.

1

Drugs acting on UterusXYTOCICS & T COLYTICS

1

Dr. Shipra JainAssociate Professor,

Dept. of Pharmacology

OXYTOCICS

▪Oxytocics are the drugs that have the power to stimulate

the contraction of uterine muscles.

▪Also called Uterotonics

▪The introduction of oxytocic drugs for the treatment of

Post Partum Hemorrhage (PPH) has been regarded as

“one of the enduring achievements of modern science”

(Moir, 1964)

2

Oxytocics / Ecbolics/ Abortifacients /

Uterine stimulants

1. Posterior Pituitary hormones - Oxytocin, Carbetocin,

Vasopressin

2. Ergot alkaloids - Ergometrine/Ergonovine,

Methylergometrine

3. Prostaglandins - PGE2, PGF2α, Misoprostol

4. Miscellaneous – Quinine, Emetine, Alcohol, Ethacridine

3

Oxytocin

4

Oxytocin

Hormone of Posterior pituitary.

The other hormone is vasopressin

5

Oxytocin( Hormone of love, cuddle chemical )

▪A nonapeptide.

▪First synthesized by Vincent du Vigneaud in

1953, for which he was awarded Nobel Prize in

Chemistry in 1955.

6

.

2

Biosynthesis

▪Synthesized in cell bodies of supraoptic & paraventricular nucleus of hypothalumus as prohormone

▪Packaged into the secretory granules by oxytocin-neurophysin complex

▪Secreted from nerve endings in posterior pituitary gland (neurohypophysis)

▪Oxytocinergic nerves project to hypothalumus, brain stem and spinal chord

▪Luteal cells of ovary and fetal membranes synthesize oxytocin

7 8

Oxytocin secretion

▪Sensory stimuli from cervix, vagina and breast suckling

▪Oestrogen increases its secretion

▪Progesterone decreases its secretion

▪Ovarian polypeptide relaxin inhibits its release

▪Pain, haemorrhage and dehydration increases secretion

9

Physiological Role

UTERUS

▪ Increase in force and frequency of contractions

▪Full relaxation occurs in between the contractions at low doses

▪Very low level of motor activity in the first two trimesters

▪3rd trimester – spontaneous motor activity progressively increases and sharp rise initiates labor

▪Exogenous oxytocin can initiate rhythmic contractions

10

▪8 fold increase in uterine sensitivity in last 9 weeks and 30 fold increase in number of oxytocin receptors between early pregnancy and early labor – estrogen

▪ Increase in contraction is restricted to fundus and the body

▪Non pregnant uterus is resistant to its action

▪Oxytocin antagonist ATOSIBAN suppresses preterm labor

11

Oxytocin

Mechanism of action:

▪Acts through oxytocin receptors present in smooth

muscles of myometrium.

▪Stimulates the amniotic and decidual prostaglandin

production.

▪Mobilization of bound intracellular calcium from

sarcoplasmic reticulum to activate the contractile protein.

▪There is increase in frequency and force of uterine

contractions, similar to physiological uterine contractions

12

.

3

Physiological RoleBREAST

▪Role in milk ejection

▪Breast suckling and manipulation induces oxytocin release

▪Contractions of myo-epithelial cells surrounding alveolar cells in mammary gland forces milk into large collecting sinuses – milk ejection reflex

13 14

Oxytocin

Effects on other systems

CVS

Small doses cause vasodilatation producing

hypotension, reflex tachycardia and flushing.

Higher doses produce tachycardia and increased

cardiac output, marked constriction of umbilical

vessels, facilitating their closure at birth.

15

KIDNEYS

Higher doses (100 mIU) produce Anti-Diuretic Action

due to constriction of renal cortical vessels (in the

presence of estrogens)

Pulmonary oedema can get precipitated if large

amounts of IV fluids and oxytocin are infused together.

16

CNS

Appears to function as a peptide neurotransmitter in

hypothalamus and brainstem to regulate autonomic

neurons, can produce emotional behavior- maternal

bonding, adult bonding, role in autism (?).

17 18

.

4

Clinical uses of oxytocin

1. Induction of labor

a) To induce or augment labor in pregnant womenb) Premature rupture of membranesc) Intra uterine growth retardation (IUGR)d) Placental insufficiency – diabetes, preeclampsia or

eclampsia

Oxytocin is the drug of choice for induction of labor

19

Before induction, rule out:

1. Abnormal fetal position

2. Cephalo-pelvic disproportion (CPD)

3. Evidence of fetal distress

4. Placental abnormalities

5. Previous uterine surgery

20

Clinical uses of oxytocin – contd.

Oxytocin (Pitocin or Syntocinon)

▪ 10 IU is diluted in 1 L of 5% glucose or 0.9% saline – 10 milli IU/ml

▪ Start at low dose of 1-2ml/min and increase at 1 ml/min every 30-40 minutes

▪ Induces labor within 2 – 4 IU

▪ Higher doses are unsuccessful

▪ If labor starts– reduce the dose progressively

21

Oxytocin infusion Monitoring

▪Presence of Physician

▪Mother and fetus monitoring – fetal and maternal heart rate, maternal BP and strength of contractions

▪ If uterine hyper stimulation – discontinue infusion

▪Short half life – 6 to 12 minutes

▪Higher dose (more than 20 mu/min) may reduce water clearance – leading to water intoxication, coma and death

22

Clinical uses of oxytocin – contd.

2. Augmentation of labor

▪ In hypotonic contractions in dysfunctional labor (nulliparous) – administer as above

▪Normal progression of labor should never be tried to hasten, because over stimulation may cause:

a) Uterine rupture

b) Trauma to mother

c) Trauma to fetus

d) Compromised fetal oxygenation

e) Useful in prolonged latent phase of

f) Cervical dilation or arrest of dilation

23

Clinical uses of oxytocin – contd

3. Post partum haemorrhage, cesarean section:

▪5 IU IM or slow IV for immediate response

▪Especially useful in hypertensive women where ergometrine cannot be used

▪Also to maintain normal tone of uterine muscle

24

.

5

4. Breast engorgement:

▪Inefficient milk ejection reflex

▪Intranasal spray before suckling

Preparations:

▪Being a peptide not effective orally

▪Available as injections for IM and IV use – 0.5 ml, 1 ml and 5 ml etc.

25

Oxytocin

Indications for stopping the infusion

1. Abnormal uterine contractions

▪occurring too frequently ( less than every 2 minutes),

▪ lasting more than 60 seconds ( hyper stimulation)

▪ increased tonus in between the contraction

2. Evidence of fetal distress

3. Appearance of untoward maternal signs and symptoms

26

OxytocinDangers of Oxytocin

Maternal

1. Uterine hyper stimulation

2. Uterine rupture - high risk in grand multipara, malpresentation,

contracted pelvis, prior uterine scar and excessive dosages

3. Water intoxication - (high dosages i.e. 30 – 40 IU/min),

manifested by hyponatremia, confusion, convulsions, coma,

CHF and even death.

It can be prevented by strict I/O record, use of salt solutions, and

by avoiding high doses of oxytocin for a longer time.

27

4. Hypotension - it is seen with bolus IV injection especially

when the patient is hypovolemic or in patients with heart

disease. Occasionally may produce anginal pain.

5. Anti- diuresis - especially with higher dosages

Foetal

▪Foetal distress, foetal hypoxia or even foetal death may

occur due to reduced placental blood flow due to uterine

hyper stimulation.

28

Contraindications

1. Contracted pelvis

2. Malpresentation

3. Cephalopelvic disproportionation

4. Obstructed labour

5. History of LSCS

6. Hypovolemic states

7. Cardiac diseases

29

Carbetocin

▪A newer analogue of Oxytocin

▪Advantages are rapid onset and longer duration of action.

▪The half life is much longer (45 minutes) as compared to

oxytocin (4- 10 minutes).

▪Controls uterine atony in nearly 84 – 94 % patients.

▪Side effects - nausea, vomiting, diarrhea, headache,

hypertension and bronchospasm.

▪Should not be used in patients with CVS, pulmonary, hepatic

and renal diseases.

30

.

6

Vasopressin

▪Not commonly used as an oxytocic.

▪ It has more prominent oxytocic effect on non pregnant

uterus than oxytocin.

▪ Foetal hypoxia is a powerful stimulus for its release

31

Ergometrine & Methyl

ergometrine (Methergine)

32

Ergometrine & Methyl ergometrine(Methergine)

• Ergometrine, an alkaloid, isolated by Dudley and Moir,(1935)

from Ergot, derived from a fungus, Claviceps purpurea,

grows on rye, wheat, etc.

• Methergine is semi synthetic, derived from lysergic acid.

• Onset of action of ergometrine is quicker (45-60 secs) than

methergine (90 secs)

• Duration is similar (3hrs).

Ergot derivatives 33 34

Ergot derivatives

Pharmacological effects

▪Act directly on myometrium and cause tonic uterine contractions without any relaxation in between. Action is through the partial agonistic action on 5HT2 /α adr. receptors. Gravid uterus is more sensitive, esp. at term & early puerperium.

▪Should not be used for induction of labour/abortion, very effective for haemostasis, to stop bleeding from uterine sinuses following delivery/abortion.

35

▪GIT - Higher doses can increase peristalsis.

▪CVS effects - adrenergic agonists, cause

contractions of smooth muscles, both arterial and

venous vasoconstriction, increased PVR, CVP and

MAP.

36

.

7

Ergometrine - Uses

1. Postpartum haemorrhage: to prevent PPH

▪Used in dose of 0.2 to 0.3 mg IM immediately after delivery

of anterior shoulder

▪Continued for 4 - 7 days post partum

▪ If already PPH, use higher dose 0.5 mg IV

2. Caesarean section and instrumental delivery – to prevent

uterine atony

3. Subinvolution - 0.125 mg orally tds for 4 – 7 days

postpartum

37

Ergot derivatives

Adverse effects

▪ Nausea, vomiting , headache, pruritus, hypertension,

blurring of vision, dizziness, seizures, retinal detachment,

suppression of lactation and gangrene of toes after prolonged

use.

▪ Contraindicated in hypertensive patients and those with pre-

eclampsia

▪ Also contra-indicated during pregnancy or before the third

stage of labor.

38

Ergometrine

39

Why Oxytocin? Why not Ergometrine?

1. Short t ½-

2. Action can be easily terminated

3. Normal relaxation of uterus allowed-Good

fetal oxygenation

4. Lower segment not affected-descent free

5. More of physiological action

40

ERGOT OXYTOCIN

ERGOT VS OXYTOCIN

▪ Acts directly on

myometrium- tetanic, loss of

polarity

▪ Onset of action slow

▪ Duration of action is long

▪ ADR: increased BP &

gangrene

▪ CI: Eclampsia, Rh –ve, heart

disease

▪ Physiological contractions

,polarity is maintained.

▪ Onset is fast

▪ Duration of action is short

▪ ADR: rupture uterus &

hypotension

▪ CI: Grand multipara

41

Prostaglandins

42

.

8

Prostaglandins

▪PGE2 (Dinoprostone)→ Vaginal application → Induce II trimester

abortion, missed abortion, ripening of cervix in near term

▪ 15-Methyl-PGF2α (Carboprost)→ II trimester abortions

▪Misoprostol → with mifepristone for early abortion

43

Prostaglandins (PGs)

Pharmacological effects :

▪Contraction of smooth muscles of uterus, blood vessels, GIT

and bronchioles

Clinical effects:

▪Myometrial contraction

▪Softening and dilatation of cervix

▪ Inhibition of secretion of progesterone by corpus luteum.

▪Prior administration of mifepristone (anti-progestin drug)

sensitizes the uterus to the action of PGs.

44

Prostaglandins (PGs)

Pharmacokinetics:

▪Rapidly metabolized in lungs and liver.

▪About 90% inactivated in one circulation.

▪Given by intra vaginal, oral, rectal, intra muscular routes.

Prostin 15m (Carboprost) has longer duration of action.

45

Side effects:

▪Nausea, vomiting, diarrhea, fever, flushing and

bronchospasm.

▪CVS side effects: tachycardia, increased mean arterial

pressure and pulmonary artery pressure.

▪Use with caution in hypertension, diabetes, angina,

epilepsy and raised IOP.

▪Contraindicated in bronchial asthma, uterine scar, cardiac

renal or hepatic diseases.

46

Ethacridine

▪ It is an acridine compound.

▪ It is used intra-amniotically for second trimester

termination of pregnancy.

▪ It takes about 30 hours to effect the abortion.

▪Side effects are adverse GI effects, nausea and

vomiting etc.

47

Drug Regimen Side effects Contraindicatio

ns/Cautions

Oxytocin 5 IU in 500 ml

glucose/saline

(10mIU/ml infusion)

Vasodilatation,

Hypotension,

Tachycardia

Hypovolemia

Do not give undiluted

as an IV bolus

Methylergometrine 0.2-0.3 mg IM Vasoconstriction,

Hypertension,

Bradycardia

Hypertension,

Cardiac disease

15-methyl PGF2α

(Carboprost)

0.25 mg IM Bronchospasm,

Pulmonary edema

Cardiac, Renal,

Hepatic & Pulmonary

disorders

Misoprostol 200-400 µg

sublingual

800-100 µg per

rectal

Uterine scar

48

.

9

Uterine relaxants/Tocolytics

49

Tocolytics

▪Decrease uterine contractility/motility.

▪Used to delay/postpone labour, arrest threatened abortion & treatment of dysmenorrhea.

▪Suppression of labour

➢Allow the foetus to mature

➢Initiate glucocorticoid therapy for foetal lung maturation

➢Transfer the woman in labour to proper facilities

They are likely to succeed only if cervical dilatation is < 4 cm, taking up of the lower segment is minimal, effective in reducing the risk of delivery within 24 to 48 hours only.

50

Contraindications for tocolytics

1. More than 37 weeks gestation

2. Fetus >2500g

3. Fetus in distress

4. Cx dilation > 4 cm

5. Ruptured membrane

6. Toxemia

7. Cardiac diseases

8. PPH

51

Classification of Tocolytics

▪β2 adrenergic receptor agonists - Terbutaline,

Ritodrine, Isoxsuprine

▪Magnesium sulphate

▪Calcium channel blockers - Nifedipine & Nicardipine

▪Oxytocin receptor antagonist - Atosiban

▪Prostaglandin synthetase inhibitors - Indomethacin,

Aspirin, Ibuprofen, Sulindac

▪Nitric oxide donors - Nitroglycerine

▪Halothane

52

β 2 adrenergic receptor

agonists

53

β 2 adrenergic receptor agonists

▪ Terbutaline

▪Ritodrine

▪ Isoxsuprine

▪Mechanism of action - beta 2 receptor stimulation, causing smooth

muscle relaxation.

▪Used in uncomplicated premature labour between 24th to 33rd weeks

of gestation.

▪Continued for 12 hours after the contractions cease. Should not be

administered for more than 48 hours, as it can lead to increased risk

to the mother.

54

.

10

β 2 adrenergic receptor agonists

▪Side effects: Nausea, vomiting, tachycardia, palpitations,

headache, tremors, hypertension, pulmonary oedema,

CHF, arrhythmias, myocardial infarction, hyperglycemia,

hyperinsulinemia and hypokalemia.

Neonates may develop hypoglycemia and ileus.

55

Contraindications: 1. Diabetes mellitus

2. Cardiac disease

3. Patients on steroids

4. Patients on beta blockers

5. Patients on digitalis

6. Hyperthyroidism

7. Hypertension

56

Magnesium sulphate

57

Magnesium sulphate

▪ Acts by competitive inhibition of calcium ions at motor

endplates/cell membrane, reducing calcium influx.

▪Direct depressant action on uterine smooth muscle

▪ Infusion continued for 12 hours after cessation of contractions.

▪Magnesium sulphate by IV or inhalation route is also used in t/t

of acute severe asthma

58

Magnesium sulphate

Side effects:

▪ Nausea, vomiting, flushing, perspiration, headache,

drowsiness, respiratory depression, muscle weakness,

blurred vision and cardiac arrhythmias.

Foetal/ neonatal: Lethargy, hypotonia and respiratory

depression

Contraindications:

▪ Myasthenia gravis, heart blocks and renal disease.

59

Calcium Channel Blockers

60

.

11

Calcium Channel Blockers

Nifedipine & Nicardipine

▪Block the influx of calcium ions, thereby reducing the intra

cellular calcium, reduces the tone of myometrium & opposes

the contraction.

Side effects - Tachycardia, hypotension, headache, flushing,

nausea and peripheral oedema

Reduced placental perfusion may cause foetal hypoxia.

Contraindications - CHF, Hypotension, Aortic stenosis.

61

Oxytocin Receptor

antagonists

62

Oxytocin Receptor antagonists

Atosiban is a peptide analogue of oxytocin, acts as an

antagonist at oxytocin receptors.

▪ Side effects: nausea, vomiting, dyspnea, chest pain.

▪Contraindications: hepatic and renal disease.

63

Prostaglandin Sythesis inhibitors

Indomethacin, Aspirin, Ibuprofen and Sulindac

▪Maternal side effects: Headache, dizziness, nausea,

vomitting, diarrhea, haematemesis, and malena.

▪Foetal side effects: Oligohydraminos, premature closure of

Ductus arteriosus and necrotizing enterocolitis

▪Contraindications: Thrombocytopenia, bronchial asthma

and renal disease

64

OTHER AGENTS

▪Nitric Oxide Donors:

Nitroglycerine patches, not very reliable.

Side effects: tachycardia, hypertension and

methaemoglobinemia.

▪Halothane:

Very effective uterine relaxant has been used as

an anaesthetic for external/ internal versions &

manual removal of retained placenta

65

Oxytocics and Tocolytics

▪The most commonly administered drugs to the parturient and other obstetric patients

▪ The varied pharmacological actions of these drugs makes them of significant importance in obstetrics

66

.

12

Thank you67