OBAT YANG MEMPENGARUHIOBAT YANG MEMPENGARUHI

UTERUSUTERUS

DR.DATTEN BANGUN MSc,SpFKDR.DATTEN BANGUN MSc,SpFK

Dept.Farmakologi & TherapeutikDept.Farmakologi & Therapeutik

Fak.Kedokteran USUFak.Kedokteran USU

MedanMedan

OBAT YANG MEMPENGARUHI UTERUSOBAT YANG MEMPENGARUHI UTERUS

I. Stimulants (uterotonic):

1.1. OxytocinOxytocin2.2. ProstaglandinsProstaglandins3.3. Ergot alkaloidsErgot alkaloids..

II.Inhibitors = (Tocolytics)

1. Beta-mimeticsRitodrine, terbutaline

2. Magnesium Sulfate 3. Indocin4. Nifedipine (CCBs)

Oxytocin (pitocin)

Oxytocin adalah hormon yang sering digunakan pada masa akhir kehamilan untuk merangsang kontraksi uterus untuk induksi partus;misalnya pada:

-partus tak maju; -ada penyulit seperti: = preeclampsia, eclampsia, diabetes). to remove placenta and to control bleeding of the womb

(uterus) after childbirth.

Oxytocin:Oxytocin

Synthesised in hypothalamus and released from the posterior pituitary

Administered by IV infusion

Indications:

1. Initiates contractions of the pregnant uterus

2. Prevention and treatment of postpartum haemorrhage

Side Effects

Nausea, vomiting, cramping, and stomach pain may occur.

Serious side effects: irregular heartbeat, dizziness, lightheadedness, swelling, severe bleeding (after childbirth), seizures, headache, blurred vision,

Serious side effects in the newborn: irregular heartbeat, yellowing eyes or skin, bleeding in the eyes, seizures.

An allergic reaction to this drug is unlikely but may occur.

2. Prostaglandins 2. Prostaglandins 1) General Informations 1) General Informations     (1) Found in ovary, myometrium, and menstrual fluid. (1) Found in ovary, myometrium, and menstrual fluid.     (2) Rise in amniotic fluid during labor (2) Rise in amniotic fluid during labor

2) Pharmacological Properties 2) Pharmacological Properties     (1) Myometrium (1) Myometrium           a. During the last two trimesters of pregnancy, PGEa. During the last two trimesters of pregnancy, PGE

22 or PGF or PGF2α 2α causes causes

strong uterine contractions and can induce delivery of the fetus. strong uterine contractions and can induce delivery of the fetus.           b. In contrast to oxytocin, prostaglandins are much more effective than b. In contrast to oxytocin, prostaglandins are much more effective than

oxytocin in the earlier months of pregnancy. oxytocin in the earlier months of pregnancy.     (2) Cervix: (2) Cervix:           a. Ripening of cervix at doses that do not affect uterine motility a. Ripening of cervix at doses that do not affect uterine motility           b. Causes softening of the cervix late in the first trimester of  pregnancy b. Causes softening of the cervix late in the first trimester of  pregnancy     (3) Toxicity (3) Toxicity           a. Stimulatory action on the smooth muscle of the alimentary tract. a. Stimulatory action on the smooth muscle of the alimentary tract.           b. Transient pyrexia (due to actions on thermoregulatory centers in the b. Transient pyrexia (due to actions on thermoregulatory centers in the

hypothalamus). hypothalamus).           c. PGFc. PGF

2α 2α - hypertension. - hypertension.

          d. PGEd. PGE2 2 - vasodilatation.- vasodilatation.

3) Therapeutic Uses 3) Therapeutic Uses

    (1) Major drugs --- PGE(1) Major drugs --- PGE2, 2, PGFPGF

2α, 2α, and 15-methyl and 15-methyl

PGFPGF2α.2α.

    (2) Used for the performance of mid trimester (2) Used for the performance of mid trimester abortions. abortions.

    (3) Potential use as cervical ripening agents to (3) Potential use as cervical ripening agents to facilitate normal or induced labor. facilitate normal or induced labor.

    (4) Potential use to soften the cervix prior to (4) Potential use to soften the cervix prior to performance of first-trimester abortions by the performance of first-trimester abortions by the method of dilatation and evacuation.method of dilatation and evacuation.

Prostaglandin

Misoprostol (PGE1 analogue, given intravaginally)

Soften and dilate the cervixStimulate uterine contraction

Termination of pregnancy in second trimester

Second or third trimester stillbirth

3. Ergot Alkaloids; 3. Ergot Alkaloids; berasal dari Claviceps purpureaberasal dari Claviceps purpurea

- Strucural simila- Strucural similarrity to lysergic acid (LSD) ity to lysergic acid (LSD)

Example Example     (1) Ergotoxine (mixture of 3 alkaloids) - first alpha (1) Ergotoxine (mixture of 3 alkaloids) - first alpha

blocker blocker     (2) Ergotamine (Gynergen) (2) Ergotamine (Gynergen)     (3) Methysergide (Sansert) (3) Methysergide (Sansert)     (4) Ergonovine (4) Ergonovine

Major effects of ergot alkaloidsMajor effects of ergot alkaloids = Serotonin receptor blockade = Serotonin receptor blockade     = Direct stimulation of vascular and nonvascular = Direct stimulation of vascular and nonvascular smooth muscle smooth muscle

Clinical uses of ergot alkaloidsClinical uses of ergot alkaloids

    = Uterine smooth muscle stimulant for treatment = Uterine smooth muscle stimulant for treatment of postpartum uterine atony or hemorrhaging of postpartum uterine atony or hemorrhaging (ergonovine, methylergonovine)(ergonovine, methylergonovine)

= migraine= migraine

Side-effects:Side-effects:          a. Methysergide - retroperitoneal fibrosis a. Methysergide - retroperitoneal fibrosis           b. Ergotamine - gangerene b. Ergotamine - gangerene

Contraindications Contraindications           a. Patients with vasospastic disorders;a. Patients with vasospastic disorders; b. pregnant womanb. pregnant woman

4. The Clinical Use of Drugs That Stimulate 4. The Clinical Use of Drugs That Stimulate Uterine Motility (UTEROTONIC)Uterine Motility (UTEROTONIC)

1) Induction of Labor1) Induction of Labor: :     = Indicated inductions include those situations = Indicated inductions include those situations (diabetes, hypertensive states, placental insufficiency)(diabetes, hypertensive states, placental insufficiency) in which the continuation of pregnancy is considered in which the continuation of pregnancy is considered to be a greater risk to the mother or the fetus thanto be a greater risk to the mother or the fetus than the risks of delivery or pharmacological induction. the risks of delivery or pharmacological induction.

    Drug of choice: Oxytocin (PITOCIN; SYNTOCINON) Drug of choice: Oxytocin (PITOCIN; SYNTOCINON)                 - IV Infusion (10 milliunits/mL) - IV Infusion (10 milliunits/mL)                 - During the entire procedure, trained personnel must - During the entire procedure, trained personnel must be present. be present.                 - Uterine activity should be carefully monitored. - Uterine activity should be carefully monitored.         - If too much activity, the infusion should be immediately - If too much activity, the infusion should be immediately discontinueddiscontinued

. .

2) Augmentation of Labor: 2) Augmentation of Labor:     (1) In most circumstances, oxytocin should not be (1) In most circumstances, oxytocin should not be

used for the augmentation of labor if labor is used for the augmentation of labor if labor is progressing normally. progressing normally.

    (2) There are occasions, however, when oxytocin can (2) There are occasions, however, when oxytocin can be used advantageously by the experienced be used advantageously by the experienced obstetrician to manage obstetrician to manage dysfunctional labordysfunctional labor. .

    (3) Oxytocin is usually effective in patients with a (3) Oxytocin is usually effective in patients with a very prolonged latent phase of cervical dilatation very prolonged latent phase of cervical dilatation as well as in those cases where there is a significant as well as in those cases where there is a significant arrest of dilatation or descent. arrest of dilatation or descent.

3) Third Stage of Labor and Puerperium: 3) Third Stage of Labor and Puerperium:

    (1) Uterine-stimulating agents are usually given after (1) Uterine-stimulating agents are usually given after delivery of the placenta. delivery of the placenta.

    (2) Oxytocin is given to aid in maintaining uterine (2) Oxytocin is given to aid in maintaining uterine tone after delivery. tone after delivery.

    (3) If oxytocin is not effective, ergonovine or (3) If oxytocin is not effective, ergonovine or methylergonovine may be used in nonhypertensive methylergonovine may be used in nonhypertensive patient. IM (0.2 mg) or IV (0.2 mg) for immediate patient. IM (0.2 mg) or IV (0.2 mg) for immediate action. action.

    (4) Alternatively, IM (0.25 mg) of 15-methyl PGF(4) Alternatively, IM (0.25 mg) of 15-methyl PGF2α2α

(carboprost) may be used.(carboprost) may be used.   

4) Therapeutic Abortion4) Therapeutic Abortion

    (1) Abortion during the first trimester most commonly is (1) Abortion during the first trimester most commonly is accomplished by means of suction curettage. accomplished by means of suction curettage.

    (2) RU486, a synthetic 19-norsteroid (mifepristone), is a (2) RU486, a synthetic 19-norsteroid (mifepristone), is a progesterone antagonist that inhibits the effect of progesterone antagonist that inhibits the effect of progesterone on the uterus. progesterone on the uterus.

    (3) Prostaglandin plus mifepristone (3) Prostaglandin plus mifepristone 99% success 99% success   (4) During the second trimester, (4) During the second trimester,           a. Intraamniotic injection of a hypertonic (20%) solution of a. Intraamniotic injection of a hypertonic (20%) solution of

sodium chloride. sodium chloride.           b. Vaginal suppositories of PGEb. Vaginal suppositories of PGE

22(dinoprostone; prostin E(dinoprostone; prostin E22). ).

          c. IM (0.25 mg) 15-metyl PGF2; HEMABATE) isc. IM (0.25 mg) 15-metyl PGF2; HEMABATE) is used. used.

The Clinical Use of Drugs ThatThe Clinical Use of Drugs That Inhibit Uterine MotilityInhibit Uterine Motility (Tocolytic agents)(Tocolytic agents)

    - Indications are: - Indications are: (1)(1) to delay or prevent premature in selected to delay or prevent premature in selected

individuals and individuals and (2)(2) to slow or arrest delivery for brief periodsto slow or arrest delivery for brief periods in order to undertake other therapeuticin order to undertake other therapeutic measures.measures. ..

Premature Labor: Premature Labor: (1) Premature births account for a large (1) Premature births account for a large fraction of perinatal mortality. fraction of perinatal mortality.     (2) It is often difficult to determine whether (2) It is often difficult to determine whether premature birth is imminent, and 50% or premature birth is imminent, and 50% or more of patients who present with regular more of patients who present with regular uterine contractions will respond to bed rest uterine contractions will respond to bed rest and hydration. and hydration.     (3) In general the use of tocolytic agents is (3) In general the use of tocolytic agents is reserved for those pregnancies where the reserved for those pregnancies where the gestational age is greater that 20 weeks and gestational age is greater that 20 weeks and less than 34 to  36 weeksless than 34 to  36 weeks..

TocolysisOnly evidence showing acute tocolysis is

beneficial for short term PTL management, and not for PTD

No evidence that maintenance tocolysis is beneficial fro PTL or PTD at this time in large studies

TocolysisCriteria:

-Assure maternal/fetal well being firstno contraindication to rxno contraindication to prolonging pregnancyDiagnosis clearCervix <4cm24-34 weeks

TocolysisGeneral Contraindications

Acute fetal distressChorioamnionitisSevere preeclampsia/eclampsiaFetal demiseFetal maturityMaternal hemodynamic instability

Tocolytic AgentsBeta-mimetics

Ritodrine, terbutalineMagnesium Sulfate IndocinNifedipine (CCBs)

Beta-mimeticsFunction:

Stimulate beta2 receptors in uterus and lung, decrease contractility

Cross react with beta2 in heartEfficacy: shown to prolong labor 24-48

hours to allow transfer and steroid benefits

Ritodrine (FDA approved) and Terbutaline

Neither beneficial to neonatal mortality, but studies done prior to steroid use

Beta-mimeticsTerbutaline

IV and multiple SC dosing effective in temporarily stopping contractions

SC 0.25 mg q 1-4 hoursIV 0.01 mg/min, 0.005 mg/min to maximum

of 0.025 mg/minOral dose not effective in PTL (ok for PTCx)

Ritodrine: iv only, 0.1 mg/min, increase by 0.05 mg/min q 30 minutes, titrate down & stop 12 hours after contractions stopped (max 0.35 mg/min)

Maternal Side Effects: Beta-mimetics•Tremor, nervousness, , N/V, anxiety, palpitations, chest pain

•Hyperglycemia, electrolyte abnormalities

•Fluid retention, hyperkinesias•Hypertension, pulmonary edema, arrhythmias, MI, tachyphylaxis

Fetal Side Effects of Beta-mimetics

Tachyarrhythmia, heart failure, MI, hypotension

Hyper/hypoglycemia, hyperbilirubinemiaDeath

Contraindications: Beta-mimetics•Absolute:

Maternal cardiac disease, eclampsia, severe pre-eclampsia, hemorrhage, uncontrolled hyperthyroid, diabetes

•Relative:Diabetes, hypertension, migraines, sepsis

Magnesium SulfateWidespread useNo clear evidence showing efficacy in

delaying/preventing PTDControversy: ?may increase infant

mortality, but studies show less gross motor dysfunction in infants

? Works by calcium antagonist activityLoad 4-6 gm IV, then 1-4 gm/hour, no

weanOral dose not effective

Magnesium SulfateSide effects:

N/V, , warmth, sweating, flushing, hypocalcemia, tetany, muscular paralysis, hypotension, palpitations, pulmonary edema, respiratory arrest (toxic levels), cardiac arrest (rare)

Pulmonary edema worse when used with terbutaline

Crosses placenta, no adverse fetal effects (may have less reactivity)

Magnesium SulfateContraindications:

Myasthenia Gravis, renal failure, hypocalcemia

Exam:Fluid I/O, VS, mental status hourlyPulmonary examinationReflexes (loss when level >8)Therapeutic level: 5.5-7.5 mg/dl, toxic >15Antidote: calcium gluconate

IndocinInhibits prostaglandins/cytokines that

trigger laborWell studied, use limited by side effectsCan inhibit PTL for 48 hrs in <37

weeksUse in cases w/ good dating, <32 weeks Dosing:

100mg rectal dose, repeat x1 in 1-2 hours if contractions persist

25-50 mg orally q4-6 hours <48 hours for cessation of contractions

IndocinWell tolerated by mom, causing usual

NSAID side effectsDoes not decrease neonatal mortalityCan cause PPH, constrict fetal ductus

arteriosis, oligohydramnios

NifedipineInhibit contraction of smooth muscleVery efficaciousNifedipine most widely studied CCBSome studies show as efficacious or better

than beta-mimetics with less side effectsGaining popularity as tocolytics of choice

NifedipineFetal effects:

No adverse fetal effectsNo increase congenital anomalies

Maternal effects:Flushing dizziness, nausea, hypotensionContraindicated if hypotensive, cardiac disease

or hemorrhage

NifedipineDosing:

30 mg oral dose load10-20 mg po q 4-6 hours

ConclusionsVarious strategies that have been used to prevent or treat preterm labor, haven't proven effective.

Tocolysis should be considered only for 2 days- if needed - for corticosteroids thereby , or in utero transfer to a tertiary center .

AntibioticsIf have specific infection, treatIf known GBS+, treat (no benefit PTL, but

decrease transmission to infant)Empiric antibiotics in PTL w/ intact

membranes:Conflicting results: no short/long term benefits,

delay of PTDAmpicillin 2 gms iv q 6 hours (macrolides

also effective) often used if unclear GBS/possible infection

USE IN PPROM- beneficial

PTL: SteroidsReduces RDS, IVH, NEC, infant mortalityOnly treatment shown to improve fetal

survival in PTLCriteria:

Delivery likely within 7 daysfetus 24-34 weeks Able to delay delivery 24-48 hr

respiratory distress syndrome (RDS) Hyaline membrane disease. (HMD)intraventricular hemorrhage

PTL: Steroids•Use between 32-34 weeks arguable- may no benefit RDS but may benefit IVH up to 34 weeks

•Regimens:-Betamethasone 12 mg IM, 2 doses, q 24 hr -Dexamethasone 6 mg IM, 4 doses, q 12 hr

PTL: SteroidsMaternal Adverse Effects

Short term: glucose control, pulmonary edema, infection

Long term: no adverse effectsFetal Adverse Effects

No long term effects of single courseMultiple course associated w/ infection,

abnormal development