DRUG TREATMENT IN THE ELDERLY OLAVI PELKONEN Department of Pharmacology and Toxicology, University of Oulu Seminar, Dept Med Univ Oulu 17.8.2000

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

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

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

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

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

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)

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

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

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

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

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

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?

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

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?)

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

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

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

DEBRISOQUINE Selective for CYP2D6 Elimination not inducible Functional polymorphisms characterised 50+ variant alleles, gene deletions or multiduplications Numerous in vivo drug-drug interactions Long experience since 1960s No data about age-related changes Not in clinical use (obsolete)

Hydroxylation of Debrisoquine

Debrisoquine: correspondence between phenotype and genotype CYP2D6 wt MR 0.1 - 3 in most cases CYP2D6 null alleles MR >12.6 practically invariably CYP2D6 “variant activity” alleles MR 1-10 in most cases CYP2D6 multiplications MR <0.1 in most cases Correspondence fairly good, but residual variability is large (depends on the specific measure)

Interethnic Differences in Polymorphic Drug Metabolism

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

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”

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