Download Review of Medications used in Preterm Labour

Review of Medications used in
Preterm Labour
HILARY ROWE BSC(PHARM)
2009-10 VIHA PHARMACY RESIDENT
J U N E 3 RD A N D 4 TH 2 0 1 0
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 death
 Respiratory distress syndrome
 Intraventricular hemorrhage
 Necrotizing 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 hrs
 Place 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 aspirin
 Stages of gestation medication is safe
o Use if < 32 weeks
o 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 safe
o All
 Side effects of medication for mom
blood pressure, dizziness, headache
Tachycardia & flushing
↓

Nitroglycerin Patches
 Risks of medication for the fetus
o 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) RCT
o 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
myometrial contractility
diminished
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 breath
o Chest discomfort, anxiety
o Hyperglycemia, hypokalemia
o Incidence of side effects are ~77%
o Medication is poorly tolerated
Salbutamol & Terbutaline
 Stages of gestation medication is safe
o Throughout gestation
 Risks of medication for the fetus:
 Tachycardia
 Hypoglycemia
from fetal hyperinsulinemia due to
prolonged maternal hyperglycemia
 Place 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 reactions
 Stages of gestation medication is safe
o >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 labour
 A 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
Thank You
ANY QUESTIONS
???
References
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?topic
Key=pregcomp/11591&selectedTitle=1%7E150&source=se
arch_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.
1.