Age features of drugs side effects. UCSF Division of Geriatrics Primary Care Lecture Series May 2001 Overview Scope of the issue Scope of the issue Pharmacokinetics.

Age features of drugs side effects

UCSF Division of Geriatrics Primary Care Lecture Series May 2001

Overview Scope of the issueScope of the issue PharmacokineticsPharmacokinetics PharmacodynamicsPharmacodynamics Adverse drug reactions and adherenceAdverse drug reactions and adherence Underuse of drugsUnderuse of drugs Nonprescription and alternative therapiesNonprescription and alternative therapies Common sense solutionsCommon sense solutions


Prescription 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 prescription One survey: Average of 5.7 prescription medicines per patientmedicines per patient

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


Medicare does not pay for prescription drugsMedicare does not pay for prescription drugs Average prescription drug cost for an older Average prescription drug cost for an older

person is $500/year, but highly variableperson is $500/year, but highly variable Nonprescription drugs and herbals can be quite Nonprescription drugs and herbals can be quite

expensiveexpensive Many Medicare Managed Care Plans have Many Medicare Managed Care Plans have

dropped or severely limited drug coveragedropped or severely limited drug coverage Drugs cost more in US than any other countryDrugs cost more in US than any other country New drugs cost moreNew drugs cost more

Costs of Drugs


Non-prescription Drugs

Surveys indicate that elders take average Surveys indicate that elders take average of 2-4 nonprescription drugs of 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 constipated- many who are not constipated

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


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, trazadoneFat soluble: diazepam, thiopental, trazadone

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

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 Liver

Acetylation and conjugation do not Acetylation and conjugation do not change appreciably with agechange appreciably with age

Oxidative metabolism through Oxidative metabolism through cytochrome P450 system does cytochrome P450 system does decrease with aging, resulting in a decrease with aging, resulting in a decresed clearance of drugsdecresed clearance of drugs

Hepatic blood flow extremely variableHepatic blood flow extremely variable


Drugs with Cytochrome P450 Effects(partial)

Inhibitors Inducers

Allopurinol Metronidazole Barbiturates

Amiodorone Quinolones Carbamazepine

Azole antifungals Phenytoin

Cimetidine Rifampin

INH Tobacco

SSRIs

Tacrine


Pharmacokinetics: Excretion and Elimination GFR generally declines with aging, GFR generally declines with aging,

but is extremely variablebut is extremely variable30% have little change30% have little change30% have moderate decrease30% have moderate decrease30% have severe decrease30% have severe decrease

Serum creatinine is an unreliable Serum creatinine is an unreliable markermarker

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: What 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, theophylline Some effects are decreasedSome effects are decreased

Diminished HR response to isoproterenol Diminished HR response to isoproterenol and beta -blockersand beta -blockers


Mrs. F. is a 92 year old nursing home resident with a history of HTN, “heart disease”, osteoarthritis, and a stroke. She has been declining recently, with a decreased appetite. Her meds are HCTZ 12.5, ASA 81, digoxin .125, and enalapril 10. She has been on the same meds and dosages for years. On exam, she looks frail BP 130/80 P60 R 16. Other than being thin, her exam is fairly unremarkable. She has no signs of CHF. She has mild left sided weakness and hyper-reflexia, and her MMSE is 27/30, she is not depressed. Her gait is slow with a walker. Labs: Hgb12, Cr 1.3, BUN 20, digoxin level 1.7, others normal. Her EKG is normal except for borderline bradycardia and nonspecific ST changes, which are old.

What do you think is wrong?


Undertreatment

CADCAD Beta blockersBeta blockers ASAASA

Anticoagulation in AFAnticoagulation in AF HTN, especially systolic HTNHTN, especially systolic HTN PainPain

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


Adverse 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


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

and computer or on-line programs and computer or on-line 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 ACE inhibitors increase hypoglycemic effect of

sulfonylureassulfonylureas


Drug-disease Interactions Patient with PD have increased risk of drug Patient with PD have increased risk of drug

induced confusioninduced confusion NSAIA (and COX-2’s) s can exacerbate CHFNSAIA (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,

ahticholinergics, calcium channel blockersahticholinergics, calcium channel blockers Neuroleptics and quinolones lower seizure Neuroleptics and quinolones lower seizure

thresholdsthresholds


The “Prescribing Cascade”

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

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


NSAIDs Acetaminophen as effective as NSAIDs Acetaminophen as effective as NSAIDs

in mild OAin mild 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, Decreased effectiveness of diuretics, anti-hypertensive agentsanti-hypertensive agents

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


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


Drugs and Falls

Biggest risk drugs are long acting Biggest risk drugs are long acting benzodiazepines and other sedative-benzodiazepines and other sedative-hypnoticshypnotics

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, type Mild increase in fall risk from diuretics, type 1A anti-arrythmics, and digoxin1A anti-arrythmics, and digoxinLeipzig, JAGSLeipzig, JAGS


Drug-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 Most 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 NSAIAs such as piroxicamLong acting NSAIAs 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’s NarcoticsNarcotics

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 Calcium interferes with absorption of

levothyroxinelevothyroxine


Severe ADE’s In a Nursing Home

Cardiovascular Cardiovascular 36%36% DigoxinDigoxin 11%11% FurosemideFurosemide 7%7%

Analgesics Analgesics 13%13% IbuprofenIbuprofen 11%11%

CNS CNS 19%19% PhenytoinPhenytoin 9% 9%

ASAASA 7%7% Gerety JAGS 1993Gerety JAGS 1993


Drug Discrepancies

Difference between medical record and Difference between medical record and medication bottles in 76% of casesmedication bottles in 76% of cases 51% of time medication not recorded51% of time medication not recorded 29% medication recorded that patient not 29% medication recorded that patient not

takingtaking 20% dosage discrepancy20% dosage discrepancy

Risk Factors: Age, number of Risk Factors: Age, number of medicationsmedications Bedell et al Arch Intern Med 160, 2000Bedell et al Arch Intern Med 160, 2000


DiscrepanDiscrepancy cy PresentPresent

DiscrepanDiscrepancy Absentcy Absent

PP

AgeAge 6464 5656 <.001<.001

CardiologCardiologistist

8282 1818 <.001<.001

InternistInternist 6565 3535 <.001<.001

>1 MD>1 MD 8080 5656 <.005<.005

# meds# meds 7.07.0 4.44.4 <.001<.001

Bedell, Arch Inter Med 2000


High Risk Situations Patient seeing multiple providersPatient seeing multiple providers Patient on multiple drugsPatient on multiple drugs Patient lives alone and/or has cognitive Patient lives alone and/or has cognitive

impairmentimpairment Discharge from hospital or any change Discharge from hospital or any change

in venuein venue


Hospitalization: A High Risk Time

At hospitalization:At hospitalization: 40% of admission medications stopped40% of admission medications stopped 45% of discharge medications were started45% of discharge medications were started 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


Nonadherence

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 take Conscious nonadherenceConscious nonadherence

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


Complementary Therapies

Very commonly used in the elderlyVery commonly used in the elderly Some common herbs and alternative Some common herbs and alternative

therapies: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


Adulterants in Products 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: Regulation Demonstration of safety is NOT required Demonstration of safety is NOT required

prior to marketingprior to marketing 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, on third of For glucosamine/chondroitin, on third of

combinations did not contain listed combinations did not contain listed ingredientingredient

www.consumerlabs.com has some drug www.consumerlabs.com has some drug informationinformation


Herbals and Supplements:Potential interactions with Rx Drugs

SAMe may increase homocysteine levelsSAMe may increase homocysteine levels St. John’s wort and Oral contraceptivesSt. John’s wort and Oral contraceptives Ginkgo may increase anticoagulant Ginkgo may increase anticoagulant

effects of ASA, warfarin, NSAIAs, effects of ASA, warfarin, NSAIAs, ticlopidine, and may interact with MAOIsticlopidine, and may interact with MAOIs

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


Use Common Sense in Applying Results to Individual Patients

SPAF: 18,000 patients screened, only 7% SPAF: 18,000 patients screened, only 7% were enrolledwere enrolled

SHEP enrolled 9% of 52,000 patientsSHEP enrolled 9% of 52,000 patients NNT to benefit one patient may be 20, 30, NNT to benefit one patient may be 20, 30,

50, or 100 in many effective drugs, so…50, or 100 in many effective drugs, so… Benefit may be marginal in a patient with Benefit may be marginal in a patient with

8 diseases, dementia, or a life expectancy 8 diseases, dementia, or a life expectancy of six monthsof six months


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, 02, 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 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 Have patient bring in medications at each

visitvisit


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

home visithome visit Discontinue drugs when possible if benefit Discontinue drugs when possible if benefit

unclear or side effects could be due to unclear or side effects could be due to drugdrug

Be cautious with newer drugsBe cautious with newer drugs Consider if the benefit of the 7th or 8th Consider if the benefit of the 7th or 8th

drug is sufficient to justify the cost, drug is sufficient to justify the cost, increase in complexity of regimen, and risk increase in complexity of regimen, and risk of side effectsof side effects


Newer 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 With third party payers cover this

product?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?


Drug Information Sources

www.centerwatch.com/drugs/druglist.htm

www.fda.gov/cder/rdmt/nmecy99.htm www.fda.gov www.pslggroup.com/NEWDRUGS.HTMwww.pslggroup.com/NEWDRUGS.HTM


Summary

The elderly take more medications than any The elderly take more medications than any other age groupother age group

Pharmacokinetics and pharmacodynamics are Pharmacokinetics and pharmacodynamics are altered altered

Adverse drug reactions are common Adverse drug reactions are common Risks go up with the number of drugs usedRisks go up with the number of drugs used Nonprescription and herbal therapies are Nonprescription and herbal therapies are

common common With care and common sense, we can probably With care and common sense, we can probably

do a better jobdo a better job

Age features of drugs side effects. UCSF Division of Geriatrics Primary Care Lecture Series May 2001 Overview Scope of the issue Scope of the issue Pharmacokinetics.

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