Pharmacologic Implications for Special Patient Populations: PregnantElderlyPediatric Judith A. Kaufmann, Dr PH, FNP-C Associate Professor of Nursing Robert.

Pharmacologic Implications Pharmacologic Implications for Special Patient for Special Patient

Populations:Populations:PregnantPregnant

ElderlyElderly

PediatricPediatric

Judith A. Kaufmann, Dr PH, FNP-C

Associate Professor of Nursing

Robert Morris University

Vulnerable Populations:Vulnerable Populations:At Most Risk for Adverse Drug At Most Risk for Adverse Drug

Effects and ReactionsEffects and Reactions

Reasons: The 5 “toos”Reasons: The 5 “toos”

Too few patients represented in studies to Too few patients represented in studies to detect rare eventsdetect rare events30,000 people in each category would need to 30,000 people in each category would need to

receive the medication to detect 1 adverse receive the medication to detect 1 adverse reaction in a drug that affects 1:10,000reaction in a drug that affects 1:10,000

Too simple: patients with multiple Too simple: patients with multiple conditions excluded from trialsconditions excluded from trials

Too median-aged: studies exclude Too median-aged: studies exclude patients at each end of the spectrumpatients at each end of the spectrum

2 More “Toos”2 More “Toos”

Too narrow: indications for newly Too narrow: indications for newly approved drugs are based on pre approved drugs are based on pre marketing clinical trials for ONE very marketing clinical trials for ONE very specific conditionspecific conditionOnce marketed, the drug may be used for Once marketed, the drug may be used for

untested indicationsuntested indicationsToo brief: most clinical trials are shortToo brief: most clinical trials are short

Some adverse effects take years to manifest Some adverse effects take years to manifest clinicallyclinically

Drugs in PregnancyDrugs in Pregnancy

Treatment GoalsTreatment GoalsUtilize appropriate resources to determine Utilize appropriate resources to determine

teratogenic risk and excretion in breast milkteratogenic risk and excretion in breast milkAssess the risk: benefit ratio of Assess the risk: benefit ratio of

pharmacotherapypharmacotherapyUtilize drug regimen that is safe, effective and Utilize drug regimen that is safe, effective and

minimizes risk to fetus or infantminimizes risk to fetus or infantMinimize drug exposure to neonate/infant Minimize drug exposure to neonate/infant

during lactationduring lactation

EpidemiologyEpidemiology ~35% of women take some medications during ~35% of women take some medications during

pregnancypregnancy Range/pregnancy = 1-15 medications (M=2.9)Range/pregnancy = 1-15 medications (M=2.9)

OTC medications not includedOTC medications not included WHO study showed WHO study showed that non-white, that non-white,

unmarried, less educated women unmarried, less educated women less likelyless likely to use medicationsto use medications

Today ~60% of women breastfeedToday ~60% of women breastfeed Over 1,000 drugs per year are evaluated for Over 1,000 drugs per year are evaluated for

teratogenic potentialteratogenic potential ~10% of children have abnormal physical or mental ~10% of children have abnormal physical or mental

developmentdevelopment Only 2-3% of these are associated with medicationsOnly 2-3% of these are associated with medications

Resources for InformationResources for Information

Data on drugs in pregnancy and lactation Data on drugs in pregnancy and lactation are almost always POST marketingare almost always POST marketingConstantly being updated-need for immediate Constantly being updated-need for immediate

access to drug updatesaccess to drug updates1979-FDA categories for Drug Use in 1979-FDA categories for Drug Use in

PregnancyPregnancyFDA’s Adverse Drug Reaction reporting FDA’s Adverse Drug Reaction reporting

system underusedsystem underusedMEDWATCH Program initiated in 1993MEDWATCH Program initiated in 1993

Lessons from the PastLessons from the Past

Thalidomide first appeared in Germany on 1st Thalidomide first appeared in Germany on 1st October 1957October 1957 marketed as a sedative with few side effectsmarketed as a sedative with few side effects Considered safe, used for morning sicknessConsidered safe, used for morning sickness Drug testing procedures were less rigorousDrug testing procedures were less rigorous limited testing failed to reveal tetragenic side effects limited testing failed to reveal tetragenic side effects

Pre-marketing tests conducted on rodents which Pre-marketing tests conducted on rodents which metabolize the drug in a different way to humans metabolize the drug in a different way to humans Subsequent tests on rabbits and monkeys produced similar SEs as in Subsequent tests on rabbits and monkeys produced similar SEs as in

humanshumans. . Late 1950’s: post marketing reportsLate 1950’s: post marketing reports

Pharcomelia: Pharcomelia: babies born withborn with flipper-like limbsflipper-like limbs AKA: AKA: 'Thalidomide Babies’ 'Thalidomide Babies’

PharcomeliaPharcomelia

FDA Categories for Drug Use in PregnancyFDA Categories for Drug Use in Pregnancy Category A: Category A:

Adequate, well-controlled studies in pregnant women have Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalitiesnot shown an increased risk of fetal abnormalities

Category B:Category B:

Animal studies have revealed no evidence of harm to the Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well-controlled fetus, however, there are no adequate and well-controlled studies in pregnant women.studies in pregnant women.ororAnimal studies have shown an adverse effect, but adequate Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus. demonstrate a risk to the fetus.

FDA Categories Category C: Category C:

Animal studies have shown an adverse effect and there Animal studies have shown an adverse effect and there are no adequate and well-controlled studies in pregnant are no adequate and well-controlled studies in pregnant women. women. or or No animal studies have been conducted and there are No animal studies have been conducted and there are no adequate and well-controlled studies in pregnant no adequate and well-controlled studies in pregnant womenwomen

Category D:Category D:Studies, adequate well-controlled or observational, in Studies, adequate well-controlled or observational, in pregnant women have demonstrated a risk to the fetus. pregnant women have demonstrated a risk to the fetus. However, the benefits of therapy may outweigh the However, the benefits of therapy may outweigh the potential risk.potential risk.

FDA Categories

Category X:Category X:

Studies, adequate well-controlled or Studies, adequate well-controlled or observational, in animals or pregnant observational, in animals or pregnant women have demonstrated positive women have demonstrated positive evidence of fetal abnormalities.evidence of fetal abnormalities. The use of the drug is contraindicated in The use of the drug is contraindicated in

women who are women who are or mayor may become pregnant. become pregnant.

Excellent WebsiteExcellent Website

Ob.Gyn. News - Editorial

X-Rated DrugsX-Rated Drugs

AccutaneAccutaneEstrogenEstrogen IsotrentinoinIsotrentinoinVaccines: MMR, VaricellaVaccines: MMR, Varicella

CDC Advisory Committee on immunization CDC Advisory Committee on immunization PracticesPracticesVaccinate all pregnant women with INACTIVATED Vaccinate all pregnant women with INACTIVATED

influenza vaccine in the fall or throughout influenza influenza vaccine in the fall or throughout influenza season season

Addressing Patients’ Concerns for Addressing Patients’ Concerns for Vaccine SafetyVaccine Safety

The US FDA approved Fluarix, an The US FDA approved Fluarix, an inactivated influenza vaccine for adults in inactivated influenza vaccine for adults in 20052005

Fear of mercury and Fear of mercury and thimerosalthimerosal Spurred by mediaSpurred by media IOM (2004) released results of analysis of IOM (2004) released results of analysis of

potential link between thimerosal and potential link between thimerosal and neurobehavioral conditions and found no neurobehavioral conditions and found no evidence of associationevidence of association

BUT… urged “full consideration …to removing BUT… urged “full consideration …to removing thimerosal from any product given to infants, children thimerosal from any product given to infants, children or pregnant women” or pregnant women”

Current Vaccines Available Current Vaccines Available

Thimerosal-free or Thimerosal-reducedThimerosal-free or Thimerosal-reducedMay be added at the end of manufacturing May be added at the end of manufacturing

process to prevent bacterial or fungal growthprocess to prevent bacterial or fungal growthResults in minute traces in final productResults in minute traces in final product

Institute for Vaccine Safety - Thimerosal TableInstitute for Vaccine Safety - Thimerosal Table

Thompson, et al, (2007). Early thimerosal exposure Thompson, et al, (2007). Early thimerosal exposure and neuropsychological outcomes at 7 to 10 Years. and neuropsychological outcomes at 7 to 10 Years. NEJMNEJM. 357 (13). 1281-1292. . 357 (13). 1281-1292.

N= 1047 children between the ages of 7 and 10 years N= 1047 children between the ages of 7 and 10 years and administered standardized tests assessing 42 and administered standardized tests assessing 42 neuropsychological outcomes neuropsychological outcomes

Findings: The detected associations were small and almost Findings: The detected associations were small and almost equally divided between positive and negative effects.equally divided between positive and negative effects.

Higher prenatal mercury exposure associated with better Higher prenatal mercury exposure associated with better performance on one measure of language and poorer performance performance on one measure of language and poorer performance on one measure of attention and functioning. on one measure of attention and functioning.

Increasing levels of mercury exposure from birth to 7 months were Increasing levels of mercury exposure from birth to 7 months were associated with better performance on one measure of fine motor associated with better performance on one measure of fine motor coordination and on one measure of attention and executive coordination and on one measure of attention and executive functioning.functioning.

Increasing mercury exposure from birth to 28 days was associated Increasing mercury exposure from birth to 28 days was associated with poorer performance on one measure of speech articulation and with poorer performance on one measure of speech articulation and better performance on one measure of fine motor coordination better performance on one measure of fine motor coordination

Pregnancy alters the Pregnancy alters the Pharmacokinetics of Most Drugs Pharmacokinetics of Most Drugs

Increase in total body water (~8L)Increase in total body water (~8L) Increase in total body fatIncrease in total body fat Increase in GFRIncrease in GFR Decrease in gastrointestinal motility Decrease in gastrointestinal motility

and changes in absorption and and changes in absorption and gastric aciditygastric acidity

Increase in CO, blood volume and Increase in CO, blood volume and plasma proteinsplasma proteins

Decrease in plasma albumin Decrease in plasma albumin concentrationconcentration Changes in serum albumin effect the Changes in serum albumin effect the

bioavailability of protein-bindingbioavailability of protein-binding

Pregnancy and Pharmacokinetics

Pregnancy often accompanied by nausea Pregnancy often accompanied by nausea and vomiting, which may prevent and vomiting, which may prevent absorption of the medication, but…absorption of the medication, but…

Increased plasma volume, fetal growth, Increased plasma volume, fetal growth, and increased interstitial tissue result in a and increased interstitial tissue result in a wider distribution of medicationswider distribution of medications

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

In Translation…In Translation… Absorption affected by decreased GI toneAbsorption affected by decreased GI tone

Drug remains in stomach longer leading to increase in Drug remains in stomach longer leading to increase in absorption through stomach and delayed in absorption through stomach and delayed in absorption of drugs absorption of drugs

Distribution affected by increased plasma Distribution affected by increased plasma volume causing prolonged half livesvolume causing prolonged half lives Fat soluble drugs stay longer in the bodyFat soluble drugs stay longer in the body Drugs with high protein binding and lower lipid Drugs with high protein binding and lower lipid

solubility (such as anticonvulsants) have longer half solubility (such as anticonvulsants) have longer half liveslives

Hormones (strongly protein bound) compete for Hormones (strongly protein bound) compete for available binding sites-resulting in wide distribution of available binding sites-resulting in wide distribution of free, unbound drug in the bodyfree, unbound drug in the body

Pregnancy and PharmacokineticsPregnancy and Pharmacokinetics

Metabolism of drugs in liver relatively Metabolism of drugs in liver relatively unchangedunchangedDrugs cleared through liver eliminated similar Drugs cleared through liver eliminated similar

to non pregnant womento non pregnant womenExcretion-increased rates of clearanceExcretion-increased rates of clearance

Renal blood flow increases by 25-50%Renal blood flow increases by 25-50%GFR increases by 50%GFR increases by 50%Serum level of drug must fall to allow diffusion Serum level of drug must fall to allow diffusion

of drug from the fetus’s circulationof drug from the fetus’s circulation

Placental TransferPlacental Transfer Simple diffusionSimple diffusion: molecular size may/not permit : molecular size may/not permit

transfertransfer Active transportActive transport: where concentration of : where concentration of

substances are higher in fetus and transported substances are higher in fetus and transported back to the mother back to the mother

PinocytosisPinocytosis: where soluble molecules (such as : where soluble molecules (such as viruses) cross membrane in small vesicles and are viruses) cross membrane in small vesicles and are releasedreleased

Facilitated diffusionFacilitated diffusion: glucose is rapidly transferred : glucose is rapidly transferred to fetusto fetus

LeakageLeakage: fetal cells enter mother’s circulation : fetal cells enter mother’s circulation through small membrane breaksthrough small membrane breaks

Properties of Medications that Properties of Medications that easily cross the placentaeasily cross the placenta

Small molecular size and weight (250-Small molecular size and weight (250-500d)500d)Most drugs have weights < 600dMost drugs have weights < 600d

Non-protein boundNon-protein boundNon-ionizedNon-ionizedLipophilicLipophilic

Selecting a Drug for a Pregnant or Selecting a Drug for a Pregnant or Nursing MotherNursing Mother

Principles of teratology:Principles of teratology: Timing of exposureTiming of exposure in fetal development in fetal development

Based on fetal developmental stage when insult is applied can help Based on fetal developmental stage when insult is applied can help predict the possible defectpredict the possible defect

Exposure at time of conception and implantation may kill the fetus Exposure at time of conception and implantation may kill the fetus ((all or nothing effect)all or nothing effect)

If exposure occurs in first 14 days after conception when the cells can If exposure occurs in first 14 days after conception when the cells can assume another cell’s function (totipotential), the fetus may not be assume another cell’s function (totipotential), the fetus may not be damageddamaged

Most sensitive period: time from implantation to the end of Most sensitive period: time from implantation to the end of organogenesis (days 18- 60)organogenesis (days 18- 60)

Damage to developing organsDamage to developing organs heart is most sensitive during the 3rd and 4th weeks of gestation, heart is most sensitive during the 3rd and 4th weeks of gestation,

external genitalia are most sensitive during the 8external genitalia are most sensitive during the 8thth and 9 and 9thth weeks weeks brain and skeleton are sensitive from the beginning of the 3brain and skeleton are sensitive from the beginning of the 3rdrd week to week to

the end of pregnancy and into the neonatal period. the end of pregnancy and into the neonatal period.

Factors that Influence Factors that Influence Teratogenicity of a drugTeratogenicity of a drug

Genotypes of the mother and fetusGenotypes of the mother and fetus Embryonic stage at exposureEmbryonic stage at exposure Drug doseDrug dose Duration of exposureDuration of exposure Nature of the agent and Nature of the agent and

mechanism by which it causes a mechanism by which it causes a defectdefect

Simultaneous exposure to other Simultaneous exposure to other drugs and environmental agents drugs and environmental agents that potentiate a drugthat potentiate a drug

Maternal and fetal metabolism of Maternal and fetal metabolism of the drugthe drug

Extent to which the drug crosses Extent to which the drug crosses the placentathe placenta

The safest pregnancy-related pharmacy is The safest pregnancy-related pharmacy is

as little pharmacy as possibleas little pharmacy as possible However, women with a history of psychiatric, However, women with a history of psychiatric,

seizure-related, or hematologic illnesses seizure-related, or hematologic illnesses frequently require medication throughout frequently require medication throughout pregnancy. pregnancy.

In such patients, care must to be taken to select In such patients, care must to be taken to select the safest drug from the necessary class of the safest drug from the necessary class of medication.medication.

Misri and Kendrick noted that prescribing drugs Misri and Kendrick noted that prescribing drugs for women during the antenatal and postnatal for women during the antenatal and postnatal period is a balancing act and that no risk-free period is a balancing act and that no risk-free alternatives exist alternatives exist

Misri S, Kendrick K. Treatment of perinatal mood and Misri S, Kendrick K. Treatment of perinatal mood and anxiety disorders: a review. anxiety disorders: a review. Can J PsychiatryCan J Psychiatry. Aug 2007 . Aug 2007

The Male Partner…The Male Partner… Research is increasingly addressing the role of paternal Research is increasingly addressing the role of paternal

exposure to medications before conception or during his exposure to medications before conception or during his partner’s pregnancypartner’s pregnancy

Certain exposures may alter the size, shape, Certain exposures may alter the size, shape, performance, and production of spermperformance, and production of sperm suggests that drug exposure in the male may put the fetus at risksuggests that drug exposure in the male may put the fetus at risk

Animal studies have shown that paternal teratogenic Animal studies have shown that paternal teratogenic exposure may lead to pregnancy loss or failure of the exposure may lead to pregnancy loss or failure of the embryo to developembryo to develop unlike teratogenic agents affecting pregnant woman, teratogenic unlike teratogenic agents affecting pregnant woman, teratogenic

agents affecting the father do not seem to directly interfere with agents affecting the father do not seem to directly interfere with normal fetal developmentnormal fetal development

  Animal studies showing that paternal teratogenic exposure may Animal studies showing that paternal teratogenic exposure may lead to pregnancy loss or embryonic failure.lead to pregnancy loss or embryonic failure.

Austin, 1994; Chatenoud, 1998Austin, 1994; Chatenoud, 1998

For example:For example:

ColchicineColchicinePregnancy category - D Pregnancy category - D Trimester of risk - Unknown Trimester of risk - Unknown Associated defects and complications - Associated defects and complications -

potential chromosome aberrations potential chromosome aberrations Studies: Colchicine has been shown to Studies: Colchicine has been shown to

cause birth defects in animals. The drug cause birth defects in animals. The drug can lower sperm counts and cause sperm can lower sperm counts and cause sperm defects, resulting in birth defects.defects, resulting in birth defects.

Current EB RecommendationsCurrent EB Recommendations In humans, no evidence of birth defects after In humans, no evidence of birth defects after

paternal exposures, but to minimize any possible paternal exposures, but to minimize any possible risk, counseling in men exposed to radio and risk, counseling in men exposed to radio and chemotherapy should delay conception ~ 3 chemotherapy should delay conception ~ 3 months after the end of therapy.months after the end of therapy.

Male patients treated with drugs with maternal Male patients treated with drugs with maternal teratogenic potential should be advised to practice teratogenic potential should be advised to practice effective birth control during therapy and up to one effective birth control during therapy and up to one or two cycles of spermatogenesis and to avoid or two cycles of spermatogenesis and to avoid semen contact with vaginal walls during first semen contact with vaginal walls during first trimester of pregnancy.trimester of pregnancy.

Reproductive ToxicologyReproductive Toxicology, 2008, 2008

Drug Exposure Options for Pregnant Drug Exposure Options for Pregnant and Lactating women and Lactating women

1.1. Withhold the drug (e.g., headache medications)Withhold the drug (e.g., headache medications) E.g., Ergotamine: E.g., Ergotamine: Pregnancy category - X Pregnancy category - X Trimesters of risk - all Trimesters of risk - all Associated defects and complications: LBW, and Associated defects and complications: LBW, and

preterm birth, ergotamine-induced vasoconstriction preterm birth, ergotamine-induced vasoconstriction in the placenta of pregnant women. in the placenta of pregnant women.

The effect of ergotamine most obvious in male The effect of ergotamine most obvious in male newborn infants, particularly after treatment in the newborn infants, particularly after treatment in the third trimesterthird trimester..

2.2. Delay drug therapy (if woman is close to end of lactation)Delay drug therapy (if woman is close to end of lactation)

Options

Choose drugs that pass poorly into placenta or Choose drugs that pass poorly into placenta or breast milk- (e.g., some variations even within breast milk- (e.g., some variations even within same class of drug)same class of drug)

e.g., e.g., Benzodiazepines-Benzodiazepines-Pregnancy category - D Pregnancy category - D or X or X

Trimesters of risk: The first, second, and third Trimesters of risk: The first, second, and third trimesters are times or risk for flurazepam trimesters are times or risk for flurazepam (dalmane), temazepam (restoril), and triazolam (dalmane), temazepam (restoril), and triazolam (Halcion) (category X). (Halcion) (category X).

Avoid alprazolam (Xanax-cat D) during Avoid alprazolam (Xanax-cat D) during pregnancy pregnancy

Chlordiazepoxide(Librium) appears to be safest Chlordiazepoxide(Librium) appears to be safest choice during pregnancy. choice during pregnancy.

OptionsOptions Choose alternate routes of administration when Choose alternate routes of administration when

possiblepossible Avoid long acting/medications with long half livesAvoid long acting/medications with long half lives Advise lactating women to time their medications Advise lactating women to time their medications

before the infant’s longest sleep periodbefore the infant’s longest sleep period Temporarily withhold breast feedingTemporarily withhold breast feeding

Can safely resume after 1-2 half lives (50%-75% Can safely resume after 1-2 half lives (50%-75% elimination)elimination)

For drugs with high toxicity, must delay 4-5 half livesFor drugs with high toxicity, must delay 4-5 half lives Discontinue nursing if medication is for life Discontinue nursing if medication is for life

threatening condition (e.g., chemotherapy)threatening condition (e.g., chemotherapy)

Treatment of Select Conditions Treatment of Select Conditions during Pregnancyduring Pregnancy

Asthma:Asthma:Asthma complicates approximately 4% of Asthma complicates approximately 4% of

pregnanciespregnancies In some cases, asthma improves during In some cases, asthma improves during

pregnancypregnancyThose with poorly controlled asthma are at Those with poorly controlled asthma are at

risk for:risk for:Hyperemesis, uterine hemorrhage, preeclampsia, Hyperemesis, uterine hemorrhage, preeclampsia,

placenta previa, hypertension and premature laborplacenta previa, hypertension and premature labor

IMPLICATIONS of Pregnancy on IMPLICATIONS of Pregnancy on AsthmaAsthma

Pregnancy has a significant effect on the respiratory Pregnancy has a significant effect on the respiratory physiology of a womanphysiology of a woman

Respiratory rate and vital capacity do not change in Respiratory rate and vital capacity do not change in pregnancy, but there is an increase in tidal volume, pregnancy, but there is an increase in tidal volume, minute ventilation (40%), and minute oxygen uptake minute ventilation (40%), and minute oxygen uptake (20%) with resultant decrease in functional residual (20%) with resultant decrease in functional residual capacity and residual volume of air due to elevation of capacity and residual volume of air due to elevation of the diaphragm the diaphragm 

Airway conductance is increased and total pulmonary Airway conductance is increased and total pulmonary resistance is reduced, possibly as a result of resistance is reduced, possibly as a result of progesterone progesterone 

Improved Outcomes associated Improved Outcomes associated with controlled asthmawith controlled asthma

Current EVIDENCE Supports TreatmentCurrent EVIDENCE Supports Treatment Almost all anti-asthma drugs are safe to use in Almost all anti-asthma drugs are safe to use in

pregnancy and pregnancy and during breastfeeding. during breastfeeding. 

Under-treating is a frequent occurrence for the pregnant Under-treating is a frequent occurrence for the pregnant patient because patients are worried about the medication patient because patients are worried about the medication effects on the fetuseffects 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.

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.

Common Asthma medicationsCommon Asthma medications

Inhaled B2 AgonistsInhaled B2 AgonistsAlbuterol-Category CAlbuterol-Category C

Mild, infrequent episodicMild, infrequent episodicMay cause maternal hyperglycemia, tachycardia, May cause maternal hyperglycemia, tachycardia,

hypotension or neonatal hypoglycemiahypotension or neonatal hypoglycemiaBriggs, et al., 2002: study of 1090 infants Briggs, et al., 2002: study of 1090 infants

exposed to albuterol in 1exposed to albuterol in 1stst trimester-possible trimester-possible association with polydactylyassociation with polydactyly

No congential defects link in 2No congential defects link in 2ndnd, 3, 3rdrd trimester trimesterNo adverse effects during lactationNo adverse effects during lactation

Possible B2Choice-Brethine (category B)Possible B2Choice-Brethine (category B)

Theophylline (Cat C)Theophylline (Cat C) Can be used along with inhalation therapyCan be used along with inhalation therapy Preferred treatment for patients requiring long term Preferred treatment for patients requiring long term

therapytherapy Must monitor levels throughout pregnancy to avoid Must monitor levels throughout pregnancy to avoid

toxicitytoxicity Especially important in 3Especially important in 3rdrd trimester d/t decrease in theophylline trimester d/t decrease in theophylline

clearance and increase in volume of distributionclearance and increase in volume of distribution Keep maternal plasma concentrations as low as therapeutically Keep maternal plasma concentrations as low as therapeutically

possiblepossible Crosses placenta in equal concentrations to motherCrosses placenta in equal concentrations to mother Not associated with congenital defects but can cause Not associated with congenital defects but can cause

jitteriness, cardiac arrythmias, hypoglycemia, feeding jitteriness, cardiac arrythmias, hypoglycemia, feeding difficulties in infantsdifficulties in infants Neonates more likely affected Neonates more likely affected

Corticosteroids (Cat C)Corticosteroids (Cat C)

Systemic corticosteroids are reserved for Systemic corticosteroids are reserved for patients who require more urgent patients who require more urgent treatment. treatment.

Conversely, Conversely, cromolyn and nedocromilcromolyn and nedocromil (Cat (Cat B) inhibit antigen- and exercise-induced B) inhibit antigen- and exercise-induced asthma.asthma. They can be They can be indicated as the first-line anti-indicated as the first-line anti-

inflammatory medicationinflammatory medication for the treatment of for the treatment of asthmaasthma

Does not have systemic absorptionDoes not have systemic absorption?crossing of placenta?crossing of placenta

Corticosteroids (cat C)Corticosteroids (cat C)

Can be given IV, PO, or inhaledCan be given IV, PO, or inhaled 2 reports congenital cataracts in infants exposed 2 reports congenital cataracts in infants exposed

to prednisone throughout gestationto prednisone throughout gestation No association found in other studiesNo association found in other studies

Spontaneous abortion, prematurity, cardiac Spontaneous abortion, prematurity, cardiac abnormalities reported in one study abnormalities reported in one study ( Greenberger,1983)( Greenberger,1983)

Prednisone <20mg/day safe in lactationPrednisone <20mg/day safe in lactation In larger doses, delay nsg 3-4hours after doseIn larger doses, delay nsg 3-4hours after dose

EpilepsyEpilepsy > 1 million women of childbearing age have epiliepsy> 1 million women of childbearing age have epiliepsy <1% of pregnancies are complicated by seizures<1% of pregnancies are complicated by seizures 25% of women will have an increase in seizures during 25% of women will have an increase in seizures during

pregnancypregnancy Women with epilepsy (Women with epilepsy (with or without medicationwith or without medication) have a ) have a

higher incidence of delivering an infant with congenital higher incidence of delivering an infant with congenital malformations and mental retardationmalformations and mental retardation Rates of major malformations affecting the heart, skeletal or Rates of major malformations affecting the heart, skeletal or

nervous system in children born to women on anticonvulsants nervous system in children born to women on anticonvulsants are at least double the rate in the general populationare at least double the rate in the general population

Occurrence: 4–6 per hundred births vs the 2-3 per hundred births Occurrence: 4–6 per hundred births vs the 2-3 per hundred births risk that all pregnant women face risk that all pregnant women face

Benefits v risk are overwhelmingly important to consider Benefits v risk are overwhelmingly important to consider

Epilepsy in PregnancyEpilepsy in Pregnancy AAP recommends that a patient who is seizure free for 2 AAP recommends that a patient who is seizure free for 2

years undergo trial medication withdrawal before years undergo trial medication withdrawal before becoming pregnantbecoming pregnant

Suggested waiting period of 6 months after d/cing Suggested waiting period of 6 months after d/cing medicationmedication

Anticonvulsant pharmacokinetics change during Anticonvulsant pharmacokinetics change during pregnancy:pregnancy: Lower serum concentrationsLower serum concentrations due to increased renal and due to increased renal and

hepatic clearancehepatic clearance Decreased protein-binding capacityDecreased protein-binding capacity Increased volume distributionIncreased volume distribution

despite lower serum concentrations, seizures may not increase due despite lower serum concentrations, seizures may not increase due to increased free drug concentrationsto increased free drug concentrations

Must monitor concentrations of anticonvulsants closelyMust monitor concentrations of anticonvulsants closely

Newborns exposed to Newborns exposed to anticonvulsantsanticonvulsants

Hemorrhagic disease in newborns in first Hemorrhagic disease in newborns in first 24 hours can be fatal24 hours can be fatalDue to deficiency in Vit K clotting factors as a Due to deficiency in Vit K clotting factors as a

result of anticonvulsant exposureresult of anticonvulsant exposureAll infants should be treated with Vit K at birthAll infants should be treated with Vit K at birthSome physicians recommend Vit K for mother in Some physicians recommend Vit K for mother in

last 2-4 weeks of pregnancylast 2-4 weeks of pregnancyAnticonvulsants also causes folate Anticonvulsants also causes folate

deficienciesdeficienciesProphylactic folic acid during gestation Prophylactic folic acid during gestation

recommended to prevent megaloblastic anemia recommended to prevent megaloblastic anemia and/or neural tube defectsand/or neural tube defects

Fetal Anticonvulsant SyndromeFetal Anticonvulsant Syndrome

Can occur with all antiepileptic drugsCan occur with all antiepileptic drugsPhenytoin (cat D) can cause Phenytoin (cat D) can cause fetal fetal

hydratoin syndromehydratoin syndromeSchool, learning and developmental School, learning and developmental

problems, craniofacial abnormalities, growth problems, craniofacial abnormalities, growth retardation, limb defects, cardiac lesions, retardation, limb defects, cardiac lesions, hernias, distal digital and nail hyoplasiahernias, distal digital and nail hyoplasia10% risk for all of above (FHS)10% risk for all of above (FHS)30% risk of partial expression of syndrome30% risk of partial expression of syndrome

Phenobarbital (cat D)Phenobarbital (cat D)

Less teratogenic that phenytoin but can Less teratogenic that phenytoin but can cause heart defects and cleft palatecause heart defects and cleft palate

Can also cause coagulopathies and folate Can also cause coagulopathies and folate deficienciesdeficiencies Also has potential to cause neonatal addictionAlso has potential to cause neonatal addiction

Found in breast milk-causes newborn Found in breast milk-causes newborn drowsiness, feeding difficulties, and infantile drowsiness, feeding difficulties, and infantile spasms after weaningspasms after weaning

Carbazamine and ValproateCarbazamine and Valproate (Cat D) (Cat D)

At first, thought to be less harmful At first, thought to be less harmful to fetusto fetus

Associated with the same Associated with the same congenital abnormalities plus spina congenital abnormalities plus spina bifida (1%)bifida (1%)

Can be used with caution in Can be used with caution in lactationlactation

Lamotrigine (Lamictal), Gabapentin Lamotrigine (Lamictal), Gabapentin (Neurontin) and Oxcarbazine (Neurontin) and Oxcarbazine

(Trileptal)= Cat C(Trileptal)= Cat C

Recent results encouragingRecent results encouragingAppear to be less teratogenic or Appear to be less teratogenic or

associated with fetal loss in 1associated with fetal loss in 1stst trimester trimesterCaution: more data needed Caution: more data needed

So…the jury is still out…So…the jury is still out… Although there appears to be a predisposition Although there appears to be a predisposition

for congenital malformations in the offspring of for congenital malformations in the offspring of women treated for epilepsy, it is hard to women treated for epilepsy, it is hard to establish a causal effect with the medicationestablish a causal effect with the medication

It may be a complex interaction of the It may be a complex interaction of the medication, the nature of their disease, and medication, the nature of their disease, and genetics rather than just the medication alonegenetics rather than just the medication alone

Samuels, 2002 Samuels, 2002

The three most common malformations noted in The three most common malformations noted in children of women treated for epilepsy are children of women treated for epilepsy are cardiac malformations, facial clefts, and cardiac malformations, facial clefts, and genital/renal malformations. genital/renal malformations.

The Teratogenicity of Anticonvulsant The Teratogenicity of Anticonvulsant DrugsDrugs

Holmes, et al: NEJM 2001-Holmes, et al: NEJM 2001- Methods: Methods: screened 128,049 pregnant women at screened 128,049 pregnant women at

delivery to identify three groups of infants: those delivery to identify three groups of infants: those exposed to anticonvulsant drugs, those unexposed to exposed to anticonvulsant drugs, those unexposed to anticonvulsant drugs but with a maternal history of anticonvulsant drugs but with a maternal history of seizures, and those unexposed to anticonvulsant drugs seizures, and those unexposed to anticonvulsant drugs with no maternal history of seizures (control group). The with no maternal history of seizures (control group). The infants were examined systematically for the presence of infants were examined systematically for the presence of major malformations, signs of hypoplasia of the midface major malformations, signs of hypoplasia of the midface and fingers, microcephaly, and small body size. and fingers, microcephaly, and small body size.

ResultsResults The combined frequency of anticonvulsant embryopathy The combined frequency of anticonvulsant embryopathy

was higher in 223 infants exposed to one anticonvulsant was higher in 223 infants exposed to one anticonvulsant drug than in 508 control infants (20.6 percent vs. 8.5 drug than in 508 control infants (20.6 percent vs. 8.5 percent; odds ratio, 2.8; 95 percent confidence interval, percent; odds ratio, 2.8; 95 percent confidence interval, 1.1 to 9.7). 1.1 to 9.7).

The frequency was also higher in 93 infants exposed to The frequency was also higher in 93 infants exposed to two or more anticonvulsant drugs than in the controls two or more anticonvulsant drugs than in the controls (28.0 percent vs. 8.5 percent; odds ratio, 4.2; 95 percent (28.0 percent vs. 8.5 percent; odds ratio, 4.2; 95 percent confidence interval, 1.1 to 5.1). confidence interval, 1.1 to 5.1).

The 98 infants whose mothers had a history of epilepsy The 98 infants whose mothers had a history of epilepsy but took no anticonvulsant drugs during the pregnancy but took no anticonvulsant drugs during the pregnancy did not have a higher frequency of those abnormalities did not have a higher frequency of those abnormalities than the control infants than the control infants

ConclusionsConclusions

A distinctive pattern of physical A distinctive pattern of physical abnormalities in infants of mothers with abnormalities in infants of mothers with epilepsy is associated with the use of epilepsy is associated with the use of anticonvulsant drugs during pregnancy, anticonvulsant drugs during pregnancy, rather than with epilepsy itself rather than with epilepsy itself

Coagulation DisordersCoagulation Disorders

Pregnancy is a hypercoagulable statePregnancy is a hypercoagulable state Incidence for DVT is still low: 0.2-0.4%Incidence for DVT is still low: 0.2-0.4%

Current recommendations for prophylaxis Current recommendations for prophylaxis based on risk factors:based on risk factors:Hereditary factors (protein C Hereditary factors (protein C

deficiencies/leiden factors)deficiencies/leiden factors)Hx of DVT/PEHx of DVT/PEAge >35Age >35Multiple miscarriagesMultiple miscarriages

Heparin: anticoagulant of choice Heparin: anticoagulant of choice (Cat C)(Cat C)

Does not cross placentaDoes not cross placenta Not associated with congenital defectsNot associated with congenital defects Late pregnancy may be associated with Late pregnancy may be associated with

increased heparin dosesincreased heparin doses Perinatal mortality rates significantly improved Perinatal mortality rates significantly improved

for patients on heparin v. coumadin (3.6% v. for patients on heparin v. coumadin (3.6% v. 26.1% mortality)26.1% mortality)

LMWH (Lovenox) safe and effectiveLMWH (Lovenox) safe and effective Less bleeding potential and less risk of osteoporosisLess bleeding potential and less risk of osteoporosis Does not cross fetal circulationDoes not cross fetal circulation Not excreted in breast milk Not excreted in breast milk

Coumadin (cat D)Coumadin (cat D)

Exposure during 6-8Exposure during 6-8thth weeks can cause weeks can cause fetal warfarin syndromefetal warfarin syndromeDefects in CNS and skeletal systemDefects in CNS and skeletal system

Exposure throughout pregnancy can Exposure throughout pregnancy can cause:cause:Stillbirths, spontaneous abortion, facial Stillbirths, spontaneous abortion, facial

abnormalitiesabnormalitiesCompatible with breast feedingCompatible with breast feeding

Treating Common Problems in Treating Common Problems in PregnancyPregnancy

Common ColdCommon ColdNausea/VomitingNausea/VomitingConstipationConstipationHeartburnHeartburnHemorrhoidsHemorrhoids

Drug ClassDrug Class During PregnancyDuring Pregnancy During LactationDuring Lactation

analgesicsanalgesics acetominophenacetominophen acetominophenacetominophen

antacidsantacids Calcium carbonateCalcium carbonate Calcium carbonateCalcium carbonate

antihistamineantihistamine chlorpheniraminechlorpheniramine chlorpheniraminechlorpheniramine

Hemorrhoidal Hemorrhoidal agentsagents

Preparation H Preparation H ointmentointment

Preparation H ointmentPreparation H ointment

decongestantdecongestant Oxymetazoline nasal Oxymetazoline nasal sprayspray

nonenone

laxativelaxative Psyllium or docusatePsyllium or docusate Psyllium or docusatePsyllium or docusate

Over the Counter Drug of Choice

The Common ColdThe Common Cold No value in treating with medicationsNo value in treating with medications If using medication, avoid combination productsIf using medication, avoid combination products Limit duration of treatmentLimit duration of treatment Antihistamine of choice: chorpheniramine (cat B) or Antihistamine of choice: chorpheniramine (cat B) or

Loratidine (cat B)Loratidine (cat B) Avoid brompheniramine (Dimetapp-Bromfed)Avoid brompheniramine (Dimetapp-Bromfed) Antihistamines excreted in breast milkAntihistamines excreted in breast milk Nasal cromolyn, beclomethasone useful alternativeNasal cromolyn, beclomethasone useful alternative Clubfoot and inguinal hernias associated with first Clubfoot and inguinal hernias associated with first

trimester use of decongestants trimester use of decongestants (e.g., Sudafed)(e.g., Sudafed) Anti-tussives and expectorants all category CAnti-tussives and expectorants all category C

No epidemiologic studies demonstrate fetal harmNo epidemiologic studies demonstrate fetal harm

Nausea and VomitingNausea and Vomiting 80% of women experience n/v during 180% of women experience n/v during 1stst

trimestertrimester Hyperemesis gravidarum-intractable, causes lyte Hyperemesis gravidarum-intractable, causes lyte

imbalances, weight loss, possible end organ imbalances, weight loss, possible end organ damagedamage Occurs in 1:1000 birthsOccurs in 1:1000 births Requires hospitalizationRequires hospitalization

Cause unknown-tx focused on sxCause unknown-tx focused on sx Non pharmacologic measures not supported by Non pharmacologic measures not supported by

evidenceevidence OTC phosphorated carbohydrate (EMETROL) safeOTC phosphorated carbohydrate (EMETROL) safe Meclizine (cat B) drug of choiceMeclizine (cat B) drug of choice

ConstipationConstipation

Etiology: increased pressure on colon, Etiology: increased pressure on colon, decreased peristalsis, increased progesterone, decreased peristalsis, increased progesterone, decreased motilin, increased colonic absorption decreased motilin, increased colonic absorption of waterof water

Bulk-forming laxatives (Metamucil) safe in Bulk-forming laxatives (Metamucil) safe in pregnancy and lactationpregnancy and lactation Increase fluids to prevent intestinal obstructionIncrease fluids to prevent intestinal obstruction

Surfactants/Stool softeners (docusate), mineral Surfactants/Stool softeners (docusate), mineral oil Cat coil Cat c

HeartburnHeartburn Affects 72% women in 3Affects 72% women in 3rdrd trimester trimester d/t relaxation of LES and uterine displacement + d/t relaxation of LES and uterine displacement +

hormonal changes in gut motilityhormonal changes in gut motility Magnesium, calcium carbonate, and/or Magnesium, calcium carbonate, and/or

aluminum hydroxides considered safealuminum hydroxides considered safe Avoid H2 blockersAvoid H2 blockers

If necessary-ranitidine preferred over cimetidine (has If necessary-ranitidine preferred over cimetidine (has anti-androngenic effects)anti-androngenic effects)

Metoclopromide (Reglan) cat BMetoclopromide (Reglan) cat B

HemorrhoidsHemorrhoids

OTC external preparations preferredOTC external preparations preferredAvoid suppositories d/t potential for Avoid suppositories d/t potential for

systemic absorption across rectal mucosasystemic absorption across rectal mucosa

General PrinciplesGeneral Principles

Limitations of Drug Therapy in Limitations of Drug Therapy in ChildrenChildren

75% of FDA approved 75% of FDA approved medications lack indications in medications lack indications in childrenchildren

Pediatric practitioners actually Pediatric practitioners actually prescibe “off label”prescibe “off label”

FDA indications for dosing FDA indications for dosing regimens are lackingregimens are lacking

Safety is based on post marketing Safety is based on post marketing reports of adverse eventsreports of adverse events

Post Marketing Adverse Drug Post Marketing Adverse Drug ReportsReports

MED WATCHMED WATCHFDAFDAhttp://www.fda.gov/safety/MedWatch/default.htmhttp://www.fda.gov/safety/MedWatch/default.htm

https://www.accessdata.fda.gov/scripts/medwatchttps://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htmh/medwatch-online.htm

Important LegislationImportant Legislation 1994: first FDA regulations regarding drug product labeling 1994: first FDA regulations regarding drug product labeling

of known use and dosing of known use and dosing Resulted in FDA approval of limited number of drugs in Resulted in FDA approval of limited number of drugs in

childrenchildren 1997: Pediatric Exclusivity Provision of FDA Modernization 1997: Pediatric Exclusivity Provision of FDA Modernization

Act passedAct passed Incentive for manufacturers to implement studies of their Incentive for manufacturers to implement studies of their

products on childrenproducts on children 1999: Pediatric Rule developed1999: Pediatric Rule developed

Mandated that manufacturers perform trials and provide Mandated that manufacturers perform trials and provide safety and efficacy datasafety and efficacy data

2003- Pediatric Research Equity Act-outlined FDA authority 2003- Pediatric Research Equity Act-outlined FDA authority to enforce Pediatric Ruleto enforce Pediatric Rule

Despite interest in pediatric Despite interest in pediatric drug therapy research, drug therapy research,

conducting clinical trials poses conducting clinical trials poses unique challengesunique challenges

Consider: Consider: Recent reports of suicide with SSRIRecent reports of suicide with SSRITreatment/ over treatment of ADHDTreatment/ over treatment of ADHD

Treatment of GERDTreatment of GERD

For ReleaseFor Release: November 5, 2007, : November 5, 2007, ANTIREFLUX MEDICATION MAY BE OVERPRESCRIBED IN INFANTSANTIREFLUX MEDICATION MAY BE OVERPRESCRIBED IN INFANTS

A majority of infants taking anti-reflux drugs did not meet the A majority of infants taking anti-reflux drugs did not meet the diagnostic criteria for gastroesophageal reflux disease (GERD), diagnostic criteria for gastroesophageal reflux disease (GERD), according to a new study, "Are We Overprescribing Antireflux according to a new study, "Are We Overprescribing Antireflux Medications for Infants With Regurgitation?" Researchers Medications for Infants With Regurgitation?" Researchers conducted esophageal pH monitoring (measuring the reflux or conducted esophageal pH monitoring (measuring the reflux or regurgitation of acid from the stomach into the esophagus) of 44 regurgitation of acid from the stomach into the esophagus) of 44 infants in a New Orleans medical center. Each of the children had infants in a New Orleans medical center. Each of the children had persistent regurgitation and was referred to a specialty service for persistent regurgitation and was referred to a specialty service for further management. The study showed that while only eight of the further management. The study showed that while only eight of the infants had abnormal pH levels indicating GERD, 42 of 44 infants infants had abnormal pH levels indicating GERD, 42 of 44 infants were on antireflux medication. When medication was withdrawn were on antireflux medication. When medication was withdrawn from the infants who did not meet GERD criteria, reflux symptoms from the infants who did not meet GERD criteria, reflux symptoms did not worsen. did not worsen. The study authors concluded that antireflux The study authors concluded that antireflux medications were unnecessary in the majority of infants who medications were unnecessary in the majority of infants who were prescribed such medicationwere prescribed such medication..

Developmental PharmacologyDevelopmental Pharmacology

Pharmacokinetic differences in children vary with Pharmacokinetic differences in children vary with ageage

Drugs considered safe in one group of pediatric Drugs considered safe in one group of pediatric patients may be ineffective or toxic in another patients may be ineffective or toxic in another groupgroup Hepatic enzymes and metabolic pathways mature at Hepatic enzymes and metabolic pathways mature at

different ratesdifferent rates E.g., maturation of each pathway is asynchronousE.g., maturation of each pathway is asynchronous

When a drug’s primary route of metabolism is immature, it may When a drug’s primary route of metabolism is immature, it may be shunted through an alternate pathwaybe shunted through an alternate pathway

Drug dosing dilemmas can be avoided by using only Drug dosing dilemmas can be avoided by using only those drugs with scientifically supported dosingthose drugs with scientifically supported dosing

Key PointsKey Points

In infants, metabolism of most drugs is In infants, metabolism of most drugs is reducedreducedGFR is 20-40% of adult capacity at birth and GFR is 20-40% of adult capacity at birth and

increases after the 1increases after the 1stst week of life-reaches week of life-reaches maximal level by 12 monthsmaximal level by 12 months

In general, children over 10 years have In general, children over 10 years have organ development and metabolism organ development and metabolism similar to adultssimilar to adultsMay require dosing adjustments based on May require dosing adjustments based on

body surface areabody surface area

Key Points (con’t)Key Points (con’t)

GI tract acidity, enzymatic activity, and GI tract acidity, enzymatic activity, and motility differences in infants and young motility differences in infants and young children alter absorption of PO drugschildren alter absorption of PO drugsDrugs that are weak bases increase drug Drugs that are weak bases increase drug

absorptionabsorptionDrugs that are weak acids reduce drug Drugs that are weak acids reduce drug

absorption absorption Reduced gastric transit in infants delays Reduced gastric transit in infants delays

absorption and peak plasma concentration absorption and peak plasma concentration time-but NOT the amount of drug absorbedtime-but NOT the amount of drug absorbed

Key PointsKey Points

Absorption from transcutaneous route is Absorption from transcutaneous route is enhanced in infants-increased risk of adverse enhanced in infants-increased risk of adverse effectseffects Caution with use of topicals in infantsCaution with use of topicals in infants

The volume of drug distribution in infants and The volume of drug distribution in infants and young children is increased due to increased young children is increased due to increased body waterbody water Results in need for increased drug doses for water-Results in need for increased drug doses for water-

soluble drugs (e.g., aminoglycosides)soluble drugs (e.g., aminoglycosides) Drugs that are lipophilic (e.g., diazepam) may exhibit Drugs that are lipophilic (e.g., diazepam) may exhibit

lower volume of distributionlower volume of distribution

Key PointsKey Points

Alterations in protein binding and tissue Alterations in protein binding and tissue penetration of drugs may lead to reduced penetration of drugs may lead to reduced OR exaggerated responseOR exaggerated response

Practical Tips for Pediatric Practical Tips for Pediatric Prescription WritingPrescription Writing

1.1. Always obtain a weight at every pediatric visitAlways obtain a weight at every pediatric visit2.2. As a rule, start with smallest dose in neonates As a rule, start with smallest dose in neonates

and infantsand infants3.3. ““round up” the dose if it falls between the given round up” the dose if it falls between the given

choices UNLESS it is a toxic drug or has choices UNLESS it is a toxic drug or has narrow therapeutic windownarrow therapeutic window

4.4. With acetominophen, calculate dosage using With acetominophen, calculate dosage using weight, not ageweight, not age

5.5. Always specify preferred formulation (e.g., Always specify preferred formulation (e.g., chewable tabs, suspension, etc)chewable tabs, suspension, etc)

6.6. Stay current with literature!!!Stay current with literature!!!

Geriatric PharmacologyGeriatric Pharmacology

Baby Boomers and Beyond…Baby Boomers and Beyond…

Medication Use StatisticsMedication Use Statistics People >65 consume 30% of People >65 consume 30% of

prescription and 40% non-prescription and 40% non-prescription drugs prescription drugs

(Cohen, 2000)(Cohen, 2000)

By 2030, the population >65 will By 2030, the population >65 will double-with largest increases in double-with largest increases in 85-older85-older

Adverse drug reactions rank in Adverse drug reactions rank in the top 5 causes of mortality and the top 5 causes of mortality and morbidity in elderlymorbidity in elderly

28% of elderly hospital 28% of elderly hospital admissions are due to adverse admissions are due to adverse drug reactions drug reactions

Adverse Drug ReactionsAdverse Drug Reactions

About 15% of hospitalizations in the About 15% of hospitalizations in the elderly are related to adverse drug elderly are related to adverse drug reactionsreactions

The more medications a person is on, The more medications a person is on, the higher the risk of drug-drug the higher the risk of drug-drug interactions or adverse drug reactionsinteractions or adverse drug reactions

The more medications a person is on, The more medications a person is on, the higher the risk of non-adherencethe higher the risk of non-adherence

Average prescription drug cost for an older person is Average prescription drug cost for an older person is $500/year, but highly variable$500/year, but highly variable

Nonprescription drugs and herbals can be quite Nonprescription drugs and herbals can be quite expensive and dangerous when mixed with prescription expensive and dangerous when mixed with prescription drugsdrugs

Many Medicare Managed Care Plans have dropped or Many Medicare Managed Care Plans have dropped or severely limited drug coverageseverely limited drug coverage

Drugs cost more in US than any other countryDrugs cost more in US than any other country Many elderly patients look toward “bootlegged” drugs”Many elderly patients look toward “bootlegged” drugs”

New drugs cost more-not coveredNew drugs cost more-not covered

Costs of DrugsCosts of Drugs

Non-prescription DrugsNon-prescription Drugs

Surveys indicate that elders take average of Surveys indicate that elders take average of 2-4 nonprescription drugs 2-4 nonprescription drugs dailydaily

Laxatives used in about 1/3-1/2 of elders - Laxatives used in about 1/3-1/2 of elders - many who are not constipatedmany who are not constipated

Non-steroidal anti-inflammatory medicines, Non-steroidal anti-inflammatory medicines, sedating antihistamines, sedatives, and H2 sedating antihistamines, sedatives, and H2 blockers are all available without a blockers are all available without a prescription, and all may cause major side prescription, and all may cause major side effects effects

Prescription DrugsPrescription Drugs

Elderly account for 1/3 of prescription Elderly account for 1/3 of prescription drug use, while only 13% of the drug use, while only 13% of the populationpopulation

Ambulatory elderly fill between 9-13 Ambulatory elderly fill between 9-13 prescriptions a year (new and refills)prescriptions a year (new and refills)

One survey: Average of 5.7 One survey: Average of 5.7 prescription medicines per patientprescription medicines per patient

Average nursing home patient on 7 Average nursing home patient on 7 medicinesmedicines

Decrease in total body water (due to Decrease in total body water (due to decrease in muscle mass) and increase in decrease in muscle mass) and increase in total body fat affects volume of distributiontotal body fat affects volume of distribution

Water soluble drugs: lithium, Water soluble drugs: lithium, aminoglycosides, alcohol, digoxinaminoglycosides, alcohol, digoxin Serum levels may go up due to decreased Serum levels may go up due to decreased

volume of distributionvolume of distribution Fat soluble: diazepam, thiopental, Fat soluble: diazepam, thiopental,

trazadonetrazadone Half life increased with increase in body fatHalf life increased with increase in body fat

PharmacokineticsPharmacokinetics

Pharmacokinetics Pharmacokinetics

Absorption: Not highly impacted by Absorption: Not highly impacted by agingaging

Variable changes in first pass Variable changes in first pass metabolism due to variable decline metabolism due to variable decline in hepatic blood flow (elders may in hepatic blood flow (elders may have have lessless first pass effect than first pass effect than younger people, but extremely younger people, but extremely difficult to predict)difficult to predict)

Pharmacokinetics and the Pharmacokinetics and the LiverLiver

Oxidative metabolism through Oxidative metabolism through cytochrome P450 system decreases cytochrome P450 system decreases with aging, resulting in a decreased with aging, resulting in a decreased clearance of drugsclearance of drugs

Hepatic blood flow extremely variableHepatic blood flow extremely variable

Drugs with Cytochrome P450 EffectsDrugs with Cytochrome P450 Effects(partial)(partial)

Inhibitors Inducers

Allopurinol Metronidazole Barbiturates

Amiodorone Quinolones

Carbamazepine

Azole antifungals Phenytoin

Cimetidine Rifampin

INH Tobacco

SSRIs

Tacrine

Pharmacokinetics: Excretion Pharmacokinetics: Excretion and Eliminationand Elimination

GFR generally declines with aging, but is GFR generally declines with aging, but is extremely variableextremely variable

30% have little change30% have little change30% have moderate decrease30% have moderate decrease30% have severe decrease30% have severe decrease

Serum creatinine is an unreliable markerSerum creatinine is an unreliable marker If accuracy needed, do Cr ClIf accuracy needed, do Cr Cl

The Cockroft and Gault Equation

Cr Cl = 140-age(yrs) X wt (kg) X .85 for women Cr (mg/100ml)X72

May overestimate Cr Cl, especially in frail elders

Useful equation, but must be aware of its limitations

Pharmacodynamics: Pharmacodynamics: What the Drug does to the BodyWhat the Drug does to the Body

Some effects are increasedSome effects are increased Alcohol causes increase is drowsiness and Alcohol causes increase is drowsiness and

lateral sway in older people than younger lateral sway in older people than younger people at same serum levelspeople at same serum levels

Fentanyl, diazepam, morphine, theophyllineFentanyl, diazepam, morphine, theophyllineSome effects are decreasedSome effects are decreased

Diminished HR response to beta -blockersDiminished HR response to beta -blockers

UndertreatmentUndertreatment

CADCADBeta blockersBeta blockersASAASA

Anticoagulation in AFAnticoagulation in AFHTN, especially systolic HTNHTN, especially systolic HTNPainPain

Particular fear of narcotics in the elderlyParticular fear of narcotics in the elderly

Drug-Drug InteractionsDrug-Drug Interactions Common cause of ADEs in elderlyCommon cause of ADEs in elderly Almost countless – good role for Almost countless – good role for

pharmacist and computer or on-line pharmacist and computer or on-line programs programs

Some common examplesSome common examples Statins and erythromycin and other antibioticsStatins and erythromycin and other antibiotics TCAs and clonidine or type 1Anti-arrythmicsTCAs and clonidine or type 1Anti-arrythmics Warfarin and multiple drugs Warfarin and multiple drugs ACE inhibitors increase hypoglycemic effect of sulfonylureasACE inhibitors increase hypoglycemic effect of sulfonylureas

Drug-disease InteractionsDrug-disease Interactions

Patient with PD have increased risk of drug Patient with PD have increased risk of drug induced confusioninduced confusion

NSAIDs (and COX-2’s) s can exacerbate CHFNSAIDs (and COX-2’s) s can exacerbate CHF Urinary retention in BPH patients on Urinary retention in BPH patients on

decongestants or anticholinergicsdecongestants or anticholinergics Constipation worsened by calcium, Constipation worsened by calcium,

anticholinergics, calcium channel blockersanticholinergics, calcium channel blockers Neuroleptics and quinolones lower seizure Neuroleptics and quinolones lower seizure

thresholdsthresholds

The “Prescribing Cascade”The “Prescribing Cascade”

Common cause of polypharmacy in elderlyCommon cause of polypharmacy in elderly Some common examplesSome common examples

NSAID ->HTN->antihypertensive therapyNSAID ->HTN->antihypertensive therapy Metoclopromide ->Parkinsonism ->SinemetMetoclopromide ->Parkinsonism ->Sinemet Dihydropyridine -> edema ->furosemideDihydropyridine -> edema ->furosemide NSAID ->H2 blocker ->delirium ->haldolNSAID ->H2 blocker ->delirium ->haldol HCTZ ->gout->NSAID ->2nd antihypertensiveHCTZ ->gout->NSAID ->2nd antihypertensive Sudafed ->urinary retention ->alpha blockerSudafed ->urinary retention ->alpha blocker Antipsychotic ->akithesia ->more medsAntipsychotic ->akithesia ->more meds

NSAIDsNSAIDs Acetaminophen as effective as NSAIDs in Acetaminophen as effective as NSAIDs in

mild OAmild OA

NSAIDs side effectsNSAIDs side effects

GI hemorrhage (less with COX-2)GI hemorrhage (less with COX-2)

Decline in GFR (COX-2 as well)Decline in GFR (COX-2 as well)

Decreased effectiveness of diuretics, anti-Decreased effectiveness of diuretics, anti-hypertensive agentshypertensive agents

Indication should justify the increased Indication should justify the increased toxicity of NSAIDstoxicity of NSAIDs

Drugs and Cognitive ImpairmentDrugs and Cognitive Impairment Common cause of potentially reversible Common cause of potentially reversible

cognitive impairment cognitive impairment Demented patients are particularly prone to Demented patients are particularly prone to

delirium from drugsdelirium from drugs Anticholinergic drugs are common offenders Anticholinergic drugs are common offenders

(TCAs, benadryl and other antihistamines, (TCAs, benadryl and other antihistamines, many others)many others)

Other offenders cimetidine, steroids, NSAIDs Other offenders cimetidine, steroids, NSAIDs Medical Letter 2000 Drug Safety 1999 Drugs and Aging 1999 Medical Letter 2000 Drug Safety 1999 Drugs and Aging 1999

Drugs and FallsDrugs and Falls Biggest risk drugs are long acting Biggest risk drugs are long acting

benzodiazepines and other sedative-hypnoticsbenzodiazepines and other sedative-hypnotics Both SSRIs and TCAs associated with Both SSRIs and TCAs associated with

increased risk of fallingincreased risk of falling Beta blockers NOT associated with increased Beta blockers NOT associated with increased

risk of falling in published literaturerisk of falling in published literature Mild increase in fall risk from diuretics, anti-Mild increase in fall risk from diuretics, anti-

arrythmics, and digoxinarrythmics, and digoxinLeipzig, 2008 Leipzig, 2008

Drug-Food InteractionsDrug-Food Interactions

Interactions between drugs and foodInteractions between drugs and food warfarin and Vitamin K containing foods warfarin and Vitamin K containing foods

(remember green tea, as well)(remember green tea, as well) Phenytoin & vitamin D metabolismPhenytoin & vitamin D metabolism Methotrexate and folate metabolismMethotrexate and folate metabolism

Drug impact on appetiteDrug impact on appetite Digoxin may cause anorexiaDigoxin may cause anorexia ACE inhibitors may alter tasteACE inhibitors may alter taste

Drugs And Dosages to Avoid in Drugs And Dosages to Avoid in Most InstancesMost Instances

MeperidineMeperidine DiphenhydramineDiphenhydramine The most anticholinergic tricyclics: The most anticholinergic tricyclics:

amitryptiline, doxepin, imipramine amitryptiline, doxepin, imipramine Long acting benzodiazepines such as Long acting benzodiazepines such as

diazepamdiazepam Long acting NSAIDs such as piroxicamLong acting NSAIDs such as piroxicam High dose thiazides (>25mg)High dose thiazides (>25mg) Iron: 325 mg once daily is enoughIron: 325 mg once daily is enough

Anticipate SE’sAnticipate SE’sNarcoticsNarcotics

Begin lactulose or sorbitol and a stimulant laxativeBegin lactulose or sorbitol and a stimulant laxative Colace is NOT sufficient in most instancesColace is NOT sufficient in most instances

SteroidsSteroids Think about osteoporosis preventionThink about osteoporosis prevention Remember steroid induced diabetesRemember steroid induced diabetes

LevothyroxineLevothyroxine Calcium interferes with absorption of levothyroxineCalcium interferes with absorption of levothyroxine

?Biphosphonates and ? Atrial fibrillation ?Biphosphonates and ? Atrial fibrillation (NEJM, 2009)(NEJM, 2009)

Calcium and MI ??(BMJ, 2010) Calcium and MI ??(BMJ, 2010)

High Risk SituationsHigh Risk SituationsPatient seeing multiple providersPatient seeing multiple providersPatient on multiple drugsPatient on multiple drugsPatient lives alone and/or has Patient lives alone and/or has

cognitive impairmentcognitive impairmentDischarge from hospital or any Discharge from hospital or any

change in venuechange in venue

Hospitalization: A High Risk Hospitalization: A High Risk TimeTime

At hospitalization:At hospitalization: 40% of admission medications stopped40% of admission medications stopped 45% of discharge medications were 45% of discharge medications were

startedstarted Serious prescribing problems in 22%Serious prescribing problems in 22% Other prescribing problems in 66%Other prescribing problems in 66%

Beers JAGS 1989, Lipton Medical Care 1992Beers JAGS 1989, Lipton Medical Care 1992

Non-adherenceNon-adherence

Lack of understanding of how to takeLack of understanding of how to take High risk times: Hospital discharge, new meds High risk times: Hospital discharge, new meds

added, complex regimensadded, complex regimens

Unable to takeUnable to takeConscious nonadherenceConscious nonadherence

Side effectsSide effects Lack of understanding of benefits of drugLack of understanding of benefits of drug FinancialFinancial

Complementary TherapiesComplementary Therapies

Very commonly used in the elderlyVery commonly used in the elderly Some common herbs and alternative therapies:Some common herbs and alternative therapies: ““Anti-aging”Anti-aging” DHEA, growth hormoneDHEA, growth hormone DementiaDementia Gingko bilobaGingko biloba BPHBPH Saw palmetto, PC-SPESSaw palmetto, PC-SPES OAOA Chondroiton sulfate, Chondroiton sulfate,

glucosamine glucosamine DepressionDepression St. John’s wort, SAMeSt. John’s wort, SAMe

““Do No Harm?”Do No Harm?” California Department of Health California Department of Health

Services, Food and Drug BranchServices, Food and Drug Branch screened 250 Asian herbal productsscreened 250 Asian herbal products collected from herbal stores in Californiacollected from herbal stores in California assayed products using gas chromatography, assayed products using gas chromatography,

mass spectrometry, and atomic-absorption mass spectrometry, and atomic-absorption techniquestechniques

Ko, NEJM 1998; 339; 847Ko, NEJM 1998; 339; 847

32% contained unlabeled medications, 32% contained unlabeled medications, 14% mercury, 14% arsenic, 10% lead14% mercury, 14% arsenic, 10% lead

Herbals and Supplements: Herbals and Supplements: RegulationRegulation

Demonstration of safety is NOT required prior to Demonstration of safety is NOT required prior to marketingmarketing

Manufacturing standards are not requiredManufacturing standards are not required Can have Can have health health claims, but not claims about claims, but not claims about

treating, preventing, or curingtreating, preventing, or curing For glucosamine/chondroitin, 1/3 of For glucosamine/chondroitin, 1/3 of

combinations did not contain listed ingredientcombinations did not contain listed ingredient www.consumerlabs.com has drug informationwww.consumerlabs.com has drug information

Herbals and Supplements:Potential Herbals and Supplements:Potential interactions with Rx Drugsinteractions with Rx Drugs

SAMe may increase SAMe may increase homocysteine levelshomocysteine levels

St. John’s wort and Oral St. John’s wort and Oral contraceptivescontraceptives

Ginkgo may increase Ginkgo may increase anticoagulant effects of ASA, anticoagulant effects of ASA, warfarin, NSAIAs, ticlopidine, warfarin, NSAIAs, ticlopidine, and may interact with MAOIsand may interact with MAOIs

Bottom line: Try to know what Bottom line: Try to know what your patient is taking, and ask in your patient is taking, and ask in a nonjudgmental waya nonjudgmental way

Mr. W. is a 86 year old man with pulmonary HTN, COPD, CRI (creatinine of 2.2), CHF with an ejection fraction of 20%, mild dementia, depression, and severe anemia. He is frequently admitted to the hospital because of severe disease and poor adherence with his medical regimen. His discharge medications on last admission one month ago were aspirin 325mg, enalapril 20mg QD, furosemide 80mg BID, combivent, and sertraline 50mg. The inpatient team decided that he was undertreated, and added metoprolol 12.5mg BID, aldactone, FeSo4 325mg TID, and 3 inhalers. He was readmitted within a week. How might you approach his regimen?

Principles for Managing DrugsPrinciples for Managing Drugs

Complete drug history, including herbs and Complete drug history, including herbs and nonprescription drugsnonprescription drugs

Avoid medications if benefit is marginal or if Avoid medications if benefit is marginal or if non-pharmacologic alternatives exist non-pharmacologic alternatives exist

Consider the costConsider the cost Start low, go slow, but get there!Start low, go slow, but get there! Keep regimen as simple as possibleKeep regimen as simple as possible Write instructions out clearlyWrite instructions out clearly Have patient bring in medications at each visitHave patient bring in medications at each visit

Principles (continued)Principles (continued) Consider medication box or “mediset”Consider medication box or “mediset” If things don’t make sense, consider a home If things don’t make sense, consider a home

visitvisit Discontinue drugs when possible if benefit Discontinue drugs when possible if benefit

unclear or side effects could be due to drugunclear or side effects could be due to drug Be cautious with newer drugsBe cautious with newer drugs Consider if the benefit of the 7th or 8th drug Consider if the benefit of the 7th or 8th drug

is sufficient to justify the cost, increase in is sufficient to justify the cost, increase in complexity of regimen, and risk of side complexity of regimen, and risk of side effectseffects

Newer drugsNewer drugs

What is unique about this compound?What is unique about this compound? What clinical data is available?What clinical data is available? How does it compare with traditional How does it compare with traditional

therapy?therapy? How expensive is it?How expensive is it? With third party payers cover this product?With third party payers cover this product? Does the potential advantage of this new Does the potential advantage of this new

drug justify the risk of using a new drug?drug justify the risk of using a new drug?

SummarySummary The elderly take more medications The elderly take more medications

than any other age groupthan any other age group Pharmacokinetics and Pharmacokinetics and

pharmacodynamics are altered pharmacodynamics are altered Adverse drug reactions are common Adverse drug reactions are common Risks go up with the number of drugs Risks go up with the number of drugs

usedused Nonprescription and herbal therapies Nonprescription and herbal therapies

are common are common With care and common sense, we With care and common sense, we

can probably do a better jobcan probably do a better job