Pharmacokinetic Changes in the

Elderly

And Implications for Drug Therapy

 Objectives
Understand physiologic changes of the elderly.
Understand how common physiologic changes may
affect the pharmacokinetics and pharmacodynamics of
drugs.
Understand the clinical significance of these
pharmacokinetic changes and offer suggestions for
dosing and monitoring drug therapy, in particular
– common drug interactions
– renally-excreted drugs
 Outline
The statistics
Physiologic changes of aging
Pharmacokinetics vs. Pharmacodynamics
Concepts of Absorption, Distribution, Metabolism
and Excretion of drugs which change with age
 The Statistics
Elderly (>65) comprise 12% of the population
• consume 33% of all prescriptions
• occupy 50% acute-care hospital beds
Elderly (>85) comprised the fastest growing segment of
US population during the 1990s.
Drug use in elderly nursing home patients is high
• Average number of medications per patient = 8.1
• 65% are prescribed at least one psychoactive medication.
• Survey: 40% of 1106 nursing home residents received at least one,
and 10% received two inappropriate medications.*
*Ann Intern Med 1992; 117: 684-9
 Physiologic changes of aging
Many body systems are affected by the aging process
• Visual impairment in 12%, hearing impairment in 28% of elderly.
• Respiratory: Vital capacity and FEV decline linearly with age
• GI: dysfunction in GI motility due to pathology vs. age. Constipation
due to diet, physical inactivity, drugs
• GU: up to 48% nursing home residents are incontinent, due to
detrusor instability, overflow incontinence, sphincter weakness
– also sexual dysfunction, BPH may occur
• Musculoskeletal: 30% loss of muscle tissue from age 30-80.
Osteoarthritis secondary to lifetime stresses of joint use.
• Peripheral Vascular System: Atherosclerosis and decreased
elasticity of vessel walls, major contributors to hypertension.
 Physiologic changes of aging
Psychiatric conditions
• Depression is the most frequent psychiatric disturbance.
– life stresses: family changes, loss of bodily functions, illnesses, change
in living quarters
– increased central MAO activity and decreased NE activity
• sleep disorders
• dementia in 10% of elderly, up to 22% in elderly >80.
– structural and functional brain changes (Alzheimer’s disease)
– multiinfarct dementia secondary to hypertension/stroke
– secondary to other disease state (Parkinson’s disease)
• delerium is experienced by 25-30% hospitalized elderly
– secondary to aging processes, brain damage, disease, sensory
impairment, drugs, infection
 Problems of Geriatric Px in Drug
Treatment:
Decreased renal, hepatic clearances  some drugs increased the risk of
ADRs
Alteration of organ response and haemostasis  unpredictable drug
concentrations achieved of a given dose
Frequently experiences multiple illness and many drugs concurrently
(OTC + many prescribed drugs)
Use of multiple drugs  ADRs ; Drug-interactions; morbidity
 may precipitate hospitalisation
disability in neurological; visual; auditory functions  leads to difficulty in
complying with complicated drug regimens
common ADRs: -confusion; -falls; postural hypotension; -ataxia; urinary
retention; constipation
 Pharmacokinetics
Defined: all aspects of drug distribution in the body after
administration, ie. “what the body does to the drug”:
• Absorption from administration site
• Distribution into body compartments
• Metabolism to active and inactive metabolites
• Elimination of parent drug and metabolites
Influences: concentration at site, response, toxicity
• Influences: Pharmacodynamics: “what the drug does to the body”
Changes in pharmacokinetics due strictly to aging
usually not well defined.
 Absorption
Gastrointestinal tract most common absorption site.
– Decrease in number of gastric and parietal cells lining GI
tract.
– Decrease secretions, e.g. saliva, gastric
– Results in increase gastric pH, achlorhydria or hypochlorhydria
– Decreased gastric motility and sphincter activity
– Delayed gastric emptying
– Mesenteric blood flow may decrease by up to 40-50%,
atrophy of micro- and macrovilli of mucosa
– Active transport system may be impaired
– Decreased hepatic blood flow, less first-pass removal
 Clinical Significance?
Normal doses of acid labile agents may elicit a greater
response
– Levodopa, erythromycins, penicillins
– Some drugs require acid for solubility (calcium salts)
Impaired absorption of drugs requiring active transport
– calcium, iron, thiamine, folic acid, B12
Drug absorption usually passive, saturable diffusion
process
If gastric emptying delayed, rate, but not extent of
absorption may be decreased.
 Clinical Significance?
Increased effect of high first pass effect drugs
– propranolol, morphine
More important are drug interactions that may affect
drug absorption in the elderly.
– Antacids: interfere with absorption of oral antibiotics, digoxin,
phenytoin.
– Laxatives and anti-motility agents: may affect the rate and/or
extent of absorption of other agents
– Antidepressant drugs that have anticholinergic effects affect
bowel motility and therefore absorption of drugs
 Drug Distribution
Volume of distribution of drugs in the elderly will be
affected by changes in
– blood flow
– plasma protein binding
• decrease in serum albumin
• increase in alpha-1-acid glycoprotein
– body composition
• decrease in total body water by 10-20%
• decrease in lean body mass by 25-30%
• increase in body fat
– males increase 84%, females increase 48%
 Clinical Significance?
Water soluble drugs will have a smaller VD and thus
greater serum levels.
• aminoglycosides, ethanol, morphine
Lipid soluble drugs will have a greater VD and thus
lower serum levels.
• Diazepam, thiopental, most psychotropics except lithium, oxazepam,
lorazepam
Changes in VD will affect amount of drug needed for a
loading dose, or time needed to achieve steady state.
• Large VD = longer time to steady state and higher loading dose
needed.
• Must be cautious with CNS drugs, e.g. benzodiazepines, and
sensitivity in elderly
 Clinical Significance?
Decline in albumin levels due to decrease in synthesis,
increase catabolism, undernutrition, uremia.
– decrease in albumin binding sites = greater free fraction
– Albumin binds acidic drugs
• naprosyn, phenytoin, warfarin, meperidine may exhibit greater effect
Increase in acute phase protein, alpha-1-acid
glycoprotein, due to stress, inflammation.
– Increase in binding = less free fraction
– Less free fraction of basic drugs; clinical effect unlikely
• lidocaine, propranolol, quinidine, imipramine
 Metabolism
Rate of metabolism of drugs is influenced by nutrition,
drugs, diseases, smoking, serum albumin, hepatic
function and age
• 1% annual reduction in hepatic blood flow after 25
• 1% annual decrease in liver mass
Phase I metabolism (hydrolysis, oxidation, reduction),
primarily oxidation, declines with age.
• Thought due to decrease liver mass, not enzymatic activity
Phase II metabolism (conjugation) is relative unaffected
by age.
 Clinical Significance?
Since blood flow is decreased, drugs with high
“extraction ratio” will be affected.
• High extraction ratio drugs are efficiently removed by the liver (high
“first pass effect”) and removal is affected by blood flow.
• Imipramine, lidocaine, morphine, propranolol will experience a
decreased clearance and increased half-life.
Drugs metabolized by oxidation will be affected.
• Piroxicam, theophylline, quinidine, diazepam, many SSRIs will
experience a decreased clearance and increased half-life
– Bupropion, nefazodone, mirtazepine start at 25-50% lower dose
Drugs metabolized by conjugation or glucuronidation
will not be significantly affected.
• APAP (conjugation), lorazepam, oxazepam (glucuronidation)
 Clinical Significance?
Drug interactions which affect all age groups are
prevalent in the elderly because of poly-pharmacy.
Common drugs known to influence metabolism of other
drugs:
• cimetidine and erythromycin are enzyme inhibitors and will increase
serum blood levels of warfarin, theophylline, phenytoin, and
carbamazepime.
• rifampin induces liver enzymes which may decrease serum
concentrations of verapamil, digoxin, and warfarin.
• amiodarone may increase levels of digoxin, warfarin, and phenytoin.
 Elimination
Renal function may decline by 40-50% with age
– Kidney mass decreases by 10-20% by age 80.
– GFR decreases by 1ml/min/year from age 20-90.
• decreased cortical perfusion rate and filtration pressure, atrophy,
vascular lesions of small arteries, loss of glomeruli.
– Renal plasma flow decreases by 1-2% per year from age 20-
90.
Decrease in renal blood flow exceeds the decrease in
cardiac output.
• compounded by various disease states, eg. CHF, hypotension.
Tubular function decreases in proportion to GFR.
 Clinical Significance?
SCr often remains stable, but CrCl measurements must
consider decrease in lean body mass.
• CrCl (ml/min) = (140-age)(IBW/72 x SCr) F=CrCl(.85)
• 24 hour urine collection will be more accurate
Drugs which are excreted unchanged by the kidney
may accumulate even in “normal” dosing and should be
carefully monitored.
• Aminoglycosides, digoxin, lithium (low TI), gabapentin
Decreased tubular function is important for drugs which
are eliminated by tubular secretion
• penicillin, cimetidine, lithium
 Clinical Significance?
Aminoglycoside dosing
– Use Ideal Body Weight to estimate lean mass
• IBW(male) = (height in inches-60) x 2.3 +50 kg
• IBW(female) =(height in inches-60) x 2.3 + 45 kg
– Adjust upward for increase extracellular fluid volume
– Adjust downward for decreased extracellular fluid volume
– Monitor for ototoxicity, nephrotoxicity
– Monitor drug levels with conventional and once-daily
regimens
– Consult your clinical pharmacist for recommendations
 Clinical Significance?
Coadministration of loop diuretics will contract
extracellular fluid volume and may cause prerenal
azotemia
• serum levels of drugs which distribute to body water
(aminoglycosides) will increase
Drugs with active metabolites which are excreted
renally may accumulate if not dosed properly
• meperidine (nor-meperidine--siezure potential),
• procainamide (N-acetyl procainamide)
• propoxyphene (nor-propoxyphene)
• carbamazepine (epoxide form)
 Important points
Acid production is decreased in elderly, but most
alterations in GI absorption are due to drug interactions
and effects on GI motility. The rate, not the extent of
absorption is usually decreased.
Distribution volume of lipid soluble drugs will increase
and that of water soluble drugs will decrease, due to
changes in body composition.
Decreases in albumin binding will result in a greater
free-fraction for high protein-bound drugs. Monitor free-
fraction if possible.
 Important points
Oxidation is the metabolic pathway most affected by
aging. Also, drugs with a high extraction ratio will be
cleared from the circulation slower due to decrease in
hepatic blood flow.
Decrease in lean body mass must be considered when
calculating creatinine clearance. Use IBW.
Also consider active metabolites, and co-administration
of drugs which may affect total body water when dosing
renally eliminated drugs.
Factors affecting drug dispositions:

Factors affecting drug disposition in the geriatric patients

Pharmacokine Age-related physiological Pathological conditions Therapeutics and
tics variable changes environmental
affected factors
Absorption Increased gastric pH Achlorhydria Drug interaction (e.g.
Decreased absorptive surface Diarrhoea antacids,
Decreased splanchnic blood flow Postgastrectomy anticholinergics,
Decreased gastrointestinal motility Malabsorption syndromes cholestyramine)
Pancreatitis Food/meals
Distribution Decreased cardiac output Congestive heart failure
Decreased total body water Dehydration
Decreased lean body mass Oedema or ascites
Decreased serum albumin Hepatic failure
concentration Malnutrition
Increased 1-acid glycoprotein Renal failure
concentration
Increased proportion of body fat
Metabolism Decreased hepatic mass Congestive heart failure Dietary composition
Decreased hepatic blood flow Fever Drug interactions
Hepatic insufficiency Insecticides
Malignancy Tobacco (smoking)
Malnutrition
Thyroid disease
Viral infection or
immunisation
Excretion Decreased renal blood flow Hypovolemia Drug interactions
Decreased glomerular filtration rate Renal failure
Decreased tubular secretion
Factors contributing to ADRs:

Impaired organ
function

Altered drug Altered organ Decreased homeostatic

concentrations response regulation

Adverse drug
reaction

Multiple disease Multiple drug Altered

states administration compliance

Factors contributing to adverse drug reactions in elderly patients.

 Decreased organ reserve/ adaptation

• Heart  adaptation

• Lungs  compliance

• Kidneys  renal reserve

• Nervous system  cognitive function

• Bone  bone mass

 Pharmacotherapy elderly
differences in
 Pharmacokinetics

Pharmacodynamics

Clinical application
 Comorbidity
 Polypharmacy
 Compliance
 Polypharmacy in the elderly in GP
practice
Mostly in patients between 75 and 84 years old
Polypharmacy is found in 35% of elderly in
general practice
indication psycholeptic drugs quite often not
clear
CHF, astma/COPD and DM were mainly
responsible for major polypharmacy

Veehof/Haaijer -Ruskamp
 Problems in achieving drug
compliance in the elderly
visual impairment
inability to discriminate between coloured tablets
motoric impairment
impaired memory
financial problems
Basic principles of good prescribing practice
in elderly people

• Think again before starting treatment

• Consider altered pharmacokinetics
• Monitor plasma levels if indicated
• Start low, go slow
• Titrate on the basis of PD response
• Pay attention to co-morbidity
• Look for drug interactions
• Prescribe a friendly formulation
• Check compliance
• Always look for adverse drug effects
 Case study
Which of the following medication(s) require dose adjustments in
older patients?
– A. amantadine
– B. paroxetine
– C. heparin
– D. nortriptyline
– E. piroxicam
 Answer
A. amantadine
Amantadine dose should be reduced to compensate for slowed renal
clearance
B. paroxetine
Paroxetine is an SSRI which is primarily eliminated by oxidative metabolism
via cytochrome P450 enzymes, decreased in the elderly. The recommended
starting dose is 10mg.
D. nortriptyline
The dose of nortriptyline should be reduced because of slowed hepatic
metabolism (ie, decreased first pass effect).
Piroxicam and heparin do not need to be dose adjusted in older patients,
although NSAIDS should be avoided if renal function is compromised.
Questions?
Thank
You