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Flashcards in Teratogens LT Deck (58)
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1

 Teratogens act by

  • Producing cell death
  • Altering normal growth of tissues
  • Interfering with normal cellular differentiation 

⇒Abnormalities in form or function of fetus

  • Fetal loss
  • Growth restriction
  • Birth defects
  • Impaired Neuro
    • Fetal ALcohol Syndrome (altered neuro connections)

2

Enviornmental teratogens account for

4-6% of birth defects

3

Enviornmental teratogens include

  • Maternal ilness
    • DM
    • PKU
    • TORCH
  • Physical agents
    • Radiation
    • Heat
  • Drugs
    • Thalidomide
    • Antiepileptic
  • Chemicals
    • Hg

4

TORCH infections

  • Toxo
  • Others- syphilis, VZV, Parvo B19
  • Rubella
  • Cytomegalo
  • Herpes

5

Factors that influence response to teratogen

  • Genetic Succeptibility
  • Dose
  • Route
  • Timing
  • Concourrent exposures/maternal illnesses
  • Absorption of mom

6

Genetic succeptibility to teratogen

  • genetic makeup of BOTH fetus and mom
  • different that genetic conditions that directly cause defects

7

Example of genetic succeptibility

  • Defect in folate metabolism predisposes to a higher risk for developing structural abnormalities such as NT defects, cleft lip and palate and cardio malformations
  • MTHFR gene mutation
  • Risk of these malformations depends on the prescence of altered folate metabolism (MTHFR gene mutation) AND inadequate folate intake by mom
    • ie risk can be reduced by suplementing folate to mom in preconceptional and early pregnancy period 

8

Genetic succeptibility and interaction with antiepileptic drugs

Fetuses with low epoxide hydrolase activity  +​​  exposure to antiepileptic drugs→higher levels of teratogenic oxidative metabolites

9

Epidemiology of postaxial polydactyly

  • MORE common in African americans (1%)
    • Caucasians (0.1%)

10

Epidemiology of NT defects

  • MORE common in caucasians than African Americans

11

Epidemiology of pyloric stenosis and cleft lip

  • MALES > Females

12

Example of role of route exposure in teratogenecity

  • Absorption and action of drug differ if adminstered dermally or systemically
  • Systemic route
    • abnormalities
    • fluconazole→potentially teratogenic
    • Retinoic acid
      • oral/systemic
  • Dermal
    • safe
    • fluconazole and retinoic acid are safe if adminstered dermally

13

Dose of a drug and teratogenicity 

Threshold Effects

Threshold Effects:

  • a dose below which the drug is unlikely to increase the incidence of embryonic death, growth rstriction, functional impairment
  • 1-3 orders of magnitude below teratogenic dose

14

The use of teratogenic doses in animals

  • Used when no human doses are available
  • Teratogenic dose less than 10X the max theraputic dose in humans
    • TERATOGENIC
  • Teratogenic dose more than 100X the max theraputic dose in humans
    • SAFE

15

Teratogenicity among different species

  1. Thalidomide
    • ​​Teratogenic in humans
    • Safe in rabbits
  2. Many drugs
    • ​​Teratogenic when given at 10 to 1000 times the normal dose adminstered to humans (100 fold difference is necesary to deem a drug safe)
  3. Meclizine
    • ​​When given to mice casues cleft palate due to apetite supression
      • Therefore, force feeding the mice would prevent the occurence of cleft palate

16

The duration of dose adminstration and amount admisntered

  • Some drugs are teratogenic when given at one large dose 
    • ie spreading out this dose wouyld make it safe
    • eg. Daily intake of one alcoholic drik for a week is safer than binge drinking seven alcoholic drinks in a day
  • Another drug is teratogenic when it exposure is prolonged
    • ie giving it all at once would make it safe
    • eg. Occasional very high maternal glucose is safer than persistent high glucose levels

17

Drug drug interactions

  • Synergistic drugs
  • Independent
  • Protective against the teratogenic effects of the other
    • Folic acid is protective in patients taking antiepileptic (valproate, carbamazepine)
    • Still try to avoid giving valproate

18

Preimplantation and implantation

days 5-11

19

Formation of the three germ layers

by day 16

20

Formation of neural plate

by day 19

21

Closure of neural tube

by day 27

22

Appearance of limb buds

by day 30

23

Formation of branchial arches, clefts, pouches, optic vesicle

between weeks 4-5

24

Formation of mature heart and kidneys 

by week 5-7

25

Achievement of mature limb architecture

by week 8

26

Sexual differentiatoin of internal and external genitalia

by weeks 7-10

27

Rotation of the intestines and return into the abdominal cavity

in week 10

28

Result of significant exposure during first 10-14 days after fertilization

Cell death

  • if significant leads to spontaneous abortion
  • If only a few die, other cells will compensate for their roles
  • All or none theory
    • Eg, significant exposure to radiation results in either pregnancy loss or no abnormalities

29

Teratogenecity and the embryonic period

Embryonic period

  • From fertilization to the 8th week postconception (10 W of gestation)
  • Most vulnerable to insult since organ systems are developing

30

Teratogenecity and the Fetal period cause

  • Cell death
  • Retardation of cell growth
  • Inhibition of normal differentiation

fetal growth restriction or disorders of the CNS not apparent at birth

Eyes, genetalia, CNS, hematopoetic systems all develop during fetal period