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Life Cycles: Unit 2 > Drug Use in Pregnancy > Flashcards

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1

Normal progression of labor

  • 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

Characteristics of absorption of drugs across placenta

  • 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

Characteristics of distribution of drugs across placenta

  • 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

Characteristics of metabolism of drugs across placenta

  • 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

Potential drug effects of fetus [of drugs that cross placenta]

  • 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

General characteristics of drug use in breast-feeding women

  • 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

Medication choice in breastfeeding mother

  • 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

PDE-i: MOA

  • 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

PDE-i: pharmacokinetics

  • 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

PDE-i: adverse rxns

  • 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

PDE-i: Drug Interactions

  • Nitrate vasodilators:  Severe hypotensive episodes possible
  • Alpha-adrenergic blockers
  • symptomatic hypotension possible
  • CYP450 Inhibitors
  • lower starting doses of PDE inhibitors should be used.  

12

Oxytocic agents: examples

  • Prostaglandins
    • PGE2 / Dinoprostone (Prostin E2)
      PGE2α / Misoprostol (Cytotec)
  • Oxytocin
    • Pitocin
  • Ergot Alkaloids
    • Ergonovine, Methylergonovine

13

PGs: MOA, use

  • MOA: Prostaglandin analogues
  • Use: Cervical ripening and inducing uterine contractions

14

Oxytocin: MOA, use

  • 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

Ergot alkaloids: MOA, use

  • 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.  

16

Tocolytic agents: examples

  • Calcium Channel Blockers
    • Nifedipine
  • β2 Adrenergic Agonists
    • Tetbutaline
  • PGE Synthesis Inhibitors / COX-2 Inhibitors
    • Indomethacin, Acetominophen
  • 17 α-hydroxyprogesterone caproate
    • Makena

17

Ca-channel blockers/B2 agonists: MOA, use

  • Calcium Channel Blockers
    • Nifedipine = Oral Calcium channel blocker
    • L type calcium channels, smooth muscle selective
    • Relaxes uterine smooth muscle
  • β2 Adrenergic Agonists Tetbutaline
    • Oral, IV, SubQ
    • β2 Agonist = opens K+ channels which hyperpolarizes cells
    • Suppresses contractions

18

PGE Synthesis Inhibitors / COX-2 Inhibitors: MOA, use 

  • Indomethacin, Acetominophen
  • Oral, IV
  • NSAID therefore a prostaglandin synthesis inhibitor
  • Limited use in suppressing labor

19

17 α-hydroxyprogesterone caproate 

  • Makena
  • Natural progesterone metabolite.
  • Given once-a-week to women at high risk for preterm delivery, i.e. pregnant women with history of at least one spontaneous preterm birth. 

20

Drugs used in termination of pregnancy

  • Mifeprestone
    • Oral Progesterone antagonist
    • Decidual breakdown, detachment of blastocyst, decreases progesterone secretion from corpus luteum
  • Misoprostol
    • Oral Prostaglandin agonist
    • Uterotonic, used with mifeprestone
  • Methotrexate
    • IM Folic Acid Antagonist
    • Not FDA approved but occasionally used as a medical abortifacient.  

21