Review of Medications used in Preterm Labour
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Transcript of Review of Medications used in Preterm Labour
HILARY ROWE BSC(PHARM)2009-10 VIHA PHARMACY
RESIDENTJUNE 3R D AND 4 T H 2010
Review of Medications used in Preterm Labour
Objectives
For each medication discussed: Describe the mechanism of action Know the Loading and Maintenance dose for
medications used at VGH Name 3 side effects of each medication for
mom Name 2 risks of each medication for the fetus Know how long to use each medication List what stages of gestation each medication
is safe
Tocolytic Medications
Tocolytic: A medication used to suppress uterine contractions
Preterm Labour: Progressive dilatation of the cervix with uterine contractions between 20+0 and 36+6 weeks gestation
Goals of Therapy: Provide time for safe transport of the mother Prolong pregnancy when there are self-
limiting conditions that can cause labor
Tocolytic Medications
Goals of Therapy Continued: Delay delivery by >48 hrs so glucocorticoids
(eg. betamethasone) given to mother have time to work
Glucocorticoids reduce the risk of Neonatal deathRespiratory distress syndromeIntraventricular hemorrhageNecrotizing enterocolitis
Mechanisms of Action
1. Generation or alteration of intracellular messengers
B-agonists, Nitric oxide donors, Magnesium sulfate, Calcium channel blockers
2. Inhibiting the synthesis or blocking the action of known myometrial (muscle of the uterus) stimulants
Oxytocin antagonists or Prostaglandin synthesis inhibitors
Indomethacin (COX inhibitor)
M of A: Non-steroidal anti-inflammatory Prostaglandins enhance formation of myometrial
gap junctions Increase intracellular calcium by ↑
transmembrane influx & release of calcium from the sarcoplasmic reticulum
Indomethacin
Loading and Maintenance dose Initial Dose: 100mg rectal suppository Maintenance Dose: 25-50mg orally or rectally
q4-6 hr for 24-48 hrsPlace in Therapy
First choice providing patient is suitable BCPHP recommends this choice
Indomethacin
● Side effects for mom Headache, nausea, dizziness & dyspepsia GI bleeding and inhibition of platelet aggregation Nephritis Fluid retention & HF infection may be masked (antipyretic effects)
Avoid if asthma or allergy to aspirinStages of gestation medication is safe
o Use if < 32 weekso Use in gestational age >32 weeks is associated
with premature closure of the ductus arteriosus
Indomethacin
Risks of medication for the fetus Therapy > 48 hours may cause oligohydramnious
and platelet dysfunction Premature closure of the ductus arteriosus is related
to both gestational age and length of therapy Increase in the incidence
Neonatal pulmonary hypertension Intraventricular hemorrhage Necrotizing enterocolitis
Duration of Use Strictly limited to 48hrs
Nifedipine (Calcium Channel Blocker)
M of A: Acts as a smooth muscle relaxant Directly blocks influx of calcium through cell
membrane & release of intracellular calcium from sarcoplasmic reticulum
↓ in calcium inhibits myosin light chain kinase muscle relaxation
Nifedipine
Loading and Maintenance dose Initial dose:
Nifedipine 10mg PO q15min until contractions stop (4 doses max, or 40mg in 1 hour)
Maintenance dose: 8 hours after loading dose; Nifedipine XL
30mg PO q12h (max daily dose 120mg)
Nifedipine
Side effects of medication for mom Tachycardia, rarely palpitations, flushing Transient hypotension, weakness & dizziness Peripheral edema
Stages of gestation medication is safe All weeks
Nifedipine
Risks of each medication for the fetus Possible reductions in uterine and umbilical
blood flow (not proven in human studies)Duration of Use
No limit unless: 48 hours after the first dose of
corticosteroids has been administered to patient
Significant side effects occur Delivery is imminent
Nifedipine
Place in Therapy Not in BCPHP Guidelines (2005) Compared to older agents has a better
side effect profile First line if >32 weeks gestation
Nitroglycerin Patch (Nitric Oxide Donor)
M of A: Nitric Oxide is involved in maintaining normal uterine tone during gestation Nitroglycerin is a nitric oxide donor that ↑ cGMP
synthesis inactivates myosin light chain kinase smooth muscle relaxation
Nitroglycerin Patches
Loading and Maintenance Dose: 500 mL normal saline IV over 30 minutes Apply nitroglycerin patch (0.4 mg/hour)
transdermally If after 1 hour there is continued cervical changes
and/or contractions are more frequent than 4 in 20 minutes, apply 2nd nitroglycerin patch
If after 1 hour following 2nd patch there is additional cervical changes and/or contractions are more frequent than 4 in 20 minutes contact physician
Replace patch(es) in 24 hrs x once only
Nitroglycerin Patches
Stage of gestation medication is safeo All
Side effects of medication for mom ↓ blood pressure, dizziness, headache Tachycardia & flushing
Nitroglycerin Patches
Risks of medication for the fetuso Maternal hypotension could ↓ uterine and
placental blood flow (no adverse effects reported)Duration of Use
Remove all patches after 48hrs from initial patch application
There is little evidence: small (n=153) RCTo Use in <32 weeks gestation showed a reduction
in neonatal morbidity and mortality as a result of decreasing birth before 28 weeks
Not commonly used
Salbutamol & Terbutaline (Beta agonists)
M of A: Beta-agonists bind beta-2 adrenergic receptors and ↑ cAMP inactivates myosin light-chain kinase diminished myometrial contractility
Salbutamol & Terbutaline
Terbutaline IV or SC (not available in Canada) Salbutamol IV, PO or Inhaler available in
Canada but there are no dosing guidelines available
Side effects of medication for mom o Tremor, palpitations, shortness of breatho Chest discomfort, anxietyo Hyperglycemia, hypokalemiao Incidence of side effects are ~77%oMedication is poorly tolerated
Salbutamol & Terbutaline
Stages of gestation medication is safeoThroughout gestation
Risks of medication for the fetus: Tachycardia Hypoglycemia from fetal hyperinsulinemia
due to prolonged maternal hyperglycemiaPlace in Therapy
Rarely used in Canada, commonly used in the US
Magnesium Sulphate
M of A: Magnesium inhibits smooth muscle contractions by reducing calcium binding and distribution in the myometrium by competing for calcium binding sites.
Magnesium Sulphate
Loading and Maintenance dose Initial dose: 4 to 6g IV over 15 to 30 minutes Maintenance dose: 2 to 6g per hour (until
adequate tocolysis)Side effects of medication for mom
↓ or absent deep tendon reflexes = 1st toxicity sign
Respiratory & myocardial depression Flushing & nausea or vomiting Blurred or double vision Lethargy
Magnesium Sulphate
Stages of gestation medication is safe All
Risks of medication for the fetus Lethargy Hypotonicity Low APGAR scores Antenatal: decreased variability of the fetal
heart rate, altered cerebral blood flow, a depressed biophysical profile
Magnesium Sulphate
A systematic review including four randomized trials (n = 334 fetuses/newborns) comparing Magnesium with no treatment or placebo No evidence of a clinically important tocolytic
effect for magnesium sulfate was found Therapy did not significantly reduce the risk
of birth within 48 hours, 7 days or 37 weeks No reduction in neonatal respiratory distress,
IVH or newborn death●Place in Therapy
No longer used
Atosiban (Oxytocin Antagonist)
M of A: A selective oxytocin-vasopressin receptor antagonist. Oxytocin stimulates contractions through a
mechanism that causes release of calcium into the cytoplasm
Oxytocin receptor antagonists compete with oxytocin for binding to oxytocin receptors in the myometrium and endometrium prevention of ↑ in intracellular free calcium
Atosiban
Loading and Maintenance dose Initial Dose: IV bolus of 6.75 mg followed by a
300 mcg/min infusion for three hours Maintenance Dose: 100 mcg/min for up to 45
hours Side effects of medication for mom
Hypersensitivity and injection site reactionsStages of gestation medication is safeo>28 weeks of gestation (higher mortality <
28 weeks)
Atosiban
Risks of medication for the fetus In one study a higher rate of fetal-infant
death was noted – deaths were associated with infection and extreme prematurity (relationship to atosiban cannot be excluded)
Duration of Use Up to 45 hours
Place in Therapy Not approved in Canada or the US
Antibiotics
Infection contributes to pre-term labourA Cochrane review evaluated broad-spectrum
prophylactic antibiotics in addition to tocolysis for inhibiting PTL up to 36 weeks in women with intact membranes Use of antibiotics did not prolong pregnancy or
result in significant reductions in delivery < 48 hours from initiating treatment
A significant reduction in maternal infection (chorioamnionitis, endometritis) with use of prophylactic antibiotics was found
Antibiotics
Evidence Continued Subgroup analysis by type of antibiotic
showed antibiotics against anaerobes was associated with a significant reduction in the number of women delivering within seven days of enrollment and fewer admissions to the neonatal intensive care unit Some caution with metronidazole as it has
been found to shorten duration of pregnancy
References
1. Simhan HN and Caritis SN. NEJM. Prevention of Preterm Delivery Aug 2, 2007; 357(5):477-487.
2. Simhan HN and Caritis SN. Inhibition of acute preterm labor [Internet]. Up to date; [Updated 2010 February 3; cited 2010 May]. Available from: http://uptodateonline.com/online/content/topic.do?topicKey=pregcomp/11591&selectedTitle=1%7E150&source=search_result.
3. Lam FL and Gill PG. B-Agonist Tocolytic Therapy. Obstet Gynecol Clin N Am. 2005; 23: 457-84.
4. British Columbia Reproductive Care Program. Obstetric Guideline 2A Preterm Labour. 2005 March.: 1-18.