在妊娠哺乳期用药.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,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),Drugs in pregnancy,Introduction,About 40%,of pregnant women take drugs(at least 1drug),6%,take drugs during 1,st,trimester(exclude folic,iron,vitamins),The most common drugs are,analgesics,antibacterial,antacids.,What about new drugs?,4,I.Effect of pregnancy on drugs(,Pharmacokinetics,),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%(3,rd,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,Drug metabolism:,Hepatic microsomal mixed function oxidase,Increased during pregnancy(2,nd,3,rd,),Explain why he rate of clearance of,phenytoin,valproate,carbamazepine,is increased during pregnancy,There is no change in,hepatic blood flow,.Effect?Drugs of,first pass effect,.Examples,propranolol,7,Effect of pregnancy on drugs,B.,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.blockers,8,Effect of pregnancy on drugs,II.,Effect of drugs on fetus,Drugs can influence fetal development at 3 separate stages:,Fertilization&implantation period,:from conception to about,17,days gestation,Organogenesis,:,18-55,days,Growth&development,:,56,th,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:,Gross,structural,abnormalities,Functional,deficiencies,Intrauterine,growth restriction,Behavioral,aberrations,Demise,Teratogenic Factors,13,Timing of exposure,Developmental stage during exposure,Maternal dose and duration,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 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 deformity,Different in species(animals,humans),Thalidomide,Phenytoin 5%,warfarin 25%,The most common Teratogenic drugs are:,22,2.Organogenesis,Drug,Effect,Danazol,Sex hormones,Verilization of female fet.,Multiple,cardiac,Lithium,cardiac,Phenytoin,Craniofacial;limb,Carbamazepine,Craniofacial;limb,Valproate,Neural tube,warfarin,Multiple defects;chondrodysplasia,retinoids,CNS,craniofacial,heart,Predictable toxic drug actions in the fetus,Opioids,dependence of fetus and newborn,ACEI,irreversible,renal damage of fetus,Diethylstilbosterol,adenocarcinoma of vagina after puberty,23,Definition:,Developmental abnormality&drug,Animal studies,Rate of spontaneous is 1-2%,Teratogenic mechanisms:,Poorly,understood and multi-factorial,Direct effect,on maternal tissues with 2ry effect on fetal tissues.,Oxygen and nutrients,through placenta,Direct actions on fetal tissues e.g.differentiation of developing tissues.E.g.,Vit.A analogues,Deficiency of critical substance like,folic acid,24,Teratogenesis,Dangerous period,:,2,nd,to 8,th,weeks of pregnancy(structural abnormalities,Later on:dugs affect,growth,development,integrity,of body structure especially brain,But what about,the stored drug,?,Like,etritinate,?2 years,25,Teratogenesis,CAUSES OF BIRTH DEFECTS IN HUMANS,Schardein JL,2000.,*Evidence:Level B,Characters of the teratogen:,To be defined as,a teratogen,the substance or the process should:,Result in a characteristic set of,malformation,Exert its effect at a particular,stage,of fetal development,Shows,dose-dependence,incidence,E.g.,retinoids,warfarin,sex hormones,Food and drug administration classification of Drugs in pregnancy,FDA Categories:,teratogenic risk of drugs,DRUG LABEL,Pregnancy“Categories,”,A,Controlled studies in,humans,no risk,e.g,Penicillin?,B,animal studies,show no risk,but no controlled human,OR,animal studies show adverse effects,),e.g.,Acetaminophen,Cephalosporins,C,Animal studies,positive(teratogen)but no control.human,Human&animals,lacking.,Risk cannot ruled out,.g,Aspirin,Chloramphenicol,corticosteroid,Ciprofloxacin,Digoxin,Metronidazole,D,Human data,show risk,benefit may outweigh,e.g.,Enalapril,Captopril,Glyburide,Indapamide,Amitriptyline,X,Animal or human data positive.,Risk outweigh benefit,.,Contraindicated.,e.g.Oral contraceptives,Triazolam,Ethanol,estrogen,*,30,Drugs with high risk of causing abnormalities,Drug,Effect,Alcohol,Fetal alcohol syndrome,Androgens,Virilization;multiple defects,Anticancer,Multiple congenital defects,Carbimazole,Aplasia cutis,Corticosteroids,Cleft palate,Cyproterone,Feminization of male fetus,Ergotamine,Increase uterine tone,Misoprostol,Increase uterine tone,Fibrinolytic like streptokinase,Placental separation,Tetracyclines,Bone,yellow discoloration,Valproate,Neural tube defects,Vit.A analogues,Congenital defects,Warfarin,Multiple congenital defects,Drugs considered to be proven human teratogens,ACE inhibitors,Danazol,Cumarin derivatives(warfarin),Diethylstilbestrol,Ethanol,Lithium,Vitamin A and derivatives,e.g.isotretinoin,Phenytoin,Tetracycline,Valproic acid,Androgens,Carbamazipine,Cyclophosphamide,Thalidomide,Penicillamine,Diethylstillbestrol,32,Drugs under strong suspicion,of producing abnormalities(slightly increased risk),Drug,Efect,Amiodarone,Goitre,Chloroquine,Deafness(acute malaria),Phenytoin,Multiple congenital defects(Epilepsy),Other drugs to avoid(theoretical risk from animal and other studies),ACE inhibitors,Quinolone antibiotics,Vaccines(live),Deferoxamine,Rifampicin,Vigabatrin,CC blockers,Simvastatin,Xamoterol,Fibrates,Spironolactone,Grisofulvin,Sulfonylurea,Idoxuridine,Thiabendazole,Ketoconazole,Tocainide,Mefloquine,Trimethoprim,omiprazole,Cotrimoxazole,III.Growth&development,Major body structures have been formed,Subsequent development and function can be affected,33,34,Adverse effects of drugs on the fetus,during the later stages of pregnancy,Drugs,Risk to fetus or neonate,ACE inhibitors,fetal renal failure,PDA,RDS.,Aminoglycosides,8,th,nerve damage,Antithyroid drugs,Goitre&hypothyroidism(use dose),Aspirin,Kernicterus,hge(fetal/maternal),Benzodiazepines,Floppy infant syndrome,Fibrinolytic,Hge(infant/maternal),Narcotic analg,R depression,withdrawal if dependent,Nitrofurantoin,hemolysis,NSAIDs,Closure of DA,PH,delayed prolonged labor,hge,Novobiocin,Kernicterus,Warfarin,Fetal,placental hge,microcephaly,Sulfonyureas,Hypoglcemia,Sulfonamides,Kernictrus(Except,sulfasalazine),Tetracyclines,Yellow discoloration of teeth&bone,Thiazide diuretics,thrombocytopenia,35,Drugs that are safe in pregnancy,Class,Drugs that are safe in pregnancy,Minerals,Iron,Vitamins,Folic acid,Antiemetic,Meclozine&cyclozine,Analgesics,Paracetamol,Antibiotics,Penicillin,Tranquilizers,Hypnotics,Not completely safe,Antidiabetic,Insulin,Anticoagulants,Heparin(,osteoporosis of mothers,),Antihypertensives,Methyopa/nifedipine/labetalol-,diureics not/not ACEI,36,Treatment of some common diseases drug during pregnancy,Disease,treatment,Anemia,Iron 30 mg+folic acid 200-500 mg/day,Infections e.g.UTI,Ampicilin,amoxicillin,cephalosporines/nitrofurantoin,metronidazole,INH,ethambutol not rifampicin(TB drugs),What are the antibiotic drugs contraindicated in pregnancy?T,C,A,Diabetes milletus,Insulin(short,intermediate),Bronchial asthma,Inhaled salbutamol,steroids,theophylline.,Hyperthyroidism,Propylthiouracil,Hypertension,Pre-eclampsia,Chronic HT,Methyldpa,nifedipine,labetalol+Mg sulphate(convulsions),Not ACEI,diuretics.,Thrombosis,Heparin(warfarin in artifial valves,cong.HD,AF),Epilepsy,Fetal anticonvulsant syndrome 2.4,4.2,6%,new drugs?,Vomiting,Meclozine,cyclizine,Prevention of NTD,Folic acid 4 mg/day,400 micro for normal pregnancy/3months,Malaria prophylaxis,Chloroquine,proguanil+5 mg folic acid(PF),Meloprim(pyrimethamine+dapsone)not 1,st,trimister,Later on+folic acid,Mefloquine is contraindicated,Therapeutic drug actions in the fetus,Corticosteroids,for fetal lung maturation,Phenobarbitone,for neonatal indirect hyperbilirubinemia,Antiarrhythmic drugs,for fetal arrhythmias,Zidovudine,for protection of HIV transmission,37,Breast feeding and drugs,Drug excretion in milk:,Mechanisms of transfer from blood to milk,:,1-Diffusion of,low molecular weight,substances(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 MILK,Maternal Factors,Metabolism,dose&frequency,duration of therapy,route of administration,PPB,Infant Factors,Age,drug absorption,metabolism,extent of breastfeeding(quantity,frequency,solid foods),timing of feeds,Drug factors(transfer),Breast blood flow,breast metabolism pKa(ionization),lipid solubility,protein binding,MW,bioavailability,pH differences,Factors affecting adverse effects of drugs in suckling infants:,Passage of the drug,from the maternal blood into milk,Concentration,of the drug in milk,Volume of the milk,sucked,Pharmacokinetics of the drug,in the infants;particularly its absorption and clearance,Inherent toxicity,of the drug,What is the best time of taking the drugs for lactating mothers?,42,Drug therapy&breast feeding,43,Some drugs to,be avoided,in breast feeding mothers,High excretion or hypersensitivity,Amiodarone,Co-trimoxazole,Sulfonamides,Amphetamine,Ciclosporines,tetracyclines,Androgens,Doxazocin,trimethoprim,Anticancer,Erythromycin,Vitamin A analogue,Antipsychotics,Ethosuxamide,Vitamin D(High dosage),Antithyroid,Fluoxitine,Xanthines,Aspirin(Reyes S),Lithium,contraceptives,Barbiturates,Metronidazole,Ephedrine,Benzodiazepines,Nitrofurantoin,bromocriptine,Oral contraceptives,2.Chloramphenicol,Oral hypoglycemics,1.Ciprofloxacin,Phenytoin,Colchicine,Radioactive iodine,Corticosteroids(high dose),Statins,Drugs contraindicated during breast feeding,Radioactive materials,Alcohol,danazol,androgens,Opioids,amiodarone,iodine containing drugsSedatives/hypnoticsIsoniazid,laxatives,Tetracyclines,Amphetamine,doxepinCocaineErgotamine,Lithium,Anticancer drugs,(Methotrexate)Nicotine,gold,45,Some drugs appear to be safe during breast feeding,ACE inhibitors,Clavulinic acid,Nifedipine,Acetazolamide,Clomethiazole,Nortryptyline,ACTH,Codiene,NSAIDs,Adrenaline(,destroyed),Digoxin,Pyrizinamde,Antiasthmatic drugs(inhalation),Disopyramine,Pyridostigmine,Antihistamines,Ethambutol,Rifampicin,Baclofn,Frusemide,Terbutaline,B.Blockers(But?),Heparin,Thyroid hormones,Carbamazepine,Hydralazine,Tricyclic antidepressants except doxepin,chloroquine,Insulin(,destroyed),Valproate,Penicillins,Methydopa,Verapamil,Cephalosporines,Neuroleptic drugs in moderate doses e.g.chlorpromazine,Warfarin(,very low),Drugs safely used during breast feeding:,ACEIs,Antihistamines,-lactam antibiotic,CCBs,NSAIDs,TCAds,Drugs that affect milk production,Bromocriptine,Cabergoline,Thiazide diuretics,Combined oral contraceptive pills,Ergotamine,47,Thank you,48,Thank you,