Pharmacology of Uterotonics & Tocolytics

Rozaimah Zain-Hamid & Yazanul Anwar
Department of Pharmacology and Therapeutics

Faculty of Medicine,
Universitas Sumatera Utara
OXYTOCIC / UTEROTONIC AGENTS
Zain-Hamid R & Anwar Y, Faculty of Medicine,

Stimulation
UTERINE CONTRACTION
Induction/augment dysfunctional labor

Control of post partum hemorhage
Incomplete abortion/abortion therapeutic
Oxytocin
Derivate of Ergot Alkaloids
Derivate of Prostaglandin

Oxytocin

Direct action on Stimulation of

uterus smooth muscle prostaglandin
synthesis
At terminal stage of pregnancy

( oxytocin receptor in myometrium)
Uterine contraction
Cervix dilatation & stretching of vagina

Uterine contraction
Cervix dilatation &

stretching of vagina
Stimulation of cervix & vagina
oxytocin secretion

OXYTOCIN
(Posterior pituitary hormone)
Pharmacokinetic :
* RoA : i.v & buccal absorption
* Swallowed inactive
* Not bound to plasma protein
* Catabolized by the kidneys & liver
* Circulating t 1/2 : 5 minutes

UTEROTONIC (OXYTOCIN)
Pharmacodynamic :
Alters transmembrane ionic currents in
myometrial smooth muscle cells &
myoepithelial cells of mammary alveoli
Uterine contraction &

leads to milk ejection
Clinical pharmacology :
Diagnostic :
placental circulatory condition
= Preparation available : Syntocinon & pitocin

Clinical pharmacology :
Therapeutic :
Induce labor
Augment dysfunctional labor for :
1. Conditions requiring early vaginal delivery:
Rh problem, maternal DM, preeclampsia
2. Uterine inertia
3. Incomplete abortion
Adverse reaction :
* Maternal death hypertensive episodes

* Uterine rupture
* Water intoxication
* Fetal death
* Afibrinogenemia
Contraindication :
Fetal distress
Prematurity
Abnormal fetal presentation
Cephalo-pelvic disproportion
Other predispositions for uterine rupture
Using sympathomimetic agents
Derivate of Ergot Alkaloids

UTEROTONIC (ERGOT ALKALOIDS)
Adrenoceptors
ERGOT ALKALOIDS
Dopamine receptors
5-HT receptors
Produced by
Histamine
Claviceps purpurea
Acetylcholine
Tyramine

PHARMACOKINETICS:
Variably absorbed from g.i.t
Amino acid alkaloids (ergotamine):

oral dose > i.m
Speed of absorption & peak blood
level improved by caffeine

PHARMACOKINETICS:
Amine alkaloids
(ergonovine / ergometrine) :
Also absorbed from rectum,
buccal cavity, aerosol inhaler
After i.m : slow absorption (reliable)
Metabolism : liver
PHARMACODYNAMICS:
STIMULANT EFFECTS ON THE UTERUS:
Combine agonist, 5-HT receptors
Changes dramatically pregnancy
( dominance 1 receptors as
pregn.progresses)
Sensitivity:
uterus aterm > earlier pregn. > non pregn.
PHARMACODYNAMICS:
STIMULANT EFFECTS ON THE UTERUS:
Small doses: rhytmic contr. & relaxation

Higher doses: powerful & prolonged contr.
Ergonovine : more selective uterus
(drug of choice : obstetric application)
CLINICAL APPLICATION:
For control of late uterine bleeding

(Post-partum hemorrhage)
Should never be given before delivery
Given at the time of delivery of placenta

or immediately afterward
if bleeding is significant
SIDE EFFECTS :
Nausea, vomiting,
Blood Pressure

TOXICITY:
Gastrointestinal disturbancies:
diarrhea, nausea,
vomiting

activation of medullary vomiting center &
gastrointestinal serotonin receptors
prolonged vasospasm
(gangrene amputation)
Therapy: infusion of large doses of
nitroprusid or nitroglycerin
CONTRA INDICATION :
Obstructive vascular disease &

collagen disease

Derivate of Prostaglandin

UTEROTONIC (PGE2 & PGF2)
Contractile effects
Release of calcium ions
the frequency & strength of

uterine contraction
A. ABORTION
PGE2 & PGF2

1 st & 2 nd trimester abortion

proteoglycan &
changing biophysical properties of collagen

soften the cervix
A. ABORTION
PGE2 & PGF2 (i.v )

produced abortion in 80 % of cases rate
PGF2 (intra-amniotic): success rate 100 %
Adverse effects < i.v

Other road of administration :
i.m, intravaginal
A. ABORTION
Success rate

dose, duration of infusion & parity of the woman
Dose-limiting side effects

vomiting, diarrhea, hyperthermia &
bronchoconstriction
A. ABORTION
Dinoprost tromethamine ( der. PGF2 ) :
single 40 mg intra-amniotic injection

complete abortion 20 hours
Side Effects:
cardiovascular collaps/anaphylactic shock,
pulmonary hypertension ultrasonic guidance
A. ABORTION
Carboprost tromethamine (i.m) & multiple dose
Synthetic PGE2 analogue :

vaginal suppositoria
direct affects the collagenase

B. FACILITATION OF LABOR
PGE2 & PGF2 PGF2 > potent than PGE2
PGF2 has more g.i.t toxicity than PGE2
Success rate = oxytocin
G.i.t side effect > oxytocin

PGE2 & PGF2 pass fetoplacental barrier

fetal toxicity uncommon
Oral PGE2 superior than oral oxytocin,

but = oxytocin i.v
PGE2 & PGF2 have no antidiuretic effect

induction labor in woman :
preeclampsia, cardiac & renal disease
Uterine fetal death

prostglandine alone or + oxytocin
TOCOLYTIC AGENTS

TOCOLYTIC AGENTS
Suppress
UTERINE CONTRACTION
Inhibition, delaying or halting labor

TOCOLYTIC AGENTS
Magnesium sulphate
(MgSO4)
Adrenergic agents
(terbutaline, ritodrine)
Calcium Channel blockers

(verapamil, nifedipine)
Prostaglandin synthetase inhibitor

(indomethacin)
Magnesium sulphate
(MgSO4)

Magnesium sulphate
(MgSO4)
Acts as a calcium antagonist &

membrane stabilizer
( the force of contraction)
Prophylaxis for preeclampsia

(1st line therapy)
Prevent seizures continued for
12-24 hours after delivery
Magnesium sulphate
(MgSO4)
Route of Administration: oral & i.v

SIDE EFFECTS:
Feeling of extreme warmth, perspiration,
flushing, nausea, vomiting, blurred vision,
lightheadedness, lethargy, nasal stiffness,
constipation, affects the reflexes,
and slow breathing,
chest pain (taking together with other tocolytic)
Magnesium sulphate
(MgSO4)
TOXICITY:
Hypoxia, respiratory depression,
cardiac arrest
CONTRA INDICATION:
Heart block, myocardial infarction,
myasthenia gravis, renal impairment
Magnesium sulphate
(MgSO4)
EFFECTS TO THE NEWBORN:
Baseline heart rate, drowsy, weak cry,

sucking rate in the early postpartum period
Strict monitoring for mother & newborn

Adrenergic agents

Adrenergic agents
Level of cAMP via adenylate cyclase
level of free calcium ions
smooth muscle relaxation

Terbutaline & ritodrine
or stop uterine contraction
Preterm labor
Route of Administration:
oral & i.v, subcutaneus
controlled infusion pump
(to give continuous low dose of terbutaline)

SIDE EFFECTS:
Nervousness, restlessness, insomnia
headache, rapid heart rate, nausea,
hyperglycemia, hypokalemia,
and pulmonary edema, shortness of breath,
chest pain
WARNING:
Cardiac dysrhythmia, cardiac disease,
hypertension or thyrotoxicosis,
shortness of breath, chest pain or
contraction still exist during
administration of terbutaline & ritodrine
Terbutaline
Fast heart rate,

high or low blood sugar after birth
Strict monitoring for mother &

newborn

Calcium ions
Entering smooth muscle cells
the force of smooth muscle contraction

or stop contraction of uterus
Delay labor
(used for occasional uterus irritability)
Route of Administration: oral
SIDE EFFECTS:
Facial flushing, headache, nausea,

palpitation, lightheadedness
No serious side effects have been note

(indomethacin)

(indomethacin)
Synthesis of prostaglandin
the frequency & strength of

uterine contraction
Indomethacin
Recommended as a tocolytic
in preterm labor at << 32 weeks
of gestation

Indomethacin
Route of Administration: oral, suppository

SIDE EFFECTS:
Abdominal discomfort, nausea,

vomiting, depression & dizziness

Indomethacin
WARNING:
Pregnant woman who has a story of
bleeding disorders, aspirin sensitivity &
kidney problems

Indomethacin
Have serious side effects on the foetus


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Rozaimah Zain-Hamid & Yazanul Anwar

Department of Pharmacology and Therapeutics

Zain-Hamid R & Anwar Y, Faculty of Medicine,

Induction/augment dysfunctional labor

Derivate of Ergot Alkaloids

Zain-Hamid R & Anwar Y, Faculty of Medicine,

Zain-Hamid R & Anwar Y, Faculty of Medicine,

Direct action on Stimulation of

At terminal stage of pregnancy

Cervix dilatation & stretching of vagina

Cervix dilatation &

Stimulation of cervix & vagina

Zain-Hamid R & Anwar Y, Faculty of Medicine,

Zain-Hamid R & Anwar Y, Faculty of Medicine,

Uterine contraction &

= Preparation available : Syntocinon & pitocin

Zain-Hamid R & Anwar Y, Faculty of Medicine,

* Maternal death hypertensive episodes

Zain-Hamid R & Anwar Y, Faculty of Medicine,

Zain-Hamid R & Anwar Y, Faculty of Medicine,

Amino acid alkaloids (ergotamine):

Zain-Hamid R & Anwar Y, Faculty of Medicine,

STIMULANT EFFECTS ON THE UTERUS:

Small doses: rhytmic contr. & relaxation

For control of late uterine bleeding

Should never be given before delivery

Given at the time of delivery of placenta

Zain-Hamid R & Anwar Y, Faculty of Medicine,

Obstructive vascular disease &

Zain-Hamid R & Anwar Y, Faculty of Medicine,

Zain-Hamid R & Anwar Y, Faculty of Medicine,

Release of calcium ions

the frequency & strength of

PGE2 & PGF2 (i.v )

Adverse effects < i.v

Dose-limiting side effects

Carboprost tromethamine (i.m) & multiple dose

Synthetic PGE2 analogue :

Zain-Hamid R & Anwar Y, Faculty of Medicine,

PGE2 & PGF2 PGF2 > potent than PGE2

PGF2 has more g.i.t toxicity than PGE2

Success rate = oxytocin

G.i.t side effect > oxytocin

Zain-Hamid R & Anwar Y, Faculty of Medicine,

PGE2 & PGF2 pass fetoplacental barrier

Oral PGE2 superior than oral oxytocin,

PGE2 & PGF2 have no antidiuretic effect

Uterine fetal death

Zain-Hamid R & Anwar Y, Faculty of Medicine,

Inhibition, delaying or halting labor

Zain-Hamid R & Anwar Y, Faculty of Medicine,

Calcium Channel blockers

Prostaglandin synthetase inhibitor

Zain-Hamid R & Anwar Y, Faculty of Medicine,

Acts as a calcium antagonist &

Prophylaxis for preeclampsia

Route of Administration: oral & i.v

EFFECTS TO THE NEWBORN:

Baseline heart rate, drowsy, weak cry,

Strict monitoring for mother & newborn

Zain-Hamid R & Anwar Y, Faculty of Medicine,

Zain-Hamid R & Anwar Y, Faculty of Medicine,

Level of cAMP via adenylate cyclase

level of free calcium ions

Pharmacology of Uterotonics & Tocolytics

Pharmacology of Uterotonics & Tocolytics