Drugs affecting myometrium.

The contractile activity and tone of myometrium are regulated by

neurohumoral mechanisms. Drugs acting on uterus can primarily affect the
endometrium or the myometrium. The most important drugs affecting
endometrium are estrogens, progestins and their antagonists. Myometrium receives
both sympathetic and parasympathetic innervation: activation of M- cholinoceptors
and α-adrenoceptors stimulates the myometrium, stimulation of β2- adrenoceptors
suppresses it. However, directly acting drugs are more important and have more
selective action. The responsiveness of myometrium to drugs is markedly affected
by the hormonal and gestational status. The agents affecting the contractility and
tone of the uterus are subdivided into the following groups.

I. Drugs predominantly affecting the contractile activity of myometrium

1. Agents increasing the contractile activity of the myometrium (myometrial
stimulants)
a) Hormones and drugs of the posterior lobe of the pituitary
- Oxytocin
- Desamino-oxytocin
b) Prostaglandin drugs
- Dinoprost (prostaglandin F2a)
- Dinoproston (prostaglandin E2)

2. Agents decreasing the contractile activity of the myometrium (tocolytic drugs;

myometrial relaxants)
a) Predominantly stimulating β2-adrenoceptors
- Ritodrine
- Terbutaline
- Isoxsuprine
- Salbutamol
b) Calcium channel blockers (Nifedipine)
c) Drugs used for general anesthesia (Halothane)
d) Magnesium sulphate
e) Ethyl alcohol
f) Nitrates
g) PG synthesis inhibitors (Indomethacin)
h) Progesterone
 II. Drugs predominantly increasing the tone of the myometrium
1. Agents of plant origin (alkaloids and ergot preparations)
- Ergometrine
- Ergotamine
- Ergot extract
III. Drugs decreasing the tone of the cervix
- Atropine
- Dinoprost
- Dinoproston
Oxytocin is produced synthetically. This agent causes an increase in
myometrial regular coordinated contractions. Affected by oxytocin, the amplitude
and rate of myometrial contractions increase. At the same time the tone of the
myometrium also increases, especially if oxytocin is used in high doses. Oxytocin
can also contribute to milk secretion. Usually oxytocin is indicated in order to
induce and stimulate labor. Besides, it is used for the treatment of hemorrhage and
atonia of the uterus during the puerperium (period after labor). Oxytocin is
administered intravenously together with glucose solution. The doses are measured
in activity units.

Prostaglandins are of great interest. In the body, prostaglandins are

synthesized from arachidonic acid. Many prostaglandins produce a marked
stimulating effect on the uterus throughout the pregnancy.
Prostaglandins F2a and E2 are used to induce abortions and labor.
Dinoprost (prostaglandin F2a, enzaprost F) possesses a marked stimulating
effect on the myometrium. It produces rhythmic contractions and increases the
tone of the pregnant and nonpregnant uterus and dilates the cervix. However, the
effect of dinoprost is not limited to the myometrium. Dinoprost also increases
bronchial tone. This effect is especially marked in patients who suffer from
bronchial asthma. Dinoprost increases cardiac output and increases heart rate.
When dinoprost is used in therapeutic doses, it does not affect systemic blood
pressure. However, blood pressure may increase slightly if the drug is used in large
doses. The drug constricts pulmonary vessels and increases gastrointestinal
motility.
Dinoprostone (prostaglandin E2 enzaprost E) also causes a marked increase
in rhythmic contractions of the pregnant uterus and raises its tone. This agent
decreases the tone of the cervix. It decreases the blood pressure (by lowering
peripheral vascular resistance). It also causes compensatory tachycardia and, unlike
dinoprost, dilates the pulmonary vessels and bronchi. It also increases capillary
permeability.

Dinoprost and dinoprostone are used to perform medical abortions (the

agents can be used intravenously, intramuscularly, intravaginally, intracervically,
extraand intraamnially), and sometimes these drugs are used to accelerate labor (in
this case the agents are administered intravenously or orally).
Prostaglandins, as labor stimulating agents, differ from oxytocin because
they decrease the tone of the cervix, do not cause jaundice in newborns and do not
cause water retention in the organism. However, the use of prostaglandins can
cause an excessive stimulation of the contractile activity of the myometrium that
can disturb blood supply to the uterus and placenta. This is complicated by the fact
that prostaglandins act longer than oxytocin. This is why, considering all these
properties, oxytocin is the main drug used to stimulate labor.
Administration of prostaglandins can lead to such adverse effects as nausea,
diarrhea, headache, transient increases in temperature; intravenous administration
can lead to phlebitis. With intravaginal and intracervical administration of
prostaglandins adverse effects are less marked. The agents, which are used in
labor, also include drugs that decrease the tone of the cervix (atropine group). A
cervical dilatation is produced also by prostaglandins.
Drugs that decrease the contractile activity of the myometrium (the so called
tocolytic drugs) include agents that stimulate β2-adrenoceptors of the uterus. These
drugs are indicated to delay or prevent premature labor. Both drugs cause slight
tachycardia in mother and fetus, as well as hyperglycaemia in the fetus.
Adrenergic agonists Ritodrine, the β2 selective agonist
having more prominent uterine relaxant action is approved
to suppress premature labour and to delay delivery in case
of some exigency or acute foetal distress. For dependable
action it is started as 50 µg/min i.v. infusion, the rate is
increased every 10 min till uterine contractions cease or
maternal HR rises to 120/min. However, cardiovascular (hypotension, tachycardia,
arrhythmia, pulmonary edema) and metabolic (hyperglycaemia, hyperinsulinaemia,
hypokalaemia) complications and anxiety, restlessness, headache occur frequently.
It should not be used if mother is diabetic, having heart disease, or receiving β
blockers or steroids.

Ritodrine is used to stop or control premature labor.

Ritodrine is used between 24-33 weeks of gestation 10 tabs 10 mg
 Because influx of Ca2+ ions plays an important role in uterine contractions,
Ca2+ channel blockers reduce the tone of myometrium and oppose contractions.
These drugs, especially nifedipine, which has prominent smooth muscle relaxant
action, can postpone labour if used early enough. Efficacy comparable to β 2
adrenergic agonists has been demonstrated and side effects are fewer. Oral
nifedipine 10 mg repeated
once or twice after 20–30
min, followed by 10 mg 6
hourly has been used.
Tachycardia and hypotension are prominent at doses which suppress uterine
contractions. Reduced placental perfusion causing foetal hypoxia is apprehended.
However, fewer babies delivered after nifedipine needed intensive care.
Sometimes, certain general anaesthetic drugs are used to decrease severe
labor pain, for example, halothane.
The contractile activity of the myometrium can also be decreased by the
parenteral administration of magnesium sulphate. Obviously, it is associated with
the fact that magnesium sulphate prevents penetration of calcium ions essential for
contraction into the myometrium cells. Magnesium sulphate is also considered to
produce a direct suppressing effect on the myometrium.
The drugs that mostly increase the tone of the myometrium are primarily
used to stop uterine hemorrhage. The mechanism of their action consists of the
stable increase of the myometrium tone and mechanical compression of the small
vessels. With this purpose, ergot alkaloids.

Ergot (Secale cornutum) is a resting stage of the Claviceps purpurea fungus

which is a parasite that lives on rye. It contains alkaloids that are derivatives of
lysergic acid. There are 3 groups of alkaloids.
 • Ergotamine group
- Ergotamine - Ergotaminine - Ergosin – Ergosinin

• Ergotoxine group
- Ergocristine - Ergocristinine - Ergocornine - Ergocorninine - Ergocriptine -
Ergocriptinine
• Ergometrine group
- Ergometrine
- Ergometrinine

The alkaloids of first two groups are not water soluble, but the alkaloids of
the third group are water soluble.
 Ergot alkaloids increase the tone of the myometrium, as well as the tone of
smooth muscles of the visceral organs and vessels. Continuous oral or parenteral
use of large doses of ergot alkaloids can cause vascular spasm and damage to the
endothelium. Vascular spasm is associated with the presence of α-adrenomimetic
properties and, perhaps, with the direct myotropic effect of these alkaloids. This
negative effect is not as strong for ergometrine as it is for ergotoxine and
ergotamine.
Ergot alkaloids produce some effect on the CNS as well. It manifests as a
sedating effect, suppression of the vasomotor center and vasoconstricting reflexes
and stimulation of the vagal nerve centers and the trigger zone of the emetic center.
Ergot alkaloids should not be used to accelerate labor, because they do not
intensify physiological rhythmic contractions of the myometrium; instead they
rapid increase the tone of the myometrium and can be the cause of fetal asphyxia.
The administration of ergot drugs can cause such adverse effects as nausea,
vomiting, diarrhea and headache.
Acute intoxication with ergot drugs (usually associated with an attempt to
perform an abortion) may include the symptoms of motor excitation, convulsions,
nausea, vomiting, diarrhea, epigastric pain, tachycardia and sensory problems.
Long-term administration of these drugs can lead to chronic intoxication
(ergotism). Ergotism can manifest in two forms.

One of them is called gangrenous («St. Anthony's fire») and is associated with
peripheral vascular spasm and damage to the vascular endothelium leading to
tissue necrosis (especially, tissues of the limbs).
 The second form of ergotism is called convulsive («evil writhe»). It is
caused by the effect of the drugs on the CNS.

Indications of drugs affecting myometrium

Stimulate labor Treatment of uterine Prevent premature labor

bleeding

Oxytocin Ergometrine Fenoterol

Dinoprost (prostaglandin Ergotamine Salbutamol
F2α) Ergot extract Magnesium sulphate
Dinoproston Ergotalum Ritodrine
(prostaglandin E2)
 Questions.

I. Drugs predominantly affecting the contractile activity of myometrium

1) Agents increasing the contractile activity of the myometrium
(myometrial stimulants). Classification. Clinical uses. Adverse
effects.
2) Agents decreasing the contractile activity of the myometrium
(tocolytic drugs; myometrial relaxants). Classification. Clinical
uses. Adverse effects.
II. Drugs predominantly increasing the tone of the myometrium
1) Agents of plant origin (alkaloids and ergot preparations)
Classification. Clinical uses. Adverse effects.
III. Drugs decreasing the tone of the cervix. Classification. Clinical uses.
Adverse effects.