Pharmacologic Implications for Special Patient Populations:

1. Pharmacologic Implications for Special Patient Populations: Pregnant Elderly Pediatric Judith A. Kaufmann, Dr PH, FNP-C Associate Professor of Nursing Robert Morris University

2. Vulnerable Populations:At Most Risk for Adverse Drug Effects and Reactions

3. Reasons: The 5 “toos” • Too few patients represented in studies to detect rare events • 30,000 people in each category would need to receive the medication to detect 1 adverse reaction in a drug that affects 1:10,000 • Too simple: patients with multiple conditions excluded from trials • Too median-aged: studies exclude patients at each end of the spectrum

4. 2 More “Toos” • Too narrow: indications for newly approved drugs are based on pre marketing clinical trials for ONE very specific condition • Once marketed, the drug may be used for untested indications • Too brief: most clinical trials are short • Some adverse effects take years to manifest clinically

5. Drugs in Pregnancy • Treatment Goals • Utilize appropriate resources to determine teratogenic risk and excretion in breast milk • Assess the risk: benefit ratio of pharmacotherapy • Utilize drug regimen that is safe, effective and minimizes risk to fetus or infant • Minimize drug exposure to neonate/infant during lactation

6. Epidemiology • ~35% of women take some medications during pregnancy • Range/pregnancy = 1-15 medications (M=2.9) • OTC medications not included • WHO study showed that non-white, unmarried, less educated women less likely to use medications • Today ~60% of women breastfeed • Over 1,000 drugs per year are evaluated for teratogenic potential • ~10% of children have abnormal physical or mental development • Only 2-3% of these are associated with medications

7. Resources for Information • Data on drugs in pregnancy and lactation are almost always POST marketing • Constantly being updated-need for immediate access to drug updates • 1979-FDA categories for Drug Use in Pregnancy • FDA’s Adverse Drug Reaction reporting system underused • MEDWATCH Program initiated in 1993

8. Lessons from the Past • Thalidomide first appeared in Germany on 1st October 1957 • marketed as a sedative with few side effects • Considered safe, used for morning sickness • Drug testing procedures were less rigorous • limited testing failed to reveal tetragenic side effects • Pre-marketing tests conducted on rodents which metabolize the drug in a different way to humans • Subsequent tests on rabbits and monkeys produced similar SEs as in humans. • Late 1950’s: post marketing reports • Pharcomelia: babies born withflipper-like limbs • AKA: 'Thalidomide Babies’

9. Pharcomelia

10. FDA Categories for Drug Use in Pregnancy • Category A: Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities • Category B: Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well-controlled studies in pregnant women.orAnimal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus.

11. FDA Categories • Category C: Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant women. or No animal studies have been conducted and there are no adequate and well-controlled studies in pregnant women • Category D:Studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the potential risk.

12. FDA Categories • Category X:Studies, adequate well-controlled or observational, in animals or pregnant women have demonstrated positive evidence of fetal abnormalities. • The use of the drug is contraindicated in women who are or may become pregnant.

13. Excellent Website • Ob.Gyn. News - Editorial

14. X-Rated Drugs • Accutane • Estrogen • Isotrentinoin • Vaccines: MMR, Varicella • CDC Advisory Committee on immunization Practices • Vaccinate all pregnant women with INACTIVATED influenza vaccine in the fall or throughout influenza season

15. Addressing Patients’ Concerns for Vaccine Safety • The US FDA approved Fluarix, an inactivated influenza vaccine for adults in 2005 • Fear of mercury and thimerosal • Spurred by media • IOM (2004) released results of analysis of potential link between thimerosal and neurobehavioral conditions and found no evidence of association • BUT… urged “full consideration …to removing thimerosal from any product given to infants, children or pregnant women”

16. Current Vaccines Available • Thimerosal-free or Thimerosal-reduced • May be added at the end of manufacturing process to prevent bacterial or fungal growth • Results in minute traces in final product Institute for Vaccine Safety - Thimerosal Table

17. Thompson, et al, (2007). Early thimerosal exposure and neuropsychological outcomes at 7 to 10 Years. NEJM. 357 (13). 1281-1292. N= 1047 children between the ages of 7 and 10 years and administered standardized tests assessing 42 neuropsychological outcomes Findings: The detected associations were small and almost equally divided between positive and negative effects. Higher prenatal mercury exposure associated with better performance on one measure of language and poorer performance on one measure of attention and functioning. Increasing levels of mercury exposure from birth to 7 months were associated with better performance on one measure of fine motor coordination and on one measure of attention and executive functioning. Increasing mercury exposure from birth to 28 days was associated with poorer performance on one measure of speech articulation and better performance on one measure of fine motor coordination

18. Pregnancy alters the Pharmacokinetics of Most Drugs • Increase in total body water (~8L) • Increase in total body fat • Increase in GFR • Decrease in gastrointestinal motility and changes in absorption and gastric acidity • Increase in CO, blood volume and plasma proteins • Decrease in plasma albumin concentration • Changes in serum albumin effect the bioavailability of protein-binding

19. Pregnancy and Pharmacokinetics • Pregnancy often accompanied by nausea and vomiting, which may prevent absorption of the medication, but… • Increased plasma volume, fetal growth, and increased interstitial tissue result in a wider distribution of medications

20. Bottom Line • Every woman requires thorough history of pregnancy complaints prior to pharmacologic treatment • Dosages may need to be considered based on the stage of pregnancy • Prescribing in pregnant patient requires more than just attention to FDA drug categories

21. In Translation… • Absorption affected by decreased GI tone • Drug remains in stomach longer leading to increase in absorption through stomach and delayed in absorption of drugs • Distribution affected by increased plasma volume causing prolonged half lives • Fat soluble drugs stay longer in the body • Drugs with high protein binding and lower lipid solubility (such as anticonvulsants) have longer half lives • Hormones (strongly protein bound) compete for available binding sites-resulting in wide distribution of free, unbound drug in the body

22. Pregnancy and Pharmacokinetics • Metabolism of drugs in liver relatively unchanged • Drugs cleared through liver eliminated similar to non pregnant women • Excretion-increased rates of clearance • Renal blood flow increases by 25-50% • GFR increases by 50% • Serum level of drug must fall to allow diffusion of drug from the fetus’s circulation

23. Placental Transfer • Simple diffusion: molecular size may/not permit transfer • Active transport: where concentration of substances are higher in fetus and transported back to the mother • Pinocytosis: where soluble molecules (such as viruses) cross membrane in small vesicles and are released • Facilitated diffusion: glucose is rapidly transferred to fetus • Leakage: fetal cells enter mother’s circulation through small membrane breaks

24. Properties of Medications that easily cross the placenta • Small molecular size and weight (250-500d) • Most drugs have weights < 600d • Non-protein bound • Non-ionized • Lipophilic

25. Selecting a Drug for a Pregnant or Nursing Mother • Principles of teratology: • Timing of exposure in fetal development • Based on fetal developmental stage when insult is applied can help predict the possible defect • Exposure at time of conception and implantation may kill the fetus (all or nothing effect) • If exposure occurs in first 14 days after conception when the cells can assume another cell’s function (totipotential), the fetus may not be damaged • Most sensitive period: time from implantation to the end of organogenesis (days 18- 60) • Damage to developing organs • heart is most sensitive during the 3rd and 4th weeks of gestation, external genitalia are most sensitive during the 8th and 9th weeks • brain and skeleton are sensitive from the beginning of the 3rd week to the end of pregnancy and into the neonatal period.

26. Factors that Influence Teratogenicity of a drug • Genotypes of the mother and fetus • Embryonic stage at exposure • Drug dose • Duration of exposure • Nature of the agent and mechanism by which it causes a defect • Simultaneous exposure to other drugs and environmental agents that potentiate a drug • Maternal and fetal metabolism of the drug • Extent to which the drug crosses the placenta

27. The safest pregnancy-related pharmacy is as little pharmacy as possible • However, women with a history of psychiatric, seizure-related, or hematologic illnesses frequently require medication throughout pregnancy. • In such patients, care must to be taken to select the safest drug from the necessary class of medication. • Misri and Kendrick noted that prescribing drugs for women during the antenatal and postnatal period is a balancing act and that no risk-free alternatives exist • Misri S, Kendrick K. Treatment of perinatal mood and anxiety disorders: a review. Can J Psychiatry. Aug 2007

28. The Male Partner… • Research is increasingly addressing the role of paternal exposure to medications before conception or during his partner’s pregnancy • Certain exposures may alter the size, shape, performance, and production of sperm • suggests that drug exposure in the male may put the fetus at risk • Animal studies have shown that paternal teratogenic exposure may lead to pregnancy loss or failure of the embryo to develop • unlike teratogenic agents affecting pregnant woman, teratogenic agents affecting the father do not seem to directly interfere with normal fetal development •  Animal studies showing that paternal teratogenic exposure may lead to pregnancy loss or embryonic failure. • Austin, 1994; Chatenoud, 1998

29. For example: • Colchicine • Pregnancy category - D • Trimester of risk - Unknown • Associated defects and complications - potential chromosome aberrations • Studies: Colchicine has been shown to cause birth defects in animals. The drug can lower sperm counts and cause sperm defects, resulting in birth defects.

30. Current EB Recommendations • In humans, no evidence of birth defects after paternal exposures, but to minimize any possible risk, counseling in men exposed to radio and chemotherapy should delay conception ~ 3 months after the end of therapy. • Male patients treated with drugs with maternal teratogenic potential should be advised to practice effective birth control during therapy and up to one or two cycles of spermatogenesis and to avoid semen contact with vaginal walls during first trimester of pregnancy. • Reproductive Toxicology, 2008

31. Drug Exposure Options for Pregnant and Lactating women • Withhold the drug (e.g., headache medications) • E.g., Ergotamine: Pregnancy category - X • Trimesters of risk - all • Associated defects and complications: LBW, and preterm birth, ergotamine-induced vasoconstriction in the placenta of pregnant women. • The effect of ergotamine most obvious in male newborn infants, particularly after treatment in the third trimester. • Delay drug therapy (if woman is close to end of lactation)

32. Options • Choose drugs that pass poorly into placenta or breast milk- (e.g., some variations even within same class of drug) • e.g., Benzodiazepines-Pregnancy category - D or X • Trimesters of risk: The first, second, and third trimesters are times or risk for flurazepam (dalmane), temazepam (restoril), and triazolam (Halcion) (category X). • Avoid alprazolam (Xanax-cat D) during pregnancy • Chlordiazepoxide(Librium) appears to be safest choice during pregnancy.

33. Options • Choose alternate routes of administration when possible • Avoid long acting/medications with long half lives • Advise lactating women to time their medications before the infant’s longest sleep period • Temporarily withhold breast feeding • Can safely resume after 1-2 half lives (50%-75% elimination) • For drugs with high toxicity, must delay 4-5 half lives • Discontinue nursing if medication is for life threatening condition (e.g., chemotherapy)

34. Treatment of Select Conditions during Pregnancy • Asthma: • Asthma complicates approximately 4% of pregnancies • In some cases, asthma improves during pregnancy • Those with poorly controlled asthma are at risk for: • Hyperemesis, uterine hemorrhage, preeclampsia, placenta previa, hypertension and premature labor

35. IMPLICATIONS of Pregnancy on Asthma • Pregnancy has a significant effect on the respiratory physiology of a woman • Respiratory rate and vital capacity do not change in pregnancy, but there is an increase in tidal volume, minute ventilation (40%), and minute oxygen uptake (20%) with resultant decrease in functional residual capacity and residual volume of air due to elevation of the diaphragm  • Airway conductance is increased and total pulmonary resistance is reduced, possibly as a result of progesterone 

36. Improved Outcomes associated with controlled asthma • Current EVIDENCE Supports Treatment • Almost all anti-asthma drugs are safe to use in pregnancy and during breastfeeding.  • Under-treating is a frequent occurrence for the pregnant patient because patients are worried about the medication effects on the fetus • With a few exceptions, the medications used to treat asthma during pregnancy are similar to the medications used to treat asthma at other times during a person's life.

37. Choice of Asthma Medications • The type and dose of asthma medications will depend upon many factors. • inhaled drugs are recommended because there are limited body-wide effects in the mother and the baby. • It may be necessary to adjust the type or dose of drugs during pregnancy to compensate for changes in the woman's metabolism and changes in the severity of asthma.

38. Common Asthma medications • Inhaled B2 Agonists • Albuterol-Category C • Mild, infrequent episodic • May cause maternal hyperglycemia, tachycardia, hypotension or neonatal hypoglycemia • Briggs, et al., 2002: study of 1090 infants exposed to albuterol in 1st trimester-possible association with polydactyly • No congential defects link in 2nd, 3rd trimester • No adverse effects during lactation • Possible B2Choice-Brethine (category B)

39. Theophylline (Cat C) • Can be used along with inhalation therapy • Preferred treatment for patients requiring long term therapy • Must monitor levels throughout pregnancy to avoid toxicity • Especially important in 3rd trimester d/t decrease in theophylline clearance and increase in volume of distribution • Keep maternal plasma concentrations as low as therapeutically possible • Crosses placenta in equal concentrations to mother • Not associated with congenital defects but can cause jitteriness, cardiac arrythmias, hypoglycemia, feeding difficulties in infants • Neonates more likely affected

40. Corticosteroids (Cat C) • Systemic corticosteroids are reserved for patients who require more urgent treatment. • Conversely, cromolyn and nedocromil (Cat B) inhibit antigen- and exercise-induced asthma. • They can be indicated as the first-line anti-inflammatory medication for the treatment of asthma • Does not have systemic absorption • ?crossing of placenta

41. Corticosteroids (cat C) • Can be given IV, PO, or inhaled • 2 reports congenital cataracts in infants exposed to prednisone throughout gestation • No association found in other studies • Spontaneous abortion, prematurity, cardiac abnormalities reported in one study ( Greenberger,1983) • Prednisone <20mg/day safe in lactation • In larger doses, delay nsg 3-4hours after dose

42. Epilepsy • > 1 million women of childbearing age have epiliepsy • <1% of pregnancies are complicated by seizures • 25% of women will have an increase in seizures during pregnancy • Women with epilepsy (with or without medication) have a higher incidence of delivering an infant with congenital malformations and mental retardation • Rates of major malformations affecting the heart, skeletal or nervous system in children born to women on anticonvulsants are at least double the rate in the general population • Occurrence: 4–6 per hundred births vs the 2-3 per hundred births risk that all pregnant women face • Benefits v risk are overwhelmingly important to consider

43. Epilepsy in Pregnancy • AAP recommends that a patient who is seizure free for 2 years undergo trial medication withdrawal before becoming pregnant • Suggested waiting period of 6 months after d/cing medication • Anticonvulsant pharmacokinetics change during pregnancy: • Lower serum concentrations due to increased renal and hepatic clearance • Decreased protein-binding capacity • Increased volume distribution • despite lower serum concentrations, seizures may not increase due to increased free drug concentrations • Must monitor concentrations of anticonvulsants closely

44. Newborns exposed to anticonvulsants • Hemorrhagic disease in newborns in first 24 hours can be fatal • Due to deficiency in Vit K clotting factors as a result of anticonvulsant exposure • All infants should be treated with Vit K at birth • Some physicians recommend Vit K for mother in last 2-4 weeks of pregnancy • Anticonvulsants also causes folate deficiencies • Prophylactic folic acid during gestation recommended to prevent megaloblastic anemia and/or neural tube defects

45. Fetal Anticonvulsant Syndrome • Can occur with all antiepileptic drugs • Phenytoin (cat D) can cause fetal hydratoin syndrome • School, learning and developmental problems, craniofacial abnormalities, growth retardation, limb defects, cardiac lesions, hernias, distal digital and nail hyoplasia • 10% risk for all of above (FHS) • 30% risk of partial expression of syndrome

46. Phenobarbital (cat D) • Less teratogenic that phenytoin but can cause heart defects and cleft palate • Can also cause coagulopathies and folate deficiencies • Also has potential to cause neonatal addiction • Found in breast milk-causes newborn drowsiness, feeding difficulties, and infantile spasms after weaning

47. Carbazamine and Valproate (Cat D) • At first, thought to be less harmful to fetus • Associated with the same congenital abnormalities plus spina bifida (1%) • Can be used with caution in lactation

48. Lamotrigine (Lamictal), Gabapentin (Neurontin) and Oxcarbazine (Trileptal)= Cat C • Recent results encouraging • Appear to be less teratogenic or associated with fetal loss in 1st trimester • Caution: more data needed

49. So…the jury is still out… • Although there appears to be a predisposition for congenital malformations in the offspring of women treated for epilepsy, it is hard to establish a causal effect with the medication • It may be a complex interaction of the medication, the nature of their disease, and genetics rather than just the medication alone • Samuels, 2002 • The three most common malformations noted in children of women treated for epilepsy are cardiac malformations, facial clefts, and genital/renal malformations.

50. The Teratogenicity of Anticonvulsant Drugs • Holmes, et al: NEJM 2001- • Methods: screened 128,049 pregnant women at delivery to identify three groups of infants: those exposed to anticonvulsant drugs, those unexposed to anticonvulsant drugs but with a maternal history of seizures, and those unexposed to anticonvulsant drugs with no maternal history of seizures (control group). The infants were examined systematically for the presence of major malformations, signs of hypoplasia of the midface and fingers, microcephaly, and small body size.