Psychopharmakologie

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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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Contents

• Background
• Absorption, Distribution, and Elimination
• Toxicity
• Therapeutic and Steady-State Levels
• Considerations and Recommendations
• Summary
• Suggested Reading

Background

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 body.

Toxicity

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 patients.

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 general.

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 Psychiatric Annals.

Adapted from Tierney & Wise, 1992.

Summary

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 best results.

Suggested Reading:

1. Roose SP. Risks of antidepressants in the elderly: tricyclic antidepressants and arrhythmia-revising risks. Gerontology, 40 Suppl 1: 1994, 15-20.