Presentation on theme: "Pharmacologic Implications for Special Patient Populations:"— Presentation transcript:
1Pharmacologic Implications for Special Patient Populations: PregnantElderlyPediatricJudith A. Kaufmann, Dr PH, FNP-CAssociate Professor of NursingRobert Morris University
2Vulnerable Populations: At Most Risk for Adverse Drug Effects and Reactions
3Reasons: The 5 “toos”Too few patients represented in studies to detect rare events30,000 people in each category would need to receive the medication to detect 1 adverse reaction in a drug that affects 1:10,000Too simple: patients with multiple conditions excluded from trialsToo median-aged: studies exclude patients at each end of the spectrum
42 More “Toos”Too narrow: indications for newly approved drugs are based on pre marketing clinical trials for ONE very specific conditionOnce marketed, the drug may be used for untested indicationsToo brief: most clinical trials are shortSome adverse effects take years to manifest clinically
5Drugs in Pregnancy Treatment Goals Utilize appropriate resources to determine teratogenic risk and excretion in breast milkAssess the risk: benefit ratio of pharmacotherapyUtilize drug regimen that is safe, effective and minimizes risk to fetus or infantMinimize drug exposure to neonate/infant during lactation
6Epidemiology ~35% of women take some medications during pregnancy Range/pregnancy = 1-15 medications (M=2.9)OTC medications not includedWHO study showed that non-white, unmarried, less educated women less likely to use medicationsToday ~60% of women breastfeedOver 1,000 drugs per year are evaluated for teratogenic potential~10% of children have abnormal physical or mental developmentOnly 2-3% of these are associated with medications
7Resources for Information Data on drugs in pregnancy and lactation are almost always POST marketingConstantly being updated-need for immediate access to drug updates1979-FDA categories for Drug Use in PregnancyFDA’s Adverse Drug Reaction reporting system underusedMEDWATCH Program initiated in 1993
8Lessons from the PastThalidomide first appeared in Germany on 1st October 1957marketed as a sedative with few side effectsConsidered safe, used for morning sicknessDrug testing procedures were less rigorouslimited testing failed to reveal tetragenic side effectsPre-marketing tests conducted on rodents which metabolize the drug in a different way to humansSubsequent tests on rabbits and monkeys produced similar SEs as in humans.Late 1950’s: post marketing reportsPharcomelia: babies born with flipper-like limbsAKA: 'Thalidomide Babies’
10FDA Categories for Drug Use in Pregnancy Category A: Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalitiesCategory B:Animal studies have revealed no evidence of harm to the fetus, however, there are no adequate and well-controlled studies in pregnant women. or Animal studies have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus.
11FDA 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 womenCategory 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.
12FDA CategoriesCategory 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.
14X-Rated Drugs Accutane Estrogen Isotrentinoin Vaccines: MMR, Varicella CDC Advisory Committee on immunization PracticesVaccinate all pregnant women with INACTIVATED influenza vaccine in the fall or throughout influenza season
15Addressing Patients’ Concerns for Vaccine Safety The US FDA approved Fluarix, an inactivated influenza vaccine for adults in 2005Fear of mercury and thimerosalSpurred by mediaIOM (2004) released results of analysis of potential link between thimerosal and neurobehavioral conditions and found no evidence of associationBUT… urged “full consideration …to removing thimerosal from any product given to infants, children or pregnant women”
16Current Vaccines Available Thimerosal-free or Thimerosal-reducedMay be added at the end of manufacturing process to prevent bacterial or fungal growthResults in minute traces in final productInstitute for Vaccine Safety - Thimerosal Table
17Thompson, et al, (2007). Early thimerosal exposure and neuropsychological outcomes at 7 to 10 Years. NEJM. 357 (13)N= 1047 children between the ages of 7 and 10 years and administered standardized tests assessing 42 neuropsychological outcomesFindings: 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
18Pregnancy alters the Pharmacokinetics of Most Drugs Increase in total body water (~8L)Increase in total body fatIncrease in GFRDecrease in gastrointestinal motility and changes in absorption and gastric acidityIncrease in CO, blood volume and plasma proteinsDecrease in plasma albumin concentrationChanges in serum albumin effect the bioavailability of protein-binding
19Pregnancy 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
20Bottom LineEvery woman requires thorough history of pregnancy complaints prior to pharmacologic treatmentDosages may need to be considered based on the stage of pregnancyPrescribing in pregnant patient requires more than just attention to FDA drug categories
21In Translation… Absorption affected by decreased GI tone Drug remains in stomach longer leading to increase in absorption through stomach and delayed in absorption of drugsDistribution affected by increased plasma volume causing prolonged half livesFat soluble drugs stay longer in the bodyDrugs with high protein binding and lower lipid solubility (such as anticonvulsants) have longer half livesHormones (strongly protein bound) compete for available binding sites-resulting in wide distribution of free, unbound drug in the body
22Pregnancy and Pharmacokinetics Metabolism of drugs in liver relatively unchangedDrugs cleared through liver eliminated similar to non pregnant womenExcretion-increased rates of clearanceRenal 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
23Placental TransferSimple diffusion: molecular size may/not permit transferActive transport: where concentration of substances are higher in fetus and transported back to the motherPinocytosis: where soluble molecules (such as viruses) cross membrane in small vesicles and are releasedFacilitated diffusion: glucose is rapidly transferred to fetusLeakage: fetal cells enter mother’s circulation through small membrane breaks
24Properties of Medications that easily cross the placenta Small molecular size and weight ( d)Most drugs have weights < 600dNon-protein boundNon-ionizedLipophilic
25Selecting a Drug for a Pregnant or Nursing Mother Principles of teratology:Timing of exposure in fetal developmentBased on fetal developmental stage when insult is applied can help predict the possible defectExposure 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 damagedMost sensitive period: time from implantation to the end of organogenesis (days )Damage to developing organsheart is most sensitive during the 3rd and 4th weeks of gestation, external genitalia are most sensitive during the 8th and 9th weeksbrain and skeleton are sensitive from the beginning of the 3rd week to the end of pregnancy and into the neonatal period.
26Factors that Influence Teratogenicity of a drug Genotypes of the mother and fetusEmbryonic stage at exposureDrug doseDuration of exposureNature of the agent and mechanism by which it causes a defectSimultaneous exposure to other drugs and environmental agents that potentiate a drugMaternal and fetal metabolism of the drugExtent to which the drug crosses the placenta
27The 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 existMisri S, Kendrick K. Treatment of perinatal mood and anxiety disorders: a review. Can J Psychiatry. Aug 2007
28The Male Partner…Research is increasingly addressing the role of paternal exposure to medications before conception or during his partner’s pregnancyCertain exposures may alter the size, shape, performance, and production of spermsuggests that drug exposure in the male may put the fetus at riskAnimal studies have shown that paternal teratogenic exposure may lead to pregnancy loss or failure of the embryo to developunlike 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
29For example: Colchicine Pregnancy category - D Trimester of risk - UnknownAssociated defects and complications - potential chromosome aberrationsStudies: Colchicine has been shown to cause birth defects in animals. The drug can lower sperm counts and cause sperm defects, resulting in birth defects.
30Current 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
31Drug Exposure Options for Pregnant and Lactating women Withhold the drug (e.g., headache medications)E.g., Ergotamine: Pregnancy category - XTrimesters of risk - allAssociated 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)
32OptionsChoose 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 XTrimesters 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 pregnancyChlordiazepoxide(Librium) appears to be safest choice during pregnancy.
33Options Choose alternate routes of administration when possible Avoid long acting/medications with long half livesAdvise lactating women to time their medications before the infant’s longest sleep periodTemporarily withhold breast feedingCan safely resume after 1-2 half lives (50%-75% elimination)For drugs with high toxicity, must delay 4-5 half livesDiscontinue nursing if medication is for life threatening condition (e.g., chemotherapy)
34Treatment of Select Conditions during Pregnancy Asthma:Asthma complicates approximately 4% of pregnanciesIn some cases, asthma improves during pregnancyThose with poorly controlled asthma are at risk for:Hyperemesis, uterine hemorrhage, preeclampsia, placenta previa, hypertension and premature labor
35IMPLICATIONS of Pregnancy on Asthma Pregnancy has a significant effect on the respiratory physiology of a womanRespiratory 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
36Improved Outcomes associated with controlled asthma Current EVIDENCE Supports TreatmentAlmost 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 fetusWith 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.
37Choice 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.
38Common Asthma medications Inhaled B2 AgonistsAlbuterol-Category CMild, infrequent episodicMay cause maternal hyperglycemia, tachycardia, hypotension or neonatal hypoglycemiaBriggs, et al., 2002: study of 1090 infants exposed to albuterol in 1st trimester-possible association with polydactylyNo congential defects link in 2nd, 3rd trimesterNo adverse effects during lactationPossible B2Choice-Brethine (category B)
39Theophylline (Cat C) Can be used along with inhalation therapy Preferred treatment for patients requiring long term therapyMust monitor levels throughout pregnancy to avoid toxicityEspecially important in 3rd trimester d/t decrease in theophylline clearance and increase in volume of distributionKeep maternal plasma concentrations as low as therapeutically possibleCrosses placenta in equal concentrations to motherNot associated with congenital defects but can cause jitteriness, cardiac arrythmias, hypoglycemia, feeding difficulties in infantsNeonates more likely affected
40Corticosteroids (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 asthmaDoes not have systemic absorption?crossing of placenta
41Corticosteroids (cat C) Can be given IV, PO, or inhaled2 reports congenital cataracts in infants exposed to prednisone throughout gestationNo association found in other studiesSpontaneous abortion, prematurity, cardiac abnormalities reported in one study( Greenberger,1983)Prednisone <20mg/day safe in lactationIn larger doses, delay nsg 3-4hours after dose
42Epilepsy > 1 million women of childbearing age have epiliepsy <1% of pregnancies are complicated by seizures25% of women will have an increase in seizures during pregnancyWomen with epilepsy (with or without medication) have a higher incidence of delivering an infant with congenital malformations and mental retardationRates 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 populationOccurrence: 4–6 per hundred births vs the 2-3 per hundred births risk that all pregnant women faceBenefits v risk are overwhelmingly important to consider
43Epilepsy in PregnancyAAP recommends that a patient who is seizure free for 2 years undergo trial medication withdrawal before becoming pregnantSuggested waiting period of 6 months after d/cing medicationAnticonvulsant pharmacokinetics change during pregnancy:Lower serum concentrations due to increased renal and hepatic clearanceDecreased protein-binding capacityIncreased volume distributiondespite lower serum concentrations, seizures may not increase due to increased free drug concentrationsMust monitor concentrations of anticonvulsants closely
44Newborns exposed to anticonvulsants Hemorrhagic disease in newborns in first 24 hours can be fatalDue to deficiency in Vit K clotting factors as a result of anticonvulsant exposureAll infants should be treated with Vit K at birthSome physicians recommend Vit K for mother in last 2-4 weeks of pregnancyAnticonvulsants also causes folate deficienciesProphylactic folic acid during gestation recommended to prevent megaloblastic anemia and/or neural tube defects
45Fetal Anticonvulsant Syndrome Can occur with all antiepileptic drugsPhenytoin (cat D) can cause fetal hydratoin syndromeSchool, learning and developmental problems, craniofacial abnormalities, growth retardation, limb defects, cardiac lesions, hernias, distal digital and nail hyoplasia10% risk for all of above (FHS)30% risk of partial expression of syndrome
46Phenobarbital (cat D)Less teratogenic that phenytoin but can cause heart defects and cleft palateCan also cause coagulopathies and folate deficienciesAlso has potential to cause neonatal addictionFound in breast milk-causes newborn drowsiness, feeding difficulties, and infantile spasms after weaning
47Carbazamine and Valproate (Cat D) At first, thought to be less harmful to fetusAssociated with the same congenital abnormalities plus spina bifida (1%)Can be used with caution in lactation
48Lamotrigine (Lamictal), Gabapentin (Neurontin) and Oxcarbazine (Trileptal)= Cat C Recent results encouragingAppear to be less teratogenic or associated with fetal loss in 1st trimesterCaution: more data needed
49So…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 medicationIt may be a complex interaction of the medication, the nature of their disease, and genetics rather than just the medication aloneSamuels, 2002The three most common malformations noted in children of women treated for epilepsy are cardiac malformations, facial clefts, and genital/renal malformations.
50The 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.
51ResultsThe combined frequency of anticonvulsant embryopathy was higher in 223 infants exposed to one anticonvulsant drug than in 508 control infants (20.6 percent vs. 8.5 percent; odds ratio, 2.8; 95 percent confidence interval, 1.1 to 9.7).The frequency was also higher in 93 infants exposed to two or more anticonvulsant drugs than in the controls (28.0 percent vs. 8.5 percent; odds ratio, 4.2; 95 percent confidence interval, 1.1 to 5.1).The 98 infants whose mothers had a history of epilepsy but took no anticonvulsant drugs during the pregnancy did not have a higher frequency of those abnormalities than the control infants
52ConclusionsA distinctive pattern of physical abnormalities in infants of mothers with epilepsy is associated with the use of anticonvulsant drugs during pregnancy, rather than with epilepsy itself
53Coagulation Disorders Pregnancy is a hypercoagulable stateIncidence for DVT is still low: %Current recommendations for prophylaxis based on risk factors:Hereditary factors (protein C deficiencies/leiden factors)Hx of DVT/PEAge >35Multiple miscarriages
54Heparin: anticoagulant of choice (Cat C) Does not cross placentaNot associated with congenital defectsLate pregnancy may be associated with increased heparin dosesPerinatal mortality rates significantly improved for patients on heparin v. coumadin (3.6% v. 26.1% mortality)LMWH (Lovenox) safe and effectiveLess bleeding potential and less risk of osteoporosisDoes not cross fetal circulationNot excreted in breast milk
55Coumadin (cat D)Exposure during 6-8th weeks can cause fetal warfarin syndromeDefects in CNS and skeletal systemExposure throughout pregnancy can cause:Stillbirths, spontaneous abortion, facial abnormalitiesCompatible with breast feeding
56Treating Common Problems in Pregnancy Common ColdNausea/VomitingConstipationHeartburnHemorrhoids
57Over the Counter Drug of Choice Drug ClassDuring PregnancyDuring LactationanalgesicsacetominophenantacidsCalcium carbonateantihistaminechlorpheniramineHemorrhoidal agentsPreparation H ointmentdecongestantOxymetazoline nasal spraynonelaxativePsyllium or docusate
58The Common Cold No value in treating with medications If using medication, avoid combination productsLimit duration of treatmentAntihistamine of choice: chorpheniramine (cat B) or Loratidine (cat B)Avoid brompheniramine (Dimetapp-Bromfed)Antihistamines excreted in breast milkNasal cromolyn, beclomethasone useful alternativeClubfoot and inguinal hernias associated with first trimester use of decongestants (e.g., Sudafed)Anti-tussives and expectorants all category CNo epidemiologic studies demonstrate fetal harm
59Nausea and Vomiting 80% of women experience n/v during 1st trimester Hyperemesis gravidarum-intractable, causes lyte imbalances, weight loss, possible end organ damageOccurs in 1:1000 birthsRequires hospitalizationCause unknown-tx focused on sxNon pharmacologic measures not supported by evidenceOTC phosphorated carbohydrate (EMETROL) safeMeclizine (cat B) drug of choice
60ConstipationEtiology: increased pressure on colon, decreased peristalsis, increased progesterone, decreased motilin, increased colonic absorption of waterBulk-forming laxatives (Metamucil) safe in pregnancy and lactationIncrease fluids to prevent intestinal obstructionSurfactants/Stool softeners (docusate), mineral oil Cat c
61Heartburn Affects 72% women in 3rd trimester d/t relaxation of LES and uterine displacement + hormonal changes in gut motilityMagnesium, calcium carbonate, and/or aluminum hydroxides considered safeAvoid H2 blockersIf necessary-ranitidine preferred over cimetidine (has anti-androngenic effects)Metoclopromide (Reglan) cat B
62Hemorrhoids OTC external preparations preferred Avoid suppositories d/t potential for systemic absorption across rectal mucosa
64Limitations of Drug Therapy in Children 75% of FDA approved medications lack indications in childrenPediatric practitioners actually prescibe “off label”FDA indications for dosing regimens are lackingSafety is based on post marketing reports of adverse events
65Post Marketing Adverse Drug Reports MED WATCHFDAhttps://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm
66Important Legislation 1994: first FDA regulations regarding drug product labeling of known use and dosingResulted in FDA approval of limited number of drugs in children1997: Pediatric Exclusivity Provision of FDA Modernization Act passedIncentive for manufacturers to implement studies of their products on children1999: Pediatric Rule developedMandated that manufacturers perform trials and provide safety and efficacy data2003- Pediatric Research Equity Act-outlined FDA authority to enforce Pediatric Rule
67Despite interest in pediatric drug therapy research, conducting clinical trials poses unique challengesConsider:Recent reports of suicide with SSRITreatment/ over treatment of ADHDTreatment of GERD
68For Release: November 5, 2007,ANTIREFLUX MEDICATION MAY BE OVERPRESCRIBED IN INFANTSA majority of infants taking anti-reflux drugs did not meet the diagnostic criteria for gastroesophageal reflux disease (GERD), according to a new study, "Are We Overprescribing Antireflux Medications for Infants With Regurgitation?" Researchers conducted esophageal pH monitoring (measuring the reflux or regurgitation of acid from the stomach into the esophagus) of 44 infants in a New Orleans medical center. Each of the children had persistent regurgitation and was referred to a specialty service for further management. The study showed that while only eight of the infants had abnormal pH levels indicating GERD, 42 of 44 infants were on antireflux medication. When medication was withdrawn from the infants who did not meet GERD criteria, reflux symptoms did not worsen. The study authors concluded that antireflux medications were unnecessary in the majority of infants who were prescribed such medication.
69Developmental Pharmacology Pharmacokinetic differences in children vary with ageDrugs considered safe in one group of pediatric patients may be ineffective or toxic in another groupHepatic enzymes and metabolic pathways mature at different ratesE.g., maturation of each pathway is asynchronousWhen a drug’s primary route of metabolism is immature, it may be shunted through an alternate pathwayDrug dosing dilemmas can be avoided by using only those drugs with scientifically supported dosing
70Key Points In infants, metabolism of most drugs is reduced GFR is 20-40% of adult capacity at birth and increases after the 1st week of life-reaches maximal level by 12 monthsIn general, children over 10 years have organ development and metabolism similar to adultsMay require dosing adjustments based on body surface area
71Key Points (con’t)GI tract acidity, enzymatic activity, and motility differences in infants and young children alter absorption of PO drugsDrugs that are weak bases increase drug absorptionDrugs that are weak acids reduce drug absorptionReduced gastric transit in infants delays absorption and peak plasma concentration time-but NOT the amount of drug absorbed
72Key PointsAbsorption from transcutaneous route is enhanced in infants-increased risk of adverse effectsCaution with use of topicals in infantsThe volume of drug distribution in infants and young children is increased due to increased body waterResults in need for increased drug doses for water-soluble drugs (e.g., aminoglycosides)Drugs that are lipophilic (e.g., diazepam) may exhibit lower volume of distribution
73Key PointsAlterations in protein binding and tissue penetration of drugs may lead to reduced OR exaggerated response
74Practical Tips for Pediatric Prescription Writing Always obtain a weight at every pediatric visitAs a rule, start with smallest dose in neonates and infants“round up” the dose if it falls between the given choices UNLESS it is a toxic drug or has narrow therapeutic windowWith acetominophen, calculate dosage using weight, not ageAlways specify preferred formulation (e.g., chewable tabs, suspension, etc)Stay current with literature!!!
76Medication Use Statistics People >65 consume 30% of prescription and 40% non-prescription drugs(Cohen, 2000)By 2030, the population >65 will double-with largest increases in 85-olderAdverse drug reactions rank in the top 5 causes of mortality and morbidity in elderly28% of elderly hospital admissions are due to adverse drug reactions
77Adverse Drug Reactions About 15% of hospitalizations in the elderly are related to adverse drug reactionsThe more medications a person is on, the higher the risk of drug-drug interactions or adverse drug reactionsThe more medications a person is on, the higher the risk of non-adherence
78Costs of DrugsAverage prescription drug cost for an older person is $500/year, but highly variableNonprescription drugs and herbals can be quite expensive and dangerous when mixed with prescription drugsMany Medicare Managed Care Plans have dropped or severely limited drug coverageDrugs cost more in US than any other countryMany elderly patients look toward “bootlegged” drugs”New drugs cost more-not covered
79Non-prescription Drugs Surveys indicate that elders take average of 2-4 nonprescription drugs dailyLaxatives used in about 1/3-1/2 of elders - many who are not constipatedNon-steroidal anti-inflammatory medicines, sedating antihistamines, sedatives, and H2 blockers are all available without a prescription, and all may cause major side effects
80Prescription DrugsElderly account for 1/3 of prescription drug use, while only 13% of the populationAmbulatory elderly fill between 9-13 prescriptions a year (new and refills)One survey: Average of 5.7 prescription medicines per patientAverage nursing home patient on 7 medicines
81PharmacokineticsDecrease in total body water (due to decrease in muscle mass) and increase in total body fat affects volume of distributionWater soluble drugs: lithium, aminoglycosides, alcohol, digoxinSerum levels may go up due to decreased volume of distributionFat soluble: diazepam, thiopental, trazadoneHalf life increased with increase in body fat
82Pharmacokinetics Absorption: Not highly impacted by aging Variable changes in first pass metabolism due to variable decline in hepatic blood flow (elders may have less first pass effect than younger people, but extremely difficult to predict)
83Pharmacokinetics and the Liver Oxidative metabolism through cytochrome P450 system decreases with aging, resulting in a decreased clearance of drugsHepatic blood flow extremely variable
85Pharmacokinetics: Excretion and Elimination GFR generally declines with aging, but is extremely variable30% have little change30% have moderate decrease30% have severe decreaseSerum creatinine is an unreliable markerIf accuracy needed, do Cr Cl
86The Cockroft and Gault Equation Cr Cl = 140-age(yrs) X wt (kg) X .85 for womenCr (mg/100ml)X72May overestimate Cr Cl, especially in frail eldersUseful equation, but must be aware of its limitations
87Pharmacodynamics: What the Drug does to the Body Some effects are increasedAlcohol causes increase is drowsiness and lateral sway in older people than younger people at same serum levelsFentanyl, diazepam, morphine, theophyllineSome effects are decreasedDiminished HR response to beta -blockers
88Undertreatment CAD Anticoagulation in AF HTN, especially systolic HTN Beta blockersASAAnticoagulation in AFHTN, especially systolic HTNPainParticular fear of narcotics in the elderly
89Drug-Drug Interactions Common cause of ADEs in elderlyAlmost countless – good role for pharmacist and computer or on-line programsSome common examplesStatins and erythromycin and other antibioticsTCAs and clonidine or type 1Anti-arrythmicsWarfarin and multiple drugsACE inhibitors increase hypoglycemic effect of sulfonylureas
90Drug-disease Interactions Patient with PD have increased risk of drug induced confusionNSAIDs (and COX-2’s) s can exacerbate CHFUrinary retention in BPH patients on decongestants or anticholinergicsConstipation worsened by calcium, anticholinergics, calcium channel blockersNeuroleptics and quinolones lower seizure thresholds
91The “Prescribing Cascade” Common cause of polypharmacy in elderlySome common examplesNSAID ->HTN->antihypertensive therapyMetoclopromide ->Parkinsonism ->SinemetDihydropyridine -> edema ->furosemideNSAID ->H2 blocker ->delirium ->haldolHCTZ ->gout->NSAID ->2nd antihypertensiveSudafed ->urinary retention ->alpha blockerAntipsychotic ->akithesia ->more meds
92NSAIDs Acetaminophen as effective as NSAIDs in mild OA NSAIDs side effectsGI hemorrhage (less with COX-2)Decline in GFR (COX-2 as well)Decreased effectiveness of diuretics, anti-hypertensive agentsIndication should justify the increased toxicity of NSAIDs
93Drugs and Cognitive Impairment Common cause of potentially reversible cognitive impairmentDemented patients are particularly prone to delirium from drugsAnticholinergic drugs are common offenders (TCAs, benadryl and other antihistamines, many others)Other offenders cimetidine, steroids, NSAIDsMedical Letter Drug Safety Drugs and Aging 1999
94Drugs and FallsBiggest risk drugs are long acting benzodiazepines and other sedative-hypnoticsBoth SSRIs and TCAs associated with increased risk of fallingBeta blockers NOT associated with increased risk of falling in published literatureMild increase in fall risk from diuretics, anti-arrythmics, and digoxinLeipzig, 2008
95Drug-Food Interactions Interactions between drugs and foodwarfarin and Vitamin K containing foods (remember green tea, as well)Phenytoin & vitamin D metabolismMethotrexate and folate metabolismDrug impact on appetiteDigoxin may cause anorexiaACE inhibitors may alter taste
96Drugs And Dosages to Avoid in Most Instances MeperidineDiphenhydramineThe most anticholinergic tricyclics: amitryptiline, doxepin, imipramineLong acting benzodiazepines such as diazepamLong acting NSAIDs such as piroxicamHigh dose thiazides (>25mg)Iron: 325 mg once daily is enough
97Anticipate SE’s Narcotics Steroids Levothyroxine Begin lactulose or sorbitol and a stimulant laxativeColace is NOT sufficient in most instancesSteroidsThink about osteoporosis preventionRemember steroid induced diabetesLevothyroxineCalcium interferes with absorption of levothyroxine?Biphosphonates and ? Atrial fibrillation (NEJM, 2009)Calcium and MI ??(BMJ, 2010)
98High Risk Situations Patient seeing multiple providers Patient on multiple drugsPatient lives alone and/or has cognitive impairmentDischarge from hospital or any change in venue
99Hospitalization: A High Risk Time At hospitalization:40% of admission medications stopped45% of discharge medications were startedSerious prescribing problems in 22%Other prescribing problems in 66%Beers JAGS 1989, Lipton Medical Care 1992
100Non-adherence Lack of understanding of how to take Unable to take High risk times: Hospital discharge, new meds added, complex regimensUnable to takeConscious nonadherenceSide effectsLack of understanding of benefits of drugFinancial
101Complementary Therapies Very commonly used in the elderlySome common herbs and alternative therapies:“Anti-aging” DHEA, growth hormoneDementia Gingko bilobaBPH Saw palmetto, PC-SPESOA Chondroiton sulfate, glucosamineDepression St. John’s wort, SAMe
102“Do No Harm?”California Department of Health Services, Food and Drug Branchscreened 250 Asian herbal productscollected from herbal stores in Californiaassayed products using gas chromatography, mass spectrometry, and atomic-absorption techniquesKo, NEJM 1998; 339; 84732% contained unlabeled medications, 14% mercury, 14% arsenic, 10% lead
103Herbals and Supplements: Regulation Demonstration of safety is NOT required prior to marketingManufacturing standards are not requiredCan have health claims, but not claims about treating, preventing, or curingFor glucosamine/chondroitin, 1/3 of combinations did not contain listed ingredienthas drug information
104Herbals and Supplements:Potential interactions with Rx Drugs SAMe may increase homocysteine levelsSt. John’s wort and Oral contraceptivesGinkgo may increase anticoagulant effects of ASA, warfarin, NSAIAs, ticlopidine, and may interact with MAOIsBottom line: Try to know what your patient is taking, and ask in a nonjudgmental way
105Mr. 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?This man has already shown that he is not adherent, and adding medications to his regimen has probably made his adherence worse. Asking him about adherence can be revealing. In this case, he admits that he is “just taking too many medications” and so randomly stopped a few. He also is complaining about urinating all day, so almost always skips his PM furosemide.Although beta blockers improve outcomes in severe CHF, in this man is who marginal with his medications, had lung disease, and limited insight, it may not be worth it. Keeping the regimen simple is more likely to result in success. Likewise, his iron, if he needs it at all, would be adequate at a once daily dose. Probably combivent would be a better choice to improve adherence.RCTs have demonstrated decreased mortality with both beta blockers and aldactone in CHF. However, applying those results to this man with multiple severe diseases, mild dementia and decreased adherence may not be wise.So, in short we recommend:Changing furosemide to 120mg once dailyD/c feSo4 or decrease it to once dailyDrop metoprolol and aldactoneChange inhaler back to combivent
106Principles for Managing Drugs Complete drug history, including herbs and nonprescription drugsAvoid medications if benefit is marginal or if non-pharmacologic alternatives existConsider the costStart low, go slow, but get there!Keep regimen as simple as possibleWrite instructions out clearlyHave patient bring in medications at each visit
107Principles (continued) Consider medication box or “mediset”If things don’t make sense, consider a home visitDiscontinue drugs when possible if benefit unclear or side effects could be due to drugBe cautious with newer drugsConsider if the benefit of the 7th or 8th drug is sufficient to justify the cost, increase in complexity of regimen, and risk of side effects
108Newer drugs What is unique about this compound? What clinical data is available?How does it compare with traditional therapy?How expensive is it?With third party payers cover this product?Does the potential advantage of this new drug justify the risk of using a new drug?
109Summary The elderly take more medications than any other age group Pharmacokinetics and pharmacodynamics are alteredAdverse drug reactions are commonRisks go up with the number of drugs usedNonprescription and herbal therapies are commonWith care and common sense, we can probably do a better job