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

ANY QUESTIONS???

Thank You

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.