OBAT YANG MEMPENGARUHI UTERUS

DR.DATTEN BANGUN MSc,SpFK

Dept.Farmakologi & Therapeutik Fak.Kedokteran USU Medan

OBAT YANG MEMPENGARUHI

Stimulants 1. Oxytocin 2. Prostaglandins (uterotonic):

UTERUS

I.

3. Ergot alkaloids.

II.Inhibitors = (Tocolytics)

1. Beta-mimetics Ritodrine, terbutaline 2. Magnesium Sulfate 3. Indocin 4. 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
1) General Informations (1) Found in ovary, myometrium, and menstrual fluid. (2) Rise in amniotic fluid during labor 2) Pharmacological Properties (1) Myometrium a. During the last two trimesters of pregnancy, PGE2 or PGF2 causes strong uterine contractions and can induce delivery of the fetus. b. In contrast to oxytocin, prostaglandins are much more effective than oxytocin in the earlier months of pregnancy. (2) Cervix: 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 (3) Toxicity a. Stimulatory action on the smooth muscle of the alimentary tract. b. Transient pyrexia (due to actions on thermoregulatory centers in the hypothalamus). c. PGF2 - hypertension. d. PGE2 - vasodilatation.

3) Therapeutic Uses (1) Major drugs --- PGE2, PGF2, and 15-methyl PGF2. (2) Used for the performance of mid trimester abortions. (3) Potential use as cervical ripening agents to facilitate normal or induced labor. (4) Potential use to soften the cervix prior to performance of first-trimester abortions by the method of dilatation and evacuation.

Prostaglandin
Misoprostol (PGE1 analogue, given intravaginally) Soften and dilate the cervix Stimulate uterine contraction Termination of pregnancy in second trimester Second or third trimester stillbirth

3. Ergot Alkaloids; berasal dari Claviceps purpurea

- Strucural similarity to lysergic acid (LSD) Example (1) Ergotoxine (mixture of 3 alkaloids) - first alpha blocker (2) Ergotamine (Gynergen) (3) Methysergide (Sansert) (4) Ergonovine

Major effects of ergot alkaloids

= Serotonin receptor blockade = Direct stimulation of vascular and nonvascular smooth muscle

Clinical uses of ergot alkaloids

= Uterine smooth muscle stimulant for treatment of postpartum uterine atony or hemorrhaging (ergonovine, methylergonovine) = migraine Side-effects: a. Methysergide - retroperitoneal fibrosis b. Ergotamine - gangerene Contraindications a. Patients with vasospastic disorders; b. pregnant woman

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

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

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

2) Augmentation of Labor: (1) In most circumstances, oxytocin should not be used for the augmentation of labor if labor is progressing normally. (2) There are occasions, however, when oxytocin can be used advantageously by the experienced obstetrician to manage dysfunctional labor. (3) Oxytocin is usually effective in patients with a very prolonged latent phase of cervical dilatation as well as in those cases where there is a significant arrest of dilatation or descent.

3) Third Stage of Labor and Puerperium: (1) Uterine-stimulating agents are usually given after delivery of the placenta. (2) Oxytocin is given to aid in maintaining uterine tone after delivery. (3) If oxytocin is not effective, ergonovine or methylergonovine may be used in nonhypertensive patient. IM (0.2 mg) or IV (0.2 mg) for immediate action. (4) Alternatively, IM (0.25 mg) of 15-methyl PGF2 (carboprost) may be used.

4) Therapeutic Abortion
(1) Abortion during the first trimester most commonly is accomplished by means of suction curettage. (2) RU486, a synthetic 19-norsteroid (mifepristone), is a progesterone antagonist that inhibits the effect of progesterone on the uterus. (3) Prostaglandin plus mifepristone 99% success (4) During the second trimester, a. Intraamniotic injection of a hypertonic (20%) solution of sodium chloride. b. Vaginal suppositories of PGE2(dinoprostone; prostin E2). c. IM (0.25 mg) 15-metyl PGF2; HEMABATE) is used.

The Clinical Use of Drugs That Inhibit Uterine Motility (Tocolytic agents)
- Indications are: (1) to delay or prevent premature in selected individuals and (2) to slow or arrest delivery for brief periods in order to undertake other therapeutic measures.
.

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

Tocolysis
Only 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

Tocolysis
Criteria: -Assure maternal/fetal well being first no contraindication to rx no contraindication to prolonging pregnancy Diagnosis clear Cervix <4cm 24-34 weeks

Tocolysis
General Contraindications Acute fetal distress Chorioamnionitis Severe preeclampsia/eclampsia Fetal demise Fetal maturity Maternal hemodynamic instability

Tocolytic Agents
Beta-mimetics Ritodrine, terbutaline Magnesium Sulfate
Indocin Nifedipine (CCBs)

Beta-mimetics
Function:
Stimulate beta2 receptors in uterus and lung,

decrease contractility Cross react with beta2 in heart

Efficacy: 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-mimetics
Terbutaline
IV and multiple SC dosing effective in temporarily

stopping contractions SC 0.25 mg q 1-4 hours IV 0.01 mg/min, 0.005 mg/min to maximum of 0.025 mg/min Oral 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, hyperbilirubinemia Death

Contraindications: Beta-mimetics
Absolute:

Maternal cardiac disease, eclampsia, severe pre-eclampsia, hemorrhage, uncontrolled hyperthyroid, diabetes Relative: Diabetes, hypertension, migraines, sepsis

Magnesium Sulfate
Widespread use No clear evidence showing efficacy in delaying/preventing PTD Controversy: ?may increase infant mortality, but studies show less gross motor dysfunction in infants ? Works by calcium antagonist activity Load 4-6 gm IV, then 1-4 gm/hour, no wean Oral dose not effective

Magnesium Sulfate
Side 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 Sulfate
Contraindications: Myasthenia Gravis, renal failure, hypocalcemia Exam: Fluid I/O, VS, mental status hourly Pulmonary examination Reflexes (loss when level >8) Therapeutic level: 5.5-7.5 mg/dl, toxic >15 Antidote: calcium gluconate

Indocin
Inhibits prostaglandins/cytokines that trigger labor Well studied, use limited by side effects Can inhibit PTL for 48 hrs in <37 weeks Use 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

Indocin
Well tolerated by mom, causing usual NSAID side

effects Does not decrease neonatal mortality Can cause PPH, constrict fetal ductus arteriosis, oligohydramnios

Nifedipine
Inhibit contraction of smooth muscle
Very efficacious Nifedipine most widely studied CCB Some studies show as efficacious or better than beta-

mimetics with less side effects Gaining popularity as tocolytics of choice

Nifedipine
Fetal effects: No adverse fetal effects No increase congenital anomalies Maternal effects: Flushing dizziness, nausea, hypotension Contraindicated if hypotensive, cardiac disease or hemorrhage

Nifedipine
Dosing: 30 mg oral dose load 10-20 mg po q 4-6 hours

Conclusions
Various 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 .

Antibiotics
If have specific infection, treat If 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

PTD

Ampicillin 2 gms iv q 6 hours (macrolides also

effective) often used if unclear GBS/possible infection USE IN PPROM- beneficial

PTL: Steroids
Reduces RDS, IVH, NEC, infant mortality
Only treatment shown to improve fetal survival in

PTL Criteria:
Delivery likely within 7 days fetus 24-34 weeks Able to delay delivery 24-48 hr

respiratory distress syndrome (RDS) intraventricular hemorrhage

Hyaline membrane disease. (HMD)

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: Steroids
Maternal Adverse Effects Short term: glucose control, pulmonary edema, infection Long term: no adverse effects Fetal Adverse Effects No long term effects of single course Multiple course associated w/ infection, abnormal development