5b Drugs Used in Pregnancy

What are oxytocic drugs?

Drugs that stimulate uterine contractions

What do oxytocic drugs manage?

PPH

What are tocolytic drugs?

Drugs that inhibit uterine contractions

When are tocolytic drugs used (2)?

• Preterm labour

• Uterine hypertonus

Which G proteins are associated with uterine contractions (2)?

• Gi

• Gq

How do Gi proteins cause uterine contractions?

Inactivates adenylyl cyclase = Decreased cAMP = No sequestering Ca2+ = Contractions

How do Gq proteins cause uterine contractions?

Activates PLC = PIP is cleaved into IP3 and DAG = IP3 binds to SR to release Ca2+ and DAG binds to membrane Ca2+ channels for influx = Contraction

What do oxytocic drugs mimic?

Oxytocin

What is oxytocin?

Endogenous hormone released by the pituitary gland that causes increased contraction of the uterus during labor

What oxytocin bind to?

Gq-protein coupled receptor

When do oxytocin receptors appear in myometrium?

2nd half of gestation

Why does oxytocin receptors appear in 2nd half of gestation?

Evolutionary perspective - we do not want oxytocin to bind in first half as it would risk premature uterine contractions (harms fetus)

What is the first line of oxytocic drugs?

Pitocin, Syntocinon (P and S)

How is P and S administered (2)?

• IV

• IM

How fast does IV P and S start to work and how long does it last?

Effects starts immediately after administration and lasts for an hour

Why do we want to slowly increase increments of P and S?

Jumping to high dose can cause uterine hypertonus

Increase P and S dose every - min until normal labour pattern

15-60 min

Other than uterine hypertonus, what happens if you give a large dose of P and S?

They will bind to ADH receptors (they have high affinity for them) causing:

• Pulmonary edema

• Heart failure

• Water intoxication

How fast does IM P and S start to work and how long does it last?

Takes 3-5 minutes to start working and lasts 2-3 hours

What is IM P and S good at managing?

PPH

What other drug class can we use to induce uterine contractions?

Prostaglandin agonists

How do prostaglandin agonists work (2)?

Binds to EP1 prostaglandin receptors in uterus → Gq protein activates PLC → PIP is cleaved into IP3 and DAG → Ca2+ is release from SR and enters cell through ion channel → Uterine contractions

Binds to EP3 prostaglandin receptors in uterus → Gi protein inhibits adenylyl cyclase → Decreased cAMP → No sequestering Ca2+ → Contraction

What is Dinoprostone?

Intrauterine/vaginal gel used for cervical dilation

Do we need to give P and S with Dinoprostone and why?

No, cervical dilation is enough to stimulate oxytocin for uterine contractions

How should the patient be positioned after applying Dinoprostone?

Supine or later position for 30 min to prevent leaking of gel

Can the patient take a shower or enter bathtub after Dinoprostone application?

No, water will dilute product, reducing its effectiveness

Who uses Dinoprostone?

Patients who are 41-42 weeks pregnant with no sign of labour

Why is misoprostol used (3)?

• To induce or augment uterine contractions

• Cervical ripening

• PPH management

Is misoprostol encouraged in Canada?

No, it causes aggressive contractions (risk for uterine hypertonus)

When is misoprostol used?

When P and S are unavailable

What are Ergot Alkaloids?

Second line oxytocic used when we do not have P and S in hand to control PPH

How is Ergovine given?

IM or IV

How is Methylergovine given?

PO

How do the ergot alkaloids work?

Binds to Gq-protein coupled prostaglandin E1 receptor and a-1 adrenoceptor

What does the Gq-protein coupled prostaglandin E1 receptor cause?

Uterine contractions

What does the Gq-protein coupled a-1 adrenoceptor cause?

Vasoconstriction

Should oxytocic drugs be combined?

Never, it will increase risk of uterine hypertonus

What creates the oxytocin receptors in uterus?

Estrogen from ovaries

What does the growing fetus cause?

Stretching of smooth muscle that will stimulate production of more oxytocin receptors

What does oxytocin do (2)?

• Uterine contractions

• Formation of prostaglandin receptors

What do prostaglandin receptors cause?

More uterine contractions

Why is it important that a baby latches onto its mom's nipples ASAP?

Suckling allows for increased oxytocin production, causing more contractions which manage PPH

How do tocolytic drugs work?

Decreases intracellular Ca2+ levels in uterine smooth muscle and reduces the strength of uterine contractions

When are tocolytics commonly administered (3)?

• Uterine hypertonus

• Preterm labour

• Cephalic version

What is considered preterm labour?

24-36 weeks and 6 days

We will consider tocolytic drugs up to _____ weeks of gestation?

34

Are tocolytic agent able to completely suppress myometrial contractions in the presence of strong hormonal or nerve stimulation?

No

What does the administration of tocolytic drugs allow for (3)?

• Administration of glucocorticoids (better fetal outcomes)

• Delivery to facility with NICU

• Prolongation of pregnancy in cases of acute, self-limiting conditions that are unlikely to cause recurrent preterm labour (e.g., surgery)

When should tocolytic drugs be used (3)?

• 24-34 weeks

• During real labour

• When the cervix is dilated more than 2 cm and has begun to efface (thin)

Why do we not use tocolytic drugs after 34 weeks?

No improved outcomes past 34 weeks

What is real labour?

Contractions are 2-10 min apart and last 45 sec

Complications associated with preterm birth (increase/decrease) after 34 weeks gestation

Decrease

What is recommended in week 34-36 as tocolytic drugs should not be given?

Glucocorticoids are recommended

What are the 2 drug classes of tocolytics?

• Prostaglandin inhibitor

• Calcium channel blocker

What is the prostaglandin inhibitor used?

Indomethacin

What is indomethacin also used for (3)?

• Arthritis pain

• RA

• Post-op pain

How does indomethacin inhibit prostaglandin syntehsis?

Inhibits COX1 and COX2 enzymes

What else does indomethacin inhibit?

Platelet aggregation

What does an inhibition of platelet aggregation cause?

Increased risk of bleeding

We can use indomethacin up to _____ weeks

32

What can we use after 32 weeks of gestation as a tocolytic?

Calcium channel blocker

What is the calcium channel blocker used?

Nifedipine

What does nifedipine do?

Inhibits the entry of extracellular Ca2+ into myometrial cells and slows uterine contractions

What else is nifedipine used for (2)?

• HTN

• Gestational HTN

Is nifedipine first line treatment for HTN?

No

What is the first line treatment for HTN?

Labetalol (beta-adrenergic antagonist - beta blocker)

What are the possible side effects of nifidepine?

• Headache

• Dizziness

• Flushing

• Flex tachycardia

What is magnesium sulphate?

Poor choice of tocolytic

What does magnesium sulphate help manage?

Eclampsia

When can we use magnesium sulphate?

Less than 32 weeks of gestation

Why is beta 2 adrenergic agonist a poor tocolytic choice?

Poor adverse effect profile

What are the adverse effects of beta 2 adrenergic agonist (6)?

• Tachycardia

• Tremor

• Palpitations

• Arrhythmias

• Hyperglycemia

• Myocardial ischemia

Do we use oxytocin receptor antagonists in North America?

No, it is unavailable in North America

What does glucocorticoid do for fetus?

• Improve fetal lung development

• Reduces respiratory distress syndrome (RDS)

• Reduces bleeding in the brain

• Reduces necrotizing enterocolitis and sepsis

How is betamethasone administered?

2x 12 mg IM 24 hours apart

How is dexamethasone administered?

4x 6 mg IM 12 hours apart