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2011 International Seminar on Geriatrics (Athens, April 1-3 2011) Denutrition and drugs in the elderly Pr. Patrice QUENEAU De l’Académie Nationale de Médecine

Iatrogenesis Changes in the elderly Examples of at-risk situations 2011

INTRODUCTION Iatrogenesis : any disease or adverse event caused by a medical intervention within the health care system . The term does not prejudge in any way an error, fault or negligence : some risks are unavoidable, others not. In France, the Act of March 4 2002 allows to compensate a patient in the absence of fault (no-fault therapeutic hazard). In Geriatrics, the mere decision to hospitalize can lead to undue loss of autonomy. Iatrogenesis can result from the action of any caregiver : physician, therapist/kinesiologist, hospital porters ... 2011

INTRODUCTION 2011 Drug-induced iatrogenesis : Adverse effects without therapeutic misuse , or no fault hazard Adverse effects with therapeutic misuse Whether this "misuse" is caused by: The physician By extension, other caregivers (notably the pharmacist or the nurse) Or the patient himself , through inappropriate self-medication or poor compliance with treatment

IATROGENESIS IN THE ELDERLY The adverse effects of drugs are: More frequent, from 3 to 20 % Involved in 5 to 10 % (even more) of hospitalizations The reasons for hospitalization are: Dehydration with functional renal failure (RF) Orthostatic hypotension with falls Confusional states Gastrointestinal bleeding They are preventable in part: inadequate dosage, drug interactions, interactions with diseases => concept of misuse or inappropriate prescriptions. Certain adverse drug reactions are unpredictable or difficult to dissociate from the desired therapeutic action. 2011

Polypathology 2011 Polymedication Automedication Poor compliance Aging Adverse effect of the drug Inadequate drug concentration Altered organ response Reduction of functional capacity Homeostatic dysregulation

CONCEPT OF "INAPPROPRIATE DRUG PRESCRIPTION" Developed by Anglo-Saxon authors [Beers] . It corresponds to an insufficient consideration of drugs and/or diseases leading to prescribe a drug that is not optimal between the expected return and the risk incurred. This can be : inappropriate indications (risk factors in the very elderly), excessive risk taking (AVK in the very elderly), excessive dosages, excessive length of prescription. 2011

AGING AND CHANGES IN BODY SIZE Decrease in lean mass and increase in fat mass Frequency of hypoalbuminemia 2011

CHANGES IN COMPARTMENTAL DISTRIBUTION IN THE ELDERLY Compartments Decrease in total body water 60 % at age 20 50 % at age 85 Increase in fat mass 18 % at age 20 36 % at age 85 Decrease in lean mass Decrease in active cell mass   Membrane transport capacity +  Enzymatic capacity (liver – kidney especially) 2011

CHANGES IN BODY WATER COMPARTMENTS WITH AGING FAT MASS 26 kg LEAN MASS 44 kg LEAN MASS 55 kg FAT MASS 15 kg 42 L of water 35 L of water 20 yrs - 70 kg Water : 60% of total weight / 85 yrs - 70 kg Water : 50% of total weight 2011

CHANGES IN DRUG DISTRIBUTION LINKED TO BODY SIZE Increase in fat mass at the expense of muscle mass (1/3 greater at age 75 than at age 30)  volume of lipophilic molecules due to a greater distribution in adipose tissue (antidepressant, anaesthetic, Central nervous system) Storage in fat tissue, replenishing prolongation of half-life  volume of hydrophilic molecules (paracetamol, digoxin…), resulting in higher serum concentrations at equal dosage, hence possibility of adverse effects 2011

Hypoalbuminemia will cause a decrease in acidic binding (aspirin, warfarin, phenytoin) -> risk of overdosing Beware in case of disease reducing the synthesis of albumin : stress, denutrition, hypercatabolism Increased alpha 1 acid glycoprotein (orosomucoids) leading to increased binding capacity of basic molecules -> risk of underdosing = marginal situation CHANGES IN DRUG DISTRIBUTION LINKED TO BODY SIZE 2011

AGE-RELATED CHANGES IN THE DISTRIBUTION VOLUME (Vd) OF CERTAIN DRUGS 2011 Vd  Vd  Vd  Furosemide Amikacin Gentamycin Isoniazid Paracetamol Warfarin Alprazolam Diazepam Lidocaine Acetyl-salicylic acid Anthracyclines Morphine Digoxin Cisplatin

DENUTRITION AND CREATININE PRODUCTION 2011 In the elderly malnourished, the serum creatinine assay is insufficient to assess renal function. Influence of creatinine levels on a number of parameters Diet (low in protein) Muscle mass (+++) Physical exercise (sedentary  reduction) Certain drug treatments Certain pathological conditions Clearance estimation is essential: Cockcroft formula, study MDRD formula

PRACTICAL ASSESSMENT OF GLOMERULAR FILTRATION RATE Rev Med Int 2008 ; 29 : 364 - 69 Comparative study of Carbonnel et al. 81 patients Mean age 82.3  7.0 Mean albumin 33.3  5.2 Mean weight 59.6  14.8 120 40 80 0 Cockcroft & Gault 42.1  17.1 Creat / Urine cl. 33.7  21.3 MDRD 49.9  16.4 2011

SOME EXAMPLES OF AT-RISK SITUATIONS Anticoagulants Renal clearance drugs Psychotropic drugs Oral antidiabetic drugs Antimitotic drugs 2011

ANTIVITAMINS K AVK Currently, 1.4 % of French population on AVK ! (1 200 000 patients) Fluindione (Previscan®) 77 % ; Acenocoumarol (Sintrom®) 16 % ; Warfarin (Coumadin®) 7 % Primary cause of hospitalization for side effects : Major 2.4 - 5 % / yr Minor 6 - 10 % / yr Elderly patient Greater sensitivity due to stronger inhibition of synthesis of factors II - VII - IX - X at identical serum concentrations [Ann Int Med 2001 ; 135 : 393 - 400] 2011

ANTIVITAMINS K AVK Doses required for INR 2 - 3 Age Warfarin dosage (mg) 40 - 49 yrs 7.3 (6.2 – 8.3) 50 - 59 yrs 5.5 (5 - 6) 60 - 69 yrs 4.3 (4 – 4.5) 70 - 79 yrs 3.9 (3.7 – 4.1)  80 yrs 3.3 (3 – 3.6) [JAGS 2002 ; 50 : 1439 - 55] Longer normalization of INR if elevated Sometimes with 1 to 2 mg of Warfarin, INR can be between 6 and 10 ! 2011

ANTIVITAMINS K AVK Hemorrhagic risk factors under AVK [Am J Med 1998 ; 105 : 91 - 9] Age > 65 yrs - Diabetes ATD stroke, myocardial infarction, gastrointestinal bleeding Hematocrit < 30 % Renal failure with creatinine > 150 mcmol/L > 3 medications : drug interactions [BMJ 2003 ; 326 : 153 - 56]   INR : Paracetamol - PPI - Amiodarone - IRS - Aspirin - Antibiotics  Hence, systematic INR after introduction or discontinuation of any drug 2011

Strong corrélation ( 80 %) between % of Adverse Drug Events and number of drugs (study in Emergency Units) P. Queneau, Drugs Safety, 2006 P. Queneau

PSYCHOTROPIC DRUGS BENZODIAZEPINES Specific risks Present in 25 % of elderly subjects with risk of hip fracture x 2 The decline in hepatic redox capacity (Phase I) and renal elimination increases half-life of certain BZDs by 50 to 100 % between age 30 and 80 years. Increased sensitivity to central effects : sedation, confusion, impaired memory Recommendations Use BZD with short half-life+++ : oxazepam (Seresta), alprazolam (Xanax) Reduce posology by two or three+++ 2011

EXAMPLE OF THE METABOLISM OF BENZODIAZEPINES MALETTA G. Geriatrics 1991 ; 46 : 40 - 60 SHORR R. Drugs and Aging 1994 ; 4 : 9 - 20 G + Glucuronidation (phase II) O = Oxydation (phase I) 2011 OXAZEPAM Seresta ALPRAZOLAM Xanax DIAZEPAM Valium Half-life Adult Short (< 10 H) 7 H Intermediate 10 -> 20 H 11 H Long (> 20 H) 46 H Minimum duration of "steady state" 2 d 2 d 10 d Active metabolite No  O (G) (Alpha OH Alprazolam) + + (O) Desmethyldiazepam 29 to 223 H Temazepam 8 to 38 H Half-life Elderly 8 H 19 H 90 H

PSYCHOTROPIC DRUGS LITHIUM Risk of overdosing By interaction with diuretics Recommendation Lower residual rate NEUROLEPTICS Rise in the active free fraction via reduction in protein binding 2011

Particular risks Long acting hypoglycemic sulfonamides : sulfonylurea Ozidia ®, Glucidoral® Insulin delay Strong binding of sulfonamides to plasma proteins - > increase of their efficacy Recommendations Short half-life sulfonamides Transition to Insulin ANTIDIABETIC DRUGS 2011

ANTINEOPLASTIC DRUGS Risks linked to decrease in protein binding Reduction of transport proteins Albuminemia : 48 g/l at age 20 36 g/l at age 85 Active free fraction of the drug is increased Recommendations : dosage adjustment related to the increase in free fraction+++ Taxanes, Anthracyclines Methotrexate, Vinca alkaloids Epirubicin, Etoposide, Teniposide 2011

CONCLUSION MAJOR DRUGS INVOLVED IN CASE OF DENUTRITION Drugs with to achieve efficacy without side effects or those susceptible to affect the fate of other drugs. The classic agents are oral anticoagulants, NSAIDs, aminoglycosides, corticosteroids, opiates, antipsychotics, immunosuppressants… From a practical standpoint, all antineoplastic drugs have a narrow therapeutic margin and are at risk in case of denutrition. 2011

Evidence based medicine: what it is and what it isn ’ t L ’Evidence-Based Medicine by the Working Goup JAMA 1992, 268 (17): 2420-5 avid L Sackett, William M C Rosenberg, J A Muir Gray, R Brian Haynes, W Scott Richardson+Author Affiliations « the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients . »

Limites (et critiques) de l’EBM ? Chaque malade est UNIQUE > pas de malade « MOYEN » Essais randomisés disponibles pour une infime proportion des décisions prises quotidiennement par un médecin Publications sont anglo-saxonnes le plus souvent Etudes avec résultats négatifs : rarement publiées Efficacité : routine ≠ conditions expérimentales > la médecine : SCIENCE ET ART

l’ EBM : « l’utilisation consciencieuse et judicieuse des meilleures données actuelles de la recherche cliniqu e dans la prise en charge personnalisée de chaque patient » 6-7-8 septembre 2007 P. Queneau, J. Doucet, F. Paille L ’Evidence-Based Medicine Working Goup JAMA 1992, 268 (17): 2420-5

UNFRACTIONATED HEPARIN UFH By IV / subcutaneous (Calciparin) Anti Xa and Anti II activity or equivalent - TCA 1.5 to 2.5 / control / 6 h after injection Risk factors for bleeding complications Anti Xa dosage > 0.8 UI/ml Low weight and hypoalbuminemia Coprescription of Aspirin Surgery or trauma < 10 d Abnormal homeostasis Age [> 72 yrs Arch Int Med 1996] Renal function -> low level Equal efficacy of continuous IV route / subcutaneous route / 12 h Recommendation  2500 UI / 0.1 ml / 10 kg / 12 h 2011

LOW MOLECULAR WEIGHT HEPARIN LMWH Anti Xa activity especially Predictable activity based on weight Renal elimination, hence increased risks if long half-life LMWH AFSSAPS 2000: Preventive treatment not recommended if Creat cl < 30 ml/mn Risk factors : bleeding complications Anti Xa dosage > 0.8 UI/ml Reduced weight Renal function < 30 ml/min + + Treatment > 10 d 2011

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