Download - 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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Table 7.1. Age-related changes in bodycomposition and functionWeight Decreases
Tissues Adipose tissue doubles at expense offunctional tissue
Body water Decreases
Plasma Albumin decreases (10 %) and globulinincreases
Membrane permeability Possibly is increased
Blood flow Cardiac output decreases by 30-40 %Splanchnic and renal flows decrease by>40%
Renal function Age-related deterioration
Hepatic function Certain functions deteriorate
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Table 7.2. Main changes in drug handling inelderly patientsAbsorption Passive diffusion unaltered
Delayed by decreased motility
Bioavailability Increased by reduced first-passmetabolism in liver or gut
Distribution Volume increased or decreaseddepending on lipophilicity of drugPlasma protein binding changed
Metabolism Phase I variably decreasedPhase II relatively unaffected
Renal excretion Rate slowered by decreased glomerularfiltration or tubular secretion
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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
Drug
OxygenatedMetabolite
Excretion
ConjugatedMetabolite
Phase I
Phase II
Phase II
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KetoconazoleGestodene
MidazolamNifedipineErythromycinCyclosporine
TolbutamideWarfarinPhenytoin
MephenytoinOmeprazole
CaffeineTheophyllineTacrine
DextrometorphanSparteineDebrisoquine
Coumarin ChlorzoxazoneSUBSTRATES
INHIBITORSMethoxsalen Fluconazole Sulphaphenazole Furafylline
Fluvoxamine QuinidineTetrahydro- furane DEDTC
INDUCERSPhenobarb. Phenobarb.
RifampicinPhenobarb.Rifampicin
Phenobarb.RifampicinDexamethasoneCarbamazepine
OmeprazoleTobacco smoke
EthanolIsoniazid
CYP2C8/9/18 ~20%
CYP1A2 ~15%CYP2C19
<5%CYP2A6 <5%
CYP2D6 <5%
CYP2E1 ~10%
CYP2B6 CYP1A1CYP3A4/5/7 ~30%
No known
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DETERMINANTS OF DRUG METABOLISM
Environmental factorsdrugs, tobacco,alcohol, occupational exposures,
pollution, diet
Genetic factorsdevelopmental programs
multigene factorspolymorphismsinborn errors
Host factorstherapeutic interventionswork load, lliver disease
other diseaseshormonal 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 >50% 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
vivoSubstance 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 >50 drugs• substrates midazolam, simvastatin, • genetic polymorphisms (>50 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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