Drugs in Pregnancy and Lactation Flashcards
What are some of the conditions that may require drug use during pregnancy?
- nausea and vomiting
- cough/cold and allergic rhinitis
- prenatal supplementation
- UTI
- hypertension/preeclampsia
- gestational diabetes
- asthma
- depression
- epilepsy
What is a teratogen?
- agents that act to irreversibly alter growth, structure or function of the developing embryo or fetus
- derived for the greek word “teratos” meaning monster
What is the definition of teratology?
- the study of birth defects
- looks at the causes, mechanisms and patterns of abnormal development
What are some of the most common causes of birth defects?
- teratogens include viruses, environmental factors, chemicals and drugs
Describe the thalidomide tragedy?
- marketed as a sedative/anxiolytic and for morning sickness in pregnancy
- no defects in animals
- several years before birth defects linked to thalidomide and withdrawal of drug from the market
- causes limb malformations, ear, cardiovascular, GI anomalies
What is the pre-implantation period?
- time from conception to implantation - first 2 weeks
- characterized by all or nothing phenomenon
- significant insult will cause death
- generally not the cause of malformations
What is the embryonic period?
- defined as 2-8 weeks post conception
- organogenesis - development of the organs and specialized tissues
- formation of the organs occur at different times
What is the greatest period of vulnerability to teratogens?
- embryonic period
What is the fetal period?
- 9 weeks to birth
- period of growth and maturation or organs
- anomalies can still occur
- — we always need to know the timing of exposure
What drugs can cause a spontaneous abortion?
- warfarin
- toluene
- cocaine
- NSAIDs
What drugs can cause congenital anomalies?
- anticonvulsants
- isotretinoin
- lithium
What drugs can cause growth restriction?
- beta blockers
- nicotine
What are the different mechanisms of toxicity?
- receptor ligand interactions (includes receptors for hormones, growth factors, etc)
- covalent bonding (binds to endogenous molecule forming a DNA or protein complex)
- peroxidation of lipids and proteins
- interference/ inhibition of protein and enzyme function (methotrexate on dihydrofolate reductase- can lead to a folate deficiency and a neural tube defect)
Why is there a decreased absorption of drugs in pregnancy?
- decrease in gastric motility
Why is there an increased distribution in pregnancy?
- increase in maternal blood volume, decrease in plasma protein
What is the effect of an increased excretion of drugs in pregnancy? Why is this?
- there is an increased secretion of drugs due to an increase in renal blood flow
- clearance goes up and the half life goes down
The majority of placental drugs cross via _______
passive diffusion
A drug is more likely to cross the placenta if it is what?
- lipophilic
- unionized
- has a low molecular weight (< 500-600 Da)
- low protein binding
What are the maternal factors that will influence placental drug delivery?
- placental blood flow
- placental metabolism
What is the criteria to name something a potential teratogen?
- defect can be characterized
- drug proven to be able to cross the placenta
- exposure occurred during the critical development period for the specific defect
- association must be biologically possible
- consistent epidemiological findings
- teratogenicity in animals
What are some of the most common teratogenic drugs?
- alcohol
- ACE inhibitors
- amiodarone
- carbamazepine
- coumadin
- cyclosphosphamide
- diethylstillbestrol
- isotretinoin
- litium
- methotrexate
- misoprostal
- paroxetine
- phenytoin
- tetracyclin
- valproic acid
What is the effect of using an anticonvulsant in pregnancy?
- can cause neural tube defects
- craniofacial anomalies, cleft palate
What is the effect of using an ACE inhibitor in pregnancy?
- cardiovascular malformations, microcephaly, spina bifida
What is the effect of coumadin derivatives in pregnancy?
- hypoplasia of nose/extremities, eye abnormalities, IUGR, scoliosis, deafness, and mental retardation
- fetal hemorrhage
What is the effect of using methotrexate in pregnancy?
- craniofacial and skeletal malformations
- neural defects, mental retardation
What is the effect of using isotretinoin in pregnancy?
- craniofacial abnormalities
- cardiac defects, hydrocephalus, spontaneous abortion
What is the effect of alcoholic pregnancy?
- passes easily through the placenta, delayed clearance from the fetus
- fetal alcohol syndrome- dysmorphic features (small eye openings, flattened cheekbones, indistinct philtre), prenatal/postanatal growth retardation, cognitive deficits, behavioural and learning problems
- also effects heart, kidneys, eyes and skeletal
What is the effect of cigarettes to the placenta?
- toxic to the embryo and the fetus
- vasoactive effect and reduced oxygen levels
- cleft lip and palate
- direct dose response reduction in fetal growth
- newborns of mothers who smoke weigh an average of 200 g less than nonsmokers
What is the effect of caffeine on the fetus?
- findings are unclear and inconsistent
- greater risk of miscarriage with doses over 300 mg/day
What are the main drawbacks of FDA classifications in pregnancy?
- often based on limited data (animal studies, case reports, limited or no human data)
- infrequently updated
- inconsistent assignment
- over simplifies a complex topic and doesn’t take into account
What is the major role of the pharmacist in communicating with pregnancy?
- include discussion of risk when counselling for women of child-bearing age for drugs with significant teratogenic potential
- discuss risk to mother and unborn infant if condition is treated
- consider non-pharm options
- need to determine the timing of exposure
- review the available information
- consult prescriber if further background is required
What things should be considered if therapy is required in pregnant women?
- mono therapy at lowest effective dose for shortest amount of time
- older drugs with more information generally preferred
- do other drugs in the same class carry less risk?
What is the brig’s classification of ibuprofen?
- cannot give at all in 1st and 3rd trimester
- they are associated with pulmonary hypertension in 3rd trimester and spontaneous abortion with cardiac defects, oral clefts and gastroschisis in the 1st trimester
What are the benefits of breastfeeding?
- ideal nutrients that cannot be replaced by formula
- lower rate of infection
- decreased incidence of SIDS
- enhanced neurocognitive performance
- also benefits for mother
What is the effect of codeine in breastfeeding women?
- extensively used for postpartum pain
- minor excretion of codeine and morphine into breast milk
- metabolized by CYP2D6 liver enzymes to morphine
- CYP2D6 displays significant genetic polymorphism(ultra-rapid metabolizers)
- greater risk to the infant after 4 days
What are the 3 ways that drugs transfer into breast milk?
- Transcellular: transverse capillary wall; small un-ionized lipid soluble molecules
- Intercellular (paracellular): avoids alveolar cell entirely- large molecules lg, cow milk protein
- Ionophore: polar molecules enter via binding to carrier proteins within cell membrane
What are the different drug properties that affect the transportation of drugs into the breast milk?
- molecular size
- un-ionized
- lipid solubility
- plasma protein binding
- pKa
(has the greatest chance to enter the breast milk if it is less than 200-300 Da, poorly protein bound or highly lipophilic)
What is ion trapping?
- non-ionized forms of molecules pass easily from the lipid membrane
- basic drugs with a higher pKa- generally there is a greater amount of ionized molecules in milk, therefore it is trapped
- can result in a milk/plasma ratio of >1
- opposite effect for acidic drugs
- ionized drugs are “trapped” and cannot pass back through the membrane
A high oral bioavailability means that ____ drug is absorbed by the infant
more
A longer half life means that there is a _____ chance of accumulation
greater
What are the different drug factors that need to be considered before we give a drug to someone?
- amount transferred into the breast milk
- type of drug and adverse effect profile
- pharmacokinetic properties
- is this drug generally prescribed for infants
What are the different patient factors to consider when determining if a drug is safe with lactation?
- indication
- duration of therapy (greater risk of accumulation with prolonged treatment)
- underlying conditions
- age of infant and ADME (decreased kidney and liver function, greater relative total body water, higher pH (increased absorption of some drugs), less protein binding)
What are the ideal medication properties in breastfeeding mothers?
- large molecule
- poor lipid solubility
- low oral bioavailability
- highly protein bound
- short half life
- weak acid
- minimal side effects
- used in infants
How do you calculate milk/plasma ratio?
drug concentration in milk/drug concentration in plasma
What does a high milk/plasma ratio mean?
- high values suggest that drug concentrations in milk to large degree (does not provide information about amount of drug transferred)
How do you calculate the infant dosage?
- drug concentration in milk x volume of milk
How do you calculate the daily dose?
- average drug concentration in milk x volume of milk ingested in 24 hours
Are SSRIs compatible in pregnancy?
- yes, it is considered compatible
- sertraline, paroxetine and fluvoxamine
- fluoxetine is less preferred
Are tricyclics compatible in pregnancy?
- generally low RID
- doxepin- avoid accumulation of active metabolite
What is the safety of atypical antipsychotics in pregnancy?
- less studied
What is the safety of lithium in pregnancy?
- RID 12-30%, use if there is no other options, monitor levels
The higher the RID, the ______
less safe in pregnancy
What kind of benzos should be chosen in pregnancy?
- choose drugs with a short half life and a short course of action
How should vaccines be used in pregnancy?
- they are compatible
- maternal antibodies can be found in milk, but there is no effect on infant response
- exception- yellow fever vaccine
Large doses of alcohol can decrease _________
milk production
What happens to the baby when there is a lot of alcohol consumed while breastfeeding?
- avoid chronic use- psychomotor development is delayed
- casual use is acceptable though, delay breastfeeding 2 hours after a drink
What are galactagogues used for?
- used to stimulate lactation
- dopamine antagonists stimulate prolactin production
- they are safe- have a low RID
What is the action of fenugreek as a galactagogues?
- questionable efficacy
- safety is poorly studied
What drugs should be cautioned in lactation?
- amiodarone
- certain beta blockers (atenolol and sotalol)
- lamotrigine (may reach therapeutic plasma levels, decreased metabolism)
- lithium
- mycophenolate
What drugs are absolutely contraindicated in lactation?
- cytotoxic drugs
- radiopharmaceuticals
- drugs that inhibit lactation (bromocriptine, cabergoline, ergotamine)
What are some common strategies that minimize exposure in lactation?
- choose drugs with favourable kinetics
- time doses right after breastfeeding
- minimize dose and duration
- monitor SE and drug levels
- consider alternative drug or non-pharm measures
What are some of the causes of nausea and vomiting in pregnancy?
- unknown
- hormonal changes (elevated human gonadotropin peak in the first trimester. Levels found to be higher in women with hyperemesis)
- changes in GI motility (delayed gastric emptying, decreased esophageal sphincter tone)
- H. pylori infection
What are the symptoms and course of morning sickness?
- nausea, vomiting and retching
- can occur any time of the day, not just morning
- vomitus - non bilious and no blood
Course : - begins around 4-6 weeks
- most severe between 7-12 weeks
- lessens by 12- 20 weeks
- affects 20% of women
- onset after 8-10 weeks rare
What is hyperemesis gravidarum ?
- incidence: 0.5-2%
- persistent, intractable vomiting
- dehydration, >5% weight loss, electrolyte abnormalities, ketosis
- may require hospitalization
What are the goals of therapy associated with morning sickness?
- control of sx (prevent worsening, improve functioning and quality of life)
- maintain adequate fetal and maternal nutrition
- prevent dehydration
What are some of the non-pharm managements of treating morning sickness?
- eat small amounts of food every 1-2 hours
- separate solids and liquids about 30 minutes
- try dry, bland or salty foods high in carbohydrates
- minimize spicy, fried or high-fat foods
- snack on high protein foods
- maintain adequate fluid intake - 2 litres/day; drink cold or take ice chips, popsicles, slushies
- avoid strong smells
- reduce iron supplement intake (1st trimester only)
What are the non-pharm managements of morning sickness?
- ginger- increases gastric tone
- dose: 500-1000 mg/day divided QID
- short term studies- more effective than placebo, as effective as B6
- acupuncture/acupressure
- hypnosis
What are some of the pharmacological management of morning sickness?
- pyridoxine (vitamin B6)
- dose: 40-100 mg/day
- conflicting evidence, may be useful for mild to moderate NVP - Thiamine (vitamin B1)
- ineffective for NVP
- useful for preventing deficiency in prolonged severe NVP - Doxylamine/pyridoxine
What is doxylamine/pyridoxine?
- a 1st generation antihistamine and vitamin B6
- first drug of choice in N/V
- diclectin is the trade name
What is the efficacy of diclectin?
- there was a decreased emesis and increased well being compared to placebo in those taking diclectin
What are the AE of diclectin?
- sedation, anticholinergic
What are the drugs that are used for breakthrough N/V in pregnancy?
- dimenhydrinate, diphenhydramine
- metoclopramide is reserved for more severe cases
When should ondansetron be used in those with morning sickness?
- often used in chemotherapy for N/V
- use only if other options are ineffective (can cause QT prolongation)
When should you refer for morning sickness in pregnancy?
- unable to keep food/water down > 24 hours
- significant weight loss
- signs of dehydration (increased thirst, dry mouth, weakness)
- signs of infection
- other symptoms inconsistent with NVP (neurological, hematemesis, abdominal pain)
- onset of NVP after 10 weeks or return of symptoms
