Clinical Pharmacological Issues in the Elderly

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1 Clinical Pharmacological Issues in the Elderly Charles A. Cefalu MD, MS Professor and Chief, Section of Geriatric Medicine Department of Med, LSUHSC, New Orleans, La. Evaluation for Possible Polypharmacy 85 yr. olds and older; average 5-8 drugs per patient Association exists between increased number and severity of illnesses and increased number of adverse drug reactions Ref: Lesar, Briceland, and Stein, JAMA, 277,1997, p

2 Increased Medication Use and Perceived Health in the Oldest Old Increased medication use associated with poorer ratings on health self report Not associated with increased mortality except for use of digoxin Ref: Hershman DL et al. Drug utilization in the old and old and how it relates to selfperceived health and all-cause mortality: results from the Bronx Aging Study. J Am Geriatr Soc. 43(4), Apr 1995, p Factors Related to Adverse Drug Drug Reactions Chronicity and Multiplicity of Disease Increased Disease-Drug Interactions Increased Drug-Drug Interactions Lanoxin and Quinidine Theophylline and Erythromycin Visiting Multiple Prescribers Visiting Multiple Pharmacies Ref: Schwartz JB. Clinical Pharmacology. In: Hazzard WR et al. Principles of Geriatric Medicine and Gerontology, 4 th Ed., 2000, p. 326.

3 Factors Related to Increased Number of Adverse Drug Reactions, Cont d Multiple Diseases CHF COPD PVD CRF Chronic liver disease Dementia ASHD Diabetes Mellitus Osteoporosis DJD Others Normal Changes of Aging Increased Fat Decreased Bone Decreased Muscle Decreased Water Content Ref: Cefalu CA. Clinical Pharamcology. In: Burke MM & Laramie JA. Primary Care of the Older Adult. 2000, p. 90.

4 Normal Physiological Changes of the Organ Systems Liver- decreased blood flow; Decreased Phase I Metabolism Kidney- decreased creatinine clearance with advanced age CNS-increased risk of confusional states primarily secondary to anti-cholinergic agents Intestinal tract-- malabsorption-- not clinically significant in absence of disease Normal Changes of Aging-Hepatic Phase I Metabolism-rate of metabolism slows (oxidation, reduction, hydroxylation) Phase II Metabolism-rate stays the same (conjugation or deactivation processsulfonuralidation, methylation, acetylation) Examples-benzodiazepines Short acting-phase II only-appropriate Long acting-phase I and II-inappropriate, long half-lives Reference: Beers MH. Medication Use in the Elderly. In: Calkins, Ford & Katz, 1992, p. 40. Pharmaceutical Agents That Require Hepatic Metabolism NSAIDs; Aspirin Acetaminophen Erythromycin Ketoconazole Tetracyclines Lidocaine Metoprolol SSRIs Ca channel blockers Alpha blockers Statins Dilantin Valproic acid Carbamazepine Tricyclic Antidepres Neuroleptics

5 Pharmaceutical Agents That Require Hepatic Metabolism Benzodiazepines Cimetidine Ranitidine Famotidine Terfenadine Proton pump inhibitors Schwartz JB. Clinical Pharmacology. In: Hazzard WR et al. Principles of Geriatric Medicine and Gerontology, 4 th Ed., 2000, p The Cytochrome System CYP1A2 CYP2C CYP2D6 CYP3A Involves Model Compounds, Drug Substrates, Inducers, and Inhibitors Ref: Schwartz JB. Clinical Pharmacology. In: Hazzard WR et al. Principles of Geriatric Medicine and Gerontology, 4 th Ed., 2000, p Particular Agents of Concern in the Elderly-highly bound to protein Phenytoin Carbamazepine Barbiturates Warfarin Malnutrition or hypoproteinemia is associated with increased free fraction of drug and increased toxicity Ref: Physicians Desk Reference, Medical Economics- Thomson Healthcare,55 th Edition, 2001, p

6 Normal Changes of Aging-Renal Age-related reduction in renal blood flow and creatinine clearance in the face of a normal BUN and serum creatinine: Implications- Adjust dose of renally excreted drugs with age according to the following formula Creatinine Clearance Calculation Cr Clearance= (140-age) x weight (kg) serum creatinine x 72 (serum cr adjusted to 1, multiplied x.85 for female) Ref: Ref: Cefalu CA. Clinical Pharmacology. In: Burke MM & Laramie JA. Primary Care of the Older Adult. 2000, p. 92. Pharmaceutical Agents Primarily Eliminated In the Kidneys Requiring Dosage Adjustment Penicillins Procainamide Aminoglycosides Atenolol Fluroquinolones Clofibrate Lithium Ace Inhibitors Digoxin Metformin Fluconazole Bisphosphonates Thiazides Nizatidine Ref: Schwartz JB. Clinical Pharmacology. In: Hazzard WR et al. Principles of Geriatric Medicine and Gerontology, 4 th Ed., 2000, p

7 Inappropriate Prescribing of Renally Excreted Agents in LTC One in three renally excreted drugs prescribed in Ontario nursing homes was inappropriately dosed based on the calculated creatinine clearance. Renal function is often overlooked when prescribing renally excreted drugs to older longterm care residents and emphasizes the need for consideration of creatinine clearance when prescribing such drugs in this population. Ref: Papaioannou A et al. Assessment of Adherence to renal dosing guidelines in long-term care facilities. J Am Ger Soc. 48(11), Nov. 2000, p Aminoglycoside Dosing in the Elderly With Impaired Renal Function Once daily dosing of aminoglycosides associated with reduced risk of morbidity (ototoxicity and renal failure) in patients with reduced creatinine clearance (usually below 50 ml/minute). Also alleviates the need for expensive peak and trough testing. Ref: Cefalu CA & Agcaoli D. Preventing antibiotic misuse in older patients. Hospital Medicine, December 1998, p Good Rule of Thumb Reduce by half the dose of the particular renally excreted agent with a creatinine clearance of 50 ml/minute or less.

8 Physiological changes of the GI Tract Stomach- little change in gastric acidity with aging. In presence of dsyphagia and H2 blocker therapy, may increase risk of morbidity and mortality from pneumonia (bacteria more viable after aspiration due to reduced acidity) Decreased GI motility and blood flow-- increased frequency of constipation Ref: In: Hall KE, Wiley JW. Age-Associated Change in Gastrointestinal Function. In: Hazzard WR et al. Principles of Geriatric Medicine and Gerontology, 4 th Ed., 2000, p CNS Changes with Aging Reduced numbers of receptors Subtle structural and physiological changes consistent with Alzheimer's and Vascular Dementia Increased susceptibility to drugs with anticholinergic properties resulting in: urinary retention; constipation; dry mouth; blurred vision; sedation; cognitive dysfunction Ref: Cefalu CA. Clinical Pharmacology. In: Burke MM & Laramie JA. Primary Care of the Older Adult. 2000, p. 90.

9 Anticholinergic Agents Phenothiazine major tranquilizers (promethazine, thorazine, chlorpromazine, haloperidol) Tricyclic anti-depressants (imipramine, amitriptyline, nortriptyline, desipramine) Narcotics-demerol, codeine, morphine Anti-spasmotics-oxybutynin, diclomine, tolterodine, probanthine, atropine, hyoscyamine, probanthine, belladonna alkaloids Anti-cholinergic Agents-continued Anti-histamines Diphenhydramine Cyproheptadine OTC cold medications OTC sleep agents Trihexyphenidyl Benztropine

10 Common Clinical Conditions Necessitate Adjustment of Dosage in the Elderly: Liver- cirrhosis, malnutrition, malignancy, hepatitis with resultant decreased albumin and total protein levels (ex: sodium warfarin and phenytoin Kidney- chronic renal insufficiency, renal failure Brain-dementia, delirium Intestinal tract- malabsorption syndrome stomach- gastritis, malignancy Anorexia and Aging Reduced thirst and appetite with normal aging Reduced thirst and appetite is associated with depression and/or dementia Ref: Singh MAF & Rosenberg IH. Nutrition and Aging. IN: Hazzard WR et al. Principles of Geriatric Medicine and Gerontology, 4 th Ed., 2000, p. 88. Anorexia-Drug Induced: Theophylline Macrodantin Pronestyl Digoxin Thyroxin SSRIs Ref: Thompson MP, Morris LK. Unexplained Weight Loss In the Ambulatory Elderly. J Am Geriatr Soc. 39, 1001, p

11 Specific High Risk Drug Categories Screening for potential toxicity of prescription drugs-h2 Blockers: Confusion at high doses- Creatinine clearance below 50/ml/min.= reduce dose, except famotidine (below 20 ml/min) Nonspecific use associated with inadequate healing of gastric and duodenal ulcerations and greater chance of recurrence Nonspecific use for prophylaxis when used with NSAIDs Only two specific indications for prophylaxis to prevent gastrointestinal bleeding in the ICU setting: respiratory failure or coagulopathy H2 Blockers-continued Very common to use these agents in nursing home without specific indications Ref: Cefalu CA. Clinical Pharmacology. In: Burke MM & Laramie JA. Primary Care of the Older Adult. 2000, p. 93.

12 High Risk Drugs-Beta Blockers B-Blockers (propranolol)-side effects of: Precipitation of or exacerbation of CHF Masking of hypoglycemia Development of hypotension Masking of symptoms of endocrine disease (hypothyroidism). Reduction in exercise capacity Exacerbation of chronic lung disease or bronchospasm Depression Memory loss Production of arthropathy Ref: Cahill et al: Beta-adrenergic activation and memory for emotional events, Nature, 371, P Newbern et al. Cautionary Tales on Using Beta Blockers. Geriatric Nursing. 12(3); 1991, p Beta Blockers-continued use selective ones: atenolol and metoprolol Less side-effect profile Better compliance-once or twice daily Use associated with reduced cardiovascular morbidity and mortality in high risk patients Ref: Mangano DT et al. Effect of atenolol on mortality and cardiovascular morbidity after non-cardiac surgery. N Engl J Med, 335, 1996, p Australia/New Zealand Heart Failure Research Collaborative Group, 1997 Antihypertensives that cause Postural Hypotension or Sedation: Alpha-methyl-dopa Clonidine Alpha-blocking agents: useful for combined hypertension and prostatic hyperplasia Reserpine Ismelin- same as reserpine Physicians Desk Reference, 2003

13 Diuretics Once daily dosing increases compliance Inexpensive First line agents effective in reducing risk of stroke and CV disease Doses above 50 mg ineffective in achieving blood pressure control Thiazides generally not effective in the presence of renal insufficiency May cause hypercalcemia Contribute to or cause incontinence Use not associated with adverse effects on lipids Diuretics-continued Use in older caucasian women associated with reduced risk of hip fracture Adverse reactions Dehydration; postural hypotension; K loss (especially during the summer and sweating) Consider discontinuing in elderly when possible, especially advanced, demented, or depressed elderly (reduced thirst and appetite drive)

14 Diuretics-References Ref: SHEP (Systolic Hypertension in the Elderly) Cooperative Research Group, 1991 Heidrich et al. Diuretic drug use and the risk of hip fracture Ann Intern Med., 115, 1991, p Physicians Desk Reference, 2003 Gurwitz MM et al. The impact of thiazide diuretics on the initiation of lipid-reducing agents in older people: a population-based analysis. J Am Geriatr Soc., 45(1), Jan. 1997, p

15 Major and Minor Tranquilizers* and Hypnotics: Worsen dementia and delirium Cause hip fractures and falls Cause postural hypotension Risk of tardive dyskinesia with phenothiazines *Especially long acting minor and sedating, highly anti-cholinergic major ones Ref: Cefalu CA. Clinical Pharmacology. In: Burke MM & Laramie JA. Primary Care of the Older Adult. 2000, p Newer Atypical Antipsychotics: Much less risk of tardive dyskinesia Much more expensive Olanzepine most anti cholinergic and sedating Risperidol-increased risk of CVA, works through dopaminergic mechanism SSRIs May cause Falls Nuisance side effects-nausea, decreased appetite, insomnia, agitation Void of cardiac risks compared to tricyclic antidepressants Inappropriate-

16 Oral Hypoglycemics: Cause Hypoglycemia-- chlorpropamide SIADH more frequent with aging (idiopathic 30%) Lanoxin (Few indications currently for use except for rate control or congestive heart failure to improve function). Side-effects: Confusion Anorexia Nausea Yellow Green Colors Agitation Depression Ref: Physicians Desk Reference, 2003; Geriatrics Review Syllabus, 5 th Ed., , p. 260 NSAIDs*: Can Worsen HBP- removal of NSAID can affect mean blood pressure control Fluid retention Worsen CHF Cause confusion GI bleeding Newer Cox-2 agents, gastric sparring Less risk of Alzheimer's and cognitive decline *In big doses or used chronically Ref: Carson JL & Strom BL. Use of Nonsteroidal Anti-Inflammatory Drugs. In: Hazzard WR et al. Principles of Geriatric Medicine and Gerontology, 4 th Ed., 2000, p ; Stewart WF et al. Risk of Alzheimer s disease and duration of NSAID use. Neurology, 48, 1997, p

17 Tips for Safe Traditional NSAID Use Substitute acetaminophen when possible around the clock instead of NSAID Use PRN when possible Use lowest dose possible Use for acute flare for 7-10 days then d/c When necessary for chronic use, insist on routine q 3 month BUN and CBC Narcotics: May cause cognitive dysfunction Have anti-cholinergic side effects urinary retention constipation dry mouth sedation Theophylline Adverse Reactions: Anorexia Nausea Arrhythmias Hypotension Drug-drug interactions-erythromycin, cimetidine, diazepam, phenytoin Useful for acute wheezing or asthma, not for COPD Ref: Physicians Desk Reference, 2003; Cefalu CA. Clinical Pharmacology. In: Burke MM & Laramie JA. Primary Care of the Older Adult. 2000, p. 112.

18 Oxybutynin Anticholinergic-(XL form with less side effects) Sedation Cognitive dysfunction Dry mouth Blurred vision Constipation Urinary retention Ref: IR Katz et al. Identification of medications that cause cognitive impairment in older people: The case of oxybutynin chloride. J AM Geriatr Soc., 46, 1998, p Sedation Falls Muscle Relaxers: Anti-cholinergic side-effects Contraindicated in elderly Ref: Physicians Desk Reference, 2003 Ophthalmologic Preparations Beta blocker preparations-can achieve significant systemic absorption leading to heart block, CHF, bronchospasm. Physicians Desk Reference, 2003

19 List Of Inappropriate Drugs In Elderly- Journal of American Medical Association-July 27, 1994; Archives of Internal Medicine-July 28, 1997 and revised 2003 Inappropriate Drugs in Elderly: Diazepam Chlordiazepoxide- long acting Flurazepam- long acting Muscle relaxers- sedation, anticholinergic Vasodilators- ineffective, cause Steal Syndrome and postural hypotension-of historic interest only, no longer available Dipyridamole- ineffective Amitriptyline- sedation, anticholinergic Propranolol-??? J of Am Med Assoc, July, 1994, Arch of Int Med, July, 97,

20 Inappropriate Drugs in Elderly- Cont,d Alpha-methyl dopa (Aldomet) Depression Hemolytic anemia Drug-induced lupus Inappropriate Drugs in Elderly- Cont,d Fluoxetine-long acting, may cause weight loss and anorexia Reserpine (cheap and once per day, ganglionic blocking agent) Depression Impotence Sedation Orthostatic hypotension Inappropriate Drugs in Elderly- Cont,d Short-acting Benzodiazepines in excess of the following doses: Lorazepam- 3mg Oxazepam- 6mg Alprazolam- 2mg Temazepam- 15mg Zolpidem- 5mg Triazolam-.25mg

21 Inappropriate Drugs in Elderly- Cont,d Anticholinergic Diclomine Hyoscyamine Probanthine Belladonna alkaloids Inappropriate Drugs in Elderly- Cont,d Chlorpropamide-very old drug!!!-of historic interest only, not available Indomethacin (neurotoxic)- confusion, bleeding Propoxyphene- sedation and no more effective than acetaminophen Trimethobenzamide- extra-pyramidal sideeffects and least effective anti-emetic Pain Pill Use by Elders Lack of adequate pain assessments, little use of nonpharmacologic interventions, and inappropriate use of analgesic medication in the nursing home (Ref: Cramer GW et al. J Am Geriatr Soc, 48(4), March 2001, p Use of proxyphene in the community dwelling elders is 6.8% and double this in th elong-term setting-15.5%. Ref: Sachin JK et al. J AM Geriatr Soc., 51, 2003, p

22 Inappropriate Drugs in Elderly- Cont,d Pentazocine- sedation, confusion, and hallucinations Meprobamate- addictive and sedating-very very old drug-of historic interest only, not available Lanoxin (if higher than.125mg)- reduced renal clearance with normal aging Disopyramide- negative inotropic effect, may cause CHF, off the market-of historic interest only, not available Inappropriate Drugs in Elderly- Cont,d Phenylbutazone- excess bleeding, not available, of historic interest only Doxepin- anticholinergic and sedating Ticlopidine- no more effective than aspirin, not available, of historic interest only Meperidine- addicting, short-acting associated with breakthrough, sedation, anticholinergic Barbiturates- sedation Clonidine-sedating Inappropriate Drugs in Elderly- Cont,d Iron in doses greater than 325mg iron sulfate- constipation and no greater absorption at higher dose

23 Screening for Toxicity of OTC Drugs Laxatives- chronic use associated with development of chronic megacolon, terminal reservoir syndrome, subsequent fecal impaction, and cancer Vitamins A, C and E- added toxicity with little added benefit Acetaminophen or aspirin- several different doctors, different brand names Screening for Toxicity-OTC Drugs-Cont. Especially diphenhydramine-containing OTC agents Sleep aides Cold Medications

24 Rules for Prescribing to the Elderly Start with one-third to one-half the normal starting dose Use one drug to treat two clinical conditions PAT and HBP HBP and angina Rules, cont d Maximize dose of one agent before adding second agent to treat same clinical condition (HBP) Less confusing for elderly Less expensive Less risk of adverse drug reactions Maximize compliance to no more than once or twice daily Rules, cont d Use cheapest drug possible Review medications patient brings in at each visit Discontinue unnecessary drugs and taper psychotropic drugs when possible

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