2012 Update on “Beyond starting low and go slow- prescribing for elders”

1. 2012 Update on “Beyond starting low and go slow- prescribing for elders” Leslie-Faith Morritt Taub, ANP-C, GNP-BC, CDE, C.BSM, DNSc, FAANP Clinical Associate Professor New York University College of Nursing Senior Clinical Faculty Associate Hartford Institute for Geriatric Nursing NYU College of Nursing Faculty Practice - Nurse Practitioner

2. Faculty disclosure I have no current affiliation or financial arrangement with any grantor or commercial interests that might have a direct interest in the subject matter of this CE program.

3. Objectives • The participants will be able to: 1. specify 4 medications that have a high potential for toxicity in elders. (20 min.) 2. name 2 reasons that older adults are susceptible to adverse drug reactions (ADR). (15 min.) 3. state 2 strategies to prevent common medication-related problems.(15 min.) 4. be able to develop an individualized plan to promote medication safety for an elderly patient. (20 min.)

4. Introduction “ The proper use of medications represent one of the most crucial ways in which the practice of [geriatrics] differs from conventional..care. Pharmacotherapy … and its implementation requires a special understanding of the unique pharmacologic properties of drugs in this population…” due to the physiologic changes of aging and the chronic comorbid conditions commonly found in this group. Avorn, J., Gurwitz, J.H. & Rochon, P. (2003). Principles of pharmacology. In C. Cassel, R. Leipzig, H. Cohen, E. Larson, & D. Meier (Eds.), Geriatric Medicine: an evidence based approach (4th ed.) New York, N.Y.: Springer - Verlag

5. AGS 2012 update of the Beers Criteria is now available • The American Geriatric Society (AGS) has committed to systematic updates of the Beers Criteria using evidenced based studies and expert opinion to create a best-practice guideline. • They catalogued medications to avoid in: all older adults those with specific diseases and those medications that should be carefully monitored • Go to: • http://www.americangeriatrics.org/health_care_professionals/clinical_practice/clinical_guidelines_recommendations/2012

6. Case Study: Mr. Knowles Mr. Knowles daughter called you for an appointment saying that her Dad seems to be much less steady on his feet and she would like you to look at him. CC: 81y/o male reports being seen in the ER for an ankle sprain after he fell on arising from bed over weekend. He feels he was weaker and less able to ambulate in the days leading up to the fall that caused the ankle sprain. PMH: Major depression HTN T2DM OA Insomnia CRF – Stage 3 (GFR 30-59 ml/min/1.73m2) PSH: Tonsillectomy – age 10

7. Case Study: Mr. Knowles • Allergies: NKDA • Meds: Sertraline 50 mg daily Lisinopril 10 mg daily HCTZ 12.5 mg daily Metoprolol XL 100mg daily Glargine insulin 50 units at 10 pm Aspart insulin 5 units before breakfast and dinner Zolpidem CR 12.5 mg before bedtime Ibuprofen 400 mg tid for knee pain • Social hx: denies smoking alcohol: 1 whiskey nightly prior to sleep denies illicit drug use

8. Case Study: Mr. Knowles ROS: HEENT: some blurry vision o.u. Cor: denies chest pain or SOB Lungs: denies orthopnea Neuro: + numbness and tingling in feet x 2 yrs MS: painful knees, and R ankle (r/t fall) PE: BP 130/80 sitting, 100/50 standing, P 54, RR 16 T 98.4 HEENT: Eyes: Snellen Chart 20/70 o.u. Cor: S1S2 RRR Lungs: CTAB MS: Insensate feet by monofilament, ankle reflex absent Skin: + 2 swelling of L ankle, tender to touch, talocrural joint stable Timed Get Up and Go test - >40 seconds (normal < 20seconds) on the last visit before the fall (high scores correlate with poor functional independence and higher risk of falls. CES-D (Center for Epidemiologic Depression Scale): >30 (normal <16)

9. Age related physiologic changes… • Can result in a reduction in the ability to metabolize & excrete medication (pharmacokinetics) • vulnerability varies by person • age may be 1 variable, others: comorbidities, genetic variability, smoking, alcohol & caffeine intake, diet, viral illness, and other factors • there are limited evidence-based studies due to the lack of elders in clinical drug trials, or a “healthy cohort effect” (only inclusion of healthy elders in drug studies)

10. Age related physiologic changes… • Elders body fat ( muscle mass) the distribution of fat-soluble drugs, delaying elimination and prolonging the action of the drug • An example of a lipophilic drug is diazepam (Valium) with an ½ life of 90 h in the elder vs.24 h in the young adult • Other examples of fat-soluble drugs are: cimetidine, digoxin, ethanol, gentamycin, meperidine, phenytoin, quinine, & theophylline.

11. Age related physiologic changes… • In elders the volume of H2O soluble drugs to reach target plasma concentration is decreased because elders have reduced body water. • So, for example, a loading dose of aminoglycosides should be lower in an elder A special case: Albumin • While albumin only slightly with age it tends to with illness causing a potential for toxicity from drugs such as: thyroid hormone, digoxin, warfarin, salicyclic acid, diazepam, and phenytoin, which all bind to albumin. Decreased albumin allows more free drug into the circulation.

12. Age related physiologic changes… Phase I metabolism of drugs in the liver (drug oxidation, reduction, and hydrolysis) is catalyzed by the cytochrome P450 system in hepatocytes. Drugs that are metabolized through phase 1 enzymatic activity have prolonged ½ lives in the elderly because this process decreases substantially with age. Commonly prescribed drugs with prolonged hepatic metabolism :

13. Age related physiologic changes… • Age-related changes in phase 1 metabolism in the liver and the use of multiple meds the risk for adverse drug reactions (ADR). • ADR occur due to the inhibition (blocking) or induction (stimulating) of CYP3A enzymes (involved in the metabolism of >1/2 of currently prescribed drugs). • Clinical outcomes are determined by the potency of the CYP 3A inhibitor, the availability of alternative pathways, and the seriousness of the symptoms.

14. Age related physiologic changes… • A drug is considered a potent CYP3A inhibitor if it causes >5 fold in plasma concentration of another drug that is dependent on CYP3A for its metabolism. It causes a >80% decrease in clearance of the substrate drug. • A moderate CYP3A inhibitor causes a >2 fold increase of the substrate drug causing a 50-80% decrease in clearance of the drug. • The NP should be aware of the potential for drug interactions when prescribing drugs from classes that include potent or moderate inhibitors of CYP3A. See: http://en.wikipedia.org/wiki/CYP3A4

15. Age related physiologic changes… • If a potent CYP3A inhibitor (blocks the synthesis of the enzyme) or inducer (stimulates synthesis of the enzyme) and substrate (drug on which the enzyme acts) must be taken together dosage adjustment and close clinical monitoring must take place to avoid ADR. • Go to Indiana University School of Medicine: http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.aspx For tables of the clinically relevant drugs involved in the CYP3A enzymes. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (20011). http://medicine.iupui.edu/clinpharm/ddis/ClinicalTable.aspx Accessed 12/26/11

16. Age related physiologic changes… • And example of a drug/drug interaction involving the CYP3A enzymes is demonstrated by erythromycin (EES; a CYP3A substrate) and a CYP3A inhibitor verapamil. • levels of EES result when these drugs are taken together and since EES prolongs cardiac repolarization, sudden death by torsades de pointes (a lethal form of ventricular tachycardia) may occur. • Other drugs that prolong the qt interval can be found at http://www.qtdrugs.org/ Wilkinson, G. (2005). Drug metabolism and variability among patients in drug response. New England Journal of Medicine, 352 (21) p. 2211-2221.

17. Selected common drug substrates, inhibitors, and inducers of CYP3A by drug class • CYP3A substrates CYP3A inhibitors CYP3A Inducers Ca channel blockers Ca channel blockers Rifamycins DiltiazemDiltiazemRifabutin Felodopine Verapamil Rifampin NifedepineAzoleantifungalsRifapentine Verapamil ItraconazoleAnticonvulsant agents ImmunosuppressantsketoconazoleCarbamazepine Cyclosporine Macrolide antibiotics Phenobarbital Tacrolimus Clarithromycin Phenytoin Benzodiazepines Erythromycin Anti-HIV agents Alprazolam TroleandomycinEfavirenz Midazolam (not azithromycin) Nevirapine TriazolamAnti-HIV agents Other StatinsDelavirdine St. John’s wort AtorvastatinIndinavirHypoglycemics LovastatinRitonavirpioglitazone (not pravastatin) Saquinavir Macrolide antibiotics Others Clarithromycin grapefruit juice Erythromycin mifepristone SSRIs Sertraline Wilkinson, G. (2005). Drug metabolism and variability among patients in drug response. New England Journal of Medicine, 352 (21) p. 2211-2221.

18. Age related physiologic changes… • With aging, the liver's capacity for metabolism through the CY 450 enzyme system is reduced by ≥ 30% because liver volume and hepatic blood flow are decreased. So, drugs that are metabolized through this system reach higher levels and have prolonged half lives. (The Merck Manual for health professionals http://www.merck.com/mmpe/sec20/ch303/ch303e.html) • This would have even more of an impact on elders with comorbid conditions. For instance older adults with cirrhosis have up to a 16 fold increase in AUC (a measure of drug absorption) of atorvastatin and so this drug should be avoided in such patients. • For patients education on drug interactions go to: http://www.fda.gov/forconsumers/consumerupdates/ucm096386.htm#drugs

19. Age related physiologic changes… • Can result in changes in tissue sensitivity to medications (pharmacodynamics) due to alterations in receptor numbers. The sensitivity to drug effects may either or with age. • Elders seem to be more sensitive to the sedative effects of benzodiazepine drugs (e.g. diazepam) but less sensitive to the drugs mediated by beta adrenergic receptors (e.g. isoproterenol, propranolol)

20. Renal drug elimination in elders • There is a decline in both the glomerular filtration rate (GFR) and tubular function (TF) in elders • Drugs that depend on glomerular function (e.g. gentamycin) and those that depend on tubular secretion (e.g. PCN) have reduced excretion in elders. • Drug elimination is correlated with creatinine clearance. The average creatinine clearance declines by 50% from ages 25 to 85, despite a serum creatinine remaining at ~ 1.0 mg/dl (due to a decline in muscle mass in the aged).

21. CockroftGault equation to estimate creatinine clearance CrCl = 140-age x wt (kg) (x 0.85 if female) 72 x serum Cr (mg/dl) • A creatinine clearance of <50ml/min places an older adult at risk for ADR. • Virtually all those >70 y/o have a creatinine clearance of <50 ml/min Caution: 1. African Americans (male and female) will have a higher serum creatinine level at any level of CrCl (due to more muscle mass) than Caucasians. This results in a lower estimated CrCl.

22. CockroftGault equation to estimate creatinine clearance 2. Cachectic patients and those with cirrhosis have a very low muscle mass and a much lower excretion rate than the equation may predict. The patient with cirrhosis and a serum creatinine of 0.9mg/dl may have a moderately severe degree of renal insufficiency. 3. Risk factors for kidney disease aside from age include diabetes, HTN, family hx, and smoking 4. Since one parameter of the estimation of CrCl in this equation uses weight, it would not be accurate for those with acites or volume overload Get a 24 hour urine for CrCl when renal function needs to be assessed with precision (e.g. in those with proteinuria).

23. Drugs with decreased renal elimination in elders

24. Drugs with decreased renal elimination in elders • Decreased renal clearance causes: • The ½ life of the drug to be prolonged • The serum level to be increased This is important for drugs with a narrow therapeutic index like digoxin, and aminoglycosides, so dosage reductions should be made in elders. To further refine dose requirements therapeutic drug monitoring should take place in drugs with a narrow therapeutic index.

25. Drugs with decreased renal elimination in elders • Classic symptoms of digoxin toxicity (nausea, anorexia, and visual disturbances) may occur however symptomatic cardiac disturbance and arrhythmias are more common in elders and are sometimes assigned to other causes. • Older adults may experience toxicity symptoms even with normal plasma levels of digoxin ( Flaherty, Perry, Lynchard, & Morley, 2000)

26. ADR: Drug induced Parkinsonism • Antipsychotic therapy is used in elders for the management of behavioral problems associated with dementia. • Antidopaminergic adverse effects associated with these drugs including extrapyramidal s/s may be misdiagnosed as Parkinson’s disease. • Some of the drugs implicated are: haloperidol (Haldol), prochlorperazine (Compazine), thioridazine(Mellaril)

27. ADR: Drug induced Parkinsonism • Even the “atypical” antipsychotics such as: (aripiprazole (Abilify); clozapine (Clozaril); ziprasidone (Geodon); paliperidone (Invega); risperidone (Risperdal); quetiapine (Seroquel); olanzaine (Zyprexa) can be associated with extrapyramidal s/e’s in a dose-related fashion. • Patients placed on anti-Parkinson’s therapy because of the extrapyramidal s/e’s of antipsychotics then become vulnerable to ADR of the Parkinsons’ drugs including hypotension and delirium.

28. ADR: Drug induced Parkinsonism • If the antipsychotic is essential and cannot be discontinued select one with a more favorable adverse event profile and use it at the lowest feasible dose. Additionally: • Those on Metclopramide (used to treat gastroparesis) were 3x more likely to begin tx for Parkinson’s due to the s/e of tardivedykinesia as compared with non-users. The ADR were dose dependant (at 10mg the odds were 19% higher and at >20mg the odds were >500 % higher than the controls). This can lead to the ADR of the Parkinson’s drugs.

29. Drug induced Parkinsonism • Drug induced symptoms can be misinterpreted as indicating the presence of a disease or attributed to aging and not to an ADR. • This is more likely when the symptoms are indistinguishable from an illness that is seen more frequently in older persons.

30. Cholinesterase Inhibitors and anticholinergic therapy • Cholinesterase inhibitors (donepezil (Aricept); rivastigmine (Exelon); galantamine (Reminyl) used to manage the symptoms of Alzheimer's disease and related dementias can precipitate urge urinary incontinence, which can be mistaken as the natural history of this disease and not an ADR. • Further, the use of anticholergic drugs to treat the urinary incontinence can expose elders to the ADR of the anticholinergic drugs (e.g. oxybutynin (Ditropan); solifenicin (Vesicare); tolterodine (Detrol) which are urinary retention, postural hypotension and chronic constipation.

31. Prescribing cascades… • A prescribing cascade is defined as the prescription of another drug for the ADR caused by the first medication. Examples are: • HCTZ therapy and the initiation of anti-gout therapy • NSAID therapy and the initiation of antiHTN therapy • Tricyclic antidepressants and the initiation of laxative therapy • Diphenhydramine (for sleep) added to oxybutynin (for over active bladder) leading to urinary retention and agitation. Treatment with an antipsychotic for the agitation may result. All 3 medications have anticholinergic properties and can lead to frank delirium, hallucinations and falls.

32. Updated Beers Criteria • The number of controlled studies on medication use in those >75 y/o and those with multiple comorbid conditions is limited. • The 2003 Beers criteria was updated by the AGS using a systematic review of the literature and the consensus of experts to provide guidance to clinicians. • Fick, D., Cooper, J., Wade, W. Waller, J., Maclean, J., Beers, M. (2003). Updating the Beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts. Archives of Internal Medicine, 163 p. 2716-2724. • The AGS 2012 Beers Criteria Update Expert Panel (2012). American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. JAGS p.1-16. DOI: 10.1111/j.1532-5415.2012.03923.x

33. Medications to be avoided in those >age 65 with selected side effects

34. Selected medication classes or medications to be avoided in those > age 65 based on diagnosis , added since the 2003 Beers Criteria • Dx. Chronic constipation nondihydropyridine calcium channel blockers and oral antimuscarinics • Dx. Heart Failure NSAIDs, COX-2 inhibitors, nondihydropyridine CCBs, pioglitazone • Dx. Seizure disorder Bupropion, chlorpromazine, olanzapine • Dx. Delerium All TCAs, Anticholinergics, Benzodiazepines, Corticosteriods, Sedative hypnotics • Dx. Insomnia Pseudoephedrine, Methyphenidate, Theophylline

35. Selected medication classes or medications to be avoided in those > age 65 based on diagnosis , added since the 2003 Beers Criteria • Dx. Syncope peripheral alpha blockers, acetylcholinesterase inhibitors tertiary tricyclic antidepressants • Dx. Dementia anticholinergics, antispasmodics, first generation antihistamines • Dx. Fractures or Falls anticonvulsants, antipsychotics, benzodiazepines, nonbenzodiazepine hypnotics, SSRIs, TCAs

36. Evidence supporting the use of the Beers criteria to prevent ADR • Using the Beers criteria to assess ADR in community dwelling elders enrolled in an MCO. Participants were >65y/o (n=16, 877; 6,875 participants and 10,002 controls; 61% female, M age 73.33 SD = 6.47. • 40% filled 1 potentially inappropriate medication (PIM) and 13% filled 2 or more PIMs. • ADR prevalence among those with at least 1 PIM was 14.3% compared to 4.7% in the non-PIM group (p<.001). Fick, D., Mion, L., Beers, M., Waller, J. (2008). Health outcomes associated with potentially inappropriate medication use in older adults. Research in Nursing and Health, 31, 42-51.

37. Selected common drug-drug interactions

38. Selected common drug-drug interactions

39. Selected common drug-drug interactions

40. Selected common drug-drug interactions Capezuti, Zwicker, Mezey, et al. (2008). Evidence based Geriatric Nursing Protocols for Best Practice (3rd ed.) New York, NY: Springer

41. Pearls for practice • Severely dehydrated patients may have a marked reduction in renal clearance that is completely reversible with rehydration. • While the BP increases with age, symptomatic orthostatic hypotension also increases and should be evaluated at every visit in order to give anticipatory guidance related to fall prevention.

42. Pearls for practice • First offer nondrug therapy (weight reduction and salt restriction) in elders with hypertension. • The cardiac output required for mild-moderate exercise is provided until age 75 in those without cardiac disease, but is the result of an increased stroke volume in elders not tachycardia as in young adults. • While thiazides are a reasonable first step in therapy, the hypoglycemia, hypokalemia, and hyperurecimia caused by these drugs are important to monitor because of the higher incidence of T2DM, arrhythmias, and gout in elders. Provide a low antihypertensive dose.

43. Pearls for practice • Hypokalemia, hypomagnesemia, hypoxia (from pulmonary disease), and coronary atherosclerosis all contribute to the high incidence of digitalis-induced arrhythmias in the elderly. • The clearance of digitalis is decreased in elders and the ½ life of this drug may be increased by 50% or more. • Digoxin is cleared by the kidneys, so consider renal function when ordering.

44. Pearls for practice • NSAIDS cause toxicities to which elders are very susceptible and may result in renal damage that may be irreversible. • ASA causes GI irritation and bleeding. Ginko biloba may predispose to bleeding in those on low dose ASA. • NSAIDS are cleared by the kidney and they accumulate more rapidly in elders, especially those whose renal function is already compromised beyond the average range for age.

45. Pearls for practice • There is no evidence that COX-2 selective NSAIDS are safer in regard to renal function. • Elders on NSAID should be monitored for changes in renal function. • There is a positive association between the number of drugs taken and the incidence of ADR. The incidence of drug reactions in elders is estimated to be at least twice that of younger adults.

46. Pearls for practice • ADR can mimic almost any clinical syndrome in geriatrics. • One study of reversible dementia found that drug induced cognitive impairment was among the most common and treatable causes of syndromes that could be mistaken for dementia in the elderly (Larson, Kukull, & Buchner,1987). • Anticholinergics also have the potential to cause CNS toxicity in the elderly (Cantu & Korek , 1991; Gray, Lai, Larsen, 1999). • Exacerbation of hearing loss or impairment of the vestibular system is more likely to occur in geriatric patients treated with aminoglycosides.

47. Pearls for practice • Withholding antibacterial agents is often justified for upper respiratory infections, as these are typically caused by viral pathogens. This is also true of many diarrheal illnesses. • Some entities, such as asymptomatic bacteriuria, are not felt to represent true infection and affected patients do not benefit from therapy.

48. Pearls for practice Concurrent use of any 2 of these drug classes: antiparkinson drugs tricyclic antidepressants antipsychotics anti-arrhythmics OTC antihistamines may worsen dry mouth, gum disease, blurred vision, constipation, urinary retention, and delirium.

49. Pearls for practice • SSRIs are the preferred drug class to treat depression in elders because they do not cause cardiotoxicity or orthostatic hypotension. • They do not have anticholinergic s/e’s (except for paroxetine (Paxil)- which may have mild anticholinergic s/e’s in elders) • The most common s/e are nausea and anorexia which may be ameliorated by starting with ½ the dose of a young adult and slowly increasing after a week. • OTC St. John’s Wort or taking 2 SSRI’s may precipitate serotonin syndrome in an elder

50. Pearls for practice Serotonin syndrome Mild symptoms: increased HR shivering sweating dilated pupils intermittent tremor or twitching hyperreflexia Moderate symptoms: hyperactive bowel sounds elevated BP a temperature as high as 40 °C (104 °F) intoxication Mental status changes such as hypervigilance and agitation Severe symptoms: severe increases in heart rate and blood pressure leading to shock Temperature may rise to above 41.1 °C (106.0 °F metabolic acidosis rhabdomyolysis seizures renal failure Disseminated intravascular clotting r/t hyperthermia