1. DRUGS AFFECTING UTERINE MOTILITY

2. Objectives
At the end of the lectures, students should be able to know and understand the:
1.Drugs used to induce & augment labor.
2.Drugs used to control post partum hemorrhage.
3.Drugs used to induce pathological abortion.
4.Drugs used to arrest premature labor.
5.The mechanism of action and adverse effects of
each drug.

3. Drugs affecting uterine contractility
Oxytocic drugs :
Drugs stimulate uterine smooth muscles during pregnancy , produce contraction that promotes rapid labor ( uterine stimulant or abortifacients)
Tocolytics:
Drugs relax uterine smooth muscles

4. Oxytocin ( posterior pituitary hormone)
OXYTOCIC AGENTS
Oxytocin ( posterior pituitary hormone)
Ergot alkaloids
Ergotamine
Ergonovine
Methyl ergometrine

5. Oxytocic Agents ( cont.)
Prostaglandines
PGE2
PGF2α
Misoprostol
Miscellaneous
Quinine
Emetine
Alcohol

6. OXYTOCIN (SyntocinonR)
Synthesis
Is a posterior pituitary hormone
Oxytocin secretion occurs by sensory stimulation from cervix ,vagina , and from suckling at breast.

9. Pharmacokinetics of oxytocin
Destroyed in GIT
Not effective orally
Given IV or nasal spray ( in cases of impaired milk ejection)
Not bound to plasma proteins
Eliminated by liver & kidneys
Half life = 5 minutes

10. Pharmacodynamics of oxytocin
Mechanism of action
Acts through GPCR  activation of phospholipase C  production of IP3  mobilization of calcium from its stores (SR)
Also, activates voltage sensitive calcium channels causing an increase in cytoplasmic calcium level that stimulates uterine contraction .

11. Pharmacological actions of oxytocin
Uterus
Small doses stimulates both the frequency and force of uterine contractility particularly of the fundus segment of the uterus.
These contractions resemble the normal physiological contractions of uterus (contractions followed by relaxation)

13. Large doses causes sustained contractions
Immature uterus is resistant to oxytocin.
Contract uterine smooth muscle only at term
Sensitivity increases to 8 fold in last 9 weeks and 30 times in early labor.
Clinically oxytocin is given only when uterine cervix is soft and dilated.

14. Cont.
Mammary glands
Stimulate myoepithelial cells surrounding mammary alveoli produce milk production
Without oxytocin induced contraction lactation can not occur.
At high doses it has antidiuretic activity due to action on vasopressin receptors

15. Therapeutic Uses of Oxytocin
1- Facilitation of labor at term (I.V. infusion )
2- Induction of labor for conditions requiring early vaginal delivery (I.V. infusion ) e.g.
Placental insufficiency ( mild preeclampsia, maternal diabetes)
Post maturity
Premature rupture membranes
Uterine inertia

16. Other Therapeutic Uses of Oxytocin
3- Post partum uterine hemorrhage after vaginal or cesarean delivery ( I.M.)
(ergometrine is the drug of choice)
4- Impaired milk ejection
One puff in each nostril 2-3 min before nursing
5- Incomplete abortion

17. Adverse effects Fetal Distress, placental abruption , death Maternal
Uterine rupture
Fluid retention, water intoxication
Hyponatremia, heart failure
Seizures
Death
(Bolus injection can produce hypotension, so used as infusion at a controlled rate)

18. Contraindications a) Hypersensitivity b) Prematurity
c) Abnormal fetal position
d) Evidence of fetal distress
e) Cephalopelvic disproportion
Precautions
a) Multiple pregnancy
b) Previous c- section
c) Hypertension

19. Ergot Alkaloids Natural Synthetic Ergonovine Semisynthetic
Methyl ergonovine
Synthetic
Methyl ergometrine

20. Effects on the Uterus
Alkaloid derivatives induce TETANIC CONTRACTION of uterus without relaxation in between(not like normal physiological contractions)
It causes contractions of uterus as a whole i.e. fundus and cervix(tend to compress rather than to expel the fetus)
Difference between oxytocin & ergots??

22. Ergot alkaloids( pharmacokinetics)
Absorbed orally from GIT(tablets)
Usually given I.M
Extensively metabolized in liver.
90% of metabolites are excreted in bile

23. Preparations Clinical uses Post partum hemorrhage
Hastens involution of the uterus
Preparations
Syntometrine(ergometrine 0.5 mg
+ oxytocin 5.0 I.U), I.M.

24. Side effects Nausea, vomiting, diarrhea Hypertension
Vasoconstriction of peripheral blood vessels ( toes & fingers)
Gangrene

25. Contraindications: Induction of labor 1st and 2nd stage of labor
vascular disease
Severe hepatic and renal impairment
Severe hypertension

26. Prostaglandins Dinoprostone ( synthetic PGE2)
Given intravaginally as a gel or tablet
Given extra-amniotically as a solution
1st metabolism in lung ( 95%)
Metabolized in local tissues
Metabolites excreted in urine
Some absorption directly through cervix & lymphatics into maternal circulation
Half-life min

27. Effects of dinoprostone
Stimulation of G protein coupled PGE2 receptors
 contraction of myometrium
Ripening of cervix due to direct effect on cervical
collagenase resulting in softening
Has natriuretic effect
Superior to oxytocin for women with pre-eclampsia , as no fluid retention

28. Therapeutic uses of dinoprostone
Abortifacients
Induction of labor
Facilitate labor at term
Used as vaginal suppositories alone or with oral misoprostol

29. Adverse effects Nausea, vomiting, diarrhea Incomplete abortion
Increase blood loss

30. Carboprost: 15 methyl PGF2α Analog
Therapeutic uses
Abortion
Induction of labor
To control PPH IMI

31. Adverse effects Vomiting, diarrhea Transient rise of temperature
Bronchoconstriction
Fetal toxicity uncommon

32. Misoprostol ( synthetic PGE1)
Given intravaginally as a gel or tablets

33. Contraindications of prostaglandins:
a) Mechanical obstruction of delivery
b) Fetal distress
c) Predisposition to uterine rupture
Precautions:
a) Asthma
b) Multiple pregnancy
c) Glaucoma
d) Uterine rupture

34. Difference B/w Oxytocin and Prostaglandins
Character
Contraction through out pregnancy
Only at term
Contraction
soften the cervix
Does not soften the cervix
Cervix

35. Difference (cont’d) Prostaglandins Oxytocin Character Longer Shorter
Duration of action
Induce abortion in 2nd trimester of pregnancy.
Used as vaginal suppository for induction of labor
Induce and augment labor
post partum hemorrhage
Uses

36. Difference b/w Oxytocin and Ergometrine
Character
Tetanic contraction ; doesn't resemble normal physiological contractions
Resembles normal physiological contractions
Contractions
Only in postpartum hemorrhage
To induce &augment labor.
*Post partum hemorrhage
Uses
Moderate onset
Long duration of action
Rapid onset
Shorter duration of action
Onset and Duration

37. Drugs relax uterine muscles & inhibit uterine contractions
TOCOLYTIC DRUGS
Drugs relax uterine muscles & inhibit uterine contractions

38. Tocolytic Drugs
Uses
To arrest premature labor
Treatment of dysmenorrhea
Delay delivery for 48 hrs , this time can be used to administer glucocorticoids ( Injection betamethasone) to mother for maturation of the fetal lung
To make it possible that baby is born where facility of neonatal ICU is available

39. Classification of tocolytic drugs
B2 selective stimulants
( Ritodrine, salbutamol)
Oxytocic Antagonist
Atosiban
Other dugs
Used in treatment of dysmenorrhea COX inhibitors

40. Ritodrine (β- adrenoceptor agonist)
Mechanism of action
Bind to β-adrenoceptors , activate Adenylate cyclase , increase in the level of cAMP reducing intracellular calcium level.

41. Side effects:
Anxiety, Restlessness, Headache
Pulmonary edema
Flushing
Sweating
Tachycardia (high dose)
Hypotension
Hyperglycemia

42. ( Atosiban ) Oxytocic Antagonist
Antagonizes the effects of oxytocin at its receptors
Used as tocolytic in premature labor
Given by IV infusion for 48 hrs

43. COX inhibitors
Inhibit The synthesis of prostaglandins that prevents or reduces uterine muscle contractions
NSAID,s e.g. Non-selective Cox inhibitors : Indomethacin
Aspirin
Ibuprofen
Selective COX2 inhibitors: celecoxib
Used clinically in treatment of dysmenorrhea

44. Adverse effects
ulceration
premature closure of ductus arterious.