Psychiatric Annals

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Psychopharmacology Update 

Pharmacokinetic and Pharmacodynamic Considerations in Psychotropic Medication Use in the Elderly: An Overview

Kenneth Sakauye, MD; Gabe J Maletta, MD, PhD

Abstract

The use of psychotropic medication in the elderly requires an understanding of the physiologic differences underlying different pharmaco kinetic profiles in the elderly. Pharmacokinetics involves the characteristics of drug absorption, distribution, biotransformation, and excretion from the body. Alterations in pharmacokinetic profiles with age, thereby requiring much lower doses, explain most of the problems encountered with these drugs. In addition, pharmacodynamic differences occur between young and old in density of receptors, binding affinity, and antagonism by competitive interaction from other medications, although specific age relationships seem less predictable. A growing body of information is now available in these areas.1-4

APPLICATION OF PHARMACOKINETIC DIFFERENCES IN THE ELDERLY

Absorption

Total absorption of psychotropic medications is not greatly affected by age. However, there is often a marked slowing in the rate of absorption because of delays in gastric emptying, slower transit time in the small bowel, decreased gastric acid (which slows absorption of weak acids) , decreased pancreatic enzymes, and a possible decrease in absorptive surface area caused by gastric mucosa! and intestinal villous atrophy with advanced age and chronic disease. With oral administration of medications, the dissolution rate of many medications is slowed and absorption is delayed compared to younger patients. The clinical importance of these changes is a risk of accumulation or unintentional overdosing because medications may be taken too frequently when patients worry thaf the medicine has no effect or because dose changes are made too frequently.5

Distribution

The reservoirs of the body for storing drugs are altered in the elderly. Tissue binding to proteins and phospholipids or physical solution in fat are the main storage sites for medications. By age 65, an overall increase in the ideal weight occurs with a general decrease in total body water mass by 10% to 25%, an increase in fatty tissue by over 20% (generauy even higher in women), and an increase in the proportion of fat to both protein and total body water.fi This increased fat storage physiologic compartment, especially in obesity, increases the time necessary to reach steady state and prolongs the half-life of medications.

Table

PHARMACODYNAMIC DIFFERENCES

Variation in dose response or paradoxical reactions that do not appear related to pharmacokinetic etiologies have been noted with many medications. For example, lithium efficacy has been noted at lower plasma levels in the elderly, or paradoxical reactions are seen with small doses of sedative-hypnotics in many elderly. Table 2 describes pharmacokinetic and pharmacodynamic differences of some common psychotropics.

An increasing number of studies that address the neurobiological basis for such differences suggest compensatory changes occur when there are shifts in some aspects of neurotransrnitter function.10,12 For example, the initial finding of reduced receptor densities of beta adrenergic receptors or serotonin receptors as a possible cause for late-life depression seems to be compensated by increased norepinephrine or serotonin activity.11 Nevertheless, the complex web of changes in neuroreceptor number and activity in the elderly suggest a molecular basis underlying the variable pharmacodynamic responses in many older patients. At the present time, we still lack a means to measure predictors for clinical decisions about specific drug sensitivities. Table 3 lists changes in depression and normal aging.

Prediction of Side Effects

In clinical practice, in vitro receptor affinities have practical vaiue in predicting clinical side effects of psychotropic medications.13 These associations also are of value in predicting the relative safety of new psychotropic medications where little actual clinical experience exists with the elderly. The major complications from psychotropic medications generally involve the anticholinergic spectrum of side effects, both central and peripheral, orthostatic hypotension, and confusion (delirium). Table 4 lists common side effects by neuro transmitter receptor type.…

The use of psychotropic medication in the elderly requires an understanding of the physiologic differences underlying different pharmaco kinetic profiles in the elderly. Pharmacokinetics involves the characteristics of drug absorption, distribution, biotransformation, and excretion from the body. Alterations in pharmacokinetic profiles with age, thereby requiring much lower doses, explain most of the problems encountered with these drugs. In addition, pharmacodynamic differences occur between young and old in density of receptors, binding affinity, and antagonism by competitive interaction from other medications, although specific age relationships seem less predictable. A growing body of information is now available in these areas.1-4

APPLICATION OF PHARMACOKINETIC DIFFERENCES IN THE ELDERLY

Absorption

Total absorption of psychotropic medications is not greatly affected by age. However, there is often a marked slowing in the rate of absorption because of delays in gastric emptying, slower transit time in the small bowel, decreased gastric acid (which slows absorption of weak acids) , decreased pancreatic enzymes, and a possible decrease in absorptive surface area caused by gastric mucosa! and intestinal villous atrophy with advanced age and chronic disease. With oral administration of medications, the dissolution rate of many medications is slowed and absorption is delayed compared to younger patients. The clinical importance of these changes is a risk of accumulation or unintentional overdosing because medications may be taken too frequently when patients worry thaf the medicine has no effect or because dose changes are made too frequently.5

Distribution

The reservoirs of the body for storing drugs are altered in the elderly. Tissue binding to proteins and phospholipids or physical solution in fat are the main storage sites for medications. By age 65, an overall increase in the ideal weight occurs with a general decrease in total body water mass by 10% to 25%, an increase in fatty tissue by over 20% (generauy even higher in women), and an increase in the proportion of fat to both protein and total body water.fi This increased fat storage physiologic compartment, especially in obesity, increases the time necessary to reach steady state and prolongs the half-life of medications.

Table

TABLE 1Factors Affecting Drug Disposition and Response in the Elderly*

TABLE 1

Factors Affecting Drug Disposition and Response in the Elderly*

In circulation, most psychotropic medications are highly bound to albumin, with greater than 90% binding for most benzodiazepines, tricyclic antidepressants, and neuroleptics. Barbiturates have less albumin affinity (eg, barbital is only 5% bound). With aging, there is often a decrease in albumin and variable displacement of binding due to competition from other medications for relatively limited binding sites. For highly bound medications such as dia/epam (99% bound), a 1% displacement of albumin binding leads to a doubling of the free drug blood level.7 Thus, there is a higher bioavailability of psychotropic medications, reflected in the amount of circulating free drug, that occurs at lower daily doses than in younger patients.

Metabolism/Excretion

Drug elimination half-life is often markedly increased in the elderly because of both reduced blood flow to the liver and kidney, and to reduced metabolic functions in general. Because cardiac output decreases 30% to 40% with age, there are corresponding decreases in hepatic and renal blood flow. Hepatic mass decreases with age, and delayed as well as reduced microsomal enzyme activity (eg, oxidation, reauction, and hydrolysis) as well as nonmicrosomal conjugation mechanisms (eg, acetylation, glucuronidation, and methylation) have been noted.

Table

TABLE 2Clinical Examples of Pharmacokinetic and Pharmacodynamic Differences With Some Common Psychotropic Medications

TABLE 2

Clinical Examples of Pharmacokinetic and Pharmacodynamic Differences With Some Common Psychotropic Medications

Table

TABLE 3Changes in Depression and Normal Aging*

TABLE 3

Changes in Depression and Normal Aging*

In hepatic disease, the use of psychotropic medications is more complex than simply knowing which medications are eliminated primarily by the liver versus the kidney. Medications metabolized in the liver can be highly extracted or poorly extracted from blood. The rate of extraction depends on dissociation from protein binding, the type of hepatic metabolism, and a variety of less predictable factors. Highly extracted medications such as short-acting barbiturates are dependent on blood flow as well as hepatocyte function and have expectedly reduced clearance in all hepatic disease. However, the ratelimiting step for poorly extracted drugs is not blood flow. Poorly extracted drugs are generally still acceptable when there is reduced hepatic blood flow if there is still good functioning of remaining hepatocytes, such as in cirrhosis.

Metabolism of different poorly extracted drugs varies with acute or chronic hepatitis and which metabolic pathway is involved in metabolism. For example, benzodiazepines are poorly extracted drugs that can generally be used in cirrhosis, but some are not safe in hepatitis. Lorazepam and oxazepam, which are eliminated through glucuronidation, are generally safe even in chronic hepatitis. Diazepam and chlordiazepoxide, which require microsomal nonconjugative pathways for elimination, cannot be used in acute hepatitis.8

For most drugs, these hepatic extraction profiles and biotransfbrmation effects in disease states are poorly established, and peripheral biochemical indices of hepatobiliary function do not predict extraction ratios or microsomal enzyme activity. Also, determination of differences by age in the half-life of medications is rarely done empirically even in healthy elderly. Thus, safety demands that one conservatively estimates a prolonged half-life for all medications in the elderly and takes special caution in individuals with cardiac, hepatic, or renal disease (Table 1).

Table

TABLE 4Side Effects of Psychotropic Medications by Neurotransmitter Receptor Type*

TABLE 4

Side Effects of Psychotropic Medications by Neurotransmitter Receptor Type*

PHARMACODYNAMIC DIFFERENCES

Variation in dose response or paradoxical reactions that do not appear related to pharmacokinetic etiologies have been noted with many medications. For example, lithium efficacy has been noted at lower plasma levels in the elderly, or paradoxical reactions are seen with small doses of sedative-hypnotics in many elderly. Table 2 describes pharmacokinetic and pharmacodynamic differences of some common psychotropics.

An increasing number of studies that address the neurobiological basis for such differences suggest compensatory changes occur when there are shifts in some aspects of neurotransrnitter function.10,12 For example, the initial finding of reduced receptor densities of beta adrenergic receptors or serotonin receptors as a possible cause for late-life depression seems to be compensated by increased norepinephrine or serotonin activity.11 Nevertheless, the complex web of changes in neuroreceptor number and activity in the elderly suggest a molecular basis underlying the variable pharmacodynamic responses in many older patients. At the present time, we still lack a means to measure predictors for clinical decisions about specific drug sensitivities. Table 3 lists changes in depression and normal aging.

Prediction of Side Effects

In clinical practice, in vitro receptor affinities have practical vaiue in predicting clinical side effects of psychotropic medications.13 These associations also are of value in predicting the relative safety of new psychotropic medications where little actual clinical experience exists with the elderly. The major complications from psychotropic medications generally involve the anticholinergic spectrum of side effects, both central and peripheral, orthostatic hypotension, and confusion (delirium). Table 4 lists common side effects by neuro transmitter receptor type.

GENERAL GUIDELINES

Baseline Tests

Baseline studies are required in the elderly for cardiac, renal, hepatic, and hematologie status before initiating treatment with any psychotropic medication. Screening for balance disturbance, abnormal movements and preexisting orthostatic hypotension, as well as obtaining a complete list of both prescription and over-the-counter medications the patient is taking also are essential.

General Recommendations

It is important to start at a lower dosage in the elderly and delay frequency of dose increases. Accumulation effects from medications as well as prolonged side effects are more likely. It is especially important not to start medication for "diagnostic confirmation." Instead, clear clinical indicators, ie, target signs and symptoms, should be present for psychotropic medication use. This will minimize the likelihood of overprescribing and creating iatrogenic problems from side effects. The use of seemingly homeopathic low doses of a medication as a placebo should generally be avoided.

In situations where patients have difficulty communicating, such as advanced Alzheimer's disease or other dementias, direct assessments of benefit or detriment are especially important before dose increases are made. Often decisions òr dose changes are based on colateral information. This can be miseading as family members' perceptions of the emotional state of a demented relative are often more closely associated with their own mood than with direct evaluation of the patient.14

Generally, a medication should je initiated at one third to one half the usual starting dose used for Ounger adults, and necessary increases should be made by small ncrements following a reasonable period after achieving steady state, which is usually bimonthly. Medications with a long biological half-life OT with long-acting active metaDolites, such as diazepam (Valium), chlordiazepoxide (Librium), flurazepam (Dalmane), imipramine (Tofranil), amitriptyline (Elavil), or chlorpromazine (Thorazine), should be avoided. Although such medications may be spaced at long dose intervals, control of the medications is more difficult to achieve, and negative side effects tend to persist for excessively long periods while the medication is slowly cleared from the body.

Despite the limited value of blood levels in determining efficacy for most psychotropic medications, they can be of value in determining the cause for poor response or excessive side effects caused by accumulation effects, nonoral/ gastrointestinal absorption, or poor compliance. Blood levels may be of special importance in patients with chronic disease, poor nutritional status, or with multiple medication regimens where competitive binding displacement or mild drug-drug interactions may be difficult to determine.

REFERENCES

1. Bowden CL, Giffen MB. Psyckopharmacology for Primary Care Physiciatis. 2nd ed. Baltimore, Md: Williams & Wilkins; 1987.

2. Jenike MA. Geriatric Psychiatty and Psychophartrutcology: A Clinical Approach, Boca Raion, Fla: CRC Press; 1989.

3. Thompson TL, Moran MG, Ntew AS. Psychotropic drug use in the elderly, part I. N Engl J Med. 1983; 308:134-138.

4. Thompson TL, Moran MC, Niew AS. Psycholropic drug use in the elderly, part II. N Engl J Med. 1983: 308:194-199.

5. Hicks R, Dysken MW, Davis JM, Lesser J, Ripeckyi A, Lazarus L. The pharmacokinetics of psychotropic medication in the elderly: a review. J Clin Psychiatry. 1981; 42:374-386.

6. Andres R. Mortality and obesity: the rationale for age-specific height-weight tables. In: Andres R, Eierman EL, Hazzard WR, eds. Piindples of Geriatric Medicine. New York, NY: McGraw-Hill Book Co; 1985:311-318.

7. Curry SH. Drug Disposition and Pharmacokinetics with a Consideration of Pharmaeological and Cliniral Relationships. 3rd ed. Oxford, England: Blackwell Scientific Publications; 1980.

8. Williams RL. Drug administration in hepatic disease. N Engl J Mea. 1983; 309:1616-1622.

9. Juan D. Drug therapy in the elderly. Presented at Geriatrics: Board Review, Cook County Graduate School of Medicine; March 1988; Chicago, Illinois.

10. Meltzer HY ed. Psychopharmacology; The Third Generation of Progress. New York, NY: Raven Press; 1987.

11. Morley JE. Neuropeptides, behavior, and aging. J Am Geriatr Soc. 1986; 34:52-62.

12. Fitten LF, Morley JE, Gross PL, Petry SD, Cole KD. Depression: UCLA grand geriatric rounds, J Am Geriair Sue. 1989; 37:459-472.

13. Richelson E. Pharmacology of neuroleptics in use in the United States. J Clin Psychiatry 1985:46 (8-Section 2):8-14.

14. Light E, Lebowitz BD, eds. Akheimer's Disease Treatment and Family Stress: Directions for Research. Rockville, Md: US Dept of Health and Human Services; 1989.

TABLE 1

Factors Affecting Drug Disposition and Response in the Elderly*

TABLE 2

Clinical Examples of Pharmacokinetic and Pharmacodynamic Differences With Some Common Psychotropic Medications

TABLE 3

Changes in Depression and Normal Aging*

TABLE 4

Side Effects of Psychotropic Medications by Neurotransmitter Receptor Type*

10.3928/0048-5713-19910101-12

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