutamide

•A very low level of sugar in the blood of the newborn •Inadequate control of diabetes in the pregnant woman

Vaccines Live-virus vaccines

•rubella vaccine potential infection of the placenta and developing fetus; •other vaccines (measles, mumps, polio, chickenpox, and yellow fever) potential but unknown risks

TYPE EXAMPLES PROBLEMSex hormones •Danazol

•Synthetic progestins (but not the low doses used in oral contraceptives)

•Masculinization of a female fetus's genitals, sometimes requiring surgery to correct

  •Diethylstilbestrol (DES)

•Abnormalities of the uterus, menstrual problems, and an increased risk of vaginal cancer and complications during pregnancy in daughters •Abnormalities of the penis in sons

Skin treatments

•Etretinate •Isotretinoin

Birth defects, such as heart defects, small ears, and hydrocephalus

Thyroid drugs •Methimazole •Propylthiouracil •Radioactive iodine

•An overactive and enlarged thyroid gland in the fetus •An underactive thyroid gland in the fetus

Drug Trimester EffectBarbiturates All Chronic use can lead

to neonatal dependence. Cognitive loss has been described.

Busulfan All Various congenital malformations; low birth weight

Carbamazepine First Neural tube defectsChlorpropamide All Prolonged

symptomatic neonatal hypoglycemia

Clomipramine Third Neonatal lethargy, hypotonia, cyanosis, hypothermia

Drug Trimester EffectCocaine All Increased risk of spontaneous

abortion, abruptio placentae, and premature labor; neonatal cerebral infarction, abnormal development, and decreased school performance

Cyclophosphamide First Various congenital malformations

Cytarabine First, second Various congenital malformations

Diazepam All Chronic use may lead to neonatal dependence and increase risk for oral cleft

Diethylstilbestrol All Vaginal adenosis, clear cell vaginal adenocarcinoma

Drug Trimester EffectEthanol All Risk of fetal alcohol syndrome

and alcohol-related neurodevelopmental defects

Etretinate All High risk of multiple congenital malformations

Heroin All Chronic use leads to neonatal dependence

Iodide All Congenital goiter, hypothyroidism

Isotretinoin All Extremely high risk of CNS, face, ear, and other malformations

Lithium First Ebstein's anomaly

Drug Trimester EffectMethadone All Chronic use leads to neonatal

dependence

Methotrexate First Multiple congenital malformations

Methylthiouracil All HypothyroidismMetronidazole First May be mutagenic (from animal

studies; there is no evidence for mutagenic or teratogenic effects in humans)

Organic solvents First Multiple malformations and effects on brain development

Misoprostol First Möbius sequencePenicillamine First Cutis laxa, other congenital

malformations

Drug Trimester Effect

Phencyclidine All Abnormal neurologic examination, poor suck reflex and feeding

Phenytoin All Fetal hydantoin syndrome

Propylthiouracil All Congenital goiter

Streptomycin All Eighth nerve toxicity described in a few cases

Smoking (constituents of tobacco smoke)

All Intrauterine growth retardation; prematurity; sudden infant death syndrome; perinatal complications

Tamoxifen All Increased risk of spontaneous abortion or fetal damage

Drug Trimester Effect

Tetracycline All Discoloration and defects of teeth

Thalidomide First Phocomelia (shortened or absent long bones of the limbs) and many internal malformations

Trimethadione All Multiple congenital anomalies

Valproic acid All Neural tube defects

Warfarin First Hypoplastic nasal bridge, chondrodysplasia

Second CNS malformations

Third Risk of bleeding. Discontinue use 1 month before delivery.

Nutritional issues in pregnancy

300 calorie / a day increase during second and third trimesterNo increase needs in first trimester25-35 # weight gain60 gms protein/ a day

Nutritional supplementation

Routine supplementation (other than folic acid) is not recommended for women reporting adequate dietary intakeThere are high risk conditions requiring supplementation

Pregnancies requiring nutritional supplementation

Multiple gestationFrequent pregnancies (<3 month intervals)Illicit drug useHyperemesisAdolescenceVegetariansChronic illnessPrevious history of obstetricalcomplications/ low birth weight or preterm labor

Calcium

Nonpregnant women consume only 75% of recommended calciumAdolescent diet poor in calciumBone mass increases up to age 25Pregnancy can cause bone lossDaily requirement of 1200mg/day

Fe

Maternal volume increases by 50%Iron needed for increase production of RBCs for mom and fetusFetal needs increase in third trimesterSupplement in second and third trimester : 27 mg elemental iron/ dayFor women who are anemic (Hct<33%) : 60 - 120 mg/day

Folic acid ?

Shown to decrease risk of NTDs recurrence and occurrenceBegin 3 months prior to conception and 4 weeks into pregnancyOccurrence: 400 microgram (prenatal vitamins have 800 micrograms)Recurrence: 4 mg/day

Issues for patients

Avoid all meds except those prescribed or approved by youAbstain from alcoholCheck rubella status prior to pregnancyTake prenatal folic acid