XYTOCICS & T COLYTICS

Dr. Mrs. Minnu M. Panditrao

ConsultantDepartment of Anesthesiology

& Intensive Care

Public Hospital Authority’s Rand Memorial Hospital

Freeport, Bahamas

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)

OXYTOCICSPosterior Pituitary hormones Oxytocin Carbetocin Vasopressin

Ergot alkaloids Ergometrine/ErgonovieMethylergometrine

Prostaglandins PGE2

PGF2α Misoprostol

MiscellaneousQuinine EmetineAlcoholEthacridine

METHERGINE

“Speedy”OXYTOCIN

“The Champ”

CytotecInexpensive (?) Effective

Medications for Uterine Atony

OXYTOCIN

• The common medication used to achieve uterine contraction

• First-line agent to prevent and treat PPH

OXYTOCIN“The Champ”

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.

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

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.

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.

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 (?).

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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

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).

Ergot derivatives

METHERG

INE

“Speed

y”

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.

Ergot derivatives

• Partly metabolized in liver and excreted in urine.• Can be given by oral, intramuscular and i.v.

routes.

IndicationsUsed for prevention/control of PPH (delivery/LSCS)bleeding after abortion& to ensure normal involution of uterus.

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.

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

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.

Pharmacology of oxytocic agentsDrug Regimen Side-effects Contra-indications/

cautions

Oxytocin 10 unit i.m. /or 10units/hr infusion

Vasodilatation Hypotension, Tachycardia

Hypovolemia Do not give undiluted as an i.v. bolus

Methyl ergometrine 250µgm i.m./ slow i.v. repeat every 5-15 min. as needed (max 5 doses)

Vasoconstriction Hypertension, bradycardia

Hypertension, cardiac disease

15 methyl PGF2α (Carboprost)

250 µgm i.m./intra myometrial Repeat every 15 min. as needed (max 8 doses)

Bronchospasm, pulmonary edema,

Cardiac, renal, hepatic and pulmonary disorders

Misoprostol 200- 400 µgm sublingual, 800- 1000 µgm per rectally

Uterine scar

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 matureo Initiate glucocorticoid therapy for foetal lung maturationo 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.

Tocolytics

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

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

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.

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.

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.

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.

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.

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

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.

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.

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

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

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

ConclusionOxytocics 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!

THANK

YOU!