Teratogenic Drug

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 2^ND – 3^RD 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