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

• 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)

Table 7.1. Age-related changes in bodycomposition and function

Weight 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

Table 7.2. Main changes in drug handling inelderly patients

Absorption Passive diffusion unalteredDelayed 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

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

Drug

OxygenatedMetabolite

Excretion

ConjugatedMetabolite

Phase I

Phase II

Phase II

KetoconazoleGestodene

MidazolamNifedipineErythromycinCyclosporine

TolbutamideWarfarinPhenytoin

MephenytoinOmeprazole

CaffeineTheophyllineTacrine

DextrometorphanSparteineDebrisoquine

Coumarin Chlorzoxazone

SUBSTRATES

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

DETERMINANTS OF DRUG METABOLISM

Environmental factorsdrugs, tobacco,alcohol,

occupational exposures,

pollution, diet

Genetic factorsdevelopmental programs

multigene factors

polymorphisms

inborn errors

Host factorstherapeutic 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

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

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

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”

CONCLUSIONSCONCLUSIONS

• 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