uterine motilitymd20.8.55 sheet.pdf

7/28/2019 uterine motilityMD20.8.55 sheet.pdf

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Agent affecting uterine motility

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Objective & OutlineReview physiology of uterine contractionPharmacolgy of drugs that affect uterine contraction

: Oxytocic drugs : oxytocin, ergometrine,PG, and the others : Tocolytics : 2-adrenergic agonists,MgSO 4 , PG synthetase inhibitors and the others

Each group of drugs Mechanism of actions Pharmacokinetics & clinical uses

Adverse drug reactions


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The Uterus

The motility:is under Myogenic control

Neuronal control

Hormonal controlUterine muscle contracts rhythmicallyForce and frequency of uterine contraction greatlyduring the menstrual cycle. Due to the effect of thecomplex hormonal changes which occur during thecycle


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Non pregnant uterus := First part of menstruation cycle weakspontaneous contractions= During menstruation strong contraction~ pregnant uterus during labor stage.

1 st trimester pregnancy , uterine movementare depressed by progesterone (markedlyinhibits uterine activity) from corpus luteum

At the end of 3 rd trimester , the contractionsstart to occur, and increase in force andbecome fully coordinated during labor stage.


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Innervation: No evidence for the existence of intrinsic nerve

plexus which controls the muscle (as occurs inGI-tract)Parasympathetic: muscarinic cholinergic fibers

have a role in the control of uterine motility ,but not have the effective contraction, not usein clinical practiceSympathetic:

1 receptor, excitatory2 receptor, inhibitory

All subtype adreno-receptors are clearlydemonstrated in the myometrium,and other receptors : PG, ergot alkaloid, oxytocin receptor


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Pharmacology of the drugs

Drugs : change([Ca2+

]I) by or Ca2+

influx or efflux tothe cellAgonist bind receptor initiate

Contraction

: Ca 2+ by activate- Voltage operated Ca 2+channels (VOC) or - Receptor operated Ca 2+channel(ROC)

and Ca 2+ release from SR by inositol triphosphate(IP 3) Relaxation

: Ca 2+ by inactivate VOC or ROC intracellular

Ca 2+ or Ca 2+ efflux from cytoplasm


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Physiology of muscle contraction

Review


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+


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: Oxytocic drugs

Oxytocin(Syntocinon,Pitocin),O*Ergometrine (Ergonovine), (Methergin )PG-analogues : E1,E 2,F 2 ,E 2 Hormone: Estrogen

Peptides: Substance PCalcium channel activator Histamine receptor agonist

Others: RU486 , Relaxin, NO, Cytokines


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Oxytocic drugs

Clinical Use :Induce or augment labor: O*, PG

Control postpartum uterine atony andhemorrhage: Methergin, PG, O*Cause uterine contraction after cesarean

section: Methergin, PG, O*Induce therapeutic abortion: RU486, PG, O*


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Induction of labor

Caution : continuation of pregnancy is consideredrisk to the mother or fetus than risk of pharmacological induction.

Maternal DM: LGAIso-immunization: Rh incompatibilityHypertensive states: Preeclampsia, eclampsia

AnemiaProlong pregnancy with placentalinsufficiency


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Contraindication (C/I)

Abnormal fetal positionEvidence of fetal distress,

Previous uterine surgery


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1. Oxytocin (Syntocinon, Pitocin)

1mg(O*)=500 1cc(O*) O*= 10


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Action on Uterus :

:contracts mammalian uterus

:pregnant, at term, O*, i.v.causes regular coordinatedcontraction which travel from fundus to cervix


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:Amplitude and frequency of the contractions dose, complete relaxation between contractions.

Large dose of oxytocin ::Increase in frequency of contraction, incompleterelaxation between contraction

Very high dose :

:Sustained contractions interfere with blood flow

through the placenta fetal distress

Action on the mammary glandContraction of the myo-epithelial cells of themammary gland milk let down


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Action on the CVS : the vasculatureIntravenous push marked relaxation of

vascular smooth muscle : sudden drop of BP reflex tachycardia ,flushing

should dilute and use slow rate of infusion

Action on the kidneyWeak vasopressin-like antidiuretic action ,

If large doses >20 m

/ml: potent diuretics water intoxication, convulsion, coma, death


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Oxytoxin : stimulate production of PGF 2alpha by the decidua cell chorion

initiate labor: endo O * & exo O*action on decidua cell, chorionaction on myometrium: susceptibility

Low~ GA (20-30 wks.)-(34-term)High ~ Term-labor

Vasopressin + another neurohypophysealhormone : more potent in myometrialstimulant>O* in non preg. ut.&1 st trimester


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PharmacokineticsIV route & effective in short period

Distribution through placenta10 O*+1,000 cc. isotonic solution(conc.=10m /ml)

Dose 10-20 m / ml continuous iv drip 5-10drop/min

= Keep contraction 45-60 sec= Duration q 2-3 min., adjust q 15-30 min.

= Not more than 40m /ml


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i.v.

Onset ~1-2 minDuration~60 minT1/2 ~ 3-5 minMaximal steady-state ~30-60 min


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Inactivated removal of oxytocin fromplasma by Kidney, Liver

During pregnancy oxytocinase enzyme,derived from the placenta : localregulation of oxytocin in the uterus


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Clinical use The drug of choice (well established) to induce labor and toaugment labor : close adjust dose clinical evaluation

success indicator are Bishop score, paturition and GATreat post-partum hemorrhage,10 i.m. or intramyometrium routePromote lactation

Side effects : = Serious hypotension with associatedtachycardia: rare

= Water intoxication,volume overload: rare= Uterine hyperstimulation: fetal distress:

can correct by terbutaline 0.25mg iv. or im.


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2. Ergometrine (Ergonovine), (Methergin R/)Ergot is the product of a fungus ( Carviceps purpurea ).

ergometrine recognised as the oxytocic alkaloid

Actions

Selective action on the myometrium.Use in 3 rd/ labor(placenta delivery)If use in 2 nd/ labor can cause hypoxia,retain

placentaC/I - HT :can cause severe HT

- Heart dz.pregnancy: can cause increasepreload may produce CHF


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Rapid stimulant effect,on the post-partumperiod

( so use for control ______________ )Little effect,on a normally uterusProlong series of strong contractions +

markedly increased resting tone sustainedcontracture not suitable for facilitation of labor

Moderate vasoconstriction actionMechanism of action

Act on ergot alkaloid in the myometrium

action -


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3. Ecosanoids ,PG-analogues : E1,E2,F2 ,E 2

Found in ovary, myometrium and menstrualfluid: mostly E and FE&F: NP and P uterus

= Induce retraction of internal os of cervix (thining Cx)= Cervix dilatation

In P uterus at term and during labor, PG conc.

rise in amniotic fluid,umbilical cord bl. andmaternal bl. [source : fetal mb.: decidual cell]


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Actions : myometrium

Cause coordinated contractions of the body of theuterus along with relaxation of the cervix (butincreases uterine tone and may produce prolonguterine contractions fetal distress)

Effective > oxytocin in earlier months

Mechanism of actions


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Clinical use E2 ,F2 (carboprost) ,E1(misoprostal) , E2 E2 and F2alpha, : midtrimester therapeutic abortions

Alternative to ergometrine in postpartum hemorrhage20 tri.,PG much more effective > oxytocin


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First -trimester abortions: the combination of methodof evacuation with PG: PGE 1 analogue (gemeprost),vaginal pessary

Side effects Hyperstimulation (uterine pain) can causeut.rupture

Nausea, vomiting, headache, diarrheaPhlebitis at the site of injectionTransient pyrexia


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5. Peptides

Vasoactive intestinal peptides ( VIP)

inh .ut.contractn/

both NP and early P Substance P sti .ut.contract n/

6. lon channels

Ca 2+entry blocker inh .ut.contract n/ Ca 2+channel activator sti .ut.contract n/

7. Histamine pass H 1-receptor sti ut. contract n/


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Drugs that inhibit uterine motility

Tocolytics drugs

Rx dysmenorheaRx or prevent abortion


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Premature labor Termination ? Y or N ? Continue ?Dangerous ? Risk for fetus ?absolute bed rest (quieting uterus), maternalhydration: independent factor?? Success or notIf this fails : tocolytics may be administeredRx : tocolytic drugs, steroids, antibioticsTocolysis is usually not attempted if themembrane have rupture, since there is riskof infection.


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Other C/I for tocolysis:

1. Active labor(Cx dilate 3-5 cm)2. PROM-rupture mb.3. Severe medical complication of mother : eclampsia, severe pre-

eclampsia -HEELP syndrome, CVS dz.4. High risk pregnancy : antepartum hmg.,

, chorioamnionitis, premature detachment of the placenta,abruptio placenta

5. High risk of fetus: fetal distress , death fetus in utero, major congenital malformation-incompatible with life, IUGR,fetaldistress, Rh isoimmunization, Hb Barts hydrops fetalis

6. Serious underlying of maternal dz. that C/I in use 2-agonist :uncontroll DM,heart dz., HT, hyperthyroid, severe liver dz.


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Tocolytic drugsI/D

Delay or prevent premature labor: -agonistSlow or arrest delivery for brief period(


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1. 2-adrenergic agonistsIsoxuprine (Duvadilan R)

Hexoprenaline(Ipradol), orciprenaline(Alupent)Ritodrine (Yutopar R- FDA approve) Terbutaline (Bricanyl R)***( ), sc,iv(risk

pulmonary edema)Albuterol, buphenin(Nylidrin)Fenoterol (Berotec R)Salbutamol(Ventolin R)***

Tocolytic drugs


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Oral -agonist: salbutamol(ventolin),terbutaline(bricanyl)

parenteral (subcutaneous) 48 hrs Ritodine (USA-FDA approve1980)

iv. Tocolysis Terbutaline

S/E


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S/E Metabolic :

hyperglycemia

hypokalemialactic&ketoacidosis

CVS : tachycardia140, hypotension, arrhythmia,

CHF, pulmonary edemaOther S/E : N/V,headache,fever,chill

Stop 2 when

HR(mother)>140Hypotension sys >20,Dias >10Fetal distress

Labor progress : contraction,Cx dilate


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Mechanism of MgSO 4 : Mg 2+ 1. Inhibit neuromuscular & cardiac conduction system

transmission :Prevent convulsionMild vasodilator BP(minimal effective)

Cant Rx HT 2. Decrease contractility of smooth muscle from

competitive antagonist to Ca in cellular diffusion

process intracellular Ca to bind with MCLK :Ut.,heart3. Suppress CNS,RS

l h ( d l ) h d h


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S/E : Flushing(vasodilate), headacheLethargy, muscle weaknessChest painN/V, dryness of mouth

High plasma concentration produce inhibition of cardiac conduction and neuromuscular transmission

3.Anti PG:PG synthetase inhibitors

Salicylates, ketorolac, sulindac Indomethacin(more limitation,


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Mechanism: inh. PG synthesis (PG : ut.contraction)Disadvantage :

Premature closure of ductus arteriosus Pulmonary HT in newborn

HF Coagulation disorder

4. Ca channel blocking drugs : nifedipine*** tocolytics ( , S/E,sublingual ) , verapamil

Decrease intracellular Ca : ut.relax

S/E : hypercapnia, acidosis, hypoxia, decreaseut. & pla. bl. low, not recommend in inh. labor


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5. Oxytocin antagonist(Atosiban): actionat O*- in myometrium and decidua cell

6. Other : progesterone, ethanol, diazoxide,nitroglycerine, nitric oxide

Conclusion


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Factors affecting uterus smooth muscle activity

Factor Receptor

Cholinergic

AdrenergicHormones

Female sex

Neurohypophyseal

AutocoidsHistamine

5-HTPG-NPPG-P

PeptidesIon channels

Excitation

Muscarinic Alpha 1

Estrogen

OxytocinVasopressin

H1

5-HT 2F2alpha E2,F 2alphaSubstance PCa 2+ ch.activator

Inhibition

Beta 2

Progestins

H2(rat/mouse)

E2 I2VIP(NP,early P)Ca 2+entry blocker

Conclusion

uterine motilitymd20.8.55 sheet.pdf

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