在妊娠哺乳期用药.ppt

Drugs in pregnancy&lactation By Dr Attia M Jabr Dr Amal Hassanain Faculty of Medicine Qassim University 1 There are two major considerations regarding drug use in pregnant women:Effect of pregnancy on:drugs (pharmacokinetics)Effect of drugs on:pregnancy(fetus)Introduction 1.About 40%of pregnant women take drugs(at least 1drug)2.6%take drugs during 1st trimester(exclude folic,iron,vitamins)3.The most common drugs are analgesics,antibacterial,antacids.4.What about new drugs?4 I.Effect of pregnancy on drugs(Pharmacokinetics)A.Absorption:The rate may be reduced because of delayed gastric emptying The extent may not be absorbed Vomiting is common.Effect?Reduced bioavailability 5 Effect of pregnancy on drugs B)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.Serum 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.phenytoin 6 A.Drug metabolism:1.Hepatic microsomal mixed function oxidase 2.Increased during pregnancy(2nd,3rd)3.Explain why he rate of clearance of phenytoin,valproate,carbamazepine is increased during pregnancy 4.There is no change in hepatic blood flow.Effect?Drugs of first pass effect.Examples propranolol 7 Effect of pregnancy on drugs B.Excretion:1.Effective renal plasma flow (doubles)2.GFR by 70%3.Clearance rate increases e.g.ampicillin.Solve?What about dose in UTI?4.Explain why the dosages of digoxin and lithium,are increased during pregnancy?Do you think that pregnancy can also affect drug pharmaco-dyamics?B.blockers 8 Effect of pregnancy on drugs II.Effect of drugs on fetus Drugs can influence fetal development at 3 separate stages:1.Fertilization&implantation period:from conception to about 17 days gestation 2.Organogenesis:18-55 days 3.Growth&development:56th day onward 9 Terminology:Dysmorphogenesis&teratogenicity 1-Teratogen:agent that interferes with normal growth&development of Foetus describe drugs or chemicals that cause major or gross birth Defects 2-Congenital malformations:structural abnormalities of prenatal origin that are present at birth 12 Teratogens A substance,organism,physical agents or deficiency state capable of inducing abnormal structure or function such as:1.Gross structural abnormalities 2.Functional deficiencies 3.Intrauterine growth restriction 4.Behavioral aberrations 5.Demise Teratogenic Factors 13 1.Timing of exposure 2.Developmental stage during exposure 3.Maternal dose and duration 4.Maternal pharmacokinetics 5.Genetic factors/phenotypes 6.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 disorders)within utero,alcohol exposure)4-Dysmorphogenesis:structural&functional defects Thalidomide Isotretinoin Warfarin Valproic Acid Carbamezepine Coumarin Phenytoin Effect of drugs on pregnancy(fetus):1-Placental drug transfer:Factors affecting the rate of drug transfer across placenta and its effect 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 cross b)Lipid solubility:Lipid soluble(un-ionized)substances cross rapidly Weakly basic drugs may become trapped in fetal 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 placenta 2.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-stimulant b.Maternal diseases pregnancy-induced hypertension,DM change permeability of placenta c)Placental transporters:e.g.PGp with anticancer drugs,protease inhibitors d.Placental and fetal drug metabolism e.g.oxidation reactions of placenta,fetal liver 50%3.The duration of exposure to the drug 4.Distribution characteristics in different fetal tissues 5.Stage of placental and fetal development at the time of exposure to the drug 6.The effects of drugs used in combination 19 2-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 Organ function 1.Fertilization&implantation period Interference by drugs in this stage leads to failure of pregnancy(death of fetus)at a very early and probably sub-clinical stage.21 The most sensitive period to Teratogenic effects Tetragon=any substance that produces d