Teratogenicity - pps

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Tetragenicity is a side effect of medicine which taken by Mother but iffect to unborn child,, It is difficult to study this topic in humans because there are serious ethical issues involved with exposing pregnant women to substances that might cause birth defects. As a result, the dosage at which substances become harmful is often not known because healthcare professionals do not want to expose(free) women to various dosages in a controlled experiment to see which of them had babies with developmental abnormalities. {other side}lab animals safely, but animal testing does not always categorically demonstrate that a substance is safe to use in pregnant women.

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Sub. by- Aqsa Ibrar D/o.Muhammad Ibrar Khan Roll.No-13661,MBBS 4 th Prof. (Kust Institute of Medical Sciences,kohat Peshawar) Khyber pakhtunwa state, Pakistan, Teratogenecity A persentation on

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Teratogenicity : It is the science dealing with the development of congenital malformations. A teratogen ( terato= monster or ugly animal): It is a substance that alters embryonic or fetal development resulting in structural or functional alterations.

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History:  In 1928 : Exposure to therapeutic radiation during pregnancy microcephaly baby .  In 1933 : Deficiency of vitamin A in the 1st month before pregnancy & during pregnancy anophthalmia (deficiency in eye)  In 1941 : German measles ( rubella ) infection in pregnancy cause teratogenicity ( blindness, deafness, death, mental retardation ).  In 1944 : Malformation due to nutritional deficiency .  In 1961 : Correlation between Thalidomide ( used as sedative , hypnotic and anti emetic) ingestion in pregnancy & phocomelia ( phoco= seal , melia= extremities).

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Sensitivity to teratogens according to the stage of development: The attack by the teratogen could be at any stage of development as follows : 1-Pre-implantation Stage (All or Non) : From fertilization till implantation During this stage : the embryo is NOT susceptible to teratogenic agents which either kill the embryo ( embryolethality ), or have no effect ( i.e. in both cases there is NO teratogenicity ) .

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2-Embryonic Stage: stage of organogenesis from the 3rd to the 8th week of gestation . *6-7 days after gestation ,implantation occurs followed by gastrulation ( formation of ectoderm, mesoderm & endoderm).It is characterized by differentiation and organization. During this stage, the embryo is highly susceptible to teratogens, it produce major morphological changes ( especially brain & face). 3-Fetogenesis Stage: stage of histogenesis It is characterized by growth and functional maturation. During this stage, the fetus is less sensitive to morphologic changes; however minor structural deviation is possible. The teratogen affects mainly growth or functional aspects ( e.g. intelligence, reproduction

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Mechanism of action of teratogens: 1- Interference with nucleic acids : ( replication , transcription or RNA translation) * The antimetabolite : methotrexate. * alkylating agents : Chlorambucil, cyclophosphamide. *Active metabolites of Thalidomide

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2- Inhibition of enzymes : * Methotrexate ( dihydrofoleate reductase inhibitor = DHFRI) prevents formation of folinic acid from folic acid which is essential for embryo. * 5- fluorouracil inhibits thymidylate synthase leading to inhibition of deoxythymidine monophosphate ( DTMP )synthesis inhibition of DNA synthesis . * 6- aminonicotinamide ( G6PD inhibitor) decrease energy production.

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3- Deficiency of energy supply needed to build organs : a- Glucose deficiency : - Deficiency of glucose in diet - G6PD inhibitors ( 6- aminonicotinamide ) - Drugs affecting Kreb’s cycle ( fluroacetate ) b- Interference with internal respiration : - CN toxicity : cytochrome oxidase inhibitor. c- Hypoxia : - CO toxicity (Decrease in both O2 delivery + osmotic pressure to fetus) - Drug induced ( phenytoin ).

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4-Lack of substrates : 1-Decrease of vitamins or minerals intake. 2-Failiur of absorption from GIT as in GIT infection e.g. diarrhea or bile acid deficiency. 5- Genetic mutation : X-ray ,atomic explosion &radiations DNA damage mutation congenital abnormalities. E.g.: Achondroplasia . It is characterized by congenital abnormalities in ossification of cartilage. Features include : * Dwarfism- microcephaly ( small head) * Kyphosis ( arched back)- Polydactyli ( 6 or more fingers in one hand)

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6- Chromosomal aberrations : The abnormalities may be in number ( numerical) or structural A-Numerical abnormalities : Normal no. of chromosomes= 23 pairs. Pairs from 1-22 are called somatic or autosomal chromosomes. Pair 23 is called sex chromosomes ( XX=female) & ( XY= male) Abnormalities in no. may be called: *Aneuploidy : loss or gain in chromosomes. -Monosomy = single chromosome instead of a pair -Trisomy = 3 chromosomes instead of a pair * Polyploidy : when a complete set of chromosomes is gained.  The numerical abnormality may be in the autosomes ( 1st 22 pairs) or in the sex chromoses ( pair no.23)

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i-Autosomal abnormalities Autosomal abnormalities may be caused by X-ray, viruses, F in drinking H2O , maternal diabetes & age Trisomy 21 : ( Mongolism = Down’s syndrome) It is characterized by mental retardation, heart malformations, susceptible to infections, acute leukemia & death in childhood. Trisomy 17& 18 : mental retardation, defects in heart, ears & finger. Trisomy 13 : mental retardation & microcephaly . ii Sex chromosome ( genosomal ) abnormalities Turner's syndrome : (XO)- ( Monosomy 23)

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B- Structural abnormalities : In this case the no. is normal, but there may be a breakage or a loss of a part from chromosomes mental retardation or deformity. E.g.: Cri- du chat syndrome ( cat cry syndrome):. It is characterized by mental retardation & mewing sound crying. Structural abnormalities may be caused by atomic explosion, radioactive materials, LSD, heavy smoking & viruses .

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3- pollution : a) physical Atomic and nuclear explosions e.g.: Hiroshima & Nagasaki. b) chemical *lead (pb2+) : from water pipes, or car exhaust : miscarriage ( spontaneous abortion ), stillbirth ( delivery of a dead baby ), and increased mortality rate during the 1st year of life . *Carbon monoxide CO : from cigarette smoking, car exhaust, and incomplete combustion of coal. It binds to Hb O2 supply to fetus hypoxia spontaneous abortion, stillbirth,

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*Vinyl chloride : sperm damage ( working in vinyl industry, their babies may be malformed ) . *Mercury : Minamata syndrome : A plastic factory poured is wastes, containing Hg, in Minarnata Bay Hg is converted by microorganisms in H2O to methyl Hg witch contaminated fish eating contaminated fish, the pregnant women gave birth to malformed & mentally babies . 4- infections ( biological pollution ) : a-Viral : German measles (Rubella) : deafness, blindness, cataract, retinopathy, glaucoma, microcephaly , mental retardation . Attenuated virus causes damage to the fetus, so give vaccine

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Viral: Hepatitis, small pox, chicken pox : may cause abortion, stillbirth, skin diseases, hepatitis … etc . Bacterial : Syphilis : hydrocephalus & mental retardation, deafness, tooth malformation, meningitis & CNS disturbances . Tuberculosis : Wt. loss, refusal to suckle, hepato-splenomegaly

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Protozoal : toxoplasmosis : it is transmitted to pregnant women by feces of domestic cats & birds causing hydrocephalus, CNS disturbance, microcephaly , hepatosplenomegaly & blindness . 5- Maternal diseases : uncontrolled diabetes mellitus, hyperthermia & thyrotoxicosis (hyperthyroidism) teratogenicity & toxemia of pregnancy 6- Malnutrition : Vit . A - anophthalmia . Vit . D - bone and teeth malformation . Folic acid -malformations . Minerals as iron ( anemia ), Calcium( bone malformation )& potassium( pre-term labour ).

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7-Alcohol : Fetal Alcohol syndrome ( FAS ) : growth failure & delayed development, microcephaly & mental retardation , defects in the eye, face ( cleft palate) , heart, skin & kidneys . 8-Drugs : highly teratogenic drugs as" thalidomide- warfarin -corticosteroids – anticancer drugs . Also the following drugs are hazardous if given during the 2nd or 3rd trimester, some of them are hazardous also if given during the 1st trimester :

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1-Androgens & progesterone : Musculinization of fetus. 2-Estrogens: Feminization of fetus, abnormal spermatogenesis. 3-Diethylstilbestrol ( DES ): Adenocarcinoma of vagina in girls ( 15-20 years ) whose mothers took DES during the 1st trimester Aspirin in the 1st trimester cleft palate (in a few percentages

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Best of luck... . Thanx & Regard to- Dr.Aqsa Ibrar khan ambitious.ask@facebook.com

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