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

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: , 1989)

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

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

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

13. 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

14. 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

15. 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?

16. 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

17. 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?)

18. Effect of inhibitors and inducers on midazolam metabolism in vitro and in vivo
Substance Effect AUC change (%)
Erythromycin inhibitor
Azithromycin inhibitor
Fluconazole inhibitor
Itraconazole inhibitor
Ketoconazole inhibitor
Rifampicin inducer
Neuvonen et al

19. 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

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

21. 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)

22. Hydroxylation of Debrisoquine

23. Debrisoquine: correspondence between phenotype and genotype
CYP2D6 wt
MR 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)

24. Interethnic Differences in Polymorphic Drug Metabolism

25. 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

26. 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”

27. 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