drug dosing in geriatrics

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Drug Dosing in Geriatrics:

Drug Dosing in Geriatrics First Symposium on Application of Pharmacokinetics in Clinical Practice on May 11, 2011 in Intercontinental Hotel Jeddah By Mansoor Khan, BS,MS, BCOP Clinical Pharmacist, NGHA, Jeddah


Objectives Understand key issues in geriatric pharmacotherapy Understand the effect of age on Pharmacokinetics & Pharmacodynamics Discuss risk factors for adverse drug events and ways to mitigate them Understand the principles of drug prescribing for older patients

Challenges of Geriatric Pharmacotherapy:

Challenges of Geriatric Pharmacotherapy Effects of aging physiology on drug therapy Multiple co-morbid states Polypharmacy Advanced understanding of drug-drug interactions Medication compliance New drugs available each year FDA approved and off-label indications are expanding Medication cost

The Aging Imperative:

The Aging Imperative Persons aged 65y and older constitute 13% of the population and purchase 33% of all prescription medications By 2040, 25% of the population will purchase 50% of all prescription drugs

Physiological Changes with Aging:

Physiological Changes with Aging

Effects of Aging on Absorption:

Effects of Aging on Absorption Rate of absorption may be delayed Lower peak concentration Delayed time to peak concentration Overall amount absorbed (bioavailability) is unchanged

Hepatic First-Pass Metabolism:

Hepatic First-Pass Metabolism For drugs with extensive first-pass metabolism, bioavailability may increase because less drug is extracted by the liver Decreased hepatic mass Decreased hepatic blood flow

Effects of Aging on Vd:

Effects of Aging on Vd Aging Effect Vd Effect Examples  Body water  Vd for hydrophilic drugs Ethanol, lithium  Lean body mass  Vd for for drugs that bind to muscle Digoxin  Fat stores  Vd for lipophilic drugs Diazepam, trazodone  Plasma protein (albumin)  % of unbound or free drug (active) Diazepam, valproic acid, phenytoin, warfarin  Plasma protein ( 1 -acid glycoprotein)  % of unbound or free drug (active) Quinidine , propranolol , erythromycin, amitriptyline

Aging Effects on Hepatic Metabolism:

Aging Effects on Hepatic Metabolism Metabolic clearance of drugs by the liver may be reduced due to: Decreased hepatic blood flow Decreased liver size and mass Examples : morphine, meperidine, metoprolol, propranolol, verapamil, amitryptyline, nortriptyline

Estimating GFR in the Elderly:

Estimating GFR in the Elderly Creatinine clearance (CrCl) is used to estimate glomerular rate Serum creatinine alone not accurate in the elderly  lean body mass  lower creatinine production  glomerular filtration rate Serum creatinine stays in normal range, masking change in creatinine clearance

Example: Creatinine Clearance vs. Age in a 5’5”, 55 kg Woman:

Example: Creatinine Clearance vs. Age in a 5’5”, 55 kg Woman 30 1.1 90 41 1.1 70 53 1.1 50 65 1.1 30 CrCl Scr Age

Estimation of Creatinine Clearance:

Estimation of Creatinine Clearance Estimate Cockroft Gault equation (140-Age) x (IBW in kg) ------------------------------ x (0.85 for females) 72 x (Scr in mg/dL)

Measurement of creatinine clearance:

Measurement of creatinine clearance Time consuming Requires 24 hr urine collection U Creat (mg/dL) x 24 h Urine Vol (ml) --------------------------------------------- S Creat (mg/dL) X 1440

Pharmacodynamics (PD):

Pharmacodynamics (PD) Elderly have altered drug response or “Sensitivity” due to changes in receptor number or receptor affinity Examples of Age-related changes:  sensitivity to sedation and psychomotor impairment with benzodiazepines  level and duration of pain relief with narcotic agents  drowsiness and lateral sway with alcohol  sensitivity to anti-cholinergic agents  cardiac sensitivity to digoxin  HR response to beta-blockers

PK and PD Summary:

PK and PD Summary PK and PD changes generally result in decreased clearance and increased sensitivity to medications in older adults Use of lower doses, longer intervals, slower titration are helpful in decreasing the risk of drug intolerance and toxicity Careful monitoring is necessary to ensure successful outcomes


Polypharmacy Either the concomitant use of multiple drugs or administration of more drugs than are indicated” How many prescription medications are too many? >4 or >6. Many elderly people receive 12 medications per day Can increase the risk of geriatric syndrome (falls, cognitive impairment etc)

Consequences of Overprescribing:

Consequences of Overprescribing Adverse drug events (ADEs) Drug interactions Duplication of drug therapy Decreased quality of life Unnecessary cost Medication non-adherence

Adverse Drug Events (ADEs):

Adverse Drug Events (ADEs) Responsible for 5-28% of acute geriatric hospital admissions Greater than 95% of ADEs in the elderly are considered predictable and approximately 50% are considered preventable Most errors occur at the ordering and monitoring stages

Slide 19:

Factors contributing to adverse drug reactions in elderly patients Polypharmacy How many prescription medications are too many? >4 or >6 Many elderly people receive 12 medications per day Heart, kidney, liver, thyroid Orthostatic hypotension, when they standup, blood goes to their feet - weak sympathetic nervous system response to constrict veins and increase heart rate. Low thyroid function causes lower body temperature, metabolic rate, & heart rate.

Most Common Medications Associated with ADEs in the Elderly:

Most Common Medications Associated with ADEs in the Elderly Opioid analgesics NSAIDs Anticholinergics Benzodiazepines Also : cardiovascular agents, CNS agents, and musculoskeletal agents Adverse Drug Reaction Risk Factors in Older Outpatients. Am J Ger Pharmacotherapy 2003;1(2):82-89.

What is Beers Criteria? :

What is Beers Criteria? A list of medications that are generally considered inappropriate when given to elderly people. For a wide variety of individual reasons, the medications listed tend to cause side effects in the elderly due to the physiologic changes of aging. The list was originally created by geriatrician Mark H. Beers in 1991 Last updated in 2011 but list is unchanged since 2002

Beers Criteria 2002 for Potentially Inappropriate Medication Use in Elderly:

Beers Criteria 2002 for Potentially Inappropriate Medication Use in Elderly Drug Concern Severity Amitriptyline, Doxepin Strong anticholinergic and sedative properties, rarely drug of choice for elderly High Long acting BZD, diazepam Prolonged sedation and increased risks of fall High Lorazepam > 3 mg Alprazolam > 2 mg B/C of increased sensitivity to BZD in elderly, smaller doses may be as effective High

Beers Criteria 2002 (Cont.):

Beers Criteria 2002 (Cont.) Drug Concern Severity Indomethasin Of all available NSIAD, most CNS Adverse effects High Pentazocin Of all available narcotics, most CNS adverse effects High Methyldopa Bradycardia & depression High Chlorpropamide Prolonged hypoglycemia & SIADH High

Beers Criteria 2002 (Cont.):

Beers Criteria 2002 (Cont.) Drug Concern Severity GIT Antispasmodics Highly anticholinergic and uncertain efficacy & should be avoided for long-term use High Anticholinergic & Antihistamine (Phenergan, Avil Benedril, hydroxyzine) All non-prescription and many prescription antihistamines have potent anticholinergic effects, sedative effetcs, cognitive impairment non-anticholinergic antihistamines are preferred High Barbiturates Highly addictive and more side effects than sedative and hypnotics High

Beers Criteria 2002 (Cont.):

Beers Criteria 2002 (Cont.) Drug Concern Severity Muscle Relaxants and Antispasmodics Poorly tolerated by elderly since they have ADE such as anticholinergic effects, sedation and weakness High Meperidine May cause confusion and other ADE. Not effective as well. High Ticlodipine No better than ASA but much more toxic High Ketorolac Elderly may have asymptomatic GI pathologic condition High

Beers Criteria 2002 (Cont.):

Beers Criteria 2002 (Cont.) Drug Concern Severity Amphetamines & Anorexic agents Dependence, hypertension, Angina, MI High Non-COX-Selective NSAIDS; Naproxen, Piroxicam etc Long-term use may cause: GI Bleeding, Renal Failure, Hypertension, Heart Failure High Fluoxetine Excessive CNS stimulation, Sleep disturbances, safer alternative available High

Beers Criteria 2002 (Cont.):

Beers Criteria 2002 (Cont.) Drug Concern Severity Stimulant Laxative Long-term use may exacerbate bowel dysfunction High Nitrofurantoin Potential for renal impairment, safer options available High Amiodarone QT interval prolongation, Torsade depoints High Orphenadrine Anticholinergic effects and sedation High

Beers Criteria 2002 (Cont.):

Beers Criteria 2002 (Cont.) Drug Concern Severity Digoxin Decrease renal clearance leads to toxic effects Low Ferrous Sulfate > 325 mg/day Don’t dramatically increase absorption but cause Constipation Low Doxazocin Hypotension, Dry mouth, urinary problems Low Clonidine Orthostatic hypotension and CNS Adverse effects Low Nifedipine; Short Acting Hypotension and constipation Low Cimetidine CNS adverse effects including confusion Low Mineral Oil Potential for aspiration and ADE Low

Beers Criteria 2002 (Cont.):

Beers Criteria 2002 (Cont.) Disease Drug Concern Arrhythmias Amitriptyline, Doxepin, Imipramine  QT interval Hypertension Amphetamines, pseudoephedrine  BP Gastric & Duodenal Ulcers NSAID & ASA > 325 mg (COXibs exluded) Exacerbate existing ulcers and may produce new one Bladder outflow obstruction Anticholinergics, Antihistamines, GIT anti-spasmodics, muscle relaxants  Urinary flow and  Urinary retention Blood clotting disorders ASA, NSAIDs, Dipyridamole, Ticlodipine, Clopidogrel  Clotting time and  INR and  potential for bleeding

Beers Criteria 2002 (Cont.):

Beers Criteria 2002 (Cont.) Disease Drug Concern Parkinson Disease Metoclopramide, Haloperidol EPS, anti-dopaminergic Cognitive impairment Barbiturates, Anticholinergics, Antispasmodics, CNS stimulants, Muscle relaxants Concerns due to CNS altering effects Depression Methyldopa, long-acting BZD May produce or exacerbate depression Chronic Constipation Calcium Channel blockers, Anticholinergics, TCA May exacerbate constipation Syncope or falls Short-intermediate acting BZD, TCA Ataxia, impaired psychomotor function and additional falls

Prescribing Cascade:

Prescribing Cascade Drug 1 (NSAID) ADE (GIT ulcer) interpreted as new medical condition Drug 2 (H2 blocker) ADE (Delerium) interpreted as new medical condition Drug 3(Haloperidol) Rochon PA, Gurwitz JH. Optimizing drug treatment in elderly people: the prescribing cascase. BMJ 1997;315:1097.

Common Drug-Drug Interactions:

Common Drug-Drug Interactions Combination Risk ACE inhibitor + potassium Hyperkalemia ACE inhibitor + K sparing diuretic Hyperkalemia, hypotension Digoxin + antiarrhythmic Bradycardia, arrhythmia Digoxin + diuretic Antiarrhythmic + diuretic Electrolyte imbalance; arrhythmia Diuretic + diuretic Electrolyte imbalance; dehydration Benzodiazepine + antidepressant Benzodiazepine + antipsychotic Sedation; confusion; falls Doucet J, Chassagne P, Trivalle C, et al. Drug-drug interactions related to hospital admissions in older adults: a prospective study of 1000 patients. J Am Geriatr Soc 1996;44(9):944-948.

Drug-Food Interactions:

Drug-Food Interactions Interactions between drugs and food Warfarin and Vitamin K containing foods (remember green tea, as well) Phenytoin & vitamin D metabolism Methotrexate and folate metabolism Drug impact on appetite Digoxin may cause anorexia ACE inhibitors may alter taste

Principles of Prescribing in the Elderly:

Principles of Prescribing in the Elderly Avoid prescribing prior to diagnosis Follow Beers Criteria Start with a low dose and titrate slowly Avoid starting 2 agents at the same time Reach therapeutic dose before switching or adding agents Consider non-pharmacologic agents

Prescribing Appropriately:

Prescribing Appropriately Consider risk vs. benefit Avoid prescribing to treat side effect of another drug Consider drug-drug and drug-disease interactions Use simplest regimen possible avoiding poly pharmacy Adjust doses for renal and hepatic impairment Use least expensive alternative

Enhancing Medication Adherence:

Enhancing Medication Adherence Non-adherence rate may be as high as 50% in the elderly Avoid newer, more expensive medications Simplify the regimen Utilize pill organizers or drug calendars Educate patient on medication purpose, benefits, safety, and potential ADEs


Summary Successful pharmacotherapy means using the correct drug at the correct dose for the correct indication in an individual patient Age alters PK and PD Renal & hepatic dosage adjustment required Polypharmacy & drug-drug interaction should be avoided ADEs are common & preventable among the elderly


References Hutchison & Sleeper. Fundamentals of Geriatric Pharmacotherapy an evidenced-based approach 2010; American Society of Health System Pharmacists. Pharmacotherapy 6 th Edition, A pathophysiologic approach. Copyright 2005, 2002 by The McGraw-Hill Companies, Inc. All rights reserved. A chapter on Geriatrics; 103-113. www.pharmaotherapyonline.com Donna M. Fick, PhD, RN; James W. Cooper, PhD, RPh; William E. Wade, PharmD, FASHP, FCCP; Jennifer L. Waller, PhD; J. Ross Maclean, MD; Mark H. Beers, MD. Updating the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Results of a US Consensus Panel of Experts. Arch Intern Med. 2003;163:2716-2724 Spinewine A, Schmader KE, Barber N, Hughes C, Lapane K, Swine C, Hanlon JT. Appropriate prescribing in elderly people: How can it be measured and optimized? Lancet 2007;370:173-184. Essentials of Clinical Geriatrics, 4 th Edition. Kane, Ouslander, Abrass, Eds. McGraw-Hill.



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