TERATOGENIC DRUG

1. NURUL MIZA SHASHEIHA BINTI ABDUL MUTALIB2. NURUL HUSNA BINTI MURYADI 3. WAN FATHIAH NASUHA BT WAN NUSDRI4. NURFATIN AFIQAH BT MOHD BADRONDIN5. ZATEEL FAHADA BT RUSLI6. NURUL FIRDAUS BT HANAFEE7. NURUL SAHIIRAH BT AHMAD ROFI8. WAN FARAH NASUHA BT WAN MUHAMMAD HUSNI

by:

INTRODUCTION

• WHAT IS TERATOGEN ?

• TERATOGENIC DRUG

• FDA PREGNANCY CATEGORIES

• GENERAL MECHANISMS OF ACTION OF TERATOGENIC DRUGS

• TERATOGENIC MECHANISMS OF MEDICAL DRUGS

TERATOGEN

• Is an agent that can disturb the development of the embryo or fetus

• Teratogens halt the pregnancy or produce a congenital malformation

• Include radiation, maternal infections, chemicals, and drugs.

• 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

• typically during sensitive periods of fetal development

• depending on the particular teratogenic process and target organ

TERATOGENIC DRUG

FDA PREGNANCY CATEGORIES

CATEGORY A• failed to

demonstrate a risk to the fetus in the first trimester of pregnancy

• no evidence of risk in later trimesters

CATEGORY C• shown an

adverse effect on the fetus

• no adequate and well-controlled studies in humans

• potential benefits may warrant the use of drug despite potential risks.

CATEGORY D• positive

evidence of human fetal risk based on adverse reaction data

• potential benefits may warrant use of the drug in pregnant women despite potential risks

CATEGORY B• failed to

demonstrate a risk to the fetus

• no adequate and well-controlled studies in pregnant women.

CATEGORY X• demonstrate

s fetal abnormalities

• positive evidence of human fetal risk based on adverse reaction data

• the risks involved in use of the drug in pregnant women

CATEGORY N• FDA has

not classified the drug.

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 faetal metabolism

• Drugs: -folic acid antagonists-antiepileptic drugs

TERATOGENIC MECHANISMS OFMEDICAL DRUGS

• Folate antagonism• Neural crest cell disruption• Endocrine disruption • Oxidative stress• Vascular disruption and specific

receptor• Enzyme-mediated

teratogenesis

Teratogenic Drugs

•Analgesic•Anticonvulsant•Anticoagulant

•Antidepressant•Antithyroid•Vitamin A

IN FIRST TRIMESTER OF PREGNANCY

•Metal toxic•Sedative/ hypnotics•Aminoglycosides

Analgesic (aspirin)

• Gastroschisis• Decrease prostaglandin decrease uterine

contraction delayed onset of labor & prolonged period of pregnancy

• During delivery severe 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 ( retinoic acid )

• 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 & canamycin )

• Congenital deafness• Ototoxicity

TERATOGENIC DRUGS IN SECOND TRIMESTER OF

PREGNANCY

ACE INHIBITORS

DIAZEPAM

1) ACE INHIBITOR

MECHANISM OF ACTIONS

Produce vasodilatation by

1-inhibitting formation of angiotensin 11

2- breakdown bradykinin

PHARMACOLOGICAL ACTION

Mixed vasodilator

In cases of heart failure, cardiac output is maintained / even increase

Increase renal blood flow BUT decrease glomerular filtration rate decrease glomerular hypertension

THERAPEUTIC USES

USED IN Hypertension Heart failure Myocardial infarction

SIDE EFFECTS

IF USED IN 2ND – 3RD TRIMESTER OF PREGNANCY

1- fetal hypotension

2- renal failure

3- oligohydromnios

4- death

3rd tri

2) 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

PHARMACOKINETICS

ABSORPTION:

- Delayed and decreased when administered with a moderate fat meal

DISTRIBUTION

- Highly bound to plasma protein

- Cross blood brain barrier

- Cross placental barrier

- Found in milk

METABOLISM

N-demythylated Diazepam N-desmethyldiazepam

further metabolised hydroxylated temazepam oxazepam

Temazepam and oxazepam are largely eliminated by glucoronidation

ELIMINATION

The initial distribution phase is followed by prolonged elimination phase

SIDE EFFECTS

RISKS OF…

1) cleft palate

2) cardiac and circulatory defects

TERATOGENIC DRUGS IN THIRD TRIMESTER OF PREGNANCY

TETRACYCLINEACE INHIBITORS

CHLORAMPHENICOLAMINOGLYCOSIDES

SULFAMETHOXAZOLETRIMETHOPRIM

1) TETRACYCLINEProtein synthesis inhibitorInhibit the binding of aminoacyl-tRNA to the

mRNA- ribosomes complex

Aminoacyl-tRNA mRNA-ribosomes complex

by binding to the 30S ribosomal subunit in mRNA translation complex

SIDE EFFECTSIN PREGNANCY…..

dental discolouration in chilren maternal hepatotoxicity with large

parenteral doses

2) ACE INHIBITORSAS IN SECOND TRIMESTER

Ace inhibitors in 2nd trimester

3) CHLORAMPHENICOLBacteriostatic drug that stop bacterial growth

by inhibiting protein synthesisPrevent protein chain elongation by

inhibiting peptidyl transferase activity of bacterial chromosome

Intravenous chloramphenicol use has been associated with Gray Baby syndromeThis occur in newborn infants because they

liver enzymes not yet fully developedchloramphenicol remains

unmetabolised in body

ADVERSE EFFECTSHypotensionCyanosis

The condition can be prevented by using the drug at recommended doses & monitoring blood levels

Gray Baby Syndrome

4) AMINOGLYCOSIDESEG: GENTAMICIN, STREPTOMYCINHave several potential antibiotic mechanismsThey interfere with the proofreading process increased rate of error in

synthesis with premature termination

Inhibition of ribosomal translocation peptidyl tRNA moves from A-

site to P- siteDisrupt the integrity of the bacterial cell

membrane

Aminoglycosides are in pregnancy category DThey may cause auditory or vestibular nerve

damage

5) SULFAMETHOXAZOLE, TRIMETHOPRIMSulfonamide bacteriostatic antibioticStructural analogs and competitive

antagonist of PABAInhibit normal bacterial utilisation of PABA

for the synthesis of folic acidUsed as a bacteriostatic antibiotic in

prophylaxis and treatment of urinary tract infections

Trimethoprim binds to dihydrofolate redustase and inhibit reduction of DHF to THF

Sulfamethoxazole inhibit dihydrofolate synthetase

TERATOGENIC EFFECTS1) NEONATAL HAEMOLYSIS2)METHAEMOGLOBINAEMIA

CONCLUSION• BE CAREFUL IN TAKING DRUGS DURING

PREGNANCY•ALL CLINICIANS INCLUDING PHARMACISTS

ARE RESPONSIBLE TO COUNSEL PATIENTS WITH COMPLETE , ACCURATE AND CURRENT INFORMATION ON THE RISKS AND BENEFITS

OF USING MEDICATIONS DURING PREGNANCY

THANK YOU