Oleh :

Dimas P.Nugraha
Bagian Farmakologi FK UR

DRUGS PRODUCING UTERINE

CONTRACTIONS( Oxytocic Drugs )
1. OXYTOCIN
Syntocinon
2. ERGOT ALKALOIDS
Ergometrine (Ergonovine)
3. PROSTAGLANDINS
a) PGE2
b) PGF2

Oxytocin

Oxytocin

HORMONES OF THE POSTERIOR

PITUITARY

 Oxytocin directly and indirectly

initiates contractions when it binds to
its receptor, located in the
myometrium.
The oxytocin receptor is a seven
transmembrane domain receptor,
containing 389 amino acid residues.
This receptor is coupled to a G
protein

Mechanisms of Action of
Oxytocin

Secretion of Oxytocin
Stimuli for oxytocin secretion include sensory
stimuli arising from dilation of the cervix and
vagina and from suckling at the breast.
Increases in circulating oxytocin in women in
labor are difficult to detect, partly because of the
pulsatile nature of oxytocin secretion and partly
because of the activity of circulating
oxytocinase.
Increased oxytocin in maternal circulation is
detected in the second stage of labor, likely
triggered by sustained distension of the uterine
cervix and vagina.

Role of oxytocin

Uterus
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)

Breast
Oxytocin plays an important physiological
role in milk ejection.
Stimulation of the breast through suckling or
mechanical manipulation induces oxytocin
secretion, causing contraction of the
myoepithelium that surrounds alveolar
channels in the mammary gland.
This action forces milk from the alveolar
channels into large collecting sinuses, where
it is available to the suckling infant.

Umpan balik positif

Regulasi oksitosin ejeksi susu ibu

kontraksi uterus
(inpartu)

Brain
As noted earlier, oxytocin is
synthesized by hypothalamic
neurons, predominantly located in
the paraventricular and supraoptic
nuclei.
Studies in rodents and humans have
implicated oxytocin as an important
CNS regulator of trust and of
autonomic systems linked to anxiety

Pharmacokinetics of oxytocin
Absorption ,Metabolism and Excretion

Not effective orally

Administered intravenously
Also as nasal spray(impaired milk ejection)
Not bound to plasma proteins
Catabolized by liver & kidneys
Half life = 5 minutes

 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

Therapeutic Uses of Oxytocin

1. Induction & augmentation of labor**
(slow I.V infusion)
a) Mild preeclampsia
b) Uterine inertia
c) Incomplete abortion
d) Post maturity
e) Maternal diabetes

2. Post partum uterine

hemorrhage
(I.V drip)
(ergometrine is often
used)
3. Impaired milk ejection
One puff in each nostril 2-3 min
before nursing

Dosis
Dose for Labor Induction
Initial dose: 0.5 to 1 milliunits IV infusion per
hour. At 30 to 60 minute intervals the dose
should be gradually increased in increments
of 1 to 2 milliunits until the desired
contraction pattern has been established.
Postpartum Bleeding
10 to 40 units IV infusion in 1000 mL at a
rate sufficient to control bleeding.
10 units IM after delivery of placenta.

Dose for Abortion

After suction or sharp curettage for an
incomplete, inevitable or elective abortion:
10 units in 500 mL IV infusion. Adjust rate to
assist uterus in contraction.
After intra-amniotic injection for
midtrimester elective abortion:
10 to 20 milliunits per minute IV infusion. The
total dose should not exceed 30 units in a 12
hour period due to the risk of water intoxication.

Oxtytocin preparations
Nasal spray
Injection

Indicated only
for pain related
to post partum
breast
engorgement

For induction
of labor

You may not be able to use oxytocin, or you may require a dosage
adjustment or special monitoring during treatment if you have any of the
conditions :

Have or have had cervical cancer;

Have an allergy to oxytocin, other medications, dyes,
foods, or preservatives;
Have eclampsia;
Have herpes;
Have had more than 7 pregnancies;
Are experiencing premature labor;
Have had a caesarean section (C-section);
Have had any surgery on the cervix or uterus;
Have a prolapsed uterus; or
Have a breech, placenta previa or any other issues
with the fetus or umbilical cord.

Side effect
Cardiovascular
Cardiovascular side effects have included
hypertension, premature ventricular
contractions, sinus tachycardia, and other
cardiac arrhythmias.
Nervous system
Nervous system side effects have included
mania-like disturbances and seizures. The
seizures may have been related to water
intoxication.
Neonatal seizures and permanent CNS or brain
damage has been reported.

Hypersensitivity
Hypersensitivity side effects have
included anaphylactic reactions.
Genitourinary
Genitourinary side effects have
included pelvic hematoma.
Excessive doses have produced pelvic
fracture, uterine hypertonicity, spasm,
tetanic contraction and rupture.

Hematologic
Hematologic side effects have included
postpartum hemorrhage and fatal
afibrinogenemia.
Hepatic
Hepatic side effects have included neonatal
jaundice.
Gastrointestinal
Gastrointestinal side effects have included
nausea and vomiting.

Respiratory
Respiratory side effects have included
pulmonary edema.
Renal
Renal side effects have included decreases
in glomerular filtration rate and renal
plasma flow.
Doses of 40 milliunits per minute may
produce significant decreases in urine
output.

Ocular
Ocular side effects have included neonatal
retinal hemorrhages.
Psychiatric
Psychiatric side effects have included memory
impairment and mania in patients on high doses.
General
General side effects have include low Apgar
scores at 5 minutes.
Fetal death has been reported.

Contraindications
Abnormal
Prematurity
Hypersensitivity
Evidence
of
fetal
fetal
position
distress

Precautions
a) Multiple pregnancy
b) Previous c- section
c) Hypertension

Toxicities are uncommon when the drug

Ergot Alkaloids

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??

Ergot alkaloids( pharmacokinetics)

Absorption ,fate and excretion

Absorbed orally from GIT(tablets)

Usually given I.M
Extensively metabolized in liver.
90% of metabolites are excreted in bile

Clinical uses
To Control Postpartum Hemorrhage
to help deliver the placenta
other uterine problems after childbirth.

Side effects
a) Nausea, vomiting, diarrhea
b)
Hypertension
b) Vasoconstriction of peripheral blood
vessels ( toes &
fingers)
c) Gangrene

Contraindications:
Induction of labour
a) 1st and 2nd stage of labor
b) vascular disease
c) Severe hepatic and renal impairment
d) Severe hypertension

PROSTAGLANDINS
(PGE2 & PGF2)
Therapeutic uses
1. Induction of abortion (pathological)**
2. Induction of labor (fetal death in utero)
3. Postpartum hemorrhage

Prostaglandins:

Dinoprostone (PGE2 ),

Action
To promote Ripening and dilatation of the
Cervix prior to labor induction.
With Mifepristone To Terminate Pregnancy
First Trimester.
PGs promote contractility and clear the unborn
fetus.
ADE of PGs:
Uterine Pain,
Nausea, Vomiting, Headache,
Diarrhea (Increased Intestinal Motility).
Rarely ; arrhythmia, hypotension, bronchospasm

Formulations
Cervical gel
Vaginal gel , tab.
Vaginal system ( suppositories )
Oral preparations ??
short-acting (instant-release) preparation (Prostin).
A sustained release preparation of prostaglandin E2
(Propess)

Difference between PGS and Oxytocin:

PGS contract uterine smooth muscle not only at
term(as with oxytocin), but throughout pregnancy.
PGS soften the cervix; whereas oxytocin does not.
PGS have longer duration of action than oxytocin.

 Side Effects
a) Nausea , vomiting
b) Abdominal pain
c) Diarrhea
d) Bronchospasm (PGF2)
e) Flushing (PGE2)

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

Difference B/w Oxytocin and Prostaglandins

Prostaglandins

Oxytocin

Character

Contraction
through out
pregnancy

Only at term

Contraction

soften the cervix

Does not soften the

cervix

Cervix

Difference (contd)
Prostaglandins

Oxytocin

Character

Longer

Shorter

Duration of
action
uses

Induce abortion in 2nd Induce and augment

trimester of
labour and post partum
pregnancy.
hemorrhage
Used as vaginal
suppository for
induction of labor

Difference b/w Oxytocin and Ergometrine

Ergometrine

Oxytocin

Character

Tetanic contraction ;
doesn't resemble
normal physiological
contractions

Resembles normal
physiological
contractions

Contractions

Only in p.partum
hemorrhage

To induce &augment
labor.
*Post partum
hemorrhage

Uses

Moderate onset
Long duration of
action

Rapid onset
Shorter duration of
action

Onset and
Duration

UTERINE RELAXANTS
(Tocolitics)

GOAL of tocolytic therapy

to interrupt or inhibit uterine

contraction to create additional time
for in utero fetal maturation
to delay delivery so antenatal
corticosteroids can be administered
to facilitate lung maturation of the
fetus.
to allow safe transport of the mother
to an

DRUGS PRODUCING UTERINE

RELAXATION( Tocolytic Drugs )
Action and Uses
Relax the uterus and arrest threatened abortion or delay
premature labor.
1.-ADRENOCEPTOR AGONISTS**
Ritodrine, i.v. drip
Selective 2 receptor agonist used specifically as a uterine
relaxant.

- adrenoceptor agonists
Mechanism of action
Bind to -adrenoceptors , activate
enzyme Adenylate cyclase , increase in the
level of cAMP reducing intracellular
calcium level.

 Side effects:

Tremor

Nausea , vomiting

Flushing

Sweating

Tachycardia (high dose)

Hypotension

Hyperglycemia

Hypokalaemia

2.CALCIUM CHANNEL BLOCKERS

e.g., Nifedipine
Causes relaxation of myometrium
Markedly inhibits the amplitude of
spontaneous and oxytocin-induced contractions

Unwanted effects
Headache, dizziness
Hypotension
Flushing
Constipation
Ankle edema
Coughing
Wheezing
Tachycardia

3. Prostaglandin synthetase inhibitors

The depletion of prostaglandins prevents
stimulation of uterus
NSAID,s e.g. Indomethacin
Aspirin
Ibuprofen

Adverse effects
ulceration
premature closure of ductus arterious.

Atosiban:
Oxytocin R. antagonist
([1-deamino-2-D-Tyro(OEt)-4-Thr-8-Orn]
oxytocin)
is a competitive oxytocin receptor
antagonist.

There are lots of researches about

Atosiban, results are different
Used in some European countries
but not yet approved in USA
Related drugs are under clinical
trials

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