Kamal Kejriwal M.D., CMD, AGSF, FAAFP

Program DirectorGeriatric Medicine Fellowship

SCPMGFontana

Polypharmacy and Aging

Larry Zelman, Pharm.D, CGPClinical Pharmacist

VAMC San DiegoLarry.Zelman@va.gov

3

Disclosure

No relevant financial relationships with commercial interests

4

The central question in all of modern

American medicine…

Well, what pills should I give her for

that?

https://www.youtube.com/watch?v=PXoLsW0w1FE

5

6

Topics Covered

• Challenges of geriatric pharmacology

• Aging and pharmacokinetics

• Aging and pharmacodynamics

• Psychotropic use in Nursing Facilities

7

“It’s just because I’m OLD”

FALSEYou must understand the underlying

pathophysiology of diseases, normal pharmacodynamics and pharmacokinetic changes with aging, and drug-drug and drug-disease interactions!!

8

Why Geriatric Pharmacotherapy is Important

Persons aged 65 and older are prescribed thehighest proportion of medications in relation to theirpercentage of the U.S. population

• Now, 13% of total population buy 33% of all prescription drugs.

• In Elderly populations there are more deaths due to ADE than MVA, Breast cancer or AIDS.

• By 2040, 25% of total population will buy 50% of all prescription drugs.

9WHY GERIATRIC PHARMACOTHERAPY IS IMPORTANT

Present 20400

102030405060708090

100

People 65+ 65+ share of prescriptionsPeople <65 <65 share of presciptions

Now, people age 65+ are 13% of US population, buy 33% of prescription drugsBy 2040, will be 25% of population, will buy 50% of prescription drugs

10

Why Geriatric Pharmacotherapy is Challenging?

• FDA- approved and off-label indications expansion

• Managed-care formularies change frequently• Knowledge of drug-drug interactions

advances• Drugs change from prescription to OTC• “Nutriceuticals” (herbal preparations,

nutritional supplements) are booming

11

12

Pharmacokinetics

• Absorption• Distribution• Metabolism• Elimination

Case Study

An 80yo woman is taking calcium carbonate 500mg qday for osteoporosis. She is also on alendronate 70mg qweek, atenolol 50mg qday, and omeprazole 20mg qday x 2years. Which of the following pharmacokinetic properties associated with aging can change the expected outcome of treatment?

A. AbsorptionB. DistributionC. MetabolismD. Excretion

14

Aging and Absorption

• Amount absorbed (bioavailability) is not changed

• Peak serum concentration may be lower and delayed

• Exceptions: drugs with extensive first-pass effect (bioavailability may increase because less drug is extracted by the liver, which is smaller with reduced blood flow)

15

Drug Interactions: Absorption

• Cations may chelate antibiotics (quinolones, tetracyline)

• Binding resins, psyllium, sucralfate• Antacids may prevent absorption

(ketoconazole)

16

Factors that Affect Absorption (1 of 2)

• Route of administration• What is taken with the drug?• Co-morbid illnesses

17

Factors that Affect Absorption (2 of 2)

• Divalent cations (calcium, magnesium, iron) can affect absorption of many fluoroquinolones (e.g., ciprofloxacin)

• Enteral feedings interfere with absorption of some drugs (e.g., phenytoin)

• Increased gastric pH may increase or decrease absorption of some drugs

• Drugs that affect GI motility can affect absorption

18

Effects of Aging on Volume of Distribution (Vd)

• body water lower VD for hydrophilic drugs

• lean body mass lower VD for drugs that bind to muscle

• fat stores higher VD for lipophilic drugs

• plasma protein (albumin) higher percentage of drug that is unbound (active)

Case Study

A 75yo male has a 20 year history of a seizure disorder. He has been seizure free for the past 4 years. He is on phenytoin 200mg qday. Labs are drawn in your clinic today and the phenytoin level is 6.5mg/L (therapeutic range 10-20mg/L) and his albumin is 2.3gm/dl. The phenytoin dose needs to be:

A. Increased to 300mg qdayB. Increased to 400mg qdayC. Decreased to 100mg qdayD. Maintained at 200mg qday

20

Changes in Distribution: Protein Binding

• Reduced protein binding with age• Reduced protein concentrations with

disease• Affects serum levels of drugs that bind to

proteins• Examples: fentanyl, theophylline,

sulfonylureas, warfarin and digoxin

21

Aging and Metabolism

Metabolic clearance of a drug by the liver may be reduced because:

• Aging decreases liver blood flow, size, and mass, and

• The liver is the most common site of drug metabolism

Case Study

A 79yo male has history of gout, maintained on colchicine 0.6mg qday and allopurinol 300mg qday. Pt has developed a gastric ulcer and clinician starts H.Pylori regimen of amoxicillin, clarithromycin and omeprazole. Which pharmacokinetic property can change the expected outcome to treatment?

A. AbsorptionB. DistributionC. MetabolismD. Excretion

23

Cytochrome P-450• Major pathway for drug metabolism• Several isoenzymes, genetic susceptibility• Drug-drug interactions:

• Enzyme inhibition: competition with another drug for the enzyme binding site: INCREASE DRUG LEVELS

• Enzyme induction: a drug stimulates the synthesis of more enzyme protein, enhancing the enzyme’s metabolizing capacity: DECREASE DRUG LEVELS

24

Why the Metabolic Pathways Matters

• Phase I pathways (e.g., hydroxylation, oxidation, dealkylation and reduction) convert drugs to metabolites with <, =, or > effect than parent compound

• Phase II pathways convert drugs to inactive metabolites that do not accumulate

With few exceptions, drugs metabolized byPhase II pathways are preferred for older

patients.

25

Changes in Metabolism

• Reduced hepatic mass• Reduced hepatic circulation• Decreased phase I metabolism-oxidative or

reduction reactions via cytochrome P450• Examples: diazepam, barbiturates, lidocaine• No change in phase II metabolism-conjugative

reaction with glucuronyl transferase • Examples: lorazepam, oxazepam

26

CYTOCHROME P-450 CYP3A4

Metabolizes:Fentanyl, methadone,AcetaminophenErythro, ClarithromycinItra- and ketoconazole,Amiodarone, lidocaine, quinidine, Calcium channel blockersSertraline, nefazadoneAlprazolam, zolpidem, triazolamAstemizole, loratadine, terfenadineCyclosporineSex hormones, cortisolCarbamazepine

Induced by:BarbituratesCarbamazepineGlucocorticoidsPhenytoin

Inhibited by:CimetidineErythro, clarithromycinDiltiazem, nicardipine, verapamilItra-, ketoconozoleFluoxetine, methylphenidate

27

Drug Interactions: Metabolism

• Codeine is prodrug—requires 2D6 for activation

• Fluoxetine inhibits 2D6• Genetic variability

28

Other Factors that Affect Metabolism

• Gender (e.g.,oxazepam is metabolized faster in older men than older women)

• Hepatic congestion from heart failure (e.g., reduces metabolism of warfarin)

• Smoking (e.g., increases clearance of theophylline)

https://www.youtube.com/watch?v=Lp3pFjKoZl8

29

How to Avoid Getting Into Trouble with Drugs in the Elderly

31

32

ADEs Prescribing Cascade

Source Note: Rochon PA, Gurwitz JH. Optimising drug treatment for elderly people: the prescribing cascade. BMJ. 1997;315(7115):1097. Reprinted with permission.

DRUG 1

DRUG 2

Adverse drug effect- misinterpreted as a new medical condition-

Adverse drug effect- misinterpreted as a new medical condition

33

How to Avoid Getting Into Trouble with Drugs in the Elderly

• Use proper prescribing etiquette• Watch for drug-drug, drug-disease, and

drug-food interactions• Don’t prescribe bad medications

34

Appropriate Drug Prescribing (proper etiquette)

• Review current prescription and non-prescription medications, medical history, labs

• Ask about drug allergies, adverse reactions, use of alcohol

• Start low and go slow but treat adequately• Maximize dose before switching to another

drug• Avoid starting two drugs at the same time

35

Watch for Drug-Drug, Drug-Disease, and Drug-Food Interactions

36

Key Concepts in Elimination

• Half-life: time for serum concentration of drug to decline by 50%

• Clearance: volume of serum from which the drug is removed per unit of time (usually expressed in hours)

Case Study

83yo female with CAD, HTN, type 2 diabetes, depression, GERD and chronic low back pain. She weighs 72kg , height 5’3” and her SCr is 2.0mg/dl. Her med list includes metoprolol 50mg bid, gabapentin 900mg tid, glipizide ER 5mg qday, citalopram 20mg qday, acetaminophen 500mg tid and ranitidine 300mg qhs. Which of the following medication dosages should be reduced?

A. MetoprololB. GabapentinC. CitalopramD. RanitidineE. B and D

38

Kidney Function is Critical for Elimination

• Most drugs exit body via kidney• Reduced elimination drug accumulation

and toxicity• Aging and common geriatric disorders can

impair kidney function

39

Effects of Aging on the Kidney

• kidney size• renal blood flow• number of functioning nephrons• renal tubular secretion

Result: Lower glomerular filtration rate

40

Serum Creatinine Does NOT Reflect Creatinine Clearance

• lean body mass lower creatinine production

and• glomerular filtration rate (GFR)

Result: In older persons, serum creatininestays in normal range, masking change increatinine clearance (CrCl)

41

Changes in Elimination

• Decline in glomerular filtration and tubular excretion

• Estimation of Creatinine Clearance:• COCKROFT AND GAULT EQUATION

Cr Cl = [140- Age (y)] X Weight (kg) 72 X Cr

(Multiply total by .85 if pt is female)• Examples: aminoglycosides, allopurinol,

digoxin, lithium, atenolol

42

Pharmacodynamics

Definition• Time course and intensity of pharmacologic

effect of a drug

The Impact of Aging• May change with aging, e.g.:• Benzodiazepines may cause more sedation

and poorer psychomotor performance in older adults. Likely cause: reduced clearance of the drug and resultant higher plasma levels

• Older patients may experience higher levels of morphine with longer pain relief

43

Age-Related Pharmacodynamics

• Autonomic nervous system• Central nervous system• Gastrointestinal system

44

Age-Related Pharmacodynamics:Autonomic nervous system

• Decreased baroreceptor response• Increased blood pressure sensitivity to

vasodilatory agents

45

Age-Related Pharmacodynamics:Central nervous system

Increased effect at equal concentration• Benzodiazepines• Narcotics

46

Drug Interactions: Elimination

• Increased half life• Increased serum concentration• Problem for drugs with narrow therapeutic

index

47

Drug-Disease Interactions

• Urinary retention: anticholinergics, tricyclics, alpha-agonists

• Constipation: anticholinergics, narcotics, calcium channel blockers, tricyclics

• Falls: benzodiazepine• Postural hypotension: tricyclics, diuretics,

antihypertensives.

48

Drug-Disease Interactions (cont)

• Delirium: benzos, narcotics, anticholinergics• Exacerbation of CHF: NSAIDs• Worsening of urinary incontinence: diuretics,

alpha blockers

Beers list of PIMS2015 Update

Guideline for nitrofurantoin is relaxed for Creatinine Cl from 60 to 30

Opioids been added to list of CNS drugs to avoid in pt with h/o falls and fractures.

Anticoagulants dose should be adjusted based on Cr Cl.

Avoid PPI for greater than 8 weeksNasal Saline to use as alternative to

antihistamines49

CHOOSING

WISELY

50

Don’t prescribe a medication without conducting a drug regimen review.

#1 Older patients disproportionately use more prescription and non-prescription drugs than other populations, increasing the risk for side effects and inappropriate prescribing.

#2Polypharmacy may lead to diminished adherence, adverse drug reactions and increased risk of cognitive impairment, falls and functional decline

#3 Annual review of medications is an indicator for quality prescribing in vulnerable elderly.

51

Don’t use benzodiazepines or other sedative-hypnotics in older adults as first choice for

insomnia, agitation or delirium. #1Large scale studies consistently show that the risk of motor

vehicle accidents, falls and hip fractures leading to hospitalization and death can more than double in older adults taking benzodiazepines and other sedative-hypnotics.

#2 Older patients, their caregivers and their providers should recognize these potential harms when considering treatment strategies for insomnia, agitation or delirium.

#3 Use of benzodiazepines should be reserved for alcohol withdrawal symptoms/delirium tremens or severe generalized anxiety disorder unresponsive to other therapies

52

Psychotropic Use in Long Term Care Facilities

Please do not use the above medications as your First Line

Non Pharmacological Approaches first

Title 22 requires the consent to be taken by the provider prior to administration of these meds.

53

c 2007 ASCP 54

F329 - Unnecessary Meds Regulations

• Antipsychotics - Based on a comprehensive assessment of a resident, the facility must ensure that:– Residents who have not used antipsychotic drugs are

not given these drugs unless antipsychotic drug therapy is necessary to treat a specific condition as diagnosed and documented in the clinical record; and

– Residents who use antipsychotic drugs receive gradual dose reductions, and behavioral interventions, unless clinically contraindicated, in an effort to discontinue these drugs

CASE STUDY

85yo woman admitted to a nursing facility for short term rehab after a fall and wrist fracture. PMH includes Type 2 Diabetes, HTN, recent DVT, neuropathic pain, hyperlipidemia.

Current meds include: Metformin 1000mg bid, Hydrochlorothiazide 25mg qday,

Simvastatin 40mg qpm, Gabapentin 800mg tid, Pantoprazole 40mg qday. Recently started meds include Warfarin 5mg qpm, Diltiazem SA 240mg qday, Zolpidem 10mg qhs, Oxycodone 10mg q4h prn pain, Risperidone 2mg bid.

3 days later, patient was c/o lethargy, excessive sedation, constipation, muscle weakness/pain, N/V and pt seemed confused according to nursing staff.

CASE STUDY (cont)

Labs were drawn and some were as following:

BUN 55, SCr 1.9 (baseline 0.9-1.1), Na 128, K 3.1, Albumin 2.2 INR 3.8 ALT 65 AST 74

BP 98/65, HR 65 Wt 65kg Ht 64in

CASE STUDY (cont)

Thoughts/recommendations??

58

Does this sound Familiar?

Decreased use of Inappropriate meds in Elderly ( 65 yrs. and older) improves hospital safety, reduces length of stay and rate of readmissions.

Examples of potentially inappropriate meds to avoid in Elderly:

-Diphenhyramine, Promethazine, Hydroxyzine, amitriptyline, imipramine, methocarbamol, trimethobenzamide, meperidine and diazepam.

Innovative pill box reminders

Medminder® : $40-65 per month. Looks like traditional pill boxes, 7 day (qid) boxes that lock. Flashing light/audible/text message/phone calls for reminders. Also, caregivers can get reports via text/emails/internet

Locked medication systems (eg e-pill): $200-500. Dispensers that lock/alarm, like a small omnicell/pyxis machine.

iPhone apps: Free-$3.99. Virtual pillbox. Can set medications, dosages and times a dose is needed. Alarms, reminders, etc.

Thank you!