Drugs and Teratogenicity

DRUGS AND TERATOGENICITY  Teratogenicity: Capacity of a drug to cause fetal abnormalities when administered to the pregnant woman.  Teratogen: It refers to any agent that causes a structural abnormality following fetal exposure during pregnancy.  Teratogenic agents include: 1: Infectious agents 2: Physical agents 3: Environmental chemicals 4: Drugs Factors That Determines The Effect Of Teratogens  Dose reaching fetus  Point in development when drug exposure occurs  Duration of exposure  Environmental factors  Susceptibility of the fetus Lipophilic ,unionized, low molecular weight drugs in their unbound forms tend to cross the placenta.  DRUG ABSORPTION:- -due to increase in circulating level of progesterone slowing of gastric emptying occur -hence there is slow absorption of drugs during pregnancy  DRUG DISTRIBUTION:- -volume of distribution increases  DRUG METABOLISM:- -hepatic metabolising enzyme increases during pregnancy -leads to more rapid metabolic degradation  DRUG EXCRETION:- -renal plasma flow increases by 100% and glomerular filtration rate increases by 70%. -drugs which depend for their excretion on kidney eliminate more rapidly Drug can affect the fetus at 3 stages:- 1:Fertilization and implantation: conception -17 days 2:Organogenesis: 18 -55 days of gestation 3:Growth and development: 56 days onwards… Drug can affect the fetus at 3 stages:- Stage 1 Drugs classified into various groups in the light of possible adverse fetal effects as recommended by FDA. Category Description:A. No fetal risk factors demonstrated from controlled studies. Drugs proven safe for use during pregnancy. e.g. prenatal vitamins. B.Fetal risk not demonstrated in animal or human studies. Many drugs commonly used fall into this category e.g. Penicillins. Acetominophen (Paracetomol ), Insulin, Chloroquine C animal studies. In some cases, animal studies may demonstrate adverse fetal effects but no human data available e.g. Aspirin, Chlorpromazine. Again many drugs commonly used fall in this category Fetal risk may be known: No adequate human studies nor D Some evidence of fetal risk known in humans: It may however be quite necessary to use such drugs, the benefits of such drugs may thus be viewed as outweighing the risks of the drugs. e.g. Diazepam, Aspirin, Corticosteroids, Tetracyclines etc. X. Proven fetal risks. In this group the proven risks of the drugs outweigh any benefits for the drugs e.g. Isoretinein, an acne medicine. Antibiotics 1:Tetracycline: –(2nd and 3rd trimester) -chelates with calcium and deposited in developing teeth and bone of fetus - causes permanent staining of teeth 2:Aminoglycoside,Streptomycin, vancomycin:- – ototoxic to fetus 3: Chloramphenicol:-(2nd and 3rd trimester) -Grey baby syndrome -About 40% of neonates die from circulatory collapse on about the fifth day 4: Nitrofurantoin:– -causes low level of glutathione -may predispose fetus to hemolytic anemia if exposed just before birth Anti-inflammatory drugs 1:- Aspirin:- (3rd trimester) -premature closure of ductus arteriosus -spina bifida -serious hemorrhage in premature infant 2:- Colchicine:-spontaneous abortion (should be discontinued 3 months prior to conception) -down’s syndrome Alpha adrenergic blockers 1: Prazosin:- taken from 7th day of gestation resulted in-limb defects -hypoxic renal damage -intrauterine death at 20 weeks Beta adrenergic blockers  Atenolol given in early pregnancy shows fetal growth retardation  Timolol eye drops is associated with bradycardia and arrhythmia in fetus  Beta blockers eye drops should be avoided in 1st trimester ACE Inhibitors Captopril, Enalapril:-(2nd and 3rd trimester) - Oligohydramnios - Pulmonary hypoplasia - Neonatal hypotension - Patent ductus arteriosus - Hypocalvaria - Renal tubular dysgenesis Vitamin A analogues 1: Isotretinoin:-(1st trimester) -Agenesis of cerebellar vermis -abnormalities of corticospinal tract -hydrocephalus -spontaneous miscarriage -microtia -behavioural abnormalities Endocrinological drugs 1:Radioactive iodine:-(3rd trimester) taken up by fetal thyroid resulting in -thyroid ablation -hypothyroidism -risk of chromosomal damage and genetic abnormalities PREGNANCY SHOULD BE AVOIDED FOR ATLEAST 4 MONTHS AFTER IODINE THERAPY Anticancer drugs Busulphan,cyclophosphamide methotrexate:- (1st3rd trimester) Teratogenic Effect:-Agenesis of kidney -microphthalmia -cloudy cornea -malformation of eyes,ear,cleft palate Antifungal drugs 1:Fluconazole:- Antley- Bixler like malformations. Which include:- depressed nasal bridge - dysplastic ears - midfacial hypoplasia - proptosis - radioulnar synostosis - cleft palate - arachnodactyly Antipsychotic drugs 1: Lithium:- (1st trimester) -inhibition of adenylyl cyclase influencing nerve excitation -Ebstein anomaly:-tricuspid valve distortion and displacement -premature delivery 2: Chlorpromazine:-hypotonic and lethargic infant -extrapyramidal syndrome Anticoagulant drugs 1: Warfarin:- (2nd and 3rd trimester) -intake of drug between 6th to 9th week of gestation causes defective ossification of bones resulting in nasal hypoplasia -fetal warfarin syndrome (CNS abnormalities microcephaly) Anticonvulsant drugs 1:Carbamazepin,sodium valproate :– (1st trimester) -neural tube defect 2:Phenytoin:– (1st trimester) -fetal hydantoin syndrome 3:Phenytoin,sodium valproate:– -heart defects Fetal Alcohol Syndrome (1st trimester) Thalidomide (Days 34-50)  It was given as an antiemetic drug It resulted in -phocomelia -loss of hearing -microtia -abducens and facial paralysis -renal malformation Absolutely contraindicated drugs:1)Cytotoxic drugs :-busulphan, cyclophosphamide, methotrexate 2)Vit-A analogues:- isotretinoin, etretinate 3)Cardiovascular drugs:-ACE inhibitors :- captopril, enalapril -Angiotensin II inhibitors:- losartan -Spironolactone 4)Antifungal drugs:- griseofulvin,triazole,terbinafine 5)Antiinflammatory drugs:- NSAIDs 6)Endocrinological drugs:-radioactive iodine -sex hormone 7)Antihelminthic drugs:- mebendazole 8)Others:- misoprostol,mefloquine,statins SUMMARY Relatively contraindicated drugs:1)Antipsychotic drugs:- lithium 2)Anticoagulant drugs:-warfarin 3)Anticonvulsant drugs:- carbamazepine,phenytoin,sodium valproate 4)Endocrinological drugs:-carbimazole,sulhonylurea 5)Cardiovascular drugs:-beta blockers,minoxidil 6)Antibiotics:-tetracycline,ciprofloxacin,aminoglycosides, chloramphenicol,nitrofurantoin,vancomycin 7)Antiinflammatory drugs:-colchicine 8)Others:-dapsone Conclusion  Lipophilic, unionized & low molecular wt. drugs should be carefully administered to pregnant women as they may cross the placenta and have teratogenic effects on the fetus  Teratogenic agents may cause abortion, malformations, mental retardation, growth retardation or cerebral damage in the developing fetus  The risk to benefit ratio of a drug must be carefully assessed prior to administration in pregnant women. References Books:1)Pharmacolgy and Pharmacotherapeutics by S.R.Satoskar, 19th edition 2)Essentials of pharmacology by K.D.Tripathi, 4th edition Websites:1)www.amercianheart.org/presenter 2)www.nlm.nih.gov/medlineplus/ency/article 3)www.uspharmacist.org THANK YOU