Contents | CME Post-Test &
Online Coverage from the 9th Annual
U.S Psychiatric & Mental Health Congress
© 1996 Medscape, Inc.
Practical Issues in Geriatric Psychopharmacology
Speaker: John Tierney, M.D.
Reporter: Joseph F. Goldberg, M.D.
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Epidemiological studies predict that by the year 2030, nearly 20% of the
population will be over age 65. Psychotropic medications are, by some estimates,
the most frequently prescribed of all medications in this age group. For these
reasons, according to John Tierney, M.D., a fundamental grasp of geriatric
psychopharmacology is essential for psychiatrists as they treat an ever-growing
segment of society. Dr. Tierney, a geriatric and consultation-liaison
psychiatrist in private practice in Atlanta, GA, reviewed a number of basic
pharmacological principles as they relate to older patient populations, and
outlined key points regarding some of the most commonly used psychotropic
medications in the elderly.
The basic pharmacological mechanisms involved in drug dynamics --absorption,
distribution, hepatic metabolism, protein binding, and renal clearance -- all
diminish with advancing age (Table). Thus, for most medications, the amount of
drug that is actively available is often significantly less in older than
younger patients; the time required to reach a steady-state concentration is 2-3
times longer; and the rate at which a medication is eliminated from the body is
often markedly prolonged. Other factors, such as underlying medical illnesses,
erratic medication compliance, or drug-drug interactions, further contribute to
the unique problems that may arise in the proper dosing and use of psychotropic
medications in the elderly.
Absorption, Distribution, and Elimination
While the various components of digestion generally become less efficient
with aging, these changes do not generally affect absorption of psychotropic
drugs. However, drug absorption may be slower in patients who take
anti-cholinergic medications or antacids.
Certain physiological changes contribute to accumulation of medication in
the elderly. Because the ratio of body fat to lean muscle mass increases as
people age, most lipophilic medicines will accumulate over time. This factor is
compounded by a slower rate of drug elimination or clearance from the kidneys.
Additionally, medication levels can build up because the liver's ability to
metabolize most drugs also decreases with age -- by up to 40%.
Thus, in the elderly, it may take far longer to achieve a therapeutic level
of a medication. After therapeutic levels are achieved many drugs are likely to
accumulate, and then take weeks or even months before they completely leave the
Dr. Tierney cautions psychiatrists to beware of the potential for build-up of
cardiotoxic hydroxy metabolites from tricyclic antidepressants, a finding
described by Drs. Steven Roose and Alexander Glassman from Columbia University.
The amount of an "active" drug that circulates in the body is often higher and
stays in the body longer in the elderly. This is because the portion of most
medications that is biologically active is the amount not bound to proteins
(albumin, and less critically, alpha-1 glycoprotein). and the body synthesizes
less of these proteins with aging.
An important corollary to this relates to measuring drug levels in the
blood. Most medication blood levels reflect a combination of both the bound
(inactive) and unbound (active) amounts of a drug. When there is less protein
binding there, a greater amount of unbound drug is required before "normal"
therapeutic levels are achieved. Elderly patients can, therefore, experience
toxicity when blood levels are in the therapeutic range because of this greater
level of unbound drug.
In addition to considering the risk for higher unbound drug levels due to
slower hepatic metabolism and protein synthesis, Dr. Tierney points out that by
age 70, renal functioning (glomerular filtration rate and creatinine clearance)
can diminish by half. Checking a patient's routine creatinine level is often
less accurate than obtaining a 24-hour creatinine clearance. Thus, for example,
a dose of diazepam may be eliminated in 20 hours for young adults but take up to
90 hours in the elderly. When combined with the build-up of its lipophilic
metabolites, its eventual elimination may take weeks. Similarly, lithium
clearance is slowed by 20% to 30% because of changes in renal function, with a
resultant increased risk for lithium toxicity in the elderly.
Therapeutic and Steady-State Levels
Given the normal half-life of a drug, the build-up of drug metabolites,
increased fat storage, amount of active (unbound) drug, and slowed elimination,
one can appreciate how steady-state blood levels can take weeks or months to
achieve (e.g., it may take 3 to 6 months to achieve a steady-state blood level
for fluoxetine). Variation between or within individual patients creates a
potential for even more uncertainty, making algorithmic dosing dangerous and
untenable. Beyond the normal effects of aging, consider the case of an elderly
patient with liver disease (slowed metabolism), with or without kidney disease
(slowed excretion), with or without heart disease (slowed perfusion and cardiac
output); superimpose the effects of other medications, nutritional status, and
psychiatric or other illness. Clearly, appropriate psychopharmacotherapy must
always be individualized and closely supervised by the clinician.
Considerations and Recommendations
Dr. Tierney reviewed these considerations for a number of major classes of
psychotropic medications. In general, dosing should be started low and titrated
upward slowly. All tricyclics carry increased risk for anti-cholinergic effects
as well as other morbidity and mortality, although the secondary amines
(nortriptyline and desipramine) may be the best tolerated. Among other
antidepressants, sertraline and paroxetene may carry some pharmacokinetic
advantage over others; bupropion may be helpful for depression with
cognitive/attentional impairment, but dosages should be lower (under 200 mg
daily) if combined with an SSRI. Nefazodone carries some risk for orthostatic
hypotension, but may be advantageous for insomnia, and should be dosed from 200
mg to 400 mg daily, beginning at 50 mg daily. Venlafaxine, though not yet
studied in the elderly, may offer promise because it has little protein binding
and a relatively short half-life.
Useful medications for insomnia in the elderly include trazodone,
short-acting benzodiazepines (e.g., temazepam, lorazepam or oxazepam) and
chloral hydrate, while anti-cholinergic drugs (e.g., diphenhydramine or
hydroxyzine) should be avoided. Benzodiazepines are commonly used in the elderly
for anxiety or sleep, although they carry a risk for ataxia, falls, sedation,
and cognitive impairment; shorter-acting agents help minimize these problems.
Buspirone also appears well-tolerated and helpful for anxiety in a number of
Neuroleptics, according to Dr. Tierney, are best reserved for extreme
agitation, psychosis, or delirium. Higher potency medications (e.g.,
haloperidol) at low doses (e.g., 0.25-2 mg daily) are often the most effective,
although the newer atypical antipsychotics (risperidone, olanzepine) at low
doses may also prove beneficial for the elderly.
Mood stabilizers (lithium, valproic acid and carbamazepine) remain mainstays
of treatment for bipolar disorder or as agents to augment antidepressants.
Lithium levels as low as 0.4 mEq/L may be adequate for some elderly patients,
and clinicians must be cautious of a high sensitivity to these medications in
Unpredictable adverse drug events typically arise within 2 to 5 days of
exposure to most psychotropic medications, while predictable adverse effects are
less often life-threatening and usually extensions of known side effects.
Finally, extensive information is now available on drug-drug interactions
based on knowledge of the cytochrome P450 microenzyme system. This is reviewed
in detail in a recent article by Larry Ereshefsky, Pharm.D., in
Table I: Pharmacokinetic Changes in Aging
||Decreased gastric acidity
Decreased GI surface area
|In absence of gastric pathology or drug-drug interaction, absorption
of phychotropic drugs is not significantly altered.
||Increased volume of distribution of lipophilic drugs
||Prolonged elimination half-life of psychotropic drugs (except
||Decreased hepatic flow
-- decreased first pass
Decreased hepatic enzyme activity
|Increased circulating unmetabolized and partially metabolized
Prolonged time required for psychotropic drug
Prolonged exposure to unmetabolized drug.
Increased (?) alpha-1 glycoprotein
|Increase in active drug (unclear effects). Unclear effect on
||Decreased Renal blood flow
||Decreased lithium clearance and increased risk of toxicity.
||Decreased antidepressant hydroxyl metabolite clearance. Increased
|Decreased tubular excretory capacity
||Decreased benzodiazepine clearance. Prolonged elimination half-life.
Adapted from Tierney & Wise, 1992.
In summary, clinicians must consider multiple changes in the absorption,
distribution, metabolism, and elimination of psychotropic drugs among older
patients. Lower starting doses (often one-quarter to one-half the usual adult
dose) is advisable, with slow dosing adjustments (no sooner than every 5 to 7
days) as needed. The time required to see steady-state therapeutic levels, or
for elimination of most medications, are substantially longer in the elderly.
One must consider the potential for drug-drug interactions, as well as
anti-cholinergic or other side effects, when prescribing a regimen. Changes
should be made slowly, changing only one variable at a time, in order to achieve
- Roose SP. Risks of antidepressants in the elderly: tricyclic
antidepressants and arrhythmia-revising risks. Gerontology, 40 Suppl 1:
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