Drug Use in Pregnancy Flashcards
1
Q
Normal progression of labor
A
- Stage 1 = Cervical effacement and dilation
- Cervical effacement is inhibited by progesterone and stimulated by descent of the fetal head and prostaglandin synthesis.
- Dilation is dependent upon prostaglandins.
- Stage 2 = Descent of the presenting part and delivery of the fetus
- Uterine contractions are stimulated by prostaglandins and oxytocin.
- Oxytocin stimulates synthesis of PGF₂a in decidual cells.
- Prostaglandins potentiate oxytocin-induced contractions.
- Uterine smooth muscle express Beta2-adrenergic receptors that, when stimulated lead to relaxation.
- Stage 3 = Separation and delivery of the placenta
- Postpartum hemorrhage is controlled by continued contraction of the uterus
- Oxytocin promotes hemostasis.
- Stage 4 = The six hours after delivery
2
Q
Characteristics of absorption of drugs across placenta
A
- Properties of drugs that allow access to maternal circulation will also allow them access to embryonic/fetal circulation:
- Lipid solubility
- Highly lipophilic drugs will diffuse readly across the placenta and enter fetal circulation and can produce pharmacologic effects
- Highly ionized drugs such as succinylcholine or tubocurarine are used in cesarean sections but cross the placenta slowly and produce negligible plasma levels in newborns.
- Molecular size
- m.w. 250-500 [unionized, lipid soluble] ==> crosses rapidly
- 500-1000 m.w. cross with more difficulty.
- > 1000 m.w. cross very poorly.
3
Q
Characteristics of distribution of drugs across placenta
A
- Free drug equilibrates across the placenta. Total drug levels are dependent upon relative protein binding and the extent of ionization for weak acid and weak base drugs.
- Protein Binding of Drugs
- Decreased in fetal circulation relative to maternal circulation because of lower binding affinity of fetal proteins.
- Total drug lower in fetal circulation, but free drug will equilibrate.
- Fetal pH
- Fetal pH is 7.25 and maternal pH is 7.35.
- This discrepancy can lead to ion trapping especially of weak base drugs with pKa in the range of 8.0-9.0 and accumulation of drug in fetal circulation.
4
Q
Characteristics of metabolism of drugs across placenta
A
- Placenta contains numerous enzymes but the affinity of it for drugs is generally low and most drugs traverse the placenta without being metabolized.
- Important in detoxifying low level of environmental chemicals.
- Numerous enzymes capable of metabolizing xenobiotics.
- Active towards a number of steroids.
- Protects fetus against maternal hormones such as cortisol and prednisolone by converting cortisol to cortisone and prednisolone to prednisone.
- to use corticosteroids transplacentally, they cannot be substrates for placental enzymes, e.g. betamethasone.
- Drugs that cross the placenta enter fetal circulation via the umbilical vein.
- 40-60% enter the general fetal circulation directly, while the remainder will enter the fetal liver and will be subject to first pass metabolism.
5
Q
Potential drug effects of fetus [of drugs that cross placenta]
A
- Baseline risk in population for birth malformation is 3-5%. It is estimated that only 2-3% of this baseline are due to drug effects on the fetus.
- Timing of exposure is important.
- Exposure around conception can kill fetus
- First 3 months most critical in terms of anatomic malformations.
- Later stages are important for functional/behavioral deficits.
- Clinically must weigh benefits of use versus harm to fetus. Consider:
- Probability of placental transfer - drug size, charge, solubility and protein binding.
- Physiologic explanation for drug effect on fetal development or delivery process
- Risk of underlying illness to both fetus and mother
- Use of lowest therapeutic dose considering metabolic and physiologic changes in pregnancy - placental metabolism , water retention, plasma volume and heart rate.
6
Q
General characteristics of drug use in breast-feeding women
A
- Most drugs do cross into breast milk, but normally at low levels.
- Infant exposure to maternal drugs can be limited by:
- Desynchronizing breastfeeding and peak milk drug concentrations.
- Administering a dose prior to infant’s longest sleep time.
- Shorter feeding periods as fat, and thus the drug, content of milk increases during feeding period.
7
Q
Medication choice in breastfeeding mother
A
- Select drug with clinically insignificant amounts of passage into breast milk, i.e. ethanol, lithium and tetracyline concentration in milk approximates maternal plasma levels.
- Drugs with rapid clearance (>0.3L/hr/kg) and no active metabolites are generally cleared too rapidly by the mother to affect the nursing infant.
- Milk is more acidic than plasma pH 6.5 versus 7.4, and tends to accumulate basic compounds such as opioids by ion-trapping
- Lipid soluble compounds → ↑milk concentration
- High protein binding → ↓ milk concentration
- Consider drugs that impact prolactin and oxytocin: dopamine receptor agonist (↓PRL release) and antagonists that ↑PRL release and ethanol and that ↓ oxytocin release.
- Contraindicated drugs by American Academy of Pediatrics: amphetamines, cocaine, bromocriptine, ergotamine, lithium, nicotine, most antineoplastic agents and drugs of abuse.
- Drugs accumulate passively in breast milk with lipid soluble agents achieving higher concentration than in maternal blood due to the higher fat content of breast milk.
- Total dose of drugs administered to infants by this route is generally minimal.
- Possible for drugs absorbed from breast milk to accumulate in infants who are not clearing them efficiently. Measuring levels in breast milk is not clinically useful.
8
Q
PDE-i: MOA
A
- Nitric Oxide is release from cholinergically-stimulated endothelial cells and from nonadrenergic-noncholinergic neurons in the presence of sexual stimulation.
- Activates guanylyl cyclase and increases cGMP formation leading to increased vasodilation of the penile tissue.
- cGMP is metabolized by PDE type 5 in this tissue.
- PDEi’s block cGMP break down → enhance vascular relaxation → ↑blood flow.
9
Q
PDE-i: pharmacokinetics
A
- Absorption - Onset - Duration
- Sildenafil (Viagra) and vardenafil (Levitra) have onset with 1 hour, short duration of action, and delayed absorption if taken with a fatty meal.
- Tadalafil (Cialis) has a delayed onset of action of 2 hours but a prolonged duration of action (up to 36 hours).
- Can take daily
- Elimination/dosing adjustments: Hepatically metabolized → renal and fecal excretion.
- Hepatic impairment: reduce dose / avoid use for vardenafil and tadalafil
- Renal impiarment: reduce dose for sildenafil and tadalafil
- Elderly: reduce dose for sildenafil and vardenafil
10
Q
PDE-i: adverse rxns
A
- Most common side effects result from inhibition of PDE-5 in extragenital tissue → headache, facial flushing, dyspepsia, nasal congestion, and dizziness
- Sildenafil and Vardenafil produce decrease in blood pressure (generally asymptomatic). Patients with symptomatic cardiovascular disease should be evaluated prior to therapy.
- Sildenafil causes increased light sensitivity, blurred vision or loss of blue-green color discrimination due to inhibition of PDE-6 in photoreceptor cells in the retina. Mild and reversible.
- Tadalafil is associated with back and muscle pain (7-30%) that may relate to its inhibition of PDE-11 in skeletal muscle.
11
Q
PDE-i: Drug Interactions
A
- Nitrate vasodilators: Severe hypotensive episodes possible
- Alpha-adrenergic blockers
- symptomatic hypotension possible
- CYP450 Inhibitors
- lower starting doses of PDE inhibitors should be used.
12
Q
Oxytocic agents: examples
A
- Prostaglandins
- PGE2 / Dinoprostone (Prostin E2)
PGE2α / Misoprostol (Cytotec)
- PGE2 / Dinoprostone (Prostin E2)
- Oxytocin
- Pitocin
- Ergot Alkaloids
- Ergonovine, Methylergonovine
13
Q
PGs: MOA, use
A
- MOA: Prostaglandin analogues
- Use: Cervical ripening and inducing uterine contractions
14
Q
Oxytocin: MOA, use
A
- Oxytocin analogue
- Use = Augments uterine contractions at end of pregnancy, commonly induces labor after cervical ripening, postpartum hemorrhage
- Uterus is insensitive to oxytocin until weeks 20-36 weeks gestation.
15
Q
Ergot alkaloids: MOA, use
A
- Act via alpha1 and 5HT2 receptors, respectively.
- Use
- Control of late uterine bleeding and should never be given before delivery. Causes direct contraction of vascular and uterine smooth muscle.
- When oxytocin is ineffective, methylergonovine can be given at time of delivery of placenta or right after if bleeding is significant.
