medication use in older adults kimberly keefer, pharm.d., bcps

Medication Use in Older Adults

Kimberly Keefer, Pharm.D., BCPS

• Sponsored by The Penn State Site of The Geriatric Education Center of PA Consortium (Penn State, Univ. of Pittsburgh, and University of Pittsburgh Medical Center, in conjunction with The Pennsylvania Behavioral Health and Aging Coalition and Penn State College of Medicine

• Supported by funds from the Bureau of Health Professions (BHPr), Health Resources and Services Administration (HRSA), Department of Health and Human Services (DHHS) under grant number UB4HP19199 “Geriatric Education Center of Pennsylvania”.

Objectives

• Review pharmacokinetics and pharmacodynamics as they relate to the elderly population

• Present common adverse drug reactions and drug-drug interactions seen

• Manage polypharmacy in the elderly patient

Aging

• Elderly population is expected to reach 22% in 2050.

• By 2012 10,000 people will turn 65 daily.• By 2027 Inpatient admissions are

expected to increase by 78%.

Koltz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metabolism Reviews 2009; 41:67-76.

Medication Use

• Older persons over 65 represent 12% of population but receive 32% of all prescription drugs and 40% of all nonprescription medications

• Average 4 to 5 prescriptions and 2 OTC drugs at a time

Cusack B. Pharmacokinetics in Older Persons. The American Journal of Geriatric Pharmacotherapy 2004; vol 2 (number 4): 274-302.

Drugs and the Body• Pharmacokinetics: how the body handles

the drug• Pharmacodynamics: how various target

organs respond to the drug• Changes with aging:

• Drugs having prolonged durations of activity• Greater risks of toxicity• Increased frequency of adverse effects• Different effects than anticipated from a given dose

Catterson M et al. Pharmacodynamic and Pharmacokinetic , Considerations in Geriatric Psychopharmacology 1997; 20: 205-17.

Drugs and the Body (cont.)

• Differentiate multiple disease states• Neurologic• Cardiovascular• Pulmonary• Hepatic• Renal• Immunologic• Endocrine

Hayes B, et al. Polypharmacy and the Geriatric Patient. Clin Geriatr Med 2007; 23:371-390.

Pharmacokinetics

• Absorption• Distribution• Metabolism • Elimination

Absorption• Drug absorption

– Passive process (most drugs absorbed in the small bowel)

• pH • Drug binding• Gastric motility

– Delay in absorption: the onset of action will be delayed but total amount of drug absorbed not affected


Distribution


Distribution

• Polar drugs (e.g., Lithium, digoxin) ↓• Lipophilic drugs (e.g., diazepam) ↑• Albumin (10-20% decline)

• Phenytoin• Furosemide• NSAIDs• Warfarin

Hayes B, Klein-Schwartz W, Barrueto F. Polypharmacy and the Geriatric Patient. Clin Geriatr Med 2007; 23:371-390.

Metabolism• Liver by cytochrome P450 (CYP)

• Phase I reactions and/or phase II pathways such as glucuronidation, acetylation, or sulfatation

• Biosynthesis and degradation of chemicals, toxins and medications

• Water soluble to facilitate elimination• CYP3A4, 2D6, 1A2, and 2C9 IMPORTANT!

• Blood flow in the liver can decrease by up to 40% = ↓ clearance of drugs


Elimination

• Kidney mass and number of glomeruli decreases by 20-30%

• 1/3 of patients have no decrease in renal function• Confounding factors: hypertension, chronic heart

diseases, and diabetes• Half lives of drugs are prolonged• Drug serum levels ↑• Decline in renal function is closely related to

the incidence of adverse drug reactions (ADRs)

Cusack B. Pharmacokinetics in Older Persons. The American Journal of Geriatric Pharmacotherapy 2004; vol 2 (number 4): 274-302.

Factors Affecting Creatinine Generation

Stevens L et al. N England J Med 2006;354:2473-2483

Which of the following is not true of Aging?

A. Increased body fatB. Decreased gastric motility causes

decreased total amounts of drug absorbed

C. Decreased blood flow to the liver decreases clearance of drugs

D. Decreased total body water

Pharmacodynamics Dopaminergic System

Progressive loss of dopamine D2 receptors Increased incidence of extrapyramidal syndromes such as

tardive dyskinesia Associated with Parkinson’s disease

Cholinergic System Important in memory and other higher cognitive functions Associated with Alzheimer’s dementia

Adrenergic System Reduction of beta-adrenergic and Alpha2 adrenoreceptors Response to agents like clonidine is decreased

Gabaminergic System Greater impairment in psychomotor performance with agents

like BenzodiazepinesCatterson M, et al. Pharmacodynamic and Pharmacokinetic. Considerations in Geriatric Psychopharmacology 1997; 20: 205-17.

Adverse Drug Reactions (ADRs)• 7 times more common in persons aged

70 to 79 than in those 20 to 29 • Up to 17% of elderly hospital admission• Antibiotics, anticoagulants, digoxin,

diuretics, hypoglycemic agents, antineoplastic agents and NSAIDs are responsible for 60% of ADRs leading to hospital admission and 70% of ADRs occurring in hospitals

Mann HJ. Drug-Associated Disease: Cytochrome P450 Interactions. Critical Care Clinics 2006;22: 329-45.

ADRs• Discontinue the drug• Change drug therapy• Modify the dose• Necessitates admission to the hospital• Prolongs stay• Complicates diagnosis• Affects prognosis• Results in harm or death

Routledge P, et al. Adverse drug reactions in elderly patients. British Journal of Clinical Pharmacology. 2003; 57: 121-126.

Symptoms of ADRs• freq of falls• confusion• Excessive sedation• Constipation• Urinary retention• oral intake• Failure to thrive

Routledge P, et al. Adverse drug reactions in elderly patients. British Journal of Clinical Pharmacology. 2003; 57: 121-126.

Incidence and Preventability of Adverse Drug Events Among Older Persons in the

Ambulatory Setting• > 65 years of age• 12 month study ending June 2000• Ambulatory Setting• Outcome Measures: Adverse drug events

– Errors in prescribing– Dispensing– Patient adherence– Monitoring

Gurwitz J, Field T, et al. Incidence and Preventability of Adverse Drug Events Among Older Persons in the Ambulatory Setting. JAMA 2003; 289: 1107-1116.

Characteristics and Type of Adverse Event


Frequency of Event by Drug Class


Frequency of Type of Event


Conclusions from Study• Preventable efforts for those known adverse drug effects such

as electrolytes/renal, hemorrhagic and metabolic/endocrine effects.

• Most errors associated with preventable adverse drug events occurred at the prescribing and monitoring stages

• Active prompting to prescriber to perform follow-up lab testing• Anticoagulants• Thyroid medications• Anti-seizure medications• Cardiovascular drugs

• 20% contributed to patient adherence


ADRsDrug Age-Related Effects

NSAIDs (e.g. diclofenac, celecoxib) Volume overload, hypertension, decline in GFR

NSAIDs, antibiotics, diuretics, H2-blockers Idiosyncratic acute interstitial nephritis and acute kidney injury

Bisphosphonates Nephrotoxicity in 17% of elderly

Levofloxacin, moxifloxacin Confusion, seizures, psychosis

Moxifloxacin QTc interval prolongation

Anticholinergic drugs (e.g. donepezil) Cognitive impairment, psychosis

Nondihydropyridine calcium channel blockers (e.g. diltiazem, verapamil)

Decrease in PR interval without consequences

Dihydropyridine calcium channel blockers Increased effect

Opioids Impaired neurotransmitter production, increased receptor affinity

CNS drugs (e.g.benzodiazepines), psychotropic drugs, anesthetics, antiepileptics (e.g. phenytoin)

Increased sensitivity, tremor, ataxia, cognitive difficulties

Warfarin Increased sensitivity

Midazolam Increased sensitivity

Angiotensin Converting Enzyme Inhibitors Impaired renal clearance

Aymanns C, et al. Review on Pharmacokinetics and Pharmacodynamics and the Aging Kidney. Clin J Am Soc Nephrol 2010; 5: 314-27.

Avoiding ADRs

• Avoid combinations with toxic effects • Titrate slowly • Monitor levels• Keep drugs to a minimum• Limit number of physicians/pharmacies • Report ADRs

1. Fluoroquinolones (ciprofloxacin, moxifloxacin, levofloxacin)

2. NSAIDs3. Warfarin4. Donepezil

A. Volume overloadB. Acute Interstitial

NephritisC. SeizuresD. GI bleedE. Psychosis

Drug Interactions

• 50% probability for having a drug interaction when a patient is receiving five medications

• The probability increases to 100% when 7 drugs are used.

Drug InteractionsDrug or drug class Precipitant drug or drug class Interaction

Benzodiazepines (alprazolam, triazolam)

Azole antifungals (fluconazole, itraconazole, ketoconazole)

Increased benzodiazepine concentration because of inhibition of CYP

Carbamazepine Propoxyphene Increased carbamazepine concentration because of decreased hepatic metabolism

Dextromethorphan MAO inhibitors (phenelzine, selegiline, tranylcypromine)

Increased risk of serotonin syndrome due to altered catecholamine uptake and metabolism.

Serotonin syndrome symptoms: Mental status changes: anxiety, agitation, delirium, restlessness, and disorientationAutonomic manifestations: diaphoresis, tachycardia, hyperthermia, hypertension, vomiting, and diarrheaNeuromuscular hyperactivity: tremor, muscle rigidity, myoclonus, hyperreflexia

SSRIs MAO inhibitors Increased risk of serotonin syndrome


Drug Interactions (cont.)Drug or drug class Precipitant drug or drug

classInteraction

Meperidine MAO inhibitors Increased risk for cardiovascular instability, hyperpyrexia, agitation, seizures, diaphoresis (unknown mechanism)

Nitrates Sildenafil, tadalafil, vardenafil

Increased hypotensive effect due to increased levels of cGMP

Pimozide Macrolides and azole antifungals

Increased risk for cardiotoxicity due to inhibition of CYP3A

Digoxin Clarithromycin Increased digoxin toxicity due to inhibition of p-glycoprotein

Digoxin Amiodarone Decreased clearance of digoxin leading to dig toxicityDecrease dig dose by 50% when initiating amiodarone

Theophylline Fluoroquinolones (ciprofloxacin)Fluvoxamine

Increased concentration of theophylline because of inhibition of CYP


Drug Interactions (cont.)Drug or drug class Precipitant drug or drug class Interaction

Warfarin NSAIDs Increased risk for bleeding because of gastric erosion and inhibition of platelet aggregation

Warfarin Cimetidine Increased warfarin concentration leading to increased risk of bleeding

Warfarin Fibric acid (clofibrate, fenofibrate, gemfibrozil)

Increased risk of bleeding due to unknown mechanism

Warfarin Barbiturates Decreased warfarin concentration due to increased metabolism.

Warfarin Thyroid hormones Increased risk of bleeding because of increased metabolism of vitamin K-dependent clotting factors. No increased risk if warfarin is started after patient is on stable thyroid hormone therapy.


Avoiding Drug Interactions

• Avoid the combination• Adjust the dose of the object drug• Alter the administration times• Monitor for early detection

Delafuente J. Understanding and preventing drug interactions in elderly patients. Critical Reviews in Oncology/Hematology. 2003; 48: 133-143.

Which of the following is not true?

A. SSRIs and MAOIs when taken together can lead to serotonin syndrome

B. Warfarin interacts with NSAIDs by increasing risk for bleeding because of gastric erosion and inhibition of platelet aggregation

C. Amiodarone dose needs to be increased by 50% when starting warfarin therapy

D. All of the following are inhibitors of CYP 2c9: Warfarin, Fluconazole, Amiodarone, Metronidazole and Bactrim

Polypharmacy• Definition: refers to problems that can

occur when a patient is taking more medications than are actually needed

• Adverse drug reactions• Drug-drug interactions• Decreased compliance• Drug expense


Factors Leading to Polypharmacy• Complex medication regimen• Multiple physicians/pharmacies• Lack of reporting all

medications/symptoms• Prescribing without compete diagnosis• Lack of medication instructions• Daily activities


Patient Education

• Pill boxes/timers • Medication log • Report missed doses • Avoid skipping pills • Avoid cutting medication in half• Don’t stop medication if they “feel good”• Report adverse effects of medication

Compliance• Highest rates of Noncompliance

• Elderly living alone• Using > 2 medications• No assistance taking medications• Using more than 1 pharmacy• Women traditionally > men regarding noncompliance• Patient recall/Forgetfulness• Increased number of physicians • Cost of medication

» Higher monthly cost after insurance reimbursement» Not covered by insurance» Perceived expense» Household income

Warfarin• Warfarin use is rising

• Aging population• Increase in atrial fibrillation and venous

thromboembolism• Narrow therapeutic index• Risk of bleeding

– Increased sensitivity to warfarin• Reduced drug clearance• Lower body weight• Lower dietary vitamin K intake

– Concurrent use of other drugs– Co-morbidities that increase bleeding risk


Warfarin (cont.)

• Fall risk• Decline in cognitive function

– Lack of awareness of drug and food interactions

– Problems administering the medication


Monitoring Warfarin• International Normalized Ratio (INR)

– World Health Organization developed INR with the PT test for patients who are receiving warfarin

– Calculation that adjusts for changes in the PT reagents and allows for results from different laboratories to be compared

• INR will need to be monitored at least once monthly – Narrow therapeutic window– Dose is not fixed but rather based upon INR

• INR below goal -- blood clots cannot be prevented

• INR above goal -- increased risk of bleedingAntithrombotic and Thrombolytic Therapy 8th Ed: ACCP GuidelinesWarfarin. LexiComp Online. 2009

Medications that Increase INR/Risk for Bleeding

Anti-infectivesoFluoroquinolonesoCotrimoxazoleoMacrolidesoMetronidazoleoTriazole antifungalsoAmoxicillin

CardiovascularoAmiodaroneoDiltiazemoFenofibrateoGemfibroziloPropanololoStatins

AnalgesicsoNSAIDsoAspirinoAcetaminophen (≥ 4g chronically)

Herbals/supplementsoFish oil, omega-3, vitamin E oGinseng, garlic, ginko biloba, ginger oCoenzyme Q10oCranberry

OthersoSSRIsoPhenytoinoOmeprazole/esomeprazoleoCimetidineoAllopurinoloAntineoplastic agentsoCorticosteroidsoProthyroid agents

Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP GuidelinesWarfarin. LexiComp Online. 2009

Medications that Decrease INR• Rifampin• Carbamazepine• Bile acid sequestrants• Sucralafate• Oral contraceptives• Antithyroid agents• Green tea• St. John’s Wort


DietSignificant changes in vitamin K intake can upset

warfarin stability- consistency is key!o Increased intake- decreased INRo Decreased intake- increased INR

Foods high in vitamin Ko Fruits and vegetables

Especially avocado, mango, broccoli, spinach, cabbage o Mayonnaise-based dressingso Chewing tobaccoo Anise (Found in some cookies and black licorice)o Oils (Canola, corn, olive, peanut, safflower, sesame seed, soybean, and sunflower)

Alcoholo Acute alcohol consumption enhances warfarin's availability, increasing the patient's

risk for hemorrhaging.o Chronic alcohol consumption reduces warfarin's availability, lessening the patient's

anticoagulation.


Side Effects• Immediate medical attention should be

sought out for the following:• Signs of stroke/ intracranial bleeding• Severe/unusual headache, confusion,

weakness, numbness• Coughing up large amounts of bright red blood• Vomiting blood• Bleeding that will not stop• Bright red blood in stool• Fall or injury to head

Dabigatran (Pradaxa®)• Indications

• Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism)

• MOA: directly inhibits formation of thrombin• Dose

• 150mg orally twice daily• CrCl 15-30mL/min: 75mg orally twice daily• CrCl < 15mL/min or on dialysis: Not recommended

Pradaxa® Prescribing Information. Boehringer Ingelhem Pharmaceuticals, Inc, Ridgefield, CT. 2010.

Advantages of Dabigatran• Requires no monitoring• Unaffected by food• Few Drug-Drug interactions

• Concomitant use of following increase bleeding risk:

– NSAIDs– Clopidogrel– Prasugrel– Aspirin

• P-glycoprotein inducers (e.g. Rifampin)• Pregnancy Category C (Warfarin category X)


Dabigatran Pitfalls• Lack of a way to monitor adherence• No reversal agent in event of

overdose/severe bleeding• Cost is > than warfarin• Lack of coverage by insurance• Twice daily dosage regimen• Limited indications• Capsules must be swallowed whole

• Increased bioavailability of the drug by 75%


Dabigatran Side Effects• Bleeding

• Should be withheld before invasive or surgical procedures

• GI:• Dyspepsia (11.3% vs. 5.8% warfarin)• Abdominal pain• GERD• Gastric hemorrhage• GI ulcer


Conclusions• Effect of aging on medications for elderly

populations• Confounding factors such as co-

morbidities (frailty)• Drug interactions and adverse drug

effects• Impairments in organ functions

• Managing older patients with medications that have a narrow therapeutic index

ReferencesAntithrombotic and Thrombolytic Therapy 8th Ed: ACCP GuidelinesAymanns C, Keller F, Maus S, et al. Review on Pharmacokinetics and Pharmacodynamics and the Aging

Kidney. Clin J Am Soc Nephrol 2010; 5: 314-27.Catterson M, Preskorn S, Martin R. Pharmacodynamic and Pharmacokinetic Considerations in Geriatric

Psychopharmacology 1997; 20: 205-17.Cusack B. Pharmacokinetics in Older Persons. The American Journal of Geriatric Pharmacotherapy 2004;

vol 2 (number 4): 274-302.Delafuente J. Understanding and preventing drug interactions in elderly patients. Critical Reviews in

Oncology/Hematology 2003; 48: 133-143.Gurwitz J, Field T, et al. Incidence and Preventability of Adverse Drug Events Among Older Persons in the

Ambulatory Setting. JAMA 2003; 289: 1107-1116.Hayes B, Klein-Schwartz W, Barrueto F. Polypharmacy and the Geriatric Patient. Clin Geriatr Med 2007;

23:371-390.Koltz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metabolism Reviews 2009; 41:67-76.Mann HJ. Drug-Associated Disease: Cytochrome P450 Interactions. Critical Care Clinics 2006;22: 329-45. Noble R. Drug therapy in the elderly. Metabolism. 2003; 52: 27-30.Pradaxa® Prescribing Information. Boehringer Ingelhem Pharmaceuticals, Inc, Ridgefield, CT. 2010.Routledge P, O’Mahony M, Woodhouse K. Adverse drug reactions in elderly patients. British Journal of

Clinical Pharmacology 2003; 57: 121-126.Stevens L, Coresh J, Greene T, et al. Assessing Kidney Function-Measured and Estimated Glomerular

Filtration Rate. The New England Journal Of Medicine 2006; 354: 2473-83.Warfarin. LexiComp Online. 2009

QUESTIONS?

Kimberly Keefer, Pharm.D., BCPSClinical Internal Medicine PharmacistPenn State Milton S. Hershey Medical Center500 Univesity DriveP.O. Box 850Hershey, PA 17033Tel: 717-531-0003Ext: [email protected]

medication use in older adults kimberly keefer, pharm.d., bcps

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