Dr. Mrs. Minnu M. Panditrao Consultant Department 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)
Medications for Uterine Atony OXYTOCIN “The Champ”CytotecInexpensive (?) Effective
OXYTOCIN OXYTOCIN“The Champ” • The common medication used to achieve uterine contraction • First-line agent to prevent and treat PPH
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
OxytocinDangers 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 bronchiolesClinical 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
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).
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/ cautionsOxytocin 10 unit i.m. /or Vasodilatation Hypovolemia Do not 10units/hr infusion Hypotension, give undiluted as an i.v. Tachycardia bolusMethyl ergometrine 250µgm i.m./ slow i.v. Vasoconstriction Hypertension, cardiac repeat every 5-15 min. Hypertension, disease as needed (max 5 doses) bradycardia15 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
Tocolytics Tocolytics : Uterine Relaxants• Decrease uterine contractility/motility.• Used to delay/postpone labour, arrest threatened abortion & treatment of dysmenorrhea.• Suppression of labouro 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.
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
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!