4. Biosynthesis - Physiology
Synthesized as cell bodies of
praventricular nucleus and
supraoptic nucleus of
hypothalumus as prohormone
Precursor broken down to
active hormone and
neurophysin complex
Packaged into the secretor
granules by oxytocin-
neurophysin complex
Secreted from nerve endings
in posterior pituitary gland
(neurohypophysis)
6. Oxytocin secretion
Sensory stimuli from cervix, vagina and
breast suckling
Expulsive phase is triggered by sustained
distension of uterine cervix and vagina
Oestrogen increases its secretion
Ovarian polypeptide relaxin inhibits its
release
ADH: Pain, haemorrhage and dehydration
increases secretion
7. Actions of Oxytocin –
Uterus
Increase in force and frequency of contractions
Low doses: Full relaxation occurs between the contractions, but
high doses – basal tone increases
Mechanism - High electrical activity of myometrium cell
membrane – burst of discharges
Very low level of motor activity in the first two trimesters - 3rd
trimester onwards – spontaneous motor activity progressively
increases and sharp rise initiates labor
Uterine sensitivity - 8 fold increase in in last 9 weeks and 30 fold increase
in number of oxytocin receptors between early pregnancy and early labour –
estrogen
No. of receptors and myometrium sensitivity increases late in pregnancy –
labour initiation and postpartum involution
Increase in contraction is restricted to fundus and the body
Non pregnant uterus are resistant to its action
Oxytocin antagonist ATOSIBAN suppresses preterm labor
8. … Actions – contd.
Breast
Role in milk ejection
Breast suckling and manipulation induces oxytocin release
Mechanism: Contractions of myoepithelial surrounding alveolar
channels in mammary gland forces milk into large collecting
sinuses – milk ejection reflex
9. Oxytocin – other effects
CVS
No effect in low dose but at higher doses
fall in BP, reflex tachycardia and flushing
Kidney
ADH like effect in high doses – decreased
urine output, pulmonary oedema etc.
10. Oxytocin – Mechanism of
action (OXTR)
Specific G protein-coupled membrane receptors
related to Vasopressin (V1 and V2) receptors
Depolarization of muscle fibres and Ca++ influx
Human myometrium – receptors coupled to Gq
activation leads to generation of IP3 – release of Ca+
+ ions
Increase in local prostaglandin concentration –
uterine contraction
Kinetics:
Being a peptide not effective orally
Short half life – 3 to 6 minutes
Available as injections for IM and IV use – 0.5 ml, 1 ml and 5
ml etc.
11. Clinical uses of
oxytocin
1. Induction of labour To induce or augment labor in
pregnant women
Indications:
Premature rupture of membranes
Pre and post maturity
Intra uterine growth retardation (IUGR)
Placental insufficiency – diabetes, preeclampsia or eclampsia
Before induction, rule out:
Abnormal fetal position
Cephalopelvic disproportion
Evidence of fetal distress
Placental abnormalities
Previous uterine surgery
Oxytocin is the drug of choice for induction of labor
12. Clinical uses of oxytocin (Pitocin
or syntocinon) – contd.
5 IU is diluted in 500 ml of
5% glucose or 0.9% saline
– 5 milli IU/ml
Start at low dose
progressively increase
0.2 – 2 ml/min
Induces labour within 2 – 4
IU
If no induction after giving
upto 30 – 40 mU/min –
higher doses are
unsuccessful
If labour – reduce the dose
progressively
Unitage: 1 IU of Oxytocin
= 2 mcg of pure hormone
13. 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
Higher dose (more than 20 mu/min) may
reduce water clearance – leading to water
intoxication, coma and death
14. Clinical uses of oxytocin – contd.
2. Augmentation of labour
In hypotonic contractions in dysfunctional labour
(nulliparous) – administer as above
But be careful, normal progression of labor should
never be tried to hasten, because over stimulation
may cause
Uterine rupture
Trauma of mother
Trauma of fetus
Compromised fetal oxygenation
Useful in prolong latent phase of cervical dilation or arrest of
dilation
15. 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
4. Breast engorgement:
Inefficient milk ejection reflex
Intranasal spray before suckling
16. Ergometrine
Natural ergot alkaloid also
called ergonovine and
methylergometrine is its
derivative - an amine
alkaloid
Recall ergots: amino acid,
amine and semisynthetic
derivatives
Amino acid alkaloids –
ergotamine, ergotoxin etc.
Amines – ergometrine
Semisynthetic derivatives -
DHE
Claviceps purpurea
17. Pharmacological Actions -
ergometrine
Uterus:
Increases force, frequency and duration of contractions
At low dose contraction is phasic in nature with normal relaxation in
between
But moderate increase in dose – sustained contraction occurs
More sensitive - Gravid uterus and at puerperium
Contractions involve lower segment also
CVS:
Weaker vasoconstrictors than their amino acid counterparts - less chance of
developing endothelial damage
No significant rise in BP
CNS:
Interacts partially with dopaminergic, adrenergic and serotonergic receptors
No significant effect in usual doses
GIT: High doses cause increased peristalsis
18. Ergometrine – contd.
Methylergometrine is preferred over ergometrine - higher
potency and less marked other effects
Pharmacokinetics:
Near complete absorption form GIT
Immediate onset of action with IV route
Metabolized in liver and excreted in urine
Half life – 1 to 2 hrs
Adverse effects:
No complication in usual doses - Nausea, vomiting and rise in BP
may occur
Decrease in milk secretion (dopaminergic)
Contraindications: Pregnancy before 3rd
stage of labour, vascular
disease, hypertension, liver and kidney diseases
19. Ergometrine - Uses
Postpartum haemorrhage: to prevent
Used the dose of 0.2 to 0.3 mg IM immediately
after delivery
Continued for 4 - 7 days post partum
If already PPH, use higher dose 0.5 mg IV
Cesarean section and instrumental delivery –
to prevent uterine atony
For normal involution: 0.125 mg orally tds for
4 – 7 days postpartum
20. Prostaglandins
PGE2 and PGF2α – tocolytics
Uses:
Abortion
In early termination with antiprogesterone (Mifepristone)
Midtrimester abortion – extra-amniotic injection followed by
oxytocin (1o mg/ml available)
Induction/augmentation of labour – intravaginal
route is preferred
Cervical priming – intravaginal gel (cerviprime)
Post-partum haemorrhage
23. Tocolytics
Therapeutic uses:
Delay or postpone labor – to allow fetus to
mature and transfer of mother to a
healthcare centre
Threatened abortion
Dysmenorrhoea
24. Ritodrine
MOA: Relaxation of uterine smooth muscle by
stimulation of beta-2 receptors
Doses: 50 mg of ritodrine in 500 ml of 5% glucose
solution. Start by 10 drops per minute and increase
by 5 drops every 10 minutes until uterine contractions
cease
Infusion should be continued for 12-48 Hrs after cessation of
contractions
Oral therapy should be continued every 8 Hrs after food
Monitor maternal pulse, BP and FHS
Adverse effects: CVS effects like hypertension, tachycardia,
arrhythmia etc. & metabolic effects like hyperglycemia,
hyperinsulinemia and hypokalaemia – also foetal
hypoglycaemia and paralytic ileus
25. Ritodrine – contd.
Contraindications:
Heart disease - Hypertension or hypotension
Hyperthyroidism and diabetes
Antepartum haemorrhage (dilatation of the uterine
arteries may increase the bleeding)
Rupture of membrane
Preparations: available as Ritodie/yutopar
Tablet 10 mg / tablet or injections 10 mg/ml – 1ml
or 5 ml
Isoxsuprine (duvadilan) is available as
oral and injections (10, 20, 40 mg tablets)
26. Magnesium sulfate and
Calcium channel blockers
Magsulf:
Action: The intracellular calcium is displaced by magnesium
ion leading to inhibition of the uterine activity
Dosage: The initial dose is 40 cc of 10% solution given
slowly IV. The subsequent doses depend upon the response
and the development of MgSO4 toxicity so reflexes and
respiratory rate should be observed
Uses: Used for prevention of seizures in eclampsia, not
used for arrest of preterm labor for its toxicites
Nifedepine: equal efficacy with beta-2 agonists
Dose: 10 mg every 30 minutes and followed by 10 mg every
6 hrly
Problems: tachycardia, hypotension and foetal hypoxia
27. Summary – must know
Drugs used as uterine stimulants -
Classification
Oxytocin – Mechanism of action o uterus and
its therapeutic uses
Ergometrine – Pharmacological actions in
uterus and therapeutic uses
Drugs used as Tocolytics – role of ritodrine
(beta-2 agonists) in arrest of labor
Each mL of sterile nonpyrogenic solution prepared by synthesis contains: oxytocin activity 10 IU (10 USP Posterior Pituitary Units), sodium acetate 2 mg, sodium chloride 5.1 mg and chlorobutanol 5 mg (as preservative) in water for injection. pH adjusted with acetic acid to approximately 3.9. Single-dose ampuls of 0.5, 1 and 5 mL. Sleeves of 5 or 10. Use only if solution is clear. Discard unused portion. Store at room temperature (15 to 30°C). Protect from freezing.
Amino acid alkaloids – partial agonist and antagonist of alpha receptor, serotonergic and dopeminergic, Amine alkaloides – no alpha blocking action, hydrogenation – produces more alpha blocking but no vasoconstriction