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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