Presentation on theme: "Teratogens and drugs of abuse in pregnancy"— Presentation transcript:
1 Teratogens and drugs of abuse in pregnancy Prof. Hanan HagarDr. Ishfaq BukhariPharmacology UnitCollege of Medicine
2 Medications in pregnancy Placental membrane is semi-permeable.Most drugs can cross placenta by passive diffusion.
3 Factors controlling placental drug transfer 1. Physiochemical properties of the drugLipid solubility or diffusion.Molecular size.Protein binding.2. The stage of placental and fetaldevelopment at the time of exposure to the drug.3. Duration of exposure to the drug.
4 Lipid solubility of the drug Lipophilic drugs diffuse readily across theplacenta and enter fetal circulation.e.g.Thiopental crosses placenta & causes sedation, apnea in newborn infants.Ionized drugs cross the placenta very slowly very low conc. in the fetus.e.g. Succinylcholine & Tubocurarine.
5 Molecular size of the drug MW affects the rate of transfer:cross placenta easily.cross placenta with more difficulty. can not cross placenta e.g. Heparin
6 Protein bindingProtein binding in maternal circulation hinders passage of drugs especially . e.g Heparin, chloramphenicol and propythiouracil
7 The stage of mammalian fetal development Harmful action of drugs depend upon stage of fetal development at time of drug exposure.Mammalian fetal development passes throughthree phases:Blastocyste formation (up to 17 days).Organogenesis (17-60 days).Histogenesis & maturation of function.
8 Blastocyste formation (First 2 weeks) Occurs from (1-16 days) in the first trimester.Period of dividing zygote, implantationDrugs have an all-or-nothing effect.Exposure to drugs during this period death of the embryo abortion
9 Organogenesis: (2-8 weeks) Occurs in ( days) in the first trimester.The most sensitive period of pregnancy because major body organs and systems are formed.Exposure to harmful drugs during organogenesis major birth defect or gross malformation (Teratogenesis)
10 Histogenesis and functional maturation (8 weeks onwards) Maturation occurs during this stage & fetus depends upon nutrients & hormonal supply.Exposure to drugs during (8 weeks onwards) will not induce major malformation but drugs can produce minor morphologic abnormalities, growth retardation and functional defect.However, CNS is sensitive to toxic effects throughout pregnancy.
11 Teratogenesis Occurrence of congenital defects of the fetus. What is a teratogen? is any agent (medication, street drug, chemicals, disease, environmental agents) that is able to interferes with fetal development and leads to permanent birth defects.This could be more severe during critical periods of development e.g. (organogenesis).
13 FDA Classification System Category AControlled human studies with no risk to fetusDrugs can be usedCategory BAdverse effects on animal studies onlyAdequate Human studies lacking or not shown similar results. Drug can be used in pregnancyCategory CNo human studies, human fetal risk is unknown. Drug may be used in serious situation despite its potential risk.
14 FDA Classification System Category DEvidence of human fetal riskMay be used in serious diseases or life threatening situations e.g phenytoinCategory XFetal abnormalities in animal and human studiesDrugs are teratogens and contraindicated in pregnant women or planning to conceive.
16 Proven teratogens Retinoids e.g. vitamin A isotretinoin (used in treatment of Acne)Angiotensin converting enzyme inhibitors (ACEIs)Ionizing radiation (diagnostic X-ray or radiation therapy).Radioactive iodine (I131).Corticosteroids.Hormones
17 Teratogenesis of drugs Thalidomide(TheThe most notorious human teratogen) it had no teratogenic effects in mice and rats but proved teratogenic when used in pregnant women.Phocomeliashortened or absent long bones of the limbsAbsence of External Ears
18 Teratogenesis of drugs PhenytoinFetal Hydantoin SyndromeNail & Digital hypoplasiaOral Clefts (cleft lip and palate)Cardiac AnomaliesMental & growth retardationCorticosteroidsCleft lip and PalateTetracyclinesPermanent teeth stainingEnamel hypoplasiaaltered growth of teeth and bones.WarfarinHypoplasia of nasal bridgeCNS malformation
19 Teratogenesis of drugs Valproic acidAntiepileptic drugNeural tube defect (spina bifida)Impair folate absorptionHormonesEstrogensAndrogensdiethylstilbestrolSerious genital malformationTesticular atrophy in maleFetal masculinization in femaleVaginal carcinoma of female offspringLithiumCardiovascular anomalies mainly valvular heart defect involving tricuspid valve Ebstein's anomalyACE inhibitors captopril, enalaprilFetal & neonatal anurniaRenal damageFetal hypotension, hypoperfusion - growth retardationACE inhibitors disrupt the fetal renin-angiotensin system, which is essential for normal renal development
20 Fetal hydantoin syndrome Cleft lip and palatePhenytoin cuases digital hypoplasia and cleft lip and palate.
22 Cleft lipTeeth stainingTetracyclineCorticosteroids and phenytoin
23 Adverse effects of drugs During second and third trimestersSome drugs can produce adverse effects on the fetus more likely than major malformations due to their pharmacological actions.
24 Adverse effects of drugs TetracyclinesImpaired teeth & bone development, yellow-brown discoloration of teethAminoglycosidesStreptomycin, kanamycinOtotoxicity = 8th Cranial nerve damageCloramphenicolGray baby syndromeCorticosteroidsAdrenal atrophy – growth retardationPropranololBradycardia, neonatal hypoglycemia, placental insufficiency, reduced uterine blood flow, fetal distressAntithyroid drugsIodide, Methimazole, Carbimazole, propylthiouracilRisk of hypothyroidism and goitre
25 Adverse effects of drugs NSAIDse.g. Aspirin-indomethacinProstaglandin synthesis inhibitorsConstriction of ductus arteriosus (close prematurely), pulmonary hypertension in newbornsIncrease in gestation timeprolong labor, neonatal bleedingRisk of postpartum hemorrhageBenzodiazepines as DiazepamChronic use → neonatal dependence and withdrawal symptomsACEIsRenal damagewarfarinRisk of bleeding
26 Adverse effects of drugs prior to labor CNS depressantse.g. diazepam, morphineInterference with sucklingRespiratory depressionReduced blood flow, fetal distressSulfonamidesDisplacement of bilirubin from plasma protein (neonatal hyperbilirubinemia)
27 Hypertension in pregnancy -ContraindicatedACE inhibitorsAngiotensin II receptor blockersThiazide diureticsPropranololCalcium channel blockers in mild hypertensionProbably safeα- methyl dopaLabetalolEmergencyHydralazineLabetalol
28 Coagulation disorders in pregnancy Contraindicatedwarfarin is contraindicated in all trimestersCross placenta1st trimester : Teratogenicity2nd, 3rd : risk of bleedingProbably safeHeparinPolar, does not cross placentaProtamine sulphate as antidote for neutralization
29 Antithyroid drugs in pregnancy Are used in thyrotoxicosis or Grave’s diseasePropylthiouracilMethylthiouracil (Methimazole)CarbimazolRadioactive Iodine (I131)All can cross placentaAll have risk of congenital goiter and hypothyroidismThe lowest dose of antithyroid drugs should be used.Propylthiouracil is preferable over others
30 Antibiotics in pregnancy Contraindicated :Aminoglycosides: ototoxicityTetracyclines: Teeth and bones deformitySulfonamides: neonatal jaundice-kernicterusChloramphenicol: Gray baby syndromeQuinolones as ciprofloxacin: bone and cartilage damage (arthropathy)Probably safePenicillins (ampicillin, amoxicillin)CephalosporinsErythromycin and azithromycin as alternative in penicillin-sensitive individuals BUT erythromycin estolate should be avoided (risk of hepatic injury to mother).
31 Summary of Drugs of choice in pregnancy Antihypertensiveα-methyl dopaLabetalol ( - Blocker)Hydralazine (emergency only)Antibioticspenicillin, cephalosporins, erythromycinAntidiabeticsInsulin is safe, avoids oral antidiabeticsAnticoagulantsHeparinAnalgesicsAcetaminophenAntithyroid drugsPropylthiouracil (protein-bound)AnticonvulsantsAll antiepileptics have potential to cause malformations, carbamazepine may be choice.avoid valproic acid (highly teratogenic). folic acid supplementation prevents neural tube defects in women receiving AEDs
33 Drug abuseDrug abuse:Habitual use of drugs not for therapeutic purposes but for alteration of one's mood or state of consciousness.
34 Drug abuseThe most commonly abused drugs are alcohol; cocaine; nicotine; marijuana; amphetamines; barbiturates; opium alkaloids, benzodiazepines.Drug abuse may lead to organ damage, addiction, and disturbance of behavior.
35 AlcoholsThe use of alcohol is contraindicated during all trimesters of pregnancy
36 Fetal Alcohol Syndrome (FAS) Caused by chronic maternal alcoholabuse during early weeks of first trimester of pregnancy.CharactersMicrocephalyIntrauterine growth retardationCraniofacial abnormalitiesCVS abnormalitiesCNS abnormalities (attention deficits, intellectual disability, mental retardation)
41 TobaccoTobacco contains nicotine and carbon monoxide that may harm fetus.Tobacco can produce:Decreased blood flow to placentaFetal hypoxiaRetarded fetal growthLow birth weightIncreased spontaneous abortionPreterm labor and stillbirth
42 ConclusionsThe use of drugs during pregnancy should be avoided unless absolutely necessary.Most drugs cross the placenta to some extent.Birth defects are of great concern.Drugs can harm the embryo or foetus depending upon the stage of foetal development.The most critical period of pregnancy is organogenesis (17 days – 8 weeks).Alcohol, nicotine and other addicting drugs should be avoided.