在妊娠哺乳期用药

1、Drugs in pregnancy & lactationByDr Attia M JabrDr Amal HassanainFaculty of Medicine Qassim University1There are two major considerations regarding drug use in pregnant women:Effect of pregnancy on : drugs (pharmacokinetics) Effect of drugs on : pregnancy (fetus)Drugs in pregnancyIntroductionAbout 40

2、% of pregnant women take drugs (at least 1drug)6% take drugs during 1st trimester (exclude folic, iron, vitamins)The most common drugs are analgesics, antibacterial, antacids.What about new drugs?4I. Effect of pregnancy on drugs(Pharmacokinetics) Absorption:The rate may be reduced because of delayed

3、 gastric emptyingThe extent may not be absorbedVomiting is common. Effect?Reduced bioavailability5Effect of pregnancy on drugsB) Distribution: 1. Maternal plasma volume & ECF 50% (3rd trimester) 2. Total body water 20% & total body fat 3. What is the effect on Vd & steady state concentration? 4. Ser

4、um albumin by about 20% (in pre-eclampsia 35%) 5. Alpha1-acid glycoprotein By about 40% (in pre-eclampsia 100%) 6. The free fraction of acidic drugs 7. The free fraction of basic drugs 8. E.G. Diazepam, phenytoin, valproate. What?What is the effect on t of the drug? E.g. phenytoin6Drug metabolism:He

5、patic microsomal mixed function oxidaseIncreased during pregnancy (2nd, 3rd)Explain why he rate of clearance of phenytoin, valproate, carbamazepine is increased during pregnancyThere is no change in hepatic blood flow. Effect? Drugs of first pass effect . Examples propranolol7Effect of pregnancy on

6、drugsB. Excretion: Effective renal plasma flow (doubles) GFR by 70% Clearance rate increases e.g. ampicillin. Solve? What about dose in UTI? Explain why the dosages of digoxin and lithium, are increased during pregnancy?Do you think that pregnancy can also affect drug pharmaco-dyamics? B. blockers8E

7、ffect of pregnancy on drugsII. Effect of drugs on fetusDrugs can influence fetal development at 3 separate stages: Fertilization & implantation period: from conception to about 17 days gestation Organogenesis: 18-55 days Growth & development: 56th day onward 9Terminology: Dysmorphogenesis & teratoge

8、nicity 1- Teratogen: agent that interferes with normal growth & development of Foetus describe drugs or chemicals that cause major or gross birth Defects2-Congenital malformations : structural abnormalities of prenatal origin that are present at birth12TeratogensA substance, organism, physical agent

9、s or deficiency state capable of inducing abnormal structure or function such as: Gross structural abnormalities Functional deficiencies Intrauterine growth restriction Behavioral aberrations Demise Teratogenic Factors13Timing of exposure Developmental stage during exposure Maternal dose and duratio

10、n Maternal pharmacokinetics Genetic factors/phenotypes Interactions between agents 3- Congenital anomaly : non-reversible birth defects caused by genetic predisposition or drug exposure may be obvious at birth (hydrocephalus ) or delayed many years to be identified (behavioural & intellectual disord

11、ers) within utero ,alcohol exposure) 4- Dysmorphogenesis: structural & functional defectsThalidomideIsotretinoinWarfarinValproic AcidCarbamezepineCoumarinPhenytoinEffect of drugs on pregnancy (fetus):1-Placental drug transfer:Factors affecting the rate of drug transfer across placenta and its effect

12、 on fetus:1. Physico-chemical properties of the drug:a) Molecular weight (size) :Drugs with MW 600 cross easily Most drugs Drugs with very large MW e. g Insulin & Heparin Can not crossb) Lipid solubility :Lipid soluble (un-ionized )substances cross rapidly Weakly basic drugs may become trapped in fe

13、tal circulation (Slightly lower pH compared to maternal plasma) e.g. thiopental. c) Ionization :Molecules that are ionized at physiological pH cross slowly (e.g. salicylates, tubocurarine)NB. Consider any drug can cross the placenta. E.g. atenolol.d) Protein binding Only free unbound drugs ,cross pl

14、acenta2. The rate at which the drug crosses the placenta and amount reaching the fetus:a. Uterine & umbilical bl. flow Maternal blood pressure Cord compression Drug therapy alpha-stimulantb. Maternal diseases pregnancy-induced hypertension , DM change permeability of placenta c) Placental transporte

15、rs: e.g. PGp with anticancer drugs, protease inhibitorsd. Placental and fetal drug metabolism e.g. oxidation reactions of placenta, fetal liver 50%3. The duration of exposure to the drug4. Distribution characteristics in different fetal tissues5. Stage of placental and fetal development at the time

16、of exposure to the drug 6. The effects of drugs used in combination192-Pharmacological effects:Drugs crossing placenta may exert direct effect (corticosteroids adrenal suppression ) indirect effect (anti-hypertensives fetal hypoxia 2ry to maternal hypotension)Drugs may affect : Organ development Org

17、an function 1.Fertilization & implantation periodInterference by drugs in this stage leads to failure of pregnancy (death of fetus) at a very early and probably sub-clinical stage. 21The most sensitive period to Teratogenic effectsTetragon= any substance that produces deformityDifferent in species (

18、animals, humans) ThalidomidePhenytoin 5%, warfarin 25%The most common Teratogenic drugs are: 222. OrganogenesisDrug EffectDanazolSex hormonesVerilization of female fet.Multiple, cardiacLithiumcardiacPhenytoinCraniofacial;limbCarbamazepineCraniofacial;limbValproateNeural tubewarfarinMultiple defects;

19、 chondrodysplasiaretinoidsCNS, craniofacial, heartPredictable toxic drug actions in the fetusOpioids dependence of fetus and newbornACEI irreversible renal damage of fetusDiethylstilbosterol adenocarcinoma of vagina after puberty23Definition: Developmental abnormality & drugAnimal studiesRate of spo

20、ntaneous is 1-2%Teratogenic mechanisms:Poorly understood and multi-factorialDirect effect on maternal tissues with 2ry effect on fetal tissues.Oxygen and nutrients through placentaDirect actions on fetal tissues e.g. differentiation of developing tissues. E.g. Vit. A analoguesDeficiency of critical

21、substance like folic acid24TeratogenesisDangerous period: 2nd to 8th weeks of pregnancy (structural abnormalities Later on: dugs affect growth, development, integrity of body structure especially brainBut what about the stored drug? Like etritinate? 2 years25TeratogenesisCAUSES OF BIRTH DEFECTS IN H

22、UMANSSchardein JL, 2000.*Evidence: Level BCharacters of the teratogen: To be defined as a teratogen, the substance or the process should:Result in a characteristic set of malformationExert its effect at a particular stage of fetal developmentShows dose-dependence incidenceE.g. retinoids, warfarin, s

23、ex hormonesFood and drug administration classification of Drugs in pregnancyFDA Categories : teratogenic risk of drugsDRUG LABELPregnancy “Categories”AControlled studies in humans no riske.g Penicillin ?Banimal studies show no risk but no controlled humanORanimal studies show adverse effects) e.g. A

24、cetaminophen ,Cephalosporins CAnimal studies positive (teratogen) but no control. humanHuman & animals lacking. Risk cannot ruled out.g Aspirin ,Chloramphenicol, corticosteroid ,Ciprofloxacin, Digoxin, MetronidazoleDHuman data show risk, benefit may outweigh e.g. Enalapril ,Captopril ,Glyburide ,Ind

25、apamide ,Amitriptyline XAnimal or human data positive. Risk outweigh benefit. Contraindicated. e.g. Oral contraceptives ,Triazolam, Ethanol ,estrogen*30Drugs with high risk of causing abnormalitiesDrugEffectAlcoholFetal alcohol syndromeAndrogensVirilization; multiple defectsAnticancerMultiple congen

26、ital defectsCarbimazoleAplasia cutisCorticosteroidsCleft palateCyproteroneFeminization of male fetusErgotamineIncrease uterine toneMisoprostolIncrease uterine toneFibrinolytic like streptokinasePlacental separationTetracyclinesBone, yellow discolorationValproateNeural tube defectsVit.A analoguesCong

27、enital defectsWarfarinMultiple congenital defectsDrugs considered to be proven human teratogensACE inhibitorsDanazolCumarin derivatives (warfarin )DiethylstilbestrolEthanolLithiumVitamin A and derivatives , e.g.isotretinoinPhenytoinTetracyclineValproic acidAndrogensCarbamazipineCyclophosphamideThali

28、domidePenicillamineDiethylstillbestrol32Drugs under strong suspicion of producing abnormalities (slightly increased risk)DrugEfectAmiodaroneGoitreChloroquineDeafness (acute malaria)PhenytoinMultiple congenital defects ( Epilepsy)Other drugs to avoid (theoretical risk from animal and other studies)AC

29、E inhibitorsQuinolone antibioticsVaccines (live)DeferoxamineRifampicinVigabatrinCC blockersSimvastatinXamoterolFibratesSpironolactoneGrisofulvinSulfonylureaIdoxuridineThiabendazoleKetoconazoleTocainideMefloquineTrimethoprimomiprazoleCotrimoxazoleIII. Growth & development Major body structures have b

30、een formedSubsequent development and function can be affected3334Adverse effects of drugs on the fetus during the later stages of pregnancyDrugsRisk to fetus or neonateACE inhibitors fetal renal failure, PDA, RDS.Aminoglycosides8th nerve damageAntithyroid drugsGoitre & hypothyroidism (use dose)Aspir

31、inKernicterus , hge (fetal/maternal)BenzodiazepinesFloppy infant syndromeFibrinolyticHge (infant/maternal)Narcotic analgR depression, withdrawal if dependentNitrofurantoinhemolysisNSAIDsClosure of DAPH, delayed prolonged labor, hgeNovobiocinKernicterusWarfarinFetal, placental hge, microcephalySulfon

32、yureasHypoglcemiaSulfonamidesKernictrus (Except sulfasalazine)TetracyclinesYellow discoloration of teeth & boneThiazide diureticsthrombocytopenia35Drugs that are safe in pregnancyClassDrugs that are safe in pregnancyMineralsIronVitaminsFolic acidAntiemeticMeclozine & cyclozineAnalgesicsParacetamolAn

33、tibioticsPenicillinTranquilizersHypnoticsNot completely safeAntidiabeticInsulinAnticoagulantsHeparin (osteoporosis of mothers)AntihypertensivesMethyopa/nifedipine/labetalol-diureics not/ not ACEI36Treatment of some common diseases drug during pregnancyDiseasetreatmentAnemiaIron 30 mg + folic acid 20

34、0-500 mg/dayInfections e.g. UTIAmpicilin, amoxicillin, cephalosporines/nitrofurantoin, metronidazoleINH, ethambutol not rifampicin (TB drugs)What are the antibiotic drugs contraindicated in pregnancy? T,C,ADiabetes milletusInsulin (short, intermediate)Bronchial asthmaInhaled salbutamol, steroids, th

35、eophylline.HyperthyroidismPropylthiouracilHypertensionPre-eclampsiaChronic HTMethyldpa, nifedipine, labetalol + Mg sulphate (convulsions)Not ACEI, diuretics. ThrombosisHeparin (warfarin in artifial valves, cong. HD, AF)EpilepsyFetal anticonvulsant syndrome 2.4, 4.2, 6%, new drugs?VomitingMeclozine,

36、cyclizinePrevention of NTDFolic acid 4 mg/day, 400 micro for normal pregnancy /3monthsMalaria prophylaxisChloroquine, proguanil + 5 mg folic acid(PF) Meloprim (pyrimethamine + dapsone) not 1st trimisterLater on + folic acidMefloquine is contraindicatedTherapeutic drug actions in the fetusCorticoster

37、oids for fetal lung maturationPhenobarbitone for neonatal indirect hyperbilirubinemiaAntiarrhythmic drugs for fetal arrhythmiasZidovudine for protection of HIV transmission37Breast feeding and drugsDrug excretion in milk:Mechanisms of transfer from blood to milk:1-Diffusion of low molecular weight s

38、ubstances (through small ,water-filled pores).2- Diffusion of lipid soluble compounds (through lipid soluble membrane) 3-Carrier mediated , active transport.FACTORS INFLUENCING DRUG TRANSFER INTO BREAST MILKMaternal FactorsMetabolism, dose & frequency, duration of therapy, route of administration, P

39、PBInfant FactorsAge, drug absorption, metabolism, extent of breastfeeding (quantity, frequency, solid foods), timing of feedsDrug factors (transfer)Breast blood flow, breast metabolism pKa (ionization), lipid solubility, protein binding, MW, bioavailability, pH differencesFactors affecting adverse e

40、ffects of drugs in suckling infants:Passage of the drug from the maternal blood into milkConcentration of the drug in milkVolume of the milk suckedPharmacokinetics of the drug in the infants; particularly its absorption and clearanceInherent toxicity of the drugWhat is the best time of taking the dr

41、ugs for lactating mothers?42Drug therapy & breast feeding43Some drugs to be avoided in breast feeding mothersHigh excretion or hypersensitivityAmiodaroneCo-trimoxazoleSulfonamidesAmphetamineCiclosporinestetracyclinesAndrogensDoxazocintrimethoprimAnticancerErythromycinVitamin A analogueAntipsychoticsEthosuxamideVitamin D (High dosag