Agent affecting uterine motility

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Objective & Outline

Review physiology of uterine contraction Pharmacolgy of drugs that affect uterine contraction :Oxytocic drugs: oxytocin, ergometrine, PG, and the others : Tocolytics: 2-adrenergic agonists, MgSO4 , PG synthetase inhibitors and the others Each group of drugs Mechanism of actions Pharmacokinetics & clinical uses Adverse drug reactions

The Uterus The motility:is under Myogenic control Neuronal control Hormonal control Uterine muscle contracts rhythmically Force and frequency of uterine contraction greatly during the menstrual cycle. Due to the effect of the complex hormonal changes which occur during the cycle

 Non pregnant uterus: = First part of menstruation cycle weak spontaneous contractions = During menstruation strong contraction ~ pregnant uterus during labor stage. 1st trimester pregnancy, uterine movement are depressed by progesterone (markedly inhibits uterine activity) from corpus luteum At the end of 3rd trimester, the contractions start to occur, and increase in force and become fully coordinated during labor stage.

Innervation:
No evidence for the existence of intrinsic nerve
plexus which controls the muscle (as occurs in GI-tract) Parasympathetic: muscarinic cholinergic fibers have a role in the control of uterine motility , but not have the effective contraction, not use in clinical practice Sympathetic: 1 receptor, excitatory 2 receptor, inhibitory All subtype adreno-receptors are clearly demonstrated in the myometrium,and other receptors : PG, ergot alkaloid, oxytocin receptor

Pharmacology of the drugs

Drugs : change([Ca2+]I) by or Ca2+ influx or efflux to the cell Agonist bind receptor initiate Contraction : Ca2+ by activate - Voltage operated Ca2+channels (VOC) or - Receptor operated Ca2+channel(ROC) and Ca2+ release from SR by inositol triphosphate(IP3) Relaxation : Ca2+ by inactivate VOC or ROC intracellular Ca2+ or Ca2+ efflux from cytoplasm

Physiology of muscle contraction

Review

:Oxytocic drugs
Oxytocin(Syntocinon,Pitocin),O* Ergometrine (Ergonovine), (Methergin) PG-analogues : E1,E2,F2,E2 Hormone: Estrogen Peptides: Substance P Calcium channel activator Histamine receptor agonist Others: RU486, Relaxin, NO, Cytokines

Oxytocic drugs
Clinical Use:
Induce or augment labor: O*, PG Control postpartum uterine atony and hemorrhage: Methergin, PG, O* Cause uterine contraction after cesarean section: Methergin, PG, O* Induce therapeutic abortion: RU486, PG, O*

Induction of labor
Caution:
continuation of pregnancy is considered risk to the mother or fetus than risk of pharmacological induction. Maternal DM: LGA Iso-immunization: Rh incompatibility Hypertensive states: Preeclampsia, eclampsia Anemia Prolong pregnancy with placental insufficiency

Contraindication (C/I)
Abnormal fetal position Evidence of fetal distress, Previous uterine surgery

1. Oxytocin (Syntocinon, Pitocin) 1mg(O*)=500 1cc(O*) O*= 10

Action on Uterus:

:contracts mammalian uterus :pregnant, at term, O*, i.v.causes regular coordinated contraction which travel from fundus to cervix

:Amplitude and frequency of the contractions dose, complete relaxation between contractions. Large dose of oxytocin: :Increase in frequency of contraction, incomplete relaxation between contraction Very high dose:
:Sustained contractions interfere with blood flow

through the placenta fetal distress Action on the mammary gland Contraction of the myo-epithelial cells of the mammary gland milk let down

Action on the CVS : the vasculature Intravenous 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 kidney Weak vasopressin-like antidiuretic action,

If large doses >20 m/ml: potent diuretics water intoxication, convulsion, coma, death

Oxytoxin: stimulate production of PGF 2alpha by the decidua cell chorion initiate labor: endo O * & exo O* action on decidua cell, chorion action on myometrium: susceptibility Low~ GA (20-30 wks.)-(34-term) High ~ Term-labor Vasopressin + another neurohypophyseal hormone: more potent in myometrial stimulant>O* in non preg. ut.&1st trimester

Pharmacokinetics
IV route & effective in short period Distribution through placenta 10 O*+1,000 cc. isotonic solution (conc.=10m/ml)
Dose 10-20 m/ml continuous iv drip 5-10 drop/min = Keep contraction 45-60 sec = Duration q 2-3 min., adjust q 15-30 min.

= Not more than 40m/ml

 i.v.
Onset ~1-2 min Duration~60 min T1/2 ~ 3-5 min Maximal steady-state ~30-60 min

 Inactivated removal of oxytocin from plasma by Kidney, Liver During pregnancy oxytocinase enzyme, derived from the placenta : local regulation of oxytocin in the uterus

Clinical use
The drug of choice (well established) to induce labor and to augment labor : close adjust dose clinical evaluation success indicator are Bishop score, paturition and GA Treat post-partum hemorrhage,10 i.m. or intramyometrium route Promote lactation

Side effects : = Serious hypotension with associated

tachycardia: rare = Water intoxication,volume overload: rare = Uterine hyperstimulation: fetal distress: can correct by terbutaline 0.25mg iv. or im.

2. Ergometrine (Ergonovine), (MetherginR/) Ergot is the product of a fungus (Carviceps purpurea). ergometrine recognised as the oxytocic alkaloid Actions
Selective action on the myometrium. Use in 3rd/ labor(placenta delivery) If use in 2nd/ labor can cause hypoxia,retain placenta C/I - HT :can cause severe HT - Heart dz.pregnancy: can cause increase preload may produce CHF

Rapid stimulant effect,on the post-partum period ( so use for control ______________ ) Little effect,on a normally uterus Prolong series of strong contractions + markedly increased resting tone sustained contracture not suitable for facilitation of labor Moderate vasoconstriction action Mechanism of action Act on ergot alkaloid in the myometrium action -

Pharmacokinetic i.v., onset ~30 sec i.m., onset ~2-4 min Oral, onset ~ 4-8 min Duration of action ~ 3-6 hr Clinical use = Postpartum hemorrhage = Management of the third stage of labor Side effects Nausea & vomiting (effect D2- in CTZ), hypertension

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

Found in ovary, myometrium and menstrual fluid: mostly E and F E&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. and maternal bl. [source : fetal mb.: decidual cell]

 The sensitivity of ut.muscle to PGs increases during gestation E1(misoprostal,Cytotec):use in treat PU , E1( hyperstimulation, tachysystole) effective in > E2(high safety) E2(dinoprostone,cervidil,prepidyl gel): induce collagen bundle lysis + increase submucosal fluid of cervix like during on labor state (cervical ripening)

Actions : myometrium Cause coordinated contractions of the body of the uterus along with relaxation of the cervix (but increases uterine tone and may produce prolong uterine contractions fetal distress) Effective > oxytocin in earlier months Mechanism of actions

Clinical use
E2,F2(carboprost),E1(misoprostal), E2 E2 and F2alpha, : midtrimester therapeutic abortions Alternative to ergometrine in postpartum hemorrhage 20 tri.,PG much more effective > oxytocin

 First -trimester abortions: the combination of method of evacuation with PG: PGE1 analogue (gemeprost), vaginal pessary

Side effects Hyperstimulation (uterine pain) can cause ut.rupture Nausea, vomiting, headache, diarrhea Phlebitis at the site of injection Transient pyrexia

5. Peptides Vasoactive intestinal peptides (VIP) inh.ut.contractn/ both NP and early P

Substance P sti.ut.contractn/ 6. lon channels

Ca2+entry blocker inh.ut.contractn/ Ca2+channel activator sti.ut.contractn/

7. Histamine pass H1-receptor sti ut. contractn/

Drugs that inhibit uterine motility

Tocolytics drugs Rx dysmenorhea Rx or prevent abortion

Premature labor
Termination ? Y or N ? Continue ? Dangerous ? Risk for fetus ? absolute bed rest (quieting uterus), maternal hydration: independent factor?? Success or not If this fails : tocolytics may be administered Rx : tocolytic drugs, steroids, antibiotics Tocolysis is usually not attempted if the membrane have rupture, since there is risk of infection.

 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 preeclampsia -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,fetal distress, 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.

Tocolytic drugs
I/D Delay or prevent premature labor: -agonist Slow or arrest delivery for brief period(<48hrs.) in order to undertaken other therapeutic measures: FHS or wait for lung maturation of fetus by steroids induced(prevent ARDS in premature labor) Prevent abortion = Pseudopregnancy(progesterone)

Tocolytic drugs
1. 2-adrenergic agonists
Isoxuprine (DuvadilanR)
Hexoprenaline(Ipradol), orciprenaline(Alupent) Ritodrine (YutoparR- FDA approve) Terbutaline (BricanylR)***(), sc,iv(risk

pulmonary edema) Albuterol, buphenin(Nylidrin) Fenoterol (BerotecR) Salbutamol(VentolinR)***

 Oral -agonist: salbutamol(ventolin), terbutaline(bricanyl) parenteral (subcutaneous) 48 hrs Ritodine (USA-FDA approve1980) iv. Tocolysis

Terbutaline

S/E Metabolic : hyperglycemia hypokalemia lactic&ketoacidosis CVS : tachycardia140, hypotension, arrhythmia, CHF, pulmonary edema Other S/E : N/V,headache,fever,chill Stop 2 when HR(mother)>140 Hypotension sys >20,Dias >10 Fetal distress Labor progress : contraction,Cx dilate

2. MgSO4 Use to prevent & Rx convulsion from severe preeclampsia, eclampsia Not suppress mother & fetus CNS, safety, maternal Mg blood level= fetal Mg blood level, reduce uterine contraction in tocolytic regimen Pharmacokinetics Mg2+: Vd > sucrose , well distribution to enter ECF bone cell , most not binding to prot., most excrete in urine, T1/2= 4 hrs., if GFR decrease- T1/2 will increase, toxicity will increase

 HyperMg2+(normal 1.6-2.6) produce anticonvulsant prophylaxis effect, EKG change Loss of deep tendon reflex Resp.paralysis General anesthesia Cardiac arrest In normal renal function, MgSO4 may be a useful alternative when the use of -2 agonist is C/I

Mechanism of MgSO4 : Mg2+

1. Inhibit neuromuscular & cardiac conduction system transmission : Prevent convulsion Mild 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.,heart 3. Suppress CNS,RS

 S/E :

Flushing(vasodilate), headache Lethargy, muscle weakness Chest pain N/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, <48-72 hrs.) Naproxen Meclofenamic acid

 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, decrease ut. & pla. bl. low, not recommend in inh. labor

5. Oxytocin antagonist(Atosiban): action at O*- in myometrium and decidua cell 6. Other : progesterone, ethanol, diazoxide, nitroglycerine, nitric oxide

Conclusion
Factors affecting uterus smooth muscle activity Excitation Factor Inhibition Receptor Cholinergic Adrenergic Hormones Female sex Neurohypophyseal

Muscarinic Alpha1
Estrogen Oxytocin Vasopressin H1 5-HT2 F2alpha E2,F2alpha Substance P Ca2+ ch.activator

Beta2 Progestins

Autocoids Histamine 5-HT PG-NP PG-P Peptides Ion channels

H2(rat/mouse) E2 I2 VIP(NP,early P) Ca2+entry blocker