Teratogenic Drug

  • directly or indirectly, causes a structural or functional change in the fetus or child if it is administrated to pregnant mother
  • If mother is taking this drug, It can be either stopped, switched or reduced to the lowest dose possible
  • Women to avoid all medications in the first 8 weeks after conception

Thalidomide: (Thalidomide disaster 1958-61)

  • Hypnotic agent widely used in Europe in 1959
  • An estimated 7000 infants born with thalidomide syndrome or phocomelia
  • Characteristic features à include limb abnormalities

Previous classification

CATEGORY X

  • demonstrates fetal abnormalities
  • positive evidence of human fetal risk based on adverse reaction data
  • the risks involved in use of the drug in pregnant women

POSSIBLE SITES OF ACTION OF TERATOGEN

DIRECT TOXIC ACTION

  • FETUS:
    -Direct toxicity.
    -Metabolites toxic.
    -Indirectly toxic, e.g. anti-metabolites, anti-vitamin.
    -Pharmacodynamic actions, e.g. on cardiovascular system.
    -Endocrine balance altered
  • FAETOPLACENTAL UNIT:
    -Umbilical cord, e.g. spasm.
    -Amniotic fluid volume change.
    -Faetal or maternal placental blood flow.
    -Placental transfer of nutrients, e.g. decreased active transport
  • MOTHER:
    Nutritional changes, e.g. vitamin or mineral deficiencies.
    -Biochemical changes with secondary effects on the foetus, e.g. hyperglycaemia.
    -Endocrine balance
  • FATHER:
    -Sperm changes

INDIRECT TOXIC ACTION

  • Cause malformation
    -interfering with foetal metabolism
  • Drugs: folic acid antagonists, antiepileptic drugs

TERATOGENIC MECHANISMS OF MEDICAL DRUGS

  • Folate antagonism
  • Neural crest cell disruption
  • During embryogenesis the neural crest cells, differentiates into two cell populations:
  • Cranial Neural Crest cells – structures in the craniofacial region
  • Truncal Neural Crest cells – components of the peripheral   nervous system
  • A variety of molecular signals and receptors are implicated in neural crest cell development:
  • Fibroblast growth factors, Integrins, Cadherins, Pax3, Endothelins
  • Both excess and deficiency can be teratogenic
  • Retinoid teratogenicity is mediated by the retinoic acid receptors,RARs and retinoid X receptors, RXRs.
  • Endocrine disruption
  • The ability of a hormone or endocrine disrupting chemicals  to cause teratogenesis depends upon:
  • Protein binding in the mother
  • Protein binding in the fetus
  • Drug metabolism (Active metabolite), Placental transfer capabilities
  • Oxidative stress
  • The developing embryo is especially susceptible to high levels of ROS because of its weak antioxidant defense, in particular in the early stages of organogenesis.
  • Vascular disruption and specific receptor

They give rise to structural birth defects.

Disturbances in the blood circulation in:

  • Uterine-placental unit (cord obstruction)
  • Placental-fetal unit (placental insufficiency)
  • The fetus itself (hypoxia, generation of ROS)

Direct effects of vascular disturbances:

  • Aberrant differentiation
  • Distortion of contiguous tissues
  • Loss of tissue
  • Incomplete development of structures within the same or a secondary embryonic developmental field

Vasoactive agents acting through this mechanism:

  • Misoprostol
  • Aspirin
  • Ergotamine
  • Pseudoephedrine
  • Enzyme-mediated teratogenesis
  • Cyclooxygenase-1
  • Non selective NSAIDS by inhibition of COX 1 may be involved in the induction of cardiac anomalies, orofacial clefts and diaphragm defects.

Teratogenic Drugs – IN FIRST TRIMESTER OF PREGNANCY

  • Analgesic, Anticonvulsant, Anticoagulant, Antidepressant, Antithyroid, Vitamin A, Metal toxic, Sedative/ hypnotics, Aminoglycosides

Analgesic (aspirin)

  • Gastroschisis
  • Decrease prostaglandin à decrease uterine contraction àdelayed onset of labor & prolonged period of pregnancy
  • During delivery àsevere bleeding because aspirin decrease platelet aggregation

Anticonvulsant

  • Fetal hydantoin syndrome :
  •  cranio facial malformation:

     -Cleft lip and palate, Broad nasal bridge, Ocular hypertelorism, Abnormal ears

  •  congenital heart disease
  •  limb malformation
  •  mental and growth retardation

Anticoagulant ( warfarin & Coumadin )

  • Fetal wafarin syndrome:

              -Nasal hypoplasia, bone stippling, Bilateral optic atrophy, Mental retardation

  • Respiratory distress syndrome
  • Fetal and maternal hemorrhage

Antidepressant (imipramine)

  • Cleft palate
  • Defect in abdomen
  • Adrenal hypoplasia
  • Cardiovascular defect

Antithyroid ( propylthiouracil & methimazole )

  • Fetal goiter

Vitamin A derivatives ( retinoic acid ) à Isotretinoin

  • Cranio-facial dysmorphism
  • Cleft palate
  • Thymic aplasia
  • Neural tube defect ( spina bifida cystic )

Metal toxic (lithium)

  • Hypotonia
  • Cyanosis
  • Lethargy
  • Poor respiratory

Sedative / hypnotics (diazepam )

  • Cleft lip and palate
  • Inguinal hernia
  • Congenital heart disease
  • Pyloric stenosis
  • Breathing difficulties


Aminoglycosides (streptomycin & Kanamycin )

  • Congenital deafness
  • Ototoxicity

TERATOGENIC DRUGS IN SECOND TRIMESTER OF PREGNANCY

ACE INHIBITOR

  • MECHANISM OF ACTIONS
  • Produce vasodilatation by inhibiting formation of angiotensin II and breakdown bradykinin
  • Mixed vasodilator
  • In cases of heart failure, cardiac output is maintained / even increase
  • Increase renal blood flow BUT decrease glomerular filtration rate à decrease glomerular hypertension
  • IF USED IN 2ND – 3RD TRIMESTER OF PREGNANCY
  • fetal hypotension, renal failure, oligohydramnios, death

DIAZEPAM

  • Centrally acting spasmolytic drug
  • It facilitates action of GABA in CNS
  • It acts as GABA synapse and produce sedation at doses required to reduce muscles tone
  • RISKS OF…

              1) cleft palate

              2) cardiac and circulatory defects

TERATOGENIC DRUGS IN THIRD TRIMESTER OF PREGNANCY

Tetracycline, ACE inhibitors, chloramphenicol, aminoglycosides, sulfamethoxazole, trimethoprim

TETRACYCLINE

  • Protein synthesis inhibitor à by binding to the 30S ribosomal subunit in mRNA translation complex
  • IN PREGNANCY àdental discoloration in children, maternal hepatotoxicity with large parenteral doses

CHLORAMPHENICOL

  • Bacteriostatic drug that stop bacterial growth by inhibiting protein synthesis
  • Prevent protein chain elongation by inhibiting peptidyl transferase activity of bacterial chromosome
  •  Intravenous chloramphenicol use has been associated with Gray Baby syndrome
    • This occur in newborn infants because they liver enzymes not yet fully developed à chloramphenicol remains unmetabolised in body
    • Manifest as – hypotension and cyanosis

AMINOGLYCOSIDES

  • EG: GENTAMICIN, STREPTOMYCIN
  • They interfere with the proof-reading process à increased rate of error in synthesis with                                   premature termination
  • Inhibition of ribosomal translocation
  • Disrupt the integrity of the bacterial cell membrane
  • They may cause auditory or vestibular nerve damage

SULFAMETHOXAZOLE, TRIMETHOPRIM

  • Sulfonamide bacteriostatic antibiotic
  • Structural analogs and competitive antagonist of PABA
  • Inhibit normal bacterial utilization of PABA for the synthesis of folic acid
  • Used as a bacteriostatic antibiotic in prophylaxis and treatment of urinary tract infections
  • Trimethoprim binds to dihydrofolate reductase and inhibit reduction of DHF to THF
  • Sulfamethoxazole inhibit dihydrofolate synthetase
  • Neonatal haemolysis
  • Methaemoglobinaemia

Teratogenicity Test:

  • Studies are carried in two animal species (rats & rabbits)
  • Drug is given after mating, during the period of organogenesis
  • Foetus is then examined for visceral or skeletal abnormalities

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