1-DRUGS 1-DRUGS AFFECTING AFFECTING

UTERINE MUSCLE UTERINE MUSCLE CONTRACTILITYCONTRACTILITY

DRUGS PRODUCING UTERINEDRUGS PRODUCING UTERINE CONTRACTIONS( Oxytocic Drugs ) CONTRACTIONS( Oxytocic Drugs )

OXYTOCINOXYTOCIN((SyntocinonSyntocinonRR))

Synthesis

It is a posterior pituitary hormone secreted by the posterior pituitary gland, which is originally synthesized by the hypothalamus.

Oxytocin secretion occurs by sensory stimulation from areas of the cervix ,vagina , and by suckling at the breast.

Oxytocin causes

contraction of the fundus

only.

Pharmacokinetics of oxytocinPharmacokinetics of oxytocin

Absorption, Metabolism and Excretion

Not effective orallyAdministered intravenously* Also as nasal spray (to improve milk

ejection, 2-3 minutes before breast feeding)

Not bound to plasma proteins Catabolized by liver & kidneysHalf life = 5 minutes*S.C or IM difficult to

monitor

Role of oxytocinRole 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)

Immature uterus is resistant to oxytocin.

Causes the contraction of at-term uterine smooth muscles only.

Sensitivity increases to 8 fold in the last 9 weeks and 30 times in early labor.

Clinically oxytocin is given only when uterine cervix is soft and dilated. see next slide

before labor the cervix is closed

Oxytocin isn’t used at this stage

At term the cervix is fully dilated Oxytocin is used at this stage

oxytocin is not given to induce abortion because the cervix is not dilated (too early)

Mechanism of actionMechanism of action

Myometrial cell

Ca++ Receptor

Oxytocin stimulates

Ca++ to interact with its receptor

Oxytocin Intracellular fluid

Extracellular fluid

N.B. Oxytocin also causes the release of Ca++ from the sacroplasmic reticulum

Contraction occurs

Therapeutic Uses of Oxytocin1. Induction & augmentation of labor (remember only slow IV

infusion)

Mild preeclampsia (a serious condition developing in late pregnancy, characterized by sudden hypertension, proteinuria, and edema)

Uterine inertia (Uterine atony) Incomplete abortion Post maturity (post-term fetus) Maternal diabetes

Therapeutic Uses of Oxytocin (continue)

2. Postpartum uterine hemorrhage (IV drip) (ergometrine is often used

nowadays)

3. Impaired milk ejection One puff in each nostril 2-3 min before

nursing

Cephalopelvic disproportionCephalopelvic disproportionFetus’s head is much

larger than the pelvic

outlet.

*to avoid rupture of the

uterus

Effects on the UterusAlkaloid derivatives induce TETANIC

CONTRACTION of uterus without relaxation in between (unlike the normal physiologic contractions)

It causes contractions of the uterus as a whole i.e. fundus and cervix (tends to compress rather than actually expelling the fetus)

Not used anymore for labor augmentation.

Sites of ergot

contraction

Ergot alkaloids (pharmacokinetics)Ergot alkaloids (pharmacokinetics)

Absorption fate and excretion

Absorbed orally from the GIT (tablets) Usually given IMNOT given IV because it causes

severe vasoconstriction Extensively metabolized in the liver 90% of metabolites are excreted in bileUterus responds to Ergots more than

Oxytocin

Clinical usesClinical uses

Postpartum hemorrhage (used only at the 3rd stage of labor, when the baby’s head or shoulder start to appear)

PreparationsPreparations

If used I.V ↑↑↑↑ blood pressure

Why should we use this combination ?

Ergots have slow onset of action (7min) but have a long half-life.

Yet, oxytocin has a fast onset of action, 1-2 minutes, with a short half-life.

Side effectsSide effects

Nausea, vomiting, diarrheaHypertension because contraction

of blood vesselsVasoconstriction of peripheral blood

vessels ( toes & fingers) which can lead

Gangrene

Contraindications:1.Induction of labour2.1st and 2nd stage of labor3.vascular disease4.Severe hepatic and renal impairment5.Severe hypertension

PROSTAGLANDINS (PGE2 & PGF2α)

Therapeutic uses1. Induction of abortion (pathological)**

(used because the uterus is sensitive to PGs in early stages).

2. Induction of labor (fetal death in utero)

3. Postpartum hemorrhage

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. N.B. PGs at low doses physiologic

contraction at high doses Tetanic contraction

Side Effects

◦Nausea , vomiting◦Abdominal pain◦Diarrhea◦Bronchospasm (PGF2α)◦Flushing (PGE2). ◦P.S. PGE2 causes vasodilation of the

mother’s vessels thus leading to cutaneous flushing. Yet, there is vasoconstriction of the umbilical cord’s vessels.

◦PGE2 is used as a vaginal suppository for cervical dilation and softening.

Contraindications:Mechanical obstruction of deliveryFetal distress (due to umbilical cord vessels’

vasocontriction)

Predisposition to uterine rupture

Precautions:AsthmaMultiple pregnancyGlaucomaUterine rupture

Difference B/W Oxytocin and ProstaglandinsDifference B/W Oxytocin and Prostaglandins

CharacterOxytocinProstaglandins

ContractionOnly at termContraction through out pregnancy

Cervix Does not soften the cervix

soften the cervix

Cont’dCont’d

Character OxytocinProstaglandins

Duration of action

ShorterLonger

usesInduce and augment labour and post partum hemorrhage

Induce abortion in 2nd trimester of pregnancy.

Used as vaginal suppository (PGE2) for induction of labor

Difference b/w Oxytocin and ErgometrineDifference b/w Oxytocin and Ergometrine

CharacterOxytocinErgometrine

ContractionsResembles normal physiological contractions

Tetanic contraction ; doesn't resemble normal physiological contractions

UsesTo induce &augment labor.

*Post partum hemorrhage

Only in postpartum hemorrhage

Onset and Duration

Rapid onset

Shorter duration of action

Moderate onset

Long duration of action

2-UTERINE RELAXANTS

DRUGS PRODUCING UTERINE DRUGS PRODUCING UTERINE RELAXATION (Tocolytic Drugs)RELAXATION (Tocolytic Drugs)

Action and Uses Relax the uterus and arrest threatened abortion or delay premature labor.

1. β-ADRENOCEPTOR AGONISTS**

Ritodrine, i.v. dripSelective β2 receptor agonist used

specifically as a uterine relaxant.

Tocolytic drugs: drugs that cause inhibition of premature labor.

ββ- adrenoceptor agonists - adrenoceptor agonists e.g. e.g. ββ2 2 selective agonists: ritodrineselective agonists: ritodrine

Mechanism of action

Bind to β-adrenoceptors activating the enzyme adenylate cyclase increasing the level of cAMP reducing intracellular calcium level.

As the pregnancy progresses there is gradual increase of uterine β β22 receptors. This is an attempt to increase ββ2 2 responsiveness to its agonist, an important role for the stability of fetal growth.

Side effects: Tremor Nausea , vomiting Flushing Sweating Tachycardia (high dose) Hypotension Hyperglycemia Hypokalaemia

2.CALCIUM CHANNEL BLOCKERS 2.CALCIUM CHANNEL BLOCKERS Nifedipine Nifedipine

Causes relaxation of the myometrium

Markedly inhibits the amplitude of spontaneous and oxytocin-induced contractions.

Unwanted effects

Headache, dizziness Hypotension FlushingConstipation Ankle edema Coughing Wheezing Reflex tachycardia

3. Prostaglandin synthetase inhibitors 3. Prostaglandin synthetase inhibitors

The depletion of prostaglandins prevents stimulation of uterus

NSAID,s e.g. Indomethacin Aspirin

Ibuprofen

Adverse effectsUlcerationPremature closure of ductus

arterious.