Tocolytic Agents

CLASSIFICATION:
1. Calcium Channel
Blockers 4. Oxytocin Antagonists
 Nifedipine
 Atosiban
 Nicardipine
 Verapamil
5. Nitric Oxide Donors
 Glyceryl Trinitrate
2. Magnesium Sulphate

3. Betamimetics 6. COX-Inhibitor
 Terbutaline
 Ritodrine
 Isoxsuprine
 Calcium Channel Blockers
 First line tocolytic agents: Nifedipine

 Mechanism of Action:

 In response to membrane depolarization, voltage gated ca+

channels mediate the ca+ influx

 Ca+ binds to calmodulin and activates the enzyme Myosin

light chain kinase (MLCK) in the myometrial cells

 Leads to phsphorylation

 Initiates cross bridge cycling and myometrial contraction

 Nifedipine blocks these voltage gated L type Ca+ channel.

 Nifedipine cont
 Dosage:
 20-30mg stat PO
 If contraction persists
repeat after 30min
 Followed by 10-20mg
6hrly for 48-72hrs
 Max Dose: 160mg in
24hrs
 Half Life: 8hrs
 Monitoring: PR >120bpm,
dosage should be
withheld
 Nifedipine cont
 Caution:
 Nifedipine should never be used with MgSo4
 Because it enhances neuromuscular blocking effects and
interferes with pulmonary and cardiac function
 Contraindication:
 Cardiac disease
 Renal disease
 Tachycardia >120bpm
 BP<100/60mmHg

 Preparations:
 Depin, Nicardia Retard.
2. Magnesium sulphate
 Mechanism of Action:

 It acts by competitive inhibition of calcium ions at

the motor end plate at cell membrane, thus

reducing calcium influx
 Decreases Ach release and sensitivity at motor end

plate
 Direct depressant action on uterine muscle
 2. Magnesium sulphate cont
 Dosage:
 Loading dose of 4g IV(10-
20%solution) over 20-30min
 Followed by continuous infusion of
2g/hr

 Adverse drug reactions:

 Flushing
 Nausea
 Headache
 Blurring of vision
 Pulmonary edema
 Respiratory distress

 Contraindications:
 Myasthenia Gravis
 Renal and Heart diseases
 3.Oxytocin Antagonist- Atosiban
 Mechanism of Action:

 It downregulates oxytocin receptors

 Inhibits uterotonic action in a comptitive and dose dependant

manner, by inhibiting oxytocin mediated release of Inositol

Triphosphate from myometrial cell membrane
 Hence, reduced release of intracellular stored Ca+ from SR and

reduced influx
 It also supresses oxytocin mediated release of PGE and PGF from

decidua
 These actions lead to decreased myometrial contrctility
 Atosiban cont..
 Dose:
 6.75mg IV stat over 1min
 Followed by Infusion of 18mg/hr for
3hrs
 Then, 6mg/hr upto 45hrs
 Total duration not more than 48hrs
 Total dosage not more than 330mg
 Half life-18min

 Adverse drug reactions:

 Tachycardia, palpitations,
hypotension, chest pain, dyspnoea,
headache

 Preparations: Tractocile, Antocin

4.Betamimetics
 Terbutaline
 Ritodrine
 Isoxsuprine
 Mechanism of Action:
 These compounds acts on beta 2 receptors in the
myometrial cell membrane, cause increase in cGMP
and inhibit MLCK
 Hence, reduced interaction of actin and myosin causes
smooth muscle relaxation
 Beta 2 receptor stimulation causes smooth muscle
relaxation.
 Ritodrine:
 Route- IV/ oral
 50µg/min and increase every 20min
 Max dose-350µg/min

 Terbutaline:
 Route: oral/ SC / IV
 2.5-5mg every 4-6hrs for 48hrs PO
 5-10µg/min increased every 10-15min to max of 80µg/min
for 48hrs

 Isoxsuprine:
 10-20mg every 6hrs for 48hrs PO
 200-500mcg/min IV infusion till controlled is achieved
 Side effects of Betamimetics
 Headache
 Palpitations
 Tachycardia
 Hypotension
 Hyperinsulinemia
 Pulmonary edema
 IVH in neonates
 5.Prostaglandin Inhibitors
 Also known as COX-2 Inhibitors
 Mechanism Of Action:
 Prostaglandins softens the cervix by stimulating gap-junctions
and sensitizing the myometrium for oxytocin thereby leading
to progressive cervical dilatation
 COX-2 is an enzyme which converts arachidonic acid to
prostaglandin H2

 COX-2 Inhibitors
 Indomethacin
 Sulindac
 Ketorolac
 Indomethacin:
 Oral/ rectal
 50 to 100mg
 Followed by 25-50mg every 4-6hrs for max of 14days
 Max dose: 200mg/day
 Indicated in preterm associated with polyhydramnios

 Sulinac:
 200mg OD/BD for 24-48hrs orally

 Ketorolac:
 60mg IM
 Followed by 30mg IM every 6hrs for 24-48hrs
Side effects of COX inhibitors
 Premature closure of ductus arteriosus
 Oligohydramnios
 IUGR
 Neonatal pulmonary hypertension

 Contraindications:
 Peptic Ulcer
 Drug induced asthma
 Coagulation disorders
6.Nitric oxide donors
 Nitroglycerine

 Mechanism of Action

 Forms free radicle which activates enzyme GMP in

smooth muscle
 This causes dephosphorylation of MLCK(responsible for

smooth muscle contraction)

 Thus acts a smooth muscle relaxant
NO donors cont..
 Route:
 Sublingual / transdermal / IV
 Half life of transdermal – 3min

 Contraindications:
 Obstructive hypertrophic cardio myopathy
 Inferior myocardial infarction
 Raised ICP
 Cardiac Tamponade
Corticosteroids
 Corticosteroids
 These have no role in preterm labour

 They are used for benefit that accrues fetal lung

 Fetal lung are the last of fetal organs to mature

 In a mature fetal lung, the surfactants (surface-active

phospolipids) reduce the surface tension within the alveolar
spaces during labour
 This allows the alveoli to stay open for gas exchange

 Preterm labour may result in respiratory distress

syndrome due to decreased surfactant
 MOA of corticosteroids
 Corticosteroids stimulate the pulmonary beta receptors and

help in synthesis and release of surfactants into the

alveolar spaces

 This helps in fetal lung maturation so that incidence of

RDS, IVH, and NEC are minimized

 Indications
1. Used in patients with the period of gestation <34weeks in
active labour or with Threatened Preterm Labour

2. PPROM with POG<34weeks

3. IUGR (between 24 and 35+6weeks)

 Corticosteroids are beneficial when delivery is delayed beyond

48hrs of the first dose

 Benefit persists for 18days

 Dosage
Betamethasone
 12mg IM 24hrs apart for 2
doses
 Steroid of choice
 Salt in India:
 Betamethasone Phosphate
(short acting)
 Recommended salt
 Betamethasone acetate (long
acting) +Betamethasone
phosphate
 Costly
Dexamethasone
 6mg IM every 12hrs for
4 doses
 Salt in India:
 Dexamethasone sodium
phosphate
 Cheaper
 Less incidence of IVH
and shorter NICU stay
 Betamethasone  Dexamethasone
Repeated course:
 According to ACOG

 A single repeat course of antenatal steroids should be

considered in women who are <34weeks POG, who are
at risk of preterm delivery within 7days
 Whose prior course of antenatal steroids was
administered >14days previously
 Rescue course can be provided as early as 7days from
prior dose, if indicated by clinical scenario
 Risks of antenatal steroid use
1. PROM with evidence of infection, as infection can flare
up

2. Insulin dependant DM

3. Transient reduction of fetal breathing and body

movements

 Preparations:

 Betnasol, Dexasone, Dexona

Anticonvulants
 Magnesium Sulphate
 Mechanism of Action:

 Peripheral Action: Blocks the neuromuscular transmission

 Decreased Ach release from nerve endings

 Decreased motor end plate sensitivity to Ach

 Competitive inhibition of calcium channels, thereby reducing calcium influx

 Central action:

 Causes vasodilatation of cerebral blood vessels, thereby avoiding vasospasm

and tissue ischemia

 It also acts a tocolytic by direct depressant action on uterine muscle

Indication:
 For prevention of seizures inn severe pre-eclampsia
and eclampsia
 Drug of choice

 Contraindication:
 Myasthenia gravis
 Impaired renal function
 Dose of MgSo4
 Pritchard’s Regimen:
 Loading Dose:
 4g IV (20ml of 20%solution) over 3-4min
 Followed by 10g (20ml in 50%solution) deep IM, 5g in each
buttock

 Maintenance Dose:
 5g (10ml in 50% solution) deep IM on alternate buttock every
4hrs
 Maintenance dose to be continued till 24hrs after delivery or
last seizure, which ever is later
Zuspan / Sibai Regimen:

Loading Dose:

 4-6g IV slow over 15-20 min

Maintenance Dose:

 1-2g/hr IV infusion
 Monitoring
 Deep Tendon Reflexes should be present
 Disappearance of patellar reflex is the first sign of impending
toxicity.
 Patellar reflex disappear at 10mEq/L

 Respiratory >14/min. Breathing weakness at levels

>10mEq/L. Respiratory paralysis and arrest follows at
>12mEq/L

 Urine output >30mL/hr (as Mg is eliminated by kidneys)

 Pulse oximetry >96%

 Therapeutic level of S.Mg = 4-7mEq/L

Serum levels of MgSo4 and its effects

Effects Serum levels of Magnesium

Normal 0.8 – 1 mmol/L
Therapeutic levels 1.7 - 3.5 mmol/L
Prolonged PR interval and wide QRS 2.5 – 5 mmol/L
Loss of Tendon Reflexes 5 – 7.49 mmol/L
Respiratory Paralysis 7.5 – 11.9mmol/L
Cardiac arrest >12 mmol/L
Management of Toxicity

 Withhold MgSo4
administration
 Estimation of serum
Magnesium and creatinine
levels
 Inj Calcium gluconate 10ml
of 10% solution IV over
3min
 Fluid loading and forced
diuresis
 2.Diazepam - Anticonvulsant
 Mechanism of Action:
 Central muscle relaxant and anticonvulsant

 Doses:
 Initially 20-40mg IV, followed by infusion of 500ml of
dextrose with 40mg of Diazepam at 30drops/min
 In status epilepticus: 10-20mg slow IV, repeat after 1hr if
needed
 Side effects:
 Maternal Hypotension,
 Fetal respiratory depression, hypotonia
3.Phenytoin- Anticonvulsant
 Mechanism of Action:
 Centrally acting anticonvulsant

 Doses:
 In eclampsia:10mg /Kg IV at < 50mg/min followed by
5mg/Kg after 2hrs.

 In status epilepticus: 18mg /Kg slow IV at 50mg/min

- Maintenance dose of 100mg at an interval of 6-8hrs.
Side effects of Phenytoin
 Maternal:
 Hypotension, cardiac arrhythmias, phlebitis at injection site

 Fetal Hydantoin Syndrome when used in 1st trimester

 Oxytocics

These are the drugs that have the power

to excite contractions of uterine muscles
Oxytocics
1. Oxytocin

2. Ergot derivatives
1. Ergometrine
2. Methergine
3. Syntometrine

3. Prostaglandins
1. Misoprostol
2. Carboprost
 1.Oxytocin
 It is synthesized in the supra optic and para ventricular
nuclei of the hypothallamus.
 Stored and released from posterior pituitary
 Half Life: 3-4min
 Duration of action – 20min

 Mechanism of action
 It acts through receptor and voltage mediated Ca channels to
initiate myometrial contractions.
 It stimulates amniotic and decidual prostaglandin production.
 Preparations:
1. Synthetic Oxytocin: Syntocinon
( 1 Ampule contains 5 IU/ml )

2. Syntometrine: Syntocinon 5IU +

Ergometrine 0.5mg

3. Desamino Oxytocin: 50-100 times

more effective than oxytocin. Used
as buccal tab 50IU

4. Oxytocin nasal solution: Contains

40IU/ml
Indications
Therapeutic Diagnostic
 Pregnancy  Contraction stress
 Labour test
 Puerperium  Oxytocin sensitivity
 To minimise blood test
loss
 To control PPH
 Pregnancy
 Early
 To accelerate abortion- inevitable or missed and to expedite
expulsion of hydatidiform mole
 To stop bleeding following evacuation of uterus
 Used as an adjunct to induction of abortion along with other
abortifacient agents
 Late
 To induce labor
 To ripen cervix before induction
 Augmentation of labour
 Uterine inertia
 Labor:
 In active management of third stage of labor
 Side effects of Oxytocin
 Arrhythmias, Nausea, vomiting
 Uterine Hyper stimulation ( Over activity)
 Hypertonia- Excessive duration of uterine contraction
 Tachysystole- Increased frequency (>6cc in 10min)
 Uterine Rupture
 Water Intoxication ( due to antidiuretic action)
 Manifested by Hyponatremia, confusion, coma, convulsions,
CCF, death
 Prevented by- Strict I/O charting, By avoiding oxytocin for a
long time
 Hypotension
 Fetal Distress
 Monitoring during Indication of stopping
oxytocin infusion oxytocin

1. Rate of flow of 1. Abnormal uterine

infusion contraction
2. Uterine contractions- 2. Increased tonus in
number, duration between contraction
3. FHR monitoring every 3. Fetal distress
15min 4. Untoward maternal
4. Assessment of symptoms
progress of labour
 2.Ergot derivatives
 Ergometrine is an ergot derivative
 Methyl Ergometrine is a synthetic analog of ergometrine.

 Mechanism of Action:
 It acts on alpha adrenergic, dopaminergic and serotonin
receptors
 Uterine contractions are frequent that uterus goes into a state
of spasm without relaxation in between the contractions.
 Indications of Ergometrine
 To prevent PPH after
delivery of placenta
 In atonic PPH following
abortion

 Dose:
 For PPH, 0.25mg IM or IV
immediately after delivery of
placenta
 Can be repeated every
15min
 Max 5doses can be given
 Preparations:
 Methylergometrine maleate – 1ml inj contain 0.2mg/ml
 Emergen- 1ml inj contains 0.2mg /ml
 Utergin-0.125tab
 Methergine- 0.125mg tab

 Monitoring:
 PR, BP to be measured every 15min for 1hr
 Contraindications- ergometrine
1. Chronic and gestational hypertension
2. In Heart diseases
3. During pregnancy
4. Rh negative mothers
5. In multiple pregnancy, after delivery of first baby

 Adverse Effects:
 Headache, dizziness, chest pain, palpitation, dyspnoea
 High doses lead to peripheral vasoconstriction and gangrene
of toes
 3.Prostaglandins - Misoprostol
 Synthetic PGE1 analog
 Mechansim of Action:
 It binds to myometrial cells causing strong uterine
contractions leading to expulsion of contents
 It also causes ripening, softening, dilatation of cervix

 Can be given orally, rectally, vaginally

 Half life – 20-40min

 Preparations:
 Misoprost – 25, 100, 200, 600 mcg tablet
 Zitotec – 200mcg tablet
 Cytolog – 25, 100, 200 mcg tablet
Indications: Misoprostol
1. Medical Abortion, along with Mifepristone
2. Induction of abortion
3. Cervical Ripening agent prior to 1st trimester
surgical abortion
4. For prevention of PPH
 Prostaglandin- Carboprost
 It is a synthetic analog of PGF2 alpha
 Mechanism of Action:
 Acts directly on myometrium and stimulates uterine
contractions
 Because of its effect on smooth muscles of lungs, vasculature
, may cause Bronchospasm, Rise in BP and diarrhoea

 Indications:
 In PPH

 Contraindication:
 CVS, Reanl and hepatic disease
 Caution in asthamatic patients
 Preparation of Carboprost
 Prostadon, Deviprost,
Evacarb

 Dose:
 Inj carboprost 250mcg IM,
can be repeated after 15min
 Max- 8doses
 Can be given intramyometrial
during cesarean section
 Never given IV
Cervical Ripening Agents

Prostaglandins
Prostaglandins- Cervical ripening
 PGs facilitate cervical ripening by altering the extracellular

ground substance of cervix, and increasing the activity of

collagenase in cervix

 But it may also cause, Uterine Hyperstimulation, nausea,

vomiting.
 Dinoprostone (PGE2)
 Intracervical Gel:

 0.5mg in 2.5ml base in

prefilled syringe
 Can be repeated every 6hrs

 Max of 3doses in 24hrs

 Cerviprime gel, dinoripe gel

Dinoprostone (PGE2)
 Intravaginal Gel
 2mg dinoprostone gel
inserted into vagina
 Max-2 doses
 Prostin E2
Dinoprostone (PGE2)
 Intravaginal Tablet:
 Contains 3mg of
dioprostone
 Followed by another
tab after 6-8hrs
 Max dose- 6mg
 PROSTIN E2 vaginal
tablet
Dinoprostone (PGE2)
 Intravaginal insert
 Controlled release E2
vaginal tablet
 Contains 10mg of
dinoprostone,
released at rate of
0.3mg /hr for 24hrs
 Used as a single dose
 CERVIDIL
Antihypertensives
 Classification:
 Sympatholytics
 Methyldopa  Calcium channel
 Reserpine blockers
 Nifedipine
 Andrenergic receptor blockers  Nicardipine
 Labetalol
 Propranolol  ACE inhibitors
 Captopril
 Vasodilators  Lisinopril
 Hydralazine
 Nitroglycerine
 Sodium Nitroprusside
 Sympatholytics-Methyldopa
 Mechanism of Action:
 Central and peripheral antiadrenergic action

 Dose:
 250mg BD PO
 250-500mg IV infusion

 Side effects:
 Postural hypotension, excessive sedation, sodium retension
 Fetal-Intestinal Ileus
 Risk of Postpartum Depression
Labetalol
 Mechanism of Action:
 It blocks both alpha and beta receptors, which lower the
blood pressure
 It is a selective alpha 1 and non selective beta blocking agent

 Half life – oral – 6-8hrs

 Duration of action after 100mg is 8hrs
 Peak levels are achieved in 1-2hrs

 When given IV, onset of action- 2.5min

 Peak effect – in 15min
 Half life- 5.5hrs
Labetalol: Dosage
 Chronic Hypertension
and preeclampsia
 Orally -100mg TID
 Can be increased to
2400mg daily

 IV infusion- 20-40mg
every 10-15min
 Max upto 220mg
 Side effects- Labetalol
 Maternal:
 Fatigue
 Orthostatic hypotension

 Fetal:
 Reduced frequency of FHR and accelerations
 Neonatal hypoglycaemia
3.Calcium Channel Blockers
 Nifedipine: Dihydropyridine
 Mechanism of Action:
 Direct arteriolar vasodilatation by inhibition of slow inward
calcium channels in vascular smooth muscles

 Dose:
 Orally 5-10mg TID
 Max – 60-120 mg/day

 Side effects:
 Flushing, hypotension, headache, tachycardia, inhibition of
Labor
4.Vasodilators
 Hydralazine:
 Mechanism of action:
 Acts by peripheral vasodilatation, relaxes the arterial smooth
muscle

 Dose:
 Orally: 100mg/day in four divided doses
 IV- 5-10mg every 20min (max-20mg)

 Side Effects:
 Hypotension, headache, lupus like syndrome
 Late decelerations
4.Vasodilators
 Nitroglycerine:
 Refers mainly the venous smooth muscle

 Dose:
 IV infusion 0.25-8mcg/kg/min

 Side effects:
 Mainly fetal toxicity due to metabolites
5.ACE Inhibitors
 Captopril, Lisinopril
 Mechanism of action:
 Inhibits formation of angiotensinII from angiotensin I

 Dose:
 Oral- 6,25mg BID

 Side effects:
 Hypotension, headache, arrhythmias
 Fetal: oligohydramnios, IUGR, Fetal renal tubular dysgenesis,
pulmonary hypoplasia
Iron Preparations

Oral therapy
Parenteral therapy
 Oral Therapy
 Iron is best absorbed in ferrous form
 Preparations:
 Ferrous gluconate
 Ferrous Fumarate
 Ferrous Ascorbate
 Ferrous succinate

 Livogen XT tablet contains Ferrous Ascorbate equivalent to

 Elemental iron of 100mg
 Folic acid of 1500mcg
 Zinc Sulphate
Prophylaxis:
 Daily administration of 100mg of Ferrous Ascorbate
along with 1mg Folic acid is effective

 Therapeutic:
 The initial dose is one tablet TID 30min before meals
 The treatment should be continued till blood picture
becomes normal
 Thereafter maintenance dose of one tablet daily.
 Drawbacks of Oral iron
 Intolerance
 Nausea, vomiting, epigastric pain, constipation or diarrhoea
 Unpredictable absorption rate

 Response of Therapy evidenced by:

 Sense of well being
 Increased appetite
 Improved outlook of patient
 Rise in Hb
 Haematocrit coming to normal

 Contraindications:
 Intolerance to oral iron
 Severe anaemia in advanced pregnancy
Iron Sucrose
Ferric Carboxymaltose
 Indications for Parentral Iron Therapy

 Intolerance or non compliance to oral iron therapy

 Late second or third trimester with moderate to severe

anaemia
 Malabsorption

 Bleeding diastesis when haemorrhage is likely to

continue
Contraindications for Parentral Iron
Therapy
 Lack of facilities for resuscitation

 Known history of anaphylaxis or reactions

 Gestation of <12 weeks

 Known state of iron overload

 Anaemia not due to Iron deficiency

Calculation of Haemoglobin Deficit
 Ganzoni formula

 Total body iron deficit/cumulative iron dose (mg) =

body weight* (kg) x (target Hb – actual Hb in g/L) x

0.24 + iron depot (500 mg)
 Iron Sucrose
 Pharmacology:
 Pharmacokinetics: Iron sucrose is dissociated by the
reticuloendothelial system into iron and sucrose
 Pharmacodynamics: Half life of 6 hours. serum clearance
of iron is more rapid in iron deficient patients as compared
to healthy individuals.
 Distribution: Mainly in blood.

Liver, spleen and bone marrow

 Metabolism and Elimination: Sucrose component mainly
by urinary excretion
 Side Effects:
 Nausea,
 vomiting,
 diarrhoea,
 headache,
 muscle cramps,
 Hypotension

 Availibility:
 Each mL contains 20 mg elemental iron as iron sucrose in water
 Available as vials of 5ml (100mg) and 10ml (200mg)
Administartion
 100mg over 5 minutes thrice a week

 Maximum 200mg per sitting

 Rate of administration: Not more than 20mg/min

 100mg-200mg to be diluted in 100ml NS and to be

given in 15-20 minutes

Ferric Carboxy Maltose
 Mechanism Of Mechanism:
 Macrophage in RES remove ferric carboxy maltose from the
circulating plasma and release iron from the iron-
carbohydrate complex
 Transferrin binds to transferrin receptors on erythroblasts in
the bone marrow
 The transferrin receptor/ Iron-transferrin complex is
internalized to provide iron for hemoglobin synthesis and
maturation of the red cell

 Availability:
 Available as 500mg FCM in 10ml vial
Adverse Effects:
 Most adverse events noticed with FCM are mild to
moderate in intensity

 RASH (Pruritus/ urticaria are uncommon ) and local

skin reactions (generally after first dose , not recur )

 Transient and asymptomatic decrease in serum

phosphorous levels
Administartion of FCM
 Can be given IV as drip infusion (PREFERRED) (In 250ml
NS) or bolus injection

 DRIP INFUSION: maximum single dose of 1000mg of iron,

not exceeding 15mg/kg or calculated cumulative dose , over a
minimum infusion time upto 15 min

 Infusions should not be administered more than once per
week

 BOLUS INJECTION : Maximum single dose of 200mg iron,

upto 3 times per week
FCM over Iron Sucrose
Advantages
 Larger dose administration
 Early rise in Haemoglobin

Disadvantages
 Comparatively expensive
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