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| Pharmacokinetic
and Pharmacodynamic Differences in the Elderly |
Charles H. McLeskey, M.D.
Senior Director, Clinical Development
Abbott Laboratories - Hospital Products Division
Department 96R, Building AP30
200 Abbott Park Rd
Abbott Park, IL 60064
mclesch@hpd.abbott.com
Pharmacokinetic and Pharmacodynamic Differences
in the Elderly
Pharmacokinetic variables determine the relationship between
the dose of a drug administered and the concentration delivered
to the site of action. Pharmacodynamic variables determine the
relationship between the concentration of the drug at the site
of action and the intensity of the effect produced. Physiologic
changes occur during aging that impact on the pharmacokinetic
and pharmacodynamic responses of elderly patients to administered
drugs. For example, changes occur in plasma protein binding, the
percentage of body content that is lipid or lean, the efficiency
of metabolism and elimination of drugs and in the elderly patient's
sensitivity to administered drugs, an effect due to pharmacodynamic
changes. Each of these physiologic changes will be discussed.
Figure 1. Hypothetical response of young and
elderly subjects to a bolus administration of a drug.
The figure illustrates higher blood levels in the elderly, initially
due to a smaller volume of distribution, and later due to a slower
drug metabolism. Furthermore, in this example, the brain is more
sensitive to the drug in the elderly. All these effects conspire
to increase the length of time that the drug is active in the
elderly patient.
Protein Binding
All anesthetic agents are to some extent protein-bound to plasma
proteins. The portion of the drug that is bound to protein is
unable to cross membranes to produce the desired drug effect.
On the other hand, the portion that remains free in plasma is
able to cross membranes, including the blood brain barrier, and
is responsible for drug effect. In the elderly, protein binding
of anesthetic drugs is less efficient resulting in an exaggerated
pharmacologic effect.
Four factors may explain the reduced drug-binding to serum protein
in elderly individuals. First, with aging, the circulating level
of serum protein, especially albumin, decreases in quantity, reducing
available protein-binding sites for a variety of anesthetic drugs.
Second, qualitative changes may occur in circulating protein that
reduces the binding effectiveness of the available protein. Third,
co-administered drugs may interfere with the ability of anesthetic
agents to bind to available serum protein binding sites. Fourth,
certain disease states exaggerate this phenomenon. Thus, anesthetic
agents that are highly protein bound should be delivered to an
elderly individual with the expectation that reduced protein binding
will lead to higher free drug levels and an enhanced delivery
of the drug to the brain. Figure 1 illustrates
the effect of decreased plasma protein binding as a smaller difference
between brain and plasma drug levels in the elderly than in young
adults.
Change in Body Compartments
Important age-related changes in body composition include a loss
of skeletal muscle (lean body mass) and an increase in percentage
of body fat. These changes are more exaggerated in women. In addition,
it has been suggested that a 20-30 percent reduction in blood
volume occurs by age 75. Therefore, injection of anesthetic drugs
will initially be dispersed in a contracted blood volume in the
elderly patient producing a higher than expected initial plasma
drug concentration. (See Fig. 1)
The increase in percentage of body fat that occurs with age results
in an increased availability of lipid storage sites and a greater
reservoir for deposition of lipid-soluble anesthetic drugs. The
greater sequestration of anesthetic agents in the lipid storage
tissues of the elderly allows for a more gradual and protracted
elution of anesthetic agents from these storage sites, increasing
the time period required for their elimination and resulting in
greater residual plasma concentrations of drugs that contribute
to prolonged anesthetic effects.
Hepatic and Renal Function
Hepatic and renal function are reduced about one percent per
year beyond age 30. The age-related reduction in renal blood flow
is accompanied by a gradual loss of functioning glomeruli. The
combination of these changes produces a predictable decline in
glomerular filtration rate that in old age is only 60 percent
of that found in younger individuals. These renal changes result
in a reduced ability of an elderly patient to excrete administered
drugs and their metabolites. The combination of reduced hepatic
and renal elimination and more protracted elution of drug from
lipid stores contribute to the more gradual fall in plasma-drug
concentration in the elderly depicted in Figure
1, and reflected in the table below as an age-related change
in the beta elimination half-life of many of our administered
anesthetic agents.
|
T 1/2 b ö Elimination Half-life
|
| Drug |
Young Adults |
Old Adults |
| Fentanyl |
250 min |
925 min |
| Alfentanil |
90 min |
130 min |
| Diazepam |
24 hrs |
72 hrs |
| Midazolam |
2.8 hrs |
4.3 hrs |
| Vecuronium |
16 min |
45 min |
| (Return of twitch height from 25 percent to
75 percent of control) |
Central Nervous System (CNS)
Classically, it has been thought that the physiologic function
of most organs, including the central nervous system, undergoes
a gradual decline during the aging process. There is a continual
loss of neuronal substance with advancing age. On average, a daily
attrition of perhaps as many as 50,000 neurons from an initial
neuron pool of approximately 10 billion occurs during the life
span of an individual. The reduction in neuronal density that
occurs with age is accompanied by a parallel reduction in cerebral
blood flow and cerebral oxygen consumption (CMRO2).1
Regional cerebral blood flow remains as tightly coupled to cerebral
metabolic activity in the healthy elderly individual as it does
in young adults. The absence of a quantitative relationship between
age-related brain atrophy (accompanied by reduced cerebral blood
flow) and general level of mental function, however, suggests
that at the time of maximum brain weight there is considerable
redundancy of neuronal function within each cortical, subcortical
and spinal region. Although an obligatory age-induced decline
in cerebral cognitive function remains controversial, it is generally
agreed that geriatric patients have a reduced requirement for
anesthetic agents. This may not be distinguishable in any given
patient but is observed in cross-sectional studies comparing elderly
to younger individuals and is believed to be due, at least in
part, to a reduction in pre-existent CNS activity.
A classic example of age-related reduced anesthetic requirement
is the reduced minimum alveolar concentration (MAC) necessary
in elderly patients to produce anesthesia with either cyclopropane,
halothane, isoflurane or desflurane.2
The requirement for these inhalational agents decreases linearly
with patient age. The reduced anesthetic requirement for geriatric
patients applies not only to inhalational anesthetics but also
to local anesthetics, narcotics, barbiturates, benzodiazepines
and other intravenous anesthetic agents. Elderly patients achieve
a comparable level of sedation at diazepam plasma concentrations
significantly lower than that required in young adults. Equivalent
EEG suppression occurs at lower plasma concentrations of both
fentanyl and alfentanil in the aged.3
Similar to narcotics, the induction dose of barbiturates required
in 70 year old adults is approximately 30 percent less than that
required for individuals four to five decades younger. However,
it has been suggested that the greater sensitivity of the elderly
to the same dose of thiopental is dependent upon the basis of
a reduced initial volume of distribution resulting in a higher
plasma concentration following the same administered dose.
Desflurane
As indicated above, the desflurane MAC requirements are reduced
with age. In addition, similar to intravenous agents with shorter
elimination half-lives, desflurane, by virtue of its low blood/gas
and tissue/blood solubility coefficients, may have advantage over
other inhalational agents in the elderly. By virtue of its lower
solubility coefficients, following a typical anesthetic exposure,
less desflurane will be absorbed, making less of the drug available
both for metabolism and for residual postanesthetic effect. For
example, Yasuda, et al., demonstrated that two days following
an administered anesthetic, the residual desflurane end-tidal
concentration, compared to the concentration at time of discontinuing
the anesthetic, was 10-fold less for desflurane than for isoflurane.4
Five days following the anesthetic, the difference in residual
concentrations was 20-fold less for desflurane. Thus, desflurane
may be of particular value in elderly patients where residual
postoperative mental impairment may be both more severe and more
protracted. Similar arguments can be applied to sevoflurane, although
elimination of sevoflurane is not as rapid as for desflurane.
Regional Versus General Anesthesia
Selection of the anesthetic technique should be influenced not
only by the patient's clinical condition and surgical requirements,
but also by the anesthetist's skill and experience. In general,
a fragile geriatric patient should be handled gently and the anesthetic
regime maintained in as simple a fashion as possible. Evidence
suggests that geriatric patients have improved prognosis if their
surgical procedure is performed under local anesthesia rather
than general anesthesia or major regional anesthesia.5
During certain surgical procedures, regional anesthesia in the
elderly may have the advantage of: 1) reduced postoperative negative
nitrogen balance,
2) amelioration of endocrine stress responses to surgery, 3) reduction
in blood loss, 4) a reduced incidence of postoperative thromboembolic
complications and 5) reduced postoperative mental confusion.
However, Chung and colleagues have demonstrated that relatively
modest doses of sedative agents produce mental impairment postoperatively,
similar to that resulting from general anesthesia.6
Thus it is difficult to recommend regional anesthesia over general
anesthesia for all kinds of surgical procedures in the geriatric
patient group. The selection of anesthesia must be individualized.
Spinal anesthesia has particular advantage for certain types of
surgery, including transurethral resection of the prostate, where
the patient remains awake and responsive and can give early warning
signs of surgical complications not possible in a patient receiving
a general anesthetic. Similarly, allowing a patient to remain
conscious during regional anesthesia allows patient recognition
of an anginal attack or acute cerebral changes due to a variety
of causes. For older patients who are cooperative, regional techniques,
especially subarachnoid and epidural block, can be used effectively
and safely for procedures requiring anesthesia below the T-8 dermatome.
Extremity blocks may also be effectively employed for various
procedures on the extremities. However, an injudicious use of
supplemental agents may actually result in a pseudo-general anesthetic
for a patient that obviates some of the advantages of a regional
anesthetic technique. Over-sedation of a patient may lead to hypoventilation,
an unprotected airway and the possibility of postoperative mental
changes resembling those of general anesthesia.
Outpatient Anesthesia for the Elderly Patient
In our current system of health care reform, great emphasis has
been placed on cost containment. This has caused an overall shift
in perioperative health care from the inpatient to the outpatient
setting. Recent data from the American Hospital Association show
that more than 50 percent of all surgical procedures in the United
States are performed on an outpatient basis. This trend has been
seen in hospitals of all sizes and will likely continue in the
future. This of course has brought the geriatric patient, like
all other patients, into the outpatient setting. For example,
a recent report by Mark Warner, M.D., and colleagues, describing
morbidity within one month of ambulatory anesthesia and surgery,
examined 45,090 anesthetics 7. Typical
of the American trend, these adult patients ranged in age from
18 to 96 years.
Postoperative Mental Dysfunction
Postoperative confusion and mental dysfunction are of great concern
in the elderly patient. The databases of 18 studies were combined
into one comprehensive data set and subjected to meta-analysis
by Cryns and colleagues. 8 These
authors concluded that "surgery has a significantly decompensating
impact on the mental status of older persons." Spiro, in a recent
editorial in Science and Medicine, underscores the importance
of this potential complication. In his slightly alarming comments,
he describes his observation of six of his Nobel Laureate colleagues
who, as older individuals, underwent anesthesia and surgery with
demonstrable temporary or primary postoperative mental changes.9
Although this side effect may occur whether geriatric patients
are managed on an outpatient or inpatient basis, it is hoped that
it may be reduced in severity when elderly patients undergo surgery
on an outpatient basis. In this setting they will be given fewer
medications and be allowed a quicker return to their normal surroundings
with relatives and friends nearby. In fact, the overall disruption
of the perioperative period is significantly less if the geriatric
patient can be managed on an outpatient basis. For example, there
is less disruption in their sleep cycle, less disruption in their
familiar environment and less disruption in their overall daily
habits. Hopefully this reduction in disruption will reduce mental
dysfunction postoperatively. Rowe and Kahn have also suggested
that maintenance of control or autonomy for elderly individuals
(where they make decisions regarding their choice of activity,
timing, pace, etc.) have other benefits.10
Lack of control has adverse effects on the emotional state, performance,
subjective well-being and physiologic function of geriatric patients.
As a result, elderly patients undergoing surgery in an outpatient
setting where there is a lesser loss of autonomy and control may
experience distinct benefit.
Obviously, not all geriatric patients should have surgery in
an ambulatory setting. Many of these individuals have a multiplicity
of diseases or significant physiologic decrement in function that
prevents them from being adequate candidates for ambulatory surgery.
Peter Duncan and colleagues have shown that intraoperative and
postoperative adverse events are more likely to occur in patients
presenting for outpatient surgery who have preoperative medical
conditions.11 Thus, judging the
pre-existing medical conditions of each patient requires an individual
medical decision. However, if an elderly patient does pass a routine
preoperative screening visit, then there is no reason why age
alone should prevent him from being considered a candidate for
an outpatient procedure. Meridy has found that age alone does
not affect the duration of recovery from anesthesia nor the rate
of complications following outpatient surgery.12
However, others have observed in patients emerging from thiopental,
halothane and nitrous oxide anesthesia for cervical dilation and
curettage that more time was required for older patients to successfully
complete a manipulative skill test.13
A preoperative screening visit by an anesthesiologist prior to
surgery is of prime importance. It is recommended that screening
of an elderly patient be performed prior to the day of surgery.
This enables anesthesia personnel to make rational judgments as
to the patient's acceptability for surgery as an outpatient, permits
treatment of pre-existent diseases, contributes to more efficient
scheduling, allows appropriate lab testing to be performed, enhances
the visibility of the anesthesiologist in the overall medical
practice scheme and enables an interview of the "responsible adult"
who will not only ensure the patient's delivery from the hospital
back home but who will also stay with the patient and assist with
his recovery in the home setting. Natof, in a special study sponsored
by the Federated Ambulatory Surgery Association, reviewed 87,492
patients undergoing outpatient procedures and found a relationship
between the incidence of complications and the length of the surgical
procedure.14 As a result, the type
and difficulty of the surgical procedure should be taken into
consideration prior to allowing a complex and protracted surgical
procedure to be performed on an elderly patient as an outpatient.
Similarly, the relationship of complication rate to pre-existent
disease again demonstrates the importance of preanesthesia screening
in determining if elderly individuals with one or more pre-existent
medical conditions should be allowed to undergo their surgical
procedure as an outpatient.
Not all elderly patients have multiple medical problems. Physiologic
age is obviously more important than chronological age and a profile
of the patient's past medical history and current level of physical
activity is a far better indicator of his or her ability to tolerate
a surgical procedure as an outpatient than is age alone. Ambulatory
surgery should not be denied a patient solely on the basis of
age.
Summary
Aging is an all-encompassing, multifactorial process that results
in a decreased capacity for adaptation and produces a gradual
decrease in functional reserve of many of the body's organ systems.
Aging itself is not a disease process but instead serves as a
reminder of the potential for development of many age-related
disease states. There is no ideal anesthetic for all elderly patients.
A thorough understanding of the physiological changes that occur
with aging and the altered pharmacokinetic and pharmacodynamic
responses of the elderly to a variety of anesthetic drugs help
in the design of an optimal anesthetic technique for each elderly
patient. Appropriate anesthetic management must therefore be based
on a thorough medical evaluation preoperatively, with correction,
if possible, of any detected abnormality. Intensity of monitoring
during and following anesthesia will likely be greater than that
selected for younger patients but should be determined on an individual
basis taking into consideration the patient's condition and proposed
surgical procedure. Because elderly patients are not only pharmacologically
but also physically fragile, they require great care during positioning
and moving. By offering geriatric patients the safest anesthetic
possible, we can contribute to the revolutionary increase in life
span of our citizenry and directly enhance their health-span --
the maintenance of full function as nearly as possible to the
end of life.
References:
1. Hilgenberg JC. Inhalation and intravenous
drugs in the elderly patient. Seminars in Anesthesia 1986;
5:44-53.
2. Rampil IJ, Lockhart SH, Zwass MS, et al.
Clinical characteristics of desflurane in surgical patients: Minimum
alveolar concentration. Anesthesiology. 1991; 74:429-433.
3. Scott JC, Stanski DR. Decreased fentanyl
and alfentanil dose requirements with age: A simultaneous pharmacokinetic
and pharmacodynamic evaluation. J Pharmacol Exp Ther. 1987;
240:159-166.
4. Yasuda N, Lockhart SH, Eger EI II, et al.
Kinetics of desflurane, isoflurane, and halothane in humans. Anesthesiology.
1991; 74(3):489-498.
5. Servin F, Pommereau R, Rowan C, et al.
Comparison of intraoperative course and recovery with etomidate
or propofol in patients over 80 years. Anesthesiology.
1990; 73:A318.
6. Peacock JE, Lewis RP, Reilly CS, et al.
Effect of different rates of infusion of propofol for induction
of anaesthesia in elderly patients. Br J Anaesth. 1990;
65:346-352.
7. Backer CCL, Tinker JH, Robertson DM, Vleistra
RE. Myocardial reinfarction following local anesthesia for ophthalmic
surgery. Anesth Analg. 1980; 59(4):257-262.
8. Chung FF, Chung A, Meier RH, et al. Comparison
of perioperatrive mental function after general anaesthesia and
spinal anaesthesia with intravenous sedation. Can J Anaesth.
1989; 36:382-387.
9. Warner MA, Shields SE, Chute CG. Major
morbidity and mortality within 1 month of ambulatory surgery and
anesthesia. JAMA. 1993; 270(12):1437-1441.
10. Cryns AG, Gorey KM, Goldstein MZ. Effects
of surgery on the mental status of older persons. A meta-analytic
review. J Geriatr Psychiatry Neurol. 1990; 3(4):184-191.
11. Spiro H. Science and Medicine.
May/June; 1996.
12. Rowe JW, Kahn RL. Human aging: Usual
and successful. Science. 1987; 237(4811):143-149.
13. Duncan PG, Cohen MM, Tweed WA, et al.
The Canadian four-centre study of anesthetic outcomes: III. Are
anesthetic complications predictable in day surgical practice?
Can J Anaesth. 1992; 39:440-448.
14. Meridy HW. Criteria for selection of
ambulatory surgical patients and guidelines for anesthesia management:
A retrospective study of 1,553 cases. Anesth Analg. 1982;
61(11):921-926.
15. Sear JW, Cooper GM, Kumar V. The effect
of age on recovery. A comparison of the kinetics of thiopentone
and althesin. Anaesthesia. 1983; 38(12):1158-1161.
16. Natof HE. FASA Special Study I. Federated
Ambulatory Surgery Association. Alexandria, Virginia; 1985.
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