1. The document discusses various tocolytic agents used to inhibit uterine contractions in preterm labor, including magnesium sulfate, beta-adrenergic agonists like terbutaline, calcium channel blockers like nifedipine, prostaglandin synthetase inhibitors like indomethacin, nitroglycerin, diazoxide, atosiban, and ethyl alcohol. 2. Each drug is described in terms of its mechanism of action in relaxing the uterus, recommended dosages, potential side effects on mother and fetus, and contraindications. Monitoring is important when using tocolytic drugs to prevent side effects like hypotension, respiratory depression,

1. TOCOLYSIS & FDA RISK
CATEGORIES
DR RAJEEV SOOD
ASTT.PROF.OBG
IGMC SHIMLA

2. TOCOLYSIS
Preterm labour
• Regular uterine contraction-at least 4 in 20
mts. or 8 in 60 mts. and
• cervical changes – effacement> 80% with
dilatation >=1 cm
• gestation less than 37 completed weeks.

3. DIGITAL EXAMINATION
Cx 80% effaced Cx 80% effaced Cx <80% effaced
dilated >3 cm dilated >1 &<3cm dilated <1cm
Advanced preterm Early Preterm labour
labour
TVS
Cervical Length <2.5 Cervical Length >2.5
cm cm
Threatened Preterm False Labour

4. • Incidence 5- 10 %
• Late preterm births (b/w 34w to 36w 6
d)-74%
• Very preterm (less than32 weeks)
• Perinatal mortality rate in preterm infants
in India is 40 – 150 per 1000 live births.

5. • Preterm birth is associated with a number of
complication in baby
– Asphyxia
– Hypothermia
– Pulmonary syndrome.
– Cerebral haemorage.
– Fetal shock.
– Heart failure.
– Oliguria, anuria
– Infection
– Jaundice
– Anemia
– Retinopathy of prematurity.

6. TOCOLYTIC AGENTS
• Drugs which are used to inhibit uterine
contractions.
• Can be used as
– Short term therapy (1-3days)
– Long term therapy

7. Objectives of short term therapy
• To delay delivery for atleast 24-48 hrs for glucocorticoid
therapy to enhance lung maturation
• In utero transfer of patient to an advanced neonatal
intensive care unit.
Contraindications
Maternal
• Uncontrolled diabetes
• Thyrotoxicosis
• Severe HTN
• Cardiac ds
• Placenta Previa
• Abruption

8. fetal
• fetal distress
• IUD
• Congenital malformations
• Pregnancy beyond 34 weeks
Others
• Rupture of membrane
• Chorioamnionitis
• Cervical dilatation >4 cm

9. TOCOLYTIC AGENTS
• Mgso4
• Beta agonist
• Calcium channel blockers
• Prostaglandin synthethase inhibtors
• Nitroglycerine
• Diazoxide
• Oxytocin receptor antagonist
• Ethyl alcohol.

10. MAGNESIUM SULPHATE
• Acts by competitive inhibition to calcium
ion either at motor end plate or at cell
membrane.
• Decreases acetylcholine release and its
sensitivity at motor end plate.
• Direct depressant action on uterine ms.

11. In addition, MgSO4 has been proposed to
act as neuroprotectant
Following Mechanisms are postulated.
A). Haemodynamic stability
– By stabilizing BP.
– Reducing constriction in cerebral arts.
– Restoring cerebral perfusion.

12. B.
Prevention of excitatory injury and neuronal
stabilisation
↓O 2
Anaerobic metabolism
↓ ATP, ↑ lactic acid
Intracellular accumulation of Na,
Ca, Cl, H2O (Cytotoxic odema)
Excitatory neurotransmitters
(glutamate) released
Ca, Na, influx in post synaptic neurons by
activating NMDA receptors
-Persistent depolarization

13. MgSO4 inhibits this influx and acts as a membrane
stabilizer.
C). Antioxidant Properties
– Increased intracellular Ca inhibits activation of lipases
proteases, endonucleases, phospholipases
– Leads to neuronal cell injury & irreversible brain
damage.
– MgSO4 by blocking Ca Influx reduces the brain
damage.
D). Anti inflammatory properties-
– MgSO4 reduces the synthesis of cytokines and
bacterial endotoxins, minimising the inflammatory
effects of infection.

14. Doses
10 ampoules are dissolved in 500 ml saline
• Loading doses:- 4
gms as slow i/v
Infusion over 20 mts 2 gm in 100 ml
in 100 ml saline.
100 ml/hr
Maintenance doses
• 2 grams /hr- till 12 hrs
1.6 ml in 1 minute
after labour pains
have subsided.
16 drops- 1 ml
25 drops approx. equals to 1.6
ml
25 drops/minute

15. Monitoring
• By measuring urine output/hr
• DTR’s
• Respiratory rate, presence of basilar crepts.
Side effects
Maternal
• Nausea
• Blurred vision
• Generalised weakness
• Altered sensorium
• Muscular weakness
• Headache
• Pulmonary odema
• Respiratory depression
• Neurotoxicity

16. Fetal
• Letharggy
• Hypotonia
• Respiratory depression
• Hypocalcaemia
• Increased frequency of IVH.
Contraindication
• Patients with myasthenia Gravis.
• Impaired renal function

17. β- ADRENERGIC AGONISTS
• Activate intracellular enzymes adenylate
cyclase, cAMP, Protein kinase.
• Reduces intracellular Ca.
• Inhibits activation of MLCK.
• Reduced interaction of actin & myosin- smooth
ms. Relaxation.
• Commonly used drugs are
– Terbutaline
– Ritodrine
– Isoxsuprine

18. Doses
Terbutaline
• 5 mg is dissolved in 500 ml RL (10ug/ml)
• Started at 5 ug/mt (0.5 ml)
• Increased gradually by 5 ug/mt every
10-20 mts until contraction stop or
intolerable side –effects appear.
• Max. dose is 30 ug/mt.
• 0.25 mg every 3-4 hrs sub- cutaneously
can also be given.

19. Ritodrine
• Started by i/v infusion in 5%D.
• 50 ug/mt.
• Increased by 50 ug/mt until cont. stop or toxicity
develops
• Max. dose 350 ug/mt.
• After 12hrs oral therapy with 10-20 mg tab every 4-6 hrs.
Isoxsuprine
• Orally effective long acting selective β stimulant.
• Direct smooth ms. Relaxant property.
Dose
• Initial IV drip 100mg in 5%D .
• Rate o.2ug/min gradually increased to0.8ug /min.

20. • To continue at least 2hrs after contraction
ceases.
• Maintaince-10mg 6hrly /im for 24hrs.
• Oral 10mg 6-8hrly.

21. • SALBUTAMOL-
• IV infusion 5mg in 5%D @10ug/min intially
gradually increased upto50 ug/min .
• Maintainance-4mg tab 6hrly.
• S/E-
tremors,tachycardia,hypertension,palpitati
on.

22. Side effects
Maternal
• Headache
• Palpitation
• Tachycardia
• Pulmonary odema
• Hypotension
• Cardiac failure
• Hyperglycemia
• ARDS
• Hyperinsulinemia
• Hypokalemia
• Lactic acidemia
fetal
• Tachycardia
• Heart failure
• IUD

23. Neonatal
• IVH
• Hypoglycemia
Contraindications
• Ventricular outflow obstruction
• Conduction disturbances
• Hyperthyroidism
• Sickle cell ds
• Uncontrolled insulin dependent diabetes
• Chorioamnionitis
• Eclampsia or severe pre Eclampsia
• Pts receiving MAO Inhibitions.

24. Given orally - Dose
NIFDIPINE
• Calcium channel 30 mg stat
blocker
• Causes smooth 20 mg after 90 mts
muscle relaxation
• Used for inhibiting 10 mg 8 hrly if
labour since 1980.
PR <120/minute systolic B.P. >
90mm Hg
Chest- Clear

25. Side effects
Maternal
• Headache
• Hypotension
• Flushing
• Nausea
fetal
• Apparently nil

26. INDO METHACIN
• A cyclo-oxygenase inhibitor
• Reduces synthesis of prostaglandins
leading to decreased intracellular free
calcium
• This reduces activation of myosin light
chain kinase leading to decreased uterine
contractions.
• Loading dose-50 mg orally
• Followed by – 25 mg every 6 hrs for 48
hrs.

27. Side effects
Maternal
• Asthma
• GI Bleeding
• Thrombocytopenia
• Renal Injury
Fetal
• Constriction of ductus arteriosus.
• Decreased fetal urinary output, oligohydroamnios.
• IUGR
• Neomatal Pulmonary HTN.
• Necrotising enterocolitis
• Grade III/IV intraventricular hemorrhage
Contra Indications
• Hepatic ds.
• Active peptic ulcer
• Coagulation disorders

28. NITROGLYCERIN
Nitric oxide donor
Guanyl cyclase
Guanosine 3-5 monophosphate
Activates protein kinases
Dephosphorylation of myosin light chains
Smooth ms. Relaxation

29. • Given as Transdermal patches
• A specific amount of medication is released proportional to the size
of patch.
• Varies B/W 0.1-0.8 mg/hr.
• A low dose patch is started (0.2 mg/hr)
• Add 0.1 mg/hr every hr, if no response.
Intra venous dose
• 100 ug Bolus followed by continuous 1/v infusion at a rate of 1 ug
/Kg/ minute.
Side effects
• Hypotension
• Tachycardia
• Severe headaches
• Methaemoglobinemia
• May causes cervical ripening

30. DIAZOXIDE
• Structurally related to thiazide diuretics
• Inhibits contractility of arterial and venous smooth muscles.
• Also inhibits respiratory, GIT, genitourinary smooth muscle.
Dose
• 5 mg/kg
• 1 ampoule of diazoxide is dissolved in 250 ml of normal saline
• Given slowly i/v over 30 minutes
• Can also be given in boluses of 50-100 mg every 5 minutes
• Patient should be in left recumbent position.
• Continuous monitoring of maternal heart rate, B.P. , Uterine activity
and fetal heart rate is recommended.
To avoid side-effect it is desirable to expand the maternal intra
vascular volume before diazoxide is given.
• 500-1000 ml RL or NS is given.
• Uterine contraction stop within 15 minutes.
• If labour recurs, a second doses can be given.

31. Side-effects
Maternal
• Hypotension
• Tachycardia
• Hyperglycemia
• Decreased uteroplacental flow.
Fetal
• Hyperglycemia
• fetal distress.

32. ATOSIBAN
• Oxytocin antagonist
• Blocks myometrial oxytocin receptors.
• Inhibits intracellular calcium release, PG’s release,
inhibiting myometrial contraction.
• Half life is 12 mts
• Crosses placenta but fetal levels are only 10% of
maternal levels.
Doses
• 6.75 mg bolus i/v Injection followed by 300 ug for 3 hrs.
• Maintenance dose of 100 ug/minutes for 48 hrs.
Side-effects
• Nausea
• Vomiting
• Chest Pain

33. ETHYL ALCOHOL
• Inhibitory action on hypothalamus,
preventing release of oxytocin.
• 50ml 95% ethyl alcohol in 450 ml 5% D as
i/v infusion
• Initially7.5ml/kg for first 2 hours followed
by 1.5ml/kg/hr for 10-12hrs .
• Marked maternal CNS depression.
• Risk of foetal hypoxia.
• No longer recommended.

34. ACUTE TOCOLYSIS
• Rapid uterine relaxation is required in following
clinical situations-
• Uterine hypertonus
• Breech delivery
• Intrapartum version of fetal malpresentation
• Shoulder dystocia
• Retained placetna
• Acute uterine inversion

35. Various tocolytics used are
1).Nitroglycerine
– Either sublingual or I/V
– Sublingual- aerosol spray in a dose of 400 ug.
– Intravenous
– 1 amp. Contains 5 mg. This is added to 100 ml of NS
producing a solution of 50ug/ml
For fetal entrapment-200 ug starting dose in given.
Repeated every 2 minutes.
For retained placental or uterine inversion, 100 ug
is given

36. 2). Terbutaline
– 250 ug subcutaneously
– i/V- in 5 ml saline slowly over 5 minutes.
3). Ritrodrine
– 6 mg in 10 ml NS i/V over 3 minutes.
4). Hexoprenaline
– 5 mg in 10 ml NS i/v over 5 minutes.
5.) Atosiban
– 6.75 mg in 5 ml NS i/v over 1 minutes
For malpresentations, third stage complications
Nitroglycerine is drug of choice.
For uterine hypertonus-
– Atosiban terbutaline, ritodrine is preferred.

37. FDA Risk CAtegoRies

38. • Risk of major congenital abnormalities in
each pregnancy 2-3%
• 7-10% if minor malformations included.
 25% - genetic
 2-3%- drug exposure
 65% - unknown or combination of genetic &
environmental factors

39. • Teratogen-
 Derived from word teratos
 Any chemical, virus, environmental
agent, physical factors, drugs.
 Act during embryonic or foetal
development to procedure permanent
alteration of form or function.

40. Crieteria for proof of human teratogenecity
are :-
 Defect must be completely characterized,
 Agent must cross the placenta
 Exposure must occur during a critical developmental
period
 Biologically plausible association should be there.
 Epidemiological findings must be consistent.
 Suspected teratogen causes defect in animal

41. Mechanism of teratogenecity
A. Disruption of folic acid metabolism
Responsible for production of
methionine, reqd for methylation
reactions, production of proteins, lipid,
myelin.

42. B. Foetal genetic composition anomalies
can be caused by interaction of
environment & altered genes.
• MTHFR
• Epoxide hydrolase deficiency- leads to
accumulation of oxidative intermediates like
epoxides or arena oxides having carcinogenic &
teratogenic properties.
• Associated with use of phentoin,
carbamazepine, phenobarbitone.
• Transforming growth factor-1 alteration in this
gene causes increased incidence of cleft palate
with smoking.

43. C. Homeobox Genes:- Essential for
establishing positional identity of various
structures along body axis from Brachial
axis to coccyx.
• Retonic acid activates these genes
prematurely resulting in chaoitic
expression.
• Valproic acid alters the expression of Hox
genes.

44. D. Paternal Exposure
Several theories
• Induction of gene mutation or chromosomal
abnormality in sperm
• During intercourse a drug in seminal fluid could
directly contact foetus.
• Paternal germ cell exposure to drugs or
environmental agents may alter gene
expression. eg. mercury, lead solvents,
pesticides hydrocarbons.

45. • Before Day 31- Peri-implantation period all or
none effect conceptus either does not survive or
survives without anomalies.
• Day 31 to 71- embryonic period most cruicial
period.
 Period of organogensis.
 Effects of teratogen depends on
 Amount of drug reaching foetus.
 Gestational age at time of exposure.
 Duration of exposure.
• After Day71- (Foetal period)
Certain organs remain vulnerable brain
Foetal alcohol syndrome occurs late in pregnancy

47. • Depends on
a)Molecular weight
>1000 Da not cross placenta (Insulin,
Heparin)
c)Concentration of free drug
d)Lipid solubility
e)Uteroplacental Blood flow
f) Placental surface area
g)Placental metabolism

48. DESCRIPTION OF FDA RISK
CATEGORIES OF DRUGS
• A - adequate,well tolerated studies in
pregnant women have no increased risk of
foteal abnormalities
• B – animal studies show no harm to foetus
however there is no adequate and well
controled studies in women or animal
studies have shown adverse effects,but
adequate and well controled studies in
pregnant women have failed to
demonstrate risk to foetus.

49. • C - animal studies have shown adverse
effects and there is no adequate and well
controled studies in pregnant women.or no
animal studies have been conducted and
there are no adequate and well controled
studies in pregnant women.
• D –studies,adequate well controled or
observational ,in pregnant women have
demonstrated risk to the foetus .However
the benefits of therapy may outweigh the
potential risks.

50. • X. – studies adequate well controled or
observational in animals or pregnant
women have demonstrated positive
evidence of foetal abnormalities.The use
of product is contraindicated in women
who are or may become pregnant.

51. Categories of some commonly used
drugs are:-
A. Antihypertensive
Labetalol C
Methyldopa B
Nifedipine C
Amlodipine C
Hydralazine C
Atenolol D
ACE inhibitors C- 1st Trimester
D- 2,3, Trimester

52. B. Anti-Convulsants
Magso4 B
Phenytoin D
Phenobarbitone D
Valproic acid D
Diazepam D
C.Antiemetics
Doxylamine A
Metoclopramide B
Cyclizine/ Meclizine D

53. D.Antibiotics
• Ampicillin B
• Amoxycyline B
• Amoxy-clav B
• Penicillin B
• Cephalosporins B
• Aminoglycosides C
• Ciprofloxacin C
• Doxycycline D
• Levofloxacin C
• Nitrofurantoin B
• Metronidazole B

54. E. Analgesics
• Asprin C
• Ibubrofen B (D in 3rd trimester)
• Mefanamicacid C
• Paracetamol B
• Morphine C
• Pentazocine C
• Pethidine B

55. F. Anti coagulants
• Enoxaparin B
• Heparin C
• Warfarin D
G. Antidiabetics
• Insulin B
• Metformin B
• Gilbenclamide C

56. Category ‘X’ drugs are:-
• OCP’s
• Clomiphene
• Ergotamine
• Cocaine
• I-125
• Isotretioin
• Misoprostol
• Mifepristone
• Alcohol
• ACE-inhibitors
• Lithium
• Methotrexate
• Thalidomide

57. Teratogenic Drugs With Their Effects
• Alcohol-Foetal alocohol syndrome
 Dysmorphic facial features
a) Small palpebral fissures
b) Thin vermillion Borders
c) Smooth philtrum
 Prenatal/Postnatal growth Impairment
 CNS abnormalities.

58. • Phenytoin - Foetal Hydantoin Syndrome
• Valproate - Neural Tube defects, clefts, skeletal
abnormalities, developmental delay
• Mefipristone-Sirenomelia
• Misoprostol - Mobuis Syndrome
• Lithium - Ebstein’s anomaly, foetal DI,
Polyhydraminos, neonatal goitre.
• DES - Vaginal adenosis, cervical hoods, uterine
hypoplasia.

59. • Steroids- Foetal adrenal suppression, IUGR
• Chloramphenicol- Grey Baby Syndrome
• Tetracycline- Yellow discolouration of teeth, inhibition of
bone growth.
• Quinolones-arthopathy
• Nitrofuratoin-Haemolysis in Infants with G-6- PD
deficiency if used at term.
• Narcotics- Depression of CNS- apnoea, Bradycardia,
Hypothermia.
• Warfarin- nasal midface hypoplasia, stippled vertebral &
femoral epiphysis, Dandy walker syndrome, optic
atrophy, blindness, mental retardation.
• Isotretenoin- Micro or anotia hydrocephalus, outflow tract
abnormalities, thymic abnormalities.
• ACE- Inhibitors- Oligohydraminos, IUGR, Craniofacial
and limb abnormalities.

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