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Drugs acting on Uterus
Dr. D. K. Brahma
Department of Pharmacology
NEIGRIHMS, Shillong
Uterine stimulants (oxytotics or
abortifacients)
 Posterior Pituitary hormones: Oxytocin,
Desamino oxytocin
 Ergot alkaloids: Ergometrine,
methylergometrine
 Prostaglandins: PGE2, PGF2α,
misoprostol
 Miscellaneous: ethacridine and quinine
Oxytocin
 Hormone of Posterior pituitary. The
other hormone is vasopressin
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)
Oxytocin - Physiological Role
1. Labour
2. Milk ejection reflex
3. Neurotransmission
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
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
… 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
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.
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.
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
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
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
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
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
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
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
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
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
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
Uterine relaxants
Tocolytics
Tocolytics - drugs
 These are drugs that inhibit uterine
contractions
 Beta-sympathomimetics (beta-2)

Ritodrine, isoxsuprine, terbutaline and salbutamol
 Calcium channel blockers: Nifedepine
 Magnesium sulfate
 Prostaglandin inhibiting agents: Indomethacin
 Oxytocin antagonist: Atosiban
 Ethyl alcohol
Tocolytics
 Therapeutic uses:
 Delay or postpone labor – to allow fetus to
mature and transfer of mother to a
healthcare centre
 Threatened abortion
 Dysmenorrhoea
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
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) 
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
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
Thank you

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Drugs acting on uterus - drdhriti

  • 1. Drugs acting on Uterus Dr. D. K. Brahma Department of Pharmacology NEIGRIHMS, Shillong
  • 2. Uterine stimulants (oxytotics or abortifacients)  Posterior Pituitary hormones: Oxytocin, Desamino oxytocin  Ergot alkaloids: Ergometrine, methylergometrine  Prostaglandins: PGE2, PGF2α, misoprostol  Miscellaneous: ethacridine and quinine
  • 3. Oxytocin  Hormone of Posterior pituitary. The other hormone is vasopressin
  • 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)
  • 5. Oxytocin - Physiological Role 1. Labour 2. Milk ejection reflex 3. Neurotransmission
  • 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
  • 22. Tocolytics - drugs  These are drugs that inhibit uterine contractions  Beta-sympathomimetics (beta-2)  Ritodrine, isoxsuprine, terbutaline and salbutamol  Calcium channel blockers: Nifedepine  Magnesium sulfate  Prostaglandin inhibiting agents: Indomethacin  Oxytocin antagonist: Atosiban  Ethyl alcohol
  • 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

Notas del editor

  1. 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.
  2. 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