Drugs in Pregnancy Flashcards
What is the impact of pregnancy on a woman’s GI absorption?
Increased progesterone = reduced motility and prolonged gastric emptying
Reduced gastric sections = higher pH (less acidic)
Increased mucous secretions which reduces membrane permeability
What is the impact of pregnancy on a woman’s pulmonary absorption?
Increased tidal volume = increased pulmonary blood flow and alveolar uptake
What is the impact of pregnancy on a woman’s drug distribution?
Increased body water (plasma volume) = potential decrease in Cmax (due to dilutional effect)
What is the impact of pregnancy on protein binding?
Dilutional hypoalbuminemia (due to extra fluid)
Steroid/placental hormones may displace protein binding sites (increase unbound drug)
How does pregnancy affect hepatic metabolism in pregnant women?
Increased estrogen and progesterone:
- Increased CYP 3A4 & 2D6 = lower nifidipine, methadone, paroxetine, fluoxetine
- Reduced CYP 1A2 = higher caffeine, theophylline, clozapine, olanzapine)
- Increased UGT = lower lamotrigine, acetaminophen
What is the impact of pregnancy on renal elimination?
Increased GFR, but other mechanisms counterbalance increased GFR (less clinically relevant)
How does the fetus/placenta absorb drugs from the mother?
Mostly passive diffusion → solubility, molecular size, ionization
How does a fetus/placenta distribute drugs within itself?
- Fetal protein binding affinity different from maternal protein binding
- Fetal albumin concentration progressively increases while maternal decreases
What does metabolism look like for the fetus/placenta?
- Placenta and fetus capable of metabolism
- More polar metabolites may accumulate
What does elimination look like for fetus/placenta?
- Mainly diffusion to maternal compartment, efflux transporters present
What is the impact of untreated epilepsy/seizures on the outcome of the pregnancy?
Fetal hypoxia, injury to fetus, placental abruption, miscarriage
What is the impact of untreated hypothyroidism on the outcome of the pregnancy?
Gestational HTN, placental abruption, fetal neurologic deficits, fetal death
What is the impact of untreated asthma on the outcome of pregnancy?
- Reduced respiratory function, reduced oxygen to fetus =
intrauterine growth restriction - Fetal asphyxia
- Intrauterine fetal death
Review slide 12 for impact of drugs on congenital defects
What is a teratogen?
Agents that are capable of producing structural or functional abnormalities in the embryo or fetus
What are some negative consequences of teratogen exposure to fetus?
- Spontaneous abortion
- Congenital malformations
- Intrauterine growth restriction
- Cognitive / behavioural effects
- Carcinogenesis
- Mutations
What are some considerations when it is necessary to potentially teratogenic drugs in pregnancy?
- Timing of exposure (when during pregnancy)
- Dose and frequency of exposure (threshold unknonw for most drugs, dose low for shortest time possible)
- Amount and quality of reproductive data
What are the consequences of peri-conception teratogen exposure?
No evidence for paternal exposure having influence on birth defect risk
All or none effect (exposure in first 15 days postconception = spontaneous abortion)
What are the potential consequences of teratogen exposure in the first trimester?
Most critical time for organogenesis and physical formation
Teratogen exposure during this stage more likely to cause physical malformations
What are some potential consequences of teratogen exposure in the 2nd and 3rd trimesters?
- Functional and behavioral effects if exposure later in gestation
- Growth & intrauterine growth
- CNS development – IQ, language development, behaviour
What are some potential consequences of teratogen exposure at term (~40 week)?
Premature labour (cigarette and illicit drug use)
Neonatal withdrawal (opioids and SSRIs)
Constriction of ductus arteriosis (NSAIDs)
What are some considerations when deciding to go with medication use in pregnant women?
- Non-pharm options?
- Gestational age
- Benefit vs. risk
What are some safe drug choice tips for pregnant women?
Use single entity products
Use most effective and most reassuring safety data (new gen. vs old gen drugs)
Lowest effective dose, shortest duration
Shorter half-life if possible
How can pharmacists assist with preconception planning?
Up to six months before conception
Can help with drug management to improve fertility and
reduce exposure to potential teratogens
Help weigh risks vs. benefits
What are some non-drug factors that can influence pregnancy outcome?
- Age
- Underlying medical conditions
- Genetic conditions
- Obstetrical history (screening consultation)
- Other exposures (including ethanol and smoking)
- Socioeconomic status (affects nutrition and health care received)
Review slides 31 to 34 for drugs in pregnancy resources
Are drugs considered to be unsafe in pregnancy also considered to be unsafe in lactation?
Not necessarily
Therefore, review drug list after giving birth and consider d/c or readding therapies
What are some advantages of breastfeeding?
- Bonding (physical and emotional)
- Nutritional (benefits growth and development)
- Protective (GI infections, respiratory tract infections, SIDS)
- Enhanced cognitive development
Exclusive breastfeeding is recommended for the first 6 months
Which drugs enter human milk?
Almost all drugs which reach systemic circulation will enter human milk to some degree
Fortunately in most cases, drug levels in human milk are not likely to be at a level that is harmful to an infant and rarely produces a clinical dose in the infant
What is required to maintain milk supply?
Sufficient production and effective extraction is maintained by regularly emptying of milk supply
What are some causes of insufficient milk production?
- Previous breast surgery (augmentation or reduction)
- Poor initial feeding routines early post-partum (infrequent feeding, inadequate latch-on, parent-infant separation)
- Drugs (estrogen containing oral contraceptives, oral decongestants, antihistamines, nicotine, diuretics)
What are some causes of ineffective milk extraction?
- Poor technique
- Poor initial feeding routines early postpartum (infrequent feeding, inadequate latching, parent-infant separation)
- Abnormalities of nipple or infant’s mouth
- Blocked ducts (can cause infection, make sure breast is drained regularly and fully)
What are main considerations of drug use in lactation?
Effect of drug exposure on infant via milk (dose exposure)
Effect of drug on milk production (limit nutritional access)
What are some drug factors that enhance drug exposure to breastfeeding infant?
- Drug molecular weight over 500 daltons
- Low protein binding (more unbound)
- Small Vd
- Lipid solubility (Highly lipid soluble drugs)
- Unionized
- Drug pKa (basic drugs are more likely to be unionized in plasma, but then become ionized in acidic milk and then become trapped)
- High bioavailability
- Longer half-life
What are some parent variables that may enhance drug exposure to a breastfeeding infant?
- Milk composition (last amount of milk has higher fat content, so fat soluble drugs will be concentrated
- Concentration of drug (dose, ADME, renal/hepatic impairment)
- Drug interactions
What are some infant variables that may enhance drug exposure to a breastfeeding infant?
Milk consumption (correlates with exposure to drugs)
- Frequency of feeding decreases with age
- Volume consumed increases with age
Age (GFR and hepatic metabolism increases with age, robust by 6-12 months)
For pre-term infants (immature, permeable gut, lower capacity to metabolize and excrete drugs)
What are some potential drug effects on infant via milk?
- Drowsiness
- Irritability
- GI upset
- Diarrhea
- Constipation
- Non-dose-related toxicities (allergic sensitization, hemolysis, blood dyscrasias)
What are some methods by which infant exposure to drugs can be estimated?
- Milk to Plasma Ratio
- Relative Infant Dose
- Infant Plasma Concentrations
What is Milk to Plasma Ratio (M/P)?
Concentration of the drug in the milk compared to concentration of the drug in the plasma
A M/P ratio over 1 is considered to be concentrated
What is the significance of a Milk to Plasma Ratio (M/P) over 1?
Does not necessarily indicate safety of medication, as does not consider absolute amount of drug entering milk
What is a relative infant dose (RID)?
A means of estimating infant exposure to drugs used in lactation
Infant dose(calculated by determining drug concentration and milk volume)/maternal dose x 100%
What are safe relative infant doses for term and premature infants?
Under 10% for term infants
Under 1% for premature infants
Most medications have low penetration into milk, so RID is less than 1%
What are some characteristics of measuring infant plasma concnetrations directly to determine exposure to drug via milk?
More accurate
Accounts for absorption and elimination effects, and final exposure to drug
What are some strategies to limit infant exposure to drugs while breastfeeding?
Use drugs only if necessary
Switch to formulations with lower parental systemic exposure
Avoid feeding when drug concentrations are highest in mother (relevant for PRN drugs)
What is the utility of the “pump & dump” with respect to drugs in lactation?
Substitute with previously expressed milk or formula; current milk
pumped and discarded (contains too much drug and unnecessary exposure to baby)
What are some drugs that may reduce milk production?
- Antihistamines
- Decongestants
- Stimulants
- Diuretics
- Estrogen
- Nicotine
- Ergot alkaloids - bromocriptine
What are some drugs that may increase milk production?
- Metoclopramide
- Domperidone
- Antipsychotics
What should pharmacists do if a mother believes she has low milk production?
Refer to primary care provider
What are the most commonly prescribed medications used to increase mlk production?
Known as galactagogues
Metoclopramide and domperidone (both are dopamine receptor antagonists, stimulate prolactin release)
Can galactagoges like metoclopramide and domperidone be used regularly?
Routine use is not recomended
Limited evidence to show efficacy and potential safety concerns
Try non-pharm options first
When selecting drug therapy for breastfeeding mothers, what are some considerations?
- RIsks of not breastfeeding vs not treating condition
- Necessity of pharmacotherapy
- Published safety data
- RID if available
- Infant variables
- Drug properties
What is the role of pharmacists in drug management for lactating mothers?
Help support breastfeeding where possible
Advise use of meds with widely known efficacy & safety data
Educate parents about strategies of limiting infant exposure to drug
Communicate advantages and disadvantages of galactagogues
