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DRUG TREATMENT IN THE ELDERLY

DRUG TREATMENT IN THE ELDERLY. THE BASIC PROBLEM. Drug treatment increases (almost exponentially) with age The elderly are presumed to be - because of pharmacodynamic and pharmacokinetic changes with age - more vulnerable to side effects and toxicity of drugs

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DRUG TREATMENT IN THE ELDERLY

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  1. DRUG TREATMENT IN THE ELDERLY

  2. THE BASIC PROBLEM • Drug treatment increases (almost exponentially) with age • The elderly are presumed to be - because of pharmacodynamic and pharmacokinetic changes with age - more vulnerable to side effects and toxicity of drugs • Drug treatment is more risky in the elderly

  3. DRUG TREATMENT IN THE OLD AGE: Defining the problems • "Extrinsic" problems • prescribing patterns • excessive amounts • inadequate indications • excessive duration • inappropriate regimens • drug compliance

  4. DRUG TREATMENT IN THE OLD AGE: Defining the problems • "Intrinsic" problems • pharmacokinetics • absorption • distribution • metabolism • excretion • pharmacodynamics

  5. DRUG SENSITIVITY IN ELDERLY PATIENTS • Reduced responsiveness • adrenergic drugs • Unchanged responsiveness • most drugs • Increased responsiveness • benzodiazepines • warfarin

  6. DRUG SENSITIVITY IN ELDERLY PATIENTS • Loss of homeostatic reserve • postural stability • ortostatic responses • thermoregulation • reserve of cognitive functions • bowel and bladder function

  7. RISKS FOR DRUG TOXICITY IN THE ELDERLY • Ageing • decreased lean mass • increased fat stores • decreased renal function • decreased hepatic function • (Beers and Ouslander, Drugs 37: 105-112, 1989)

  8. RISKS FOR DRUG TOXICITY IN THE ELDERLY • Disease and illness • renal failure • hepatic diseases • congestive heart failure • dementia • dehydration • prostatic hypertrophy • ortostatic hypertension • pain

  9. RISKS FOR DRUG TOXICITY IN THE ELDERLY • Psychosocial • demanding personality • care-givers • poverty • complex medication regimens • (Beers and Ouslander, Drugs 37: 105-112, 1989)

  10. DRUG METABOLISM Phase I Phase II Drug Phase II Oxygenated Metabolite Conjugated Metabolite Excretion

  11. Midazolam Nifedipine Erythromycin Cyclosporine SUBSTRATES Tolbutamide Warfarin Phenytoin Caffeine Theophylline Tacrine Dextrometorphan Sparteine Debrisoquine Mephenytoin Omeprazole Chlorzoxazone • Coumarin CYP3A4/5/7 ~30% CYP1A2 ~15% CYP2C8/9/18 ~20% CYP2D6 <5% CYP2E1 ~10% CYP2C19 <5% CYP1A1 CYP2A6 <5% CYP2B6 INHIBITORS Methoxsalen Fluconazole Sulphaphenazole Furafylline Fluvoxamine Tetrahydro- furane DEDTC Ketoconazole Gestodene Quinidine INDUCERS Phenobarb. Phenobarb. Rifampicin Phenobarb. Rifampicin Phenobarb. Rifampicin Dexamethasone Carbamazepine Omeprazole Tobacco smoke Ethanol Isoniazid No known

  12. DETERMINANTS OF DRUG METABOLISM Environmental factors drugs, tobacco,alcohol, occupational exposures, pollution, diet Genetic factors developmental programs multigene factors polymorphisms inborn errors Host factors therapeutic interventions work load, lliver disease other diseases hormonal milieu INDIVIDUAL PHENOTYPE

  13. DRUG METABOLISM IN THE ELDERLY • How important is age/ageing as a factor causing variability in drug therapy among all the other factors affecting variability? • How could age/ageing be taken into consideration in drug therapy?

  14. CYP3A4 • most abundant in liver (~30%) and gut • metabolises >50% of all drugs • substrates midazolam, simvastatin, nifedipine, cyclosporine, quinidine, • numerous interactions (antimycotics) • inducible by antiepileptics, rifampicin, steroids • declines considerably during ageing

  15. MIDAZOLAM • Elimination completely dependent on metabolism (oxidation) by CYP3A4 • Relatively rapid clearance (half-life ~2-3 hr) • Gut wall CYP3A4 participates in oral clearance • Clearance retarded ~2-fold in the elderly (only in males?)

  16. Effect of inhibitors and inducers on midazolam metabolism in vitro and in vivo Substance Effect AUC change (%) Erythromycin inhibitor 442 Azithromycin inhibitor 87 Fluconazole inhibitor 373 Itraconazole inhibitor 1080 Ketoconazole inhibitor 1590 Rifampicin inducer 4 Neuvonen et al 1993-1998

  17. CYP2D6 • relatively minor in liver (~4%) • metabolises >50 drugs • substrates midazolam, simvastatin, • genetic polymorphisms (>50 variant alleles known): poor metabolizer phenotype • numerous interactions (quinidine) • very little decline during ageing

  18. Captopril Debrisoquine Desipramine Dextrometorphan Fluoxetine Haloperidol Lidocaine Metoprolol Paroxetine Phenformin Propranolol Sparteine Thioridazine Timolol Examples of Drugs Metabolized by CYP2D6

  19. Drug treatment in elderly: beta-blockers • Metoprolol • metabolically cleared (CYP2D6, others) •  large interindividual variation •  age not an important factor • Sotalol • renally cleared •  small interindividual variation •  decrease in renal function

  20. DRUG TREATMENT IN THE ELDERLY • Is it possible to predict dose and regimen in an individual geriatric patient? • - from clinical information? • - from “general knowledge” of age-related pharmacokinetics and -dynamics • - from specific “probes”

  21. CONCLUSIONS • Aging is a factor in pharmacokinetics and pharmacodynamics • Other factors (genetic, environmental, host) may be more important than aging as such • Age-related changes are dependent on specific drugs, individuals and situations; thus generalisations are difficult and uncertain • A scheme for risk management is proposed

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