Drug Side Effects That Mimic Aging

Transcription

1 Drug Side Effects That Mimic Aging Darrell R. Abernethy, MD, PhD Associate Director for Drug Safety FDA

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5 PHARMACOKINETIC CHANGES IN THE ELDERLY Process Change with Age Drug Elimination Renal Elimination Hepatic Elimination Phase I Reactions CYP3A CYP1A2,2D6,2C9,2C19,2E1 Phase II Reactions Glucuronidation Sulfation Acetylation or or

6 PHARMACODYNAMIC CHANGES IN OLDER PATIENTS Increased sensitivity to sedatives Increased sensitivity to anticholinergics Increased sensitivity to antidopaminergics Decreased sensitivity to Beta adrenergic agents Decreased sensitivity to Angiotensin blockers Impaired baroreflex function Impaired endothelial function

7 50 40 Incidence (%) Number of Drugs (Adapted from Cluff LE et al: JAMA 188:976, 1964)

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9 Table 1. Types of the 189 Side-Effects of Drug-Drug Interactions Type of Effect % Neuropsychological disorder and/or cognitive impairment 44.1 Global or orthostatic arterial hypotension 21.8 Acute renal failure secondary to dehydration 15.7 Hypo/hyperkalemia 5.6 Impairment of heart automatism, conduction, or rhythm 4.5 Increased anticholinergic effects T 3.3 Other side effects 5.0

10 Table 1. Age-related chronic medical conditions* MEDICAL CONDITION FREQUENCY PER 1000 PERSONS IN USA Age <45 y Age y Age > 65 y Arthritis Hypertension Hearing impairment Heart disease Diabetes Visual impairment Cerebrovascular disease Constipation * From Zisook S, Downs NS. J Clin Psych 1998, 59 (suppl 4):80-91, data from Dorgan CA, editor. Statistical record of health and medicine. New York:International Thompson Publishing Co

11 HIV Drug Side Effects That Mimic Aging Lipoatrophy/Lipodystrophy Hyperlipidemia leading to CV disease?osteopenia/osteoporosis?frailty Syndrome

12 HIV Drug Side Effects that Mimic Aging Lipoatrophy/Lipodystrophy Does this mimic aging? Pattern of fat redistribution Association with atherosclerosis Is there a plausible common mechanism? Is it due to drug exposure, underlying disease, or both?

13 HIV Drug Side Effects that Mimic Aging Lipoatrophy/Lipodystrophy Is the pattern of fat redistribution similar to that seen in aging? Is the fat redistribution associated with the same clinical sequelae as seen in aging?

14 HIV Drug Side Effects that Mimic Aging Lipoatrophy/Lipodystrophy Common Mechanism? Putative mechanism for HIV drug mitochondrial toxicity Age-related fat redistribution mechanism???

15 HIV Drug Side Effects that Mimic Aging Lipoatrophy/Lipodystrophy What Drugs? NRTI Stavudine, Zidovudine, Didanosine PI--?all Individual Drugs, or Drug Combinations?

16 HIV Drug Side Effects that Mimic Aging Hyperlipidemia Does this mimic aging? Pattern of hyperlipidemia Association with atherosclerosis Is there a plausible common mechanism? Is it due to drug exposure, underlying disease, or both?

17 HIV Drug Side Effects that Mimic Aging Hyperlipidemia Age-related pattern? Common mechanism? For HIV drugs hypothesized mechanism Sterol Regulatory Element Binding Protein-1c Aging mechanism???

18 HIV Drug Side Effects that Mimic Aging Hyperlipidemia What drugs? Associated with lipoatrophy/lipodystrophy?? All PI Most NRTI Pattern clearly different

19 HIVDrug Side Effects that Mimic Aging Hyperlipidema Same association with atherosclerotic disease as seen in aging??

20 From CLIN INFECT DIS 49(11): by the Infectious Diseases Society of America. All rights reserved. For permission to reuse, contact Figure 1. Prevalence of coronary artery calcium (CAC) in the entire cohort and coronary age distribution in the subpopulation with a CAC score >0.

21 From CLIN INFECT DIS 49(11): by the Infectious Diseases Society of America. All rights reserved. For permission to reuse, contact Figure 2. Univariable linear regression analysis of increased vascular age and CD4+ cell count in the group with increased vascular age. CI, confidence interval.

22 HIV Drug Side Effects that Mimic Aging Frailty Syndrome Is it accelerated? Is it associated with drug therapy?

23 Cycle of frailty hypothesized as consistent with demonstrated pairwise associations and clinical signs and symptoms of frailty. Fried L P et al. J Gerontol A Biol Sci Med Sci 2001;56:M146-M157 The Gerontological Society of America

24 Survival curve estimates (unadjusted) over 72 months of follow-up by frailty status at baseline: Frail (3 or more criteria present); Intermediate (1 or 2 criteria present); Not frail (0 criteria present). Fried L P et al. J Gerontol A Biol Sci Med Sci 2001;56:M146-M157 The Gerontological Society of America

25 Estimated prevalence of a frailty-related phenotype (FRP) as a function of age among 1977 HIV-seronegative individuals from the Multicenter AIDS Cohort Study (MACS) cohort (April 1994 November 2004) (95% confidence interval [CI]). Desquilbet L et al. J Gerontol A Biol Sci Med Sci 2007;62: Copyright 2007 by The Gerontological Society of America

26 Adjusted prevalence of having a frailty-related phenotype according to age and presence and duration of HIV infection, for fixed values of ethnicity (white non-hispanic) and educational level ( college), among HIV-seronegative and -seroconverted men in the Multicenter AIDS Cohort Study (MACS) between April 1994 and January 1, 1996 when (a) all person-visits were included and (b) excluding person-visits occurring later than 6 months before the first AIDSdefining illness. Desquilbet L et al. J Gerontol A Biol Sci Med Sci 2007;62: Copyright 2007 by The Gerontological Society of America

27 HIV Drug Side Effects that Mimic Aging What part of HIV-related frailty is related to the underlying disease? What part of HIV-related frailty is related to drug side effects?

28 Other Concomitant Drugs that Mimic Aging Drugs with anticholinergic effects Drugs with sedating effects

29 Literature

30 Older people carry High burden of illness: medications indicated Increased risk adverse drug events Limited evidence base to guide prescribing Need evidence based model to assess functional risk/benefit

31 DRUG BURDEN DB = BAC + BS + BW DB BAC BS BW total drug burden anticholinergic burden sedative burden number of drugs (excluding those with anticholinergic or sedative effects)

32 Hypothesis: Drug Burden DB = B AC + B S + B W DB B AC B S B W total drug burden anticholinergic burden sedative burden number of drugs (excluding those with anticholinergic or sedative effects)

33 Health, Aging and Body Composition Study (Health ABC) Population Random sample of 3075 Medicare recipients Pittsburgh, Pennsylvania and Memphis, Tennessee years, high functioning, community dwelling Medication Inventory Brown Bag All medications actually taken in past 2 weeks

34 Functional Measures Physical function Health ABC Score (HABC) Objective measures: Chair stands 6 m walk Narrow 6 m walk Standing balance Higher score, better physical function Validated (Established Populations for Epidemiologic Studies of the Elderly) Digit Symbol Substitution Test (DSST) Psychomotor performance, attention, concentration, STM Higher score, better cognitive function Validated (Wechsler Adult Intelligence Scale)

35 Association of Anticholinergic Burden with Function and Sedation HABC score DSST HABC Score DSST n=2474 n=383 n=68 n=44 n=10 Anticholinergic burden

36 Association of Sedative Burden with Function and Sedation HABC Score DSST HABC Score DSST n=2704 n=102 n=163 n=54 n=24 Sedative burden 30

37 Equation Derived for Drug Burden Index (DBI) DBI D AC D S AC D AC S D S DBI AC S D δ Drug Burden Index Medications with anticholinergic properties Medications with sedative properties Daily dose Minimum recommended daily dose approved by US Food and Drug Administration; estimate of DR 50

38 Association of Increasing DBI with Decreasing Scores for Physical Function and Sedation HABC Score 2.3 * 2.2 * * n=2226 n=738 n=99 n=12 Drug burden DSST HABC Score DSST *p<0.05 between adjacent points

39 Relative Impact of Drug Burden Index on Function Multiple regression analysis Degree of variance in HABC score captured by a one point increase in drug burden index is: ~ 3 additional physical co-morbidities > cog impairment, depression or anxiety

40 Conclusions In highly functioning, community dwelling older people, objective functional outcomes are associated with drug burden index: Degree of exposure to drugs with anticholinergic and sedative effects Includes dose-response and maximal effect Further study in other populations of older people Drug burden index may predict effects of medication on function Hilmer et al., Arch Int Med, 2007

41 Longitudinal Association Between DBI and Function in Health ABC Study Participants Association of Drug Burden Index at each time point Cumulative drug burden exposure with function over 5 years

42 Higher Baseline Drug Burden Index Associated with Lower Function Year 6 Multivariate regression analysis One unit increase in drug burden in year 1 would predict at year 6 an independent decrease in: SPPB of 0.32 (p < 0.005) Gait speed of 0.05 (p < ) Grip strength of 0.62 (p=0.05) Degree of change > that of 2 additional physical or mental comorbidities for each outcome

43 Higher AUC Drug Burden Years 1 to 6 Associated with Lower Function Year 6 Multivariate regression analysis One unit increase in the AUCDB exposure over years 1 to 6 predicts significant independent decrease in: SPPB score of 0.09 (p<0.005) Gait speed of 0.01 (p<0.001) Grip strength of 0.28 (p<0.005) Degree of change greater than that associated with addition of two physical or mental comorbidities

44 Higher AUC Drug Burden Years 1 to 6 Associated with Lower Function Year 6 Five units increase in the AUCDB exposure predicts a significant independent decrease in: SPPB score of 0.45 meaningful change points* Gait speed of 0.05 m/s meaningful change 0.05 m/s* Grip strength of 1.4 kg *Perera et al., JAGS 2006

45 Other Populations Womens Health and Aging Study (WHAS) Community dwelling frail older women (USA) Concord Health in Ageing Men Project (CHAMP) Community dwelling older men (Australia) FREEDOM Older people living in low level residential aged care (Australia) Department of Veterans Affairs DVA linked data bases (Australia)

46 Conclusions Increasing DBI is independently associated with functional impairment in older adults. Results from interventional studies are required to assess whether reduction of DBI is feasible changes in DBI affect function in older adults. Optimising use of medications with anticholinergic and sedative effects using an evidence-based tool such as DBI may reduce functional decline and disability among older adults.

47 Drug-Induced Impairment in Functional Status Do these findings extrapolate to aging HIV patients? HIV treatment related polypharmacy + Sedative and Anticholinergic Drugs for treatment of coexisting conditions Drug Side Effects that Mimic Aging???

48 By the time a man gets well into the seventies, his continued existence is a mere miracle R.L. Stevenson:AES Triplex

49 Come grow old along with me, the best of things are yet to be. Rabbi Ben Ezra, Robert Browning ( )