DRUG TREATMENT IN THE ELDERLY

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DRUG TREATMENT IN THE ELDERLY
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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

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DRUG TREATMENT IN THE OLD AGE Defining the
problems

• "Extrinsic" problems
• prescribing patterns
• excessive amounts
• inadequate indications
• excessive duration
• inappropriate regimens
• drug compliance

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DRUG TREATMENT IN THE OLD AGE Defining the
problems

• "Intrinsic" problems
• pharmacokinetics
• absorption
• distribution
• metabolism
• excretion
• pharmacodynamics

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DRUG SENSITIVITY IN ELDERLY PATIENTS

• Reduced responsiveness
• adrenergic drugs
• Unchanged responsiveness
• most drugs
• Increased responsiveness
• benzodiazepines
• warfarin

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DRUG SENSITIVITY IN ELDERLY PATIENTS

• Loss of homeostatic reserve
• postural stability
• ortostatic responses
• thermoregulation
• reserve of cognitive functions
• bowel and bladder function

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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)

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RISKS FOR DRUG TOXICITY IN THE ELDERLY

• Disease and illness
• renal failure
• hepatic diseases
• congestive heart failure
• dementia
• dehydration
• prostatic hypertrophy
• ortostatic hypertension
• pain

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RISKS FOR DRUG TOXICITY IN THE ELDERLY

• Psychosocial
• demanding personality
• care-givers
• poverty
• complex medication regimens
• (Beers and Ouslander, Drugs 37 105-112, 1989)

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DRUG METABOLISM
Phase I
Phase II
Drug
Phase II
Oxygenated Metabolite
Conjugated Metabolite
Excretion
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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 lt5
CYP2E1 10
CYP2C19 lt5
CYP2A6 lt5
CYP1A1
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
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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
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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?

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CYP3A4

• most abundant in liver (30) and gut
• metabolises gt50 of all drugs
• substrates midazolam, simvastatin, nifedipine,
  cyclosporine, quinidine,
• numerous interactions (antimycotics)
• inducible by antiepileptics, rifampicin, steroids
• declines considerably during ageing

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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?)

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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
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CYP2D6

• relatively minor in liver (4)
• metabolises gt50 drugs
• substrates midazolam, simvastatin,
• genetic polymorphisms (gt50 variant alleles
  known) poor metabolizer phenotype
• numerous interactions (quinidine)
• very little decline during ageing

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Examples of Drugs Metabolized by CYP2D6

• Captopril
• Debrisoquine
• Desipramine
• Dextrometorphan
• Fluoxetine
• Haloperidol
• Lidocaine

• Metoprolol
• Paroxetine
• Phenformin
• Propranolol
• Sparteine
• Thioridazine
• Timolol

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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

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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

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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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