Prof Minnu Panditrao discusses

1. XYTOCICS & T COLYTICS

2. Dr. Mrs. Minnu M. Panditrao
Consultant
Department of Anesthesiology
&
Intensive Care
Public Hospital Authority’s
Rand Memorial Hospital
Freeport, Bahamas

3. OXYTOCICS
• Oxytocics are the drugs of varying chemical
nature 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)

4. OXYTOCICS
Posterior Pituitary hormones
Oxytocin
Carbetocin
Vasopressin
Ergot alkaloids
Ergometrine/Ergonovie
Methylergometrine
Prostaglandins
PGE2
PGF2α
Misoprostol
Miscellaneous
Quinine
Emetine
Alcohol
Ethacridine

5. Medications for Uterine Atony
OXYTOCIN
“The Champ”
Cytotec
Inexpensive (?) Effective

6. OXYTOCIN
OXYTOCIN
“The Champ”
• The common medication
used to achieve uterine
contraction
• First-line agent to
prevent and treat PPH

7. Oxytocin
( Hormone of love, cuddle chemical )
• A nonapeptide.
• Synthesized in Supraoptic and Paraventricular nuclei of
Hypothalamus
• Transported through nerve axons to posterior pituitary,
where it is stored and eventually released.
• Sensory stimuli arising from cervix, vagina and breasts,
emotional stimuli and nonspecific stimuli like pain, and
apprehension, can lead to secretion/release of oxytocin
from posterior pituitary.
• First synthesized by Vincent Du Vigneaud in 1953, for
which he was awarded Nobel Prize in Chemistry in 1955.

8. 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

9. Oxytocin
oxytocin receptors
• The concentration of oxytocin receptors in myometrium is
lower in non pregnant state and early pregnancy, but it
increases markedly as the pregnancy advances (becomes
nearly 100 folds at 32 weeks and 300 folds at the onset of
labour).
• Also the sensitivity of these receptors to oxytocin is lower
in first and second trimester, but increases tremendously in
late pregnancy and labour, due to modulation of the
oxytocin receptors by estrogen/prostaglandins, making the
uterus highly sensitive to oxytocin ( small doses ) during
labour.
• The action of oxytocin on myometrium is independent of
innervations.

10. Oxytocin
• Contraction of myoepithelial cells surrounding the
alveoli of mammary glands resulting in expulsion of
milk from alveoli and ducts into the milk sinusoids
and cisterns; ‘milk letdown / milk ejection reflex’.
• This reflex (naturally) is initiated by the stimulus of
suckling, which leads to the release of oxytocin.
• It has been (mis)used in milch cattle to facilitate
milking.

11. Oxytocin
Effects on other systems
• CVS: Small doses cause vasodilatation ,producing diastolic
hypotension, reflex tachycardia and flushing.
Higher doses produce tachycardia and increased cardiac output,
marked constriction of umbilical vessels, facilitating their
closure, at birth.
• Kidneys: Higher doses (100 m.I.U.) produce Anti-Diuretic Action
leading to decreased urine output, due to constriction of renal
cortical vessels (in the presence of oestrogens). Pulmonary
oedema can get precipitated if large amounts of i.v. fluids and
oxytocin are infused together.
• 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 (?).

12. Oxytocin
Duration of action: approximately 20 minutes. In non pregnant
women, half life (t1/2) is 10-15 minutes and the removal from
circulation is due mainly to kidneys and liver, but t1/2 in
pregnant women is only 3 minutes, because of presence of
enzyme oxytocinase in placenta, uterine tissue and plasma
which inactivates it.
• Given orally it is ineffective as it is inactivated rapidly in the
Gastro-intestinal tract by enzyme, trypsin, needs to be
administered by parenteral, nasal or buccal routes.
Unitage and Preparation: 1 international unit (i.u.) of oxytocin
is equivalent to 2 microgram of pure hormone.
• Commercially available preparation is produced synthetically.
Oxytocin injections are available in concentration of 5 i.u. / ml
(Syntocinon) , 5 i.u/ 0.5ml. (pitocin) or 2 i.u./ 2ml. (oxytocin).
• Oxytocin nasal spray contains 40 units/ ml.

13. Oxytocin
Indications
• Induction of labour: Given as a slow i.v. infusion
(5 i.u. in 500 ml of glucose or normal saline solution ).
Started at 0.2 ml/ min and gradually increased, once optimal
response ( 3 Conts. in 10 minutes, each lasting 45 seconds),
continued at that rate Aim is to initiate and maintain uterine
contractions not only till delivery but also 30 to 60 minutes
beyond that. Usual rate is 16 to 32 m.I.U. / minute.
• For uterine inertia: Admn. Same as above.
• In active management of third stage of labor:
(to reduce the blood loss) 5 I.U., i.m. or slow i.v. for an
immediate response where ergometirne is contraindicated.

14. Oxytocin
Indications
• For prevention/control of post partum haemorrhage (PPH);
Oxytocin is administered by i.m. (2-5 i.u.) inj./ i. v. infusion (10
i.u./500ml) after the delivery of placenta, to produce a firm
contraction of uterus and thus prevent PPH.
• To accelerate abortion, used along with prostaglandins,
especially in second trimester abortion
• To stop bleeding following evacuation of uterus.
• In cases of breast engorgement to promote milk ejection. It is
given intranasally, 40 i.u., 2-5 minutes before breast feeding.
• For contraction stress test, oxytocin sensitivity test ; not
commonly done these days.

15. Oxytocin
Indications for stopping the infusion
 Abnormal uterine contractions
• occurring too frequently ( less than every 2 minutes),
• lasting more than 60 seconds ( hyper stimulation)
• and increased tonus in between the contraction
 Evidence of Foetal distress
 Appearance of untoward maternal signs and symptoms

16. Oxytocin
Dangers of Oxytocin
Maternal
• Uterine hyper stimulation; increased frequency and duration of uterine
contractions & / or increased tonus, is often associated with abnormal
foetal heart rate pattern
• Urine rupture; high risk in grand multipara, malpresentation, contracted
pelvis, prior uterine scar and excessive dosages.
• Water intoxication; due to its ADH like antidiuretic action, when used in
high dosages i.e. 30 – 40 i.u. / min., manifested by hyponatremia, confusion,
convulsions, coma, CHF and even death. Can be prevented by strict intake
output record, use of salt solutions, and by avoiding high doses oxytocin for
a longer time.
• Hypotension; it is seen with bolus i.v. injection especially when the patient
is hypovolemic or in patients with heart disease. Occasionally may produce
anginal pain.
• 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.

17. Oxytocin
Drug Interactions and anaesthetic implications:
• Drugs such as Halothane, Propranolol or Quinidine can
antagonize uterotonic action of oxytocin.
• Inhaled Anaesthetics may augment hypertensive effects of
large doses of oxytocin.
• Concomitant administration of sympathomimetics,
phenylephrine or ephedrine is not associated with any
incidence of hypertension as was believed earlier
• Careful assessment of fluid and electrolyte status is necessary
in patients who have received prolonged oxytocin induction.
• I.V. Bolus of oxytocin may be avoided until the placenta is
delivered, to avoid the risk of retained placenta.

18. Carbetocin
• A newer analogue of Oxytocin, still in trial phase.
• Advantages quoted are, much rapid onset and longer
duration of action.
• Recommended dose is, 0.25 mg every 15 minutes given
upto the maximum dose of 2 mg.
• The half life is much longer (45 minutes) as compared to
that of oxytocin (4- 10 minutes).
• Reported to be successful in controlling uterine atony in
nearly 84 – 94 % patients.
• Side effects include nausea, vomiting, diarrhea, headache,
hypertension and bronchospasm. Should not be used in
patients with CVS, pulmonary, hepatic and renal diseases.

19. 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 and
foetal distress can lead to high umbilical cord blood levels
of vasopressin.
• If this vasopressin passes from foetal to maternal
circulation, significant oxytocic potency can be added to the
maternal oxytocin.

20. Prostaglandins (PGs)
• C 20 fatty acid compounds containing cyclopentane ring,
derivatives of Prostanoic acid
• Were first isolated from human seminal fluid with probable
origin from prostate gland, hence named Prostaglandins.
• Act as local hormones.
• PGE2, PGF2α and recently PGE1, found useful for the
induction of abortion, induction/augmentation of labor and
control of PPH.

21. Prostaglandins (PGs)
The pharmacological effects are:
• 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.
• Response of the uterus to PGs is maximum in the middle
trimester (13th to 20th weeks).
• Prior administration of mifepristone (anti-progestin drug)
sensitizes the uterus to the action of PGs.

22. Prostaglandins (PGs)
Pharmacokinetics:
• Rapidly metabolized in lungs and liver.
• About 90% inactivated in one circulation.
• Given by intra vaginal, oral, rectal, intra muscular or intra
myometrial routes. Prostin 15m (carboprost) has longer
duration of action.
Side effects:
• Nausea, vomiting, diarrhea, fever, flushing and
bronchospasm. CVS side effects: tachycardia, increased
mean arterial pressure and pulmonary artery pressure.
• Use caution in hypertension, diabetes, angina epilepsy and
raised intra-ocular pressure.
• Contraindicated in bronchial asthma, uterine scar, cardiac
renal or hepatic diseases.

23. Prostaglandins (PGs)
Anaesthetic implications:
• Because of their action on the bronchiolar tone
and pulmonary vasculature, they can lead to
V/ Q mismatch and arterial desaturation

24. Ergot derivatives
Ergometrine & Methyl ergometrine(Methergine)
• Ergometrine, an alkaloid, isolated by Dudley and Moir,(1935)
from Ergot, derived from a fungus, Claviseps purpurea,
growing on rye,wheat etc.
• Methergine is semi synthetic, derived from lysergic acid. Onset
of ergometrine is quicker (45-60 secs) than methergine (90 secs)
Duration is similar (3hrs).

25. 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 peurperium.
• Should not be used for induction of labour/abortion,
very effective for haemostasis, to stop bleeding from
uterine sinuses following delivery/abortion.
• Higher doses can increase peristalsis.
• CVS effects: adrenergic agonists, cause contractions of
smooth muscles, both arterial and venous vasoconstriction,
increased PVR, CVP and MAP.

26. Ergot derivatives
• Partly metabolized in liver and excreted in urine.
• Can be given by oral, intramuscular and i.v.
routes.
Indications
Used for prevention/control of PPH (delivery/LSCS)
bleeding after abortion
& to ensure normal involution of uterus.

27. 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.

28. Ergot derivatives
Anaesthetic implications
• Should be used with caution in patients with
hypertensive disorders or in patients who have
received sympathomimetics like ephedrine, as
acute hypertensive crisis may result.
• Due to severe vasoconstriction, risk of
myocardial infarction is very high following
intravenous administration.
• In cardiac patients, the increased venous tone can
precipitate pulmonary oedema

29. Ethacridine
• It’s 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.

30. Pharmacology of oxytocic agents
Drug Regimen Side-effects Contra-indications/
cautions
Oxytocin 10 unit i.m. /or Vasodilatation Hypovolemia Do not
10units/hr infusion Hypotension, give undiluted as an i.v.
Tachycardia bolus
Methyl ergometrine 250µgm i.m./ slow i.v. Vasoconstriction Hypertension, cardiac
repeat every 5-15 min. Hypertension, disease
as needed (max 5 doses) bradycardia
15 methyl PGF2α 250 µgm i.m./intra Bronchospasm, Cardiac, renal, hepatic
(Carboprost) myometrial Repeat pulmonary and pulmonary disorders
every 15 min. as needed edema,
(max 8 doses)
Misoprostol 200- 400 µgm Uterine scar
sublingual, 800- 1000
µgm per rectally

31. Tocolytics
Tocolytics : Uterine Relaxants
• Decrease uterine contractility/motility.
• Used to delay/postpone labour, arrest threatened abortion
& treatment of dysmenorrhea.
• Suppression of labour
o Allow the foetus to mature
o Initiate glucocorticoid therapy for foetal lung maturation
o Transfer the woman in labour to proper facilities
They are likely to succeed only if cervical dilatation is < 4 cms,
taking up of the lower segment is minimal,
effective in reducing the risk of delivery within 24 to 48 hours
only.

32. Tocolytics
Contraindications:
• Rupture of membranes
• Placenta previa, abruption placenta
• Severe toxemia of pregnancy
• Intra uterine infection
• Intra uterine death of the foetus.

33. Classification of Tocolytics
• β2 adrenergic receptor agonists
• Terbutaline, Retodrine, Isoxsuprine
• Magnesium Sulphate
• Calcium channel blockers
• Nifedipine & Nicardipine
• Oxytocin receptor antagonist
• Atosiban
• Prostaglandin synthetase inhibitors
• Indomethacin, aspirin, ibuprofen, sulindac
• Nitric oxide donors
• Nitroglycerine
• Halothane

34. β 2 adrenergic receptor agonists
• Terbutaline
• Retodrine
• Isoxsuprine
• Mechanism of action is through beta 2 receptor stimulation,
causing smooth muscle relaxation.
• Used in uncomplicated premature labour between 24th to
33rd weeks of gestation.
• Given as i.v. infusions. Terbutaline by i.v., oral or subcut.
Isoxsuprin by oral or i.m.
• 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.

35. 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.
• Contraindications: Pregnant diabetics or pregnancy
induced diabetic patients, cardiac disease, patients
on steroids, beta blockers, digitalis, severe anaemia,
hyperthyroidism and hypertension.

36. β 2 adrenergic receptor agonists
Anaesthetic implications:
• Patients who are being administered these
drugs, require very careful monitoring of
intake/output, minimal fluid volume loading to
be done to prevent precipitation of pulmonary
oedema
• electrolyte and CVP monitoring as there is
increased risk of tachyarrhythmias & cardiac
failure.

37. Magnesium sulphate
• Acts by competitive inhibition of calcium ions at
motor endplates/cell membrane, reducing calcium
influx.
• Direct depressant action on uterine smooth muscle
• Given by i.v. infusion, loading dose: 4-6 gm. i.v. over
15 to 20 minutes, titrated infusion: 1-2 gm/ hour
• Infusion continued for 12 hours after cessation of
contractions.

38. 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.

39. Magnesium sulphate
Anaesthetic implications:
• Delayed post-operative recovery due to CNS/
respiratory depression
• Prolongation of action of non depolarizing
NMBDs and their difficult reversal
• Risk of arrhythmias

40. 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.
• Nifedipine, which has prominent smooth muscle relaxant
action, is effective, if used early enough.
Oral nifedipine 10 mg every 20-30 minutes, till uterine
contractions subside, followed by 10 mg every 6 hourly.
• Tachycardia, hypotension, headache, flushing, nausea and
peripheral oedema are some of the important side effects.
• Reduced placental perfusion may cause foetal hypoxia.

41. Calcium Channel Blockers
Side effects.
• Tachycardia, hypotension, headache, flushing, nausea
and peripheral oedema are some of the important
• Reduced placental perfusion may cause foetal hypoxia.
Contraindications
• CHF, Hypotension, Aortic stenosis.
• Anaesthetic implications: There may be marked
hypotension, especially if the patient is volume depleted,
dehydrated or in CHF. So judicious intra and post
operative intake and output and vitals monitoring is
necessary.

42. Oxytocin Receptor antagonists
Atosiban is a peptide analogue of oxytocin, acts as an
antagonist at oxytocin receptors.
• Has been licensed in UK for use in pre-term labour
• Administered i. v., 6.75 mg as a bolus over 1 minute
followed by infusion at 18 mg/hour for 3 hours &
6mg/ hour for up to 45 hours.
Total duration of treatment not to exceed 48 hours and
total dose not to exceed 330 mg.
• Side effects: nausea, vomiting, dyspnoea, chest pain.
• Contraindication: hepatic and renal disease.
Anaesthetic implications: Very expensive

43. Prostaglandin Synthetase inhibitors
Indomethacin, aspirin, ibuprofen and sulindac
• Maternal side effects: Headache, dizziness, nausea,
vomitting, diarrhea, haematemesis, and malena.
• Foetal side effects: Oligohydramnios, premature
closure of Ductus arteriosus and necrotizing
enterocolitits
• Contraindications: Thrombocytopenia, bronchial
asthma and renal disease
• Anaesthetic implications: Can lead to platetlet
dysfunction and increased bleeding

44. 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

45. Conclusion
Oxytocics and Tocolytics
• The most commonly administered drugs to the
parturient and other obstetric patients
• The varied pharmacological actions of these drugs
and their possible interactions with anaesthetic
agents, make them of significant importance from
anaesthesiologist’s point of view!