OBAT PADA KEHAMILAN OBAT PADA KEHAMILAN Noor Wijayahadi Noor Wijayahadi
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