Polypharmacy ( polypragmasia ) in the elderly

1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011

2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Gyula Bakó and Miklós Székely Molecular and Clinical Basics of Gerontology – Lecture 20 Polypharmacy(polypragmasia)in the elderly

3. Specific therapeutic challenge of prescribing for the elderly • Principle factors: • I Multiple and severe illnesses – Multiple drug therapy • Drug use in the elderly is disproportionately high: patients over 65 constitute 12% of the US population and consume 31% of prescribed drugs secondary to: • increased severity of chronic illnesses • presence of multiple pathologies • excessive prescribing. • II Poor adherence to medication regimens • III Altered pharmacokinetics and pharmacodynamics

4. The most common chronic diseases in which the elderly need more medications • Cardiovascular diseases: • angina pectoris • cardiac failure • hypertension • atrial fibrillation • Neurologicaldiseases: • cerebral hemorrhage • Parkinson’s disease • Psychiatric disorders: • dementia • depression • confusion • Urologicaldisorders: • urinary incontinence • Musculoskeletaldisorders: • arthritis • arthrosis • osteoporosis • Endocrinologicaldisorders: • thyroid diseases • Gastrointestinal diseases: • constipation • GERD

5. Prevalence of multimorbidity Using 24 major diagnostic categories… • 82 percent of people aged65and older had one or more chronic conditions • 65 percent had two or more • 43 percent had threeor more • 24 percent had four or more. • On average there are 2.3 chronic conditions reported by people aged65 and older. 90 80 70 60 50 40 30 20 10 0 1 or more 2 or more 3 or more 4 or more Wolff JL, Starfield B, Anderson G. Arch Intern Med. 2002;162:2269-2276

6. Polypharmacy for the elderlyViennastudy • Number of agents and their distribution depending on the patients’ age 40 35 30 25 Percentage of patienton all insured person 20 15 10 5 0 61 to 70 years 71 to 80 years 81 to 90 years 91 years or older Age cohort Active substances: 1 – 4 5 – 8 9 – 12 13 or more

7. Polypharmacy for the elderly: a representative sample from Hungary • The distribution of the frequency (%) in fuction of the number of therapeutic agents. Drug consumption 19% 20% 17% 15% 14% 15% 11% 11% 11% 11% 10% 10% 10% 10% 8% Percentage of the participants 10% 7% 7% 6% 6% 6% 5% 4% 5% 1% 0% 0% 0 1 2 3 4 5 6 7 8 9 10< pill/person/day social institution health care

8. Why are so many elderly patients using a lot of drugs inappropriately? • Factors depending on the patient: • Chronic diseases requiring long-term treatment become more common. • Atypical presentation of diseases. • Expectations of both the family and the patient (people keep going to see the doctor until they get what they want). • There is no satisfactory doctor-patient relationship in time or in depth because of the crowded outpatient services. • The elderly often take OTCs (over-the-counter drugs) about which the doctor is not informed. • Due to the uncertain origin of the drugs (from friends, relatives, and commercials), side effects and interactions can appear.

9. Why are so many elderly patients using a lot of drugs inappropriately? • Factors depending on the physician: • The treatment is frequently focused on the symptoms: one additional symptom – one additional drug. • An additional drug is given to correct an existing side-effect. • Lack of personalized care: multiple parallel drug prescriptions are subscribed by different doctors. • The control of drug efficacy is also missing.

10. Physiological and pathophysiological changes in the elderly influencing drug effects • 1 reduced body weight* • 2 decreased muscle mass • 3 reduced total body water • 4increased (laterdecreased) mass of adipose tissue • 5 decreased mass of plasma proteins • 6 reduced stroke volume • 7 impaired kidney functions • 8reduced weight and blood flow of liver • 9 reduced amount of certain hormones • *The decrease in body weight is due to decreased bone mass and due to causes under #2-3.

11. Physiological and pathophysiological changes in the elderly influencing drug effects • The listed changes generally develop with aging, however, they differ individually on a case by case basis. • The degree of these changes is different and it is difficult to determine to what extent the changes can be considered physiological.

12. Altered pharmacokinetics and pharmacodynamics Age-dependent basicpharmacologicalalterations of theelderly Pharmacokinetics Pharmacodynamics

13. Pharmacokinetics in the elderly • 1 ABSORPTION • 2 TRANSPORT • 3 DISTRIBUTION • 4 METABOLISM • 5 ELIMINATION

14. Pharmacokinetics in the elderly:absorption • Aging-associated changes: • The pH in the stomach is closer to neutral. • Longer transition time in the GI system. • Decreased surface of the small intestine. • Diminished blood perfusion (GI, transdermal etc. absorption). • Consequences: • Delayed absorption as indicated by a smaller and delayed peak plasma level. The area under curve (AUC*) hardly changes. • Decreased first-pass effect after oral administration. • Overall bioavailability remains maintained (slower excretion!). Though numerous structural and physiological age-related changes in the GI tract exist, they are of minimal clinical significance in the absence of gastrointestinal pathology. • * The area under the curve depicting changes in concentration over time is proportionate with the overall amount of absorbed drug, irrespective of the speed of absorption.

15. Pharmacokinetics in the elderly:transport • Aging-associated changes: • Decrease in the albumin concentration (by 10%). • Consequences: • Free plasma drug level increases by about 10% (medication with narrow therapeutic range, e.g. digoxin); • In case of simultaneous administration of multiple drugs, the rate of binding to transporter molecules becomes unpredictable:  side effects,  drug interactions. (e.g. coumarins, theophylline, salicylates) • unexpected drug toxicity !

16. Pharmacokinetics in the elderly:distribution • Aging-associated changes: • Both the total body water and the distribution volume of water soluble drugs decrease (by about 10-15%). • The amount of the adipose tissue and the distribution volume of lipid soluble drugs increase (by about 20%). • Although the fat content is higher in women than in men, the relative change in the volume of distribution for lipophilic drugs is more marked in men than in women (18 to 36% in men, 33 to 45% in women). • Consequences: • Concentration of water soluble drugs increases(e.g. lithium, vancomycin). Diuretics and insufficient water intake may lead to enhanced (toxic) drug effects (e.g. aminoglycosides, antiarrhythmic drugs, digoxin, lidocain, theophylline)! • Underdose of fat soluble drugs (e.g. benzodiazepines).

17. Pharmacokinetics in the elderly:distribution in very old people • Very old individuals loose weight and become frail, the proportion of fat decreases so that the volume of distribution for lipophilic drugs again decreases and the serum concentrations increase. • The frailty of very old individuals tends to be overlooked, low weight patients on average receive higher doses per unit body weight than heavier patients. Hence, low body weight, in addition to advanced age, constitutes a risk factor for overmedication.

18. Pharmacokinetics in the elderly:metabolism • Aging-associated changes: • The weight of the liver (by about 25-35%) and the hepatic blood flow (by about 30-40 %) decrease. • The rate of hepatic drug clearance is impaired. • Consequences: • Increased risk for impaired liver function is seen in exsiccosis and chronic heart failure! • Decrease in hepatic blood flow is often associated with decreased first pass effect.

19. Pharmacokinetics in the elderly:elimination • Aging-associated changes: • Elimination (excretion) through the liver is usually minimally reduced. • Kidney functions are impaired due to • decrease in glomerular filtration rate • reduced tubular functions (fibrosis, atrophy). • Consequences: • Toxic effects of drugs eliminated via the kidney may increase (e.g. amikacin, amiloride, ciprofloxacin, digoxin, enalapril, furosemide, gentamycin, hydrochlorothiazide, vancomycin)!

20. Pharmacodynamic changesintheelderly • Responsiveness of the body changes with age: • Changes in theblood-brain barrier • Alteration in receptor properties • affinity • number • post-receptor response (enhanced/diminished) • Homeostatic changes: decreased capacity to respond to physiological challenges andto the adverse side effects of drug therapy (e.g. baroreceptors). • Cell-tissue response to a drug maybe changed concerningthe • mechanism, • intensity, • peak, • duration of physiological actions.

21. Pharmacodynamic changes in the elderly: increased responsiveness • Responsiveness of the body changes with age: • 1Increased responsiveness while taking • ACE-inhibitor, CCB (Ca channel blocker), coumarins. • Digoxin and antiarrhythmics: alterations in Na/K-ATPase and Ca2+ channels lead to enhanced toxicity • Opiates: may suppress respiration. • Benzodiazepines: the probability of falls increases. • Antidiabetic agents: impaired glucose counter-regulation predisposes the elderly to hypoglycemia. • Antihypertensive agents: • due to baroreceptor sensitivity: orthostatic hypotension. • due to thirst: exsiccosis. • due osmoreceptor dysfunction : hyponatremia.

22. Pharmacodynamic changes in the elderly: decreased responsiveness • 2Decreased responsiveness while taking • Diuretics. • Beta-blockers: the effect is slower due to an increased level of epinephrine. • Beta-adrenoceptor agonists: lower sensitivity of the myocardium to catecholamines.

23. Main aspects of medication in the elderly • Multimorbidityincreases with age. • The changes mentioned previously have influence on the drugeffects in the body. • Polypragmasy increases the number of side-effects and drug interactions. • Compliance decreases with age. • There is no real Evidence Based Medicine in the elderly, since they are not involved in clinical trials.

24. Main aspects of medication in the elderly: Drug side effects • Medical care of the elderly involves a 2-3 times higher risk for side effects. • Their number is endless. Typical side effects: • lack of appetite • disturbance of gustatory sensation • dryness in the mouth • malabsorption (minerals, vitamins) • iatrogenic incontinence (incontinentiaurinaeseualvi) • impaired cognitive functions • gait disorders, falls

25. Drug side effects in numbers • Regarding patients above the age of 65, iatrogenic medication-associated disorders are responsible for 5-10% of hospitalizations in Western-Europe . • Above the age of 85 every 5th hospitalization is due to side effects of medication. • Simply decreasing the number of drugs may prevent harmful side effects without affecting the quality of life or the life span.

26. Main aspects of medication in the elderly:Drug interactions • In the long run the most dangerous drug combinations are the following: • warfarin + NSAID, or sulphonamides , or macrolides, or quinolones, or phenytoin • ACE inhibitors + K-sparing diuretics, (spironolactone) • digoxin + amiodaron or verapamil • theophyllines + quinolones.

27. Illness-medication problemsto which the elderly are susceptible because of their medical problems Illness Drugadverseeffect Medication Druginteraction

28. “Start low, go slow!” • Start with a small dose, increase the dose carefully. • In case of unexplained deterioration of the patient’s condition, think about drug interaction. • In the elderly, quality of life is at least as important as the therapeutic success.