Post on 15-Jan-2017
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
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Disclosure
No relevant financial relationships with commercial interests
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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
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Topics Covered
• Challenges of geriatric pharmacology
• Aging and pharmacokinetics
• Aging and pharmacodynamics
• Psychotropic use in Nursing Facilities
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“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!!
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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
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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
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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
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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
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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)
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Drug Interactions: Absorption
• Cations may chelate antibiotics (quinolones, tetracyline)
• Binding resins, psyllium, sucralfate• Antacids may prevent absorption
(ketoconazole)
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Factors that Affect Absorption (1 of 2)
• Route of administration• What is taken with the drug?• Co-morbid illnesses
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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
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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
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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
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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
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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
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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.
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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
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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
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Drug Interactions: Metabolism
• Codeine is prodrug—requires 2D6 for activation
• Fluoxetine inhibits 2D6• Genetic variability
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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
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How to Avoid Getting Into Trouble with Drugs in the Elderly
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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
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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
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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
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Watch for Drug-Drug, Drug-Disease, and Drug-Food Interactions
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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
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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
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Effects of Aging on the Kidney
• kidney size• renal blood flow• number of functioning nephrons• renal tubular secretion
Result: Lower glomerular filtration rate
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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)
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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
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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
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Age-Related Pharmacodynamics
• Autonomic nervous system• Central nervous system• Gastrointestinal system
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Age-Related Pharmacodynamics:Autonomic nervous system
• Decreased baroreceptor response• Increased blood pressure sensitivity to
vasodilatory agents
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Age-Related Pharmacodynamics:Central nervous system
Increased effect at equal concentration• Benzodiazepines• Narcotics
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Drug Interactions: Elimination
• Increased half life• Increased serum concentration• Problem for drugs with narrow therapeutic
index
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Drug-Disease Interactions
• Urinary retention: anticholinergics, tricyclics, alpha-agonists
• Constipation: anticholinergics, narcotics, calcium channel blockers, tricyclics
• Falls: benzodiazepine• Postural hypotension: tricyclics, diuretics,
antihypertensives.
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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
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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.
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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
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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.
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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??
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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!