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Physiologic changes occur during aging that have an impact on the pharmacologic responses of elderly patients. These changes are well described and include (1) plasma protein binding, (2) body content, (3) drug metabolism, (4) and pharmacodynamics.
The main plasma binding protein for acidic drugs is albumin and, for basic drugs, α1 -acid glycoprotein. The circulating level of albumin decreases with age, whereas α1 -acid glycoprotein levels increase. The effect of alterations in plasma binding protein on drug effect depends on which protein the drug is bound to and the resulting change in fraction of unbound drug. The relationship is complex, and in general, changes in plasma binding protein levels are not a predominant factor in determining how pharmacokinetics is modified with aging.
Changes in body composition with aging reflect a decrease in lean body mass, an increase in body fat, and a decrease in total-body water. We might infer that a decrease in total-body water could lead to a smaller central compartment and increased serum concentrations after bolus administration of a drug. In addition, the increase in body fat might result in a greater volume of distribution, with the potential to prolong the clinical effect of a given medication.[20]
As discussed previously, alterations in both hepatic and renal clearance occur with aging. Depending on the degradation pathway, decreases in liver and kidney reserve can affect a drug's pharmacokinetic profile.
The clinical response to anesthetic medications in the elderly may be the result of alterations in sensitivity of the target organs (pharmacodynamics). A given agent's physical properties, as well as alterations in receptor number or sensitivity, will determine the relative influence of pharmacodynamic alterations on anesthetic effect in the elderly. In general, the elderly are more sensitive to anesthetic agents. Less medication is usually required to achieve a desired clinical effect, and drug effect is often prolonged. Undesired hemodynamic perturbations also tend to occur more frequently and in greater magnitude. For example, hemodynamic responses to intravenous anesthetics may be exaggerated because of interactions with the aging heart and vasculature. Expected compensatory or reflex responses are often blunted or absent as a result of physiologic changes associated with normal aging and age-related disease. Whatever the cause of the altered pharmacologic effect, an aged patient usually requires a downward adjustment in medication dose.
The minimum alveolar anesthetic concentration (MAC) decreases approximately 6% per decade for most inhaled anesthetics. A similar pattern is observed for MAC-awake.[21] The mechanism of action of inhaled anesthetics is related to altered activity of neuronal ion channels associated with nicotinic, acetylcholine, γ-aminobutyric acid A (GABAA ), and glutamate receptors. Perhaps with aging, alterations in ion channels, synaptic activity, or receptor sensitivity may occur to account for these pharmacodynamic changes.
No change in brain sensitivity to thiopental occurs with age. [22] However, the dose of thiopental required to achieve anesthesia decreases with age. The age-related decrease in
| Drug | Brain Sensitivity | Pharmacokinetics | Dose |
|---|---|---|---|
| Inhaled agents | ↑ |
|
↓ |
| Thiopental | — | ↓ Initial distribution volume | ↓ |
| Etomidate | — | ↓ Initial distribution volume | ↓ |
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↓ Clearance |
|
| Propofol | ↑ | ↓ Clearance | ↓ |
| Midazolam | ↑ | ↓ Clearance | ↓ |
| Morphine | ↑ | ↓ Clearance | ↓ |
| Sufentanil | ↑ | — | ↓ |
| Alfentanil |
|
|
|
| Fentanyl |
|
|
|
| Remifentanil | ↑ | ↓ Clearance |
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↓ Central compartment volume | ↓ |
| Pancuronium | NA | ↓ Clearance * | ↓ * |
| Atracurium | NA | — | — |
| Cisatracurium | NA | — | — |
| Vecuronium | NA | ↓ Clearance | ↓ |
The dose of midazolam required to produce sedation during upper gastrointestinal endoscopy is decreased approximately 75% in the aged.[25] These changes are related to both increased brain sensitivity and decreased drug clearance.[26]
Age is an important predictor of postoperative morphine requirements, with the elderly needing less drug for pain relief.[27] Both morphine and its metabolite morphine-6-glucuronide have analgesic properties. Morphine clearance is decreased in the elderly.[28] Clearance of morphine-6-glucuronide is dependent on renal excretion.[29] Patients with renal insufficiency may have impaired elimination of morphine glucuronides, which may account for some of the enhanced analgesia from a given dose of morphine in an elderly patient.[30]
A comprehensive review of the pharmacology of sufentanil, alfentanil, and fentanyl in the elderly has been provided by Shafer.[20] In summary, sufentanil, alfentanil, and fentanyl are approximately twice as potent in the elderly. These findings are primarily related to an increase in brain sensitivity to opioids with age rather than alterations in pharmacokinetics.
Aging is associated with changes in both the pharmacokinetics and pharmacodynamics of remifentanil. Brain sensitivity to remifentanil increases with age. Remifentanil is approximately twice as potent in the elderly, and half the bolus dose is required.[31] The volume of the central compartment, V1 , and clearance decrease with age,[32] and approximately one third the infusion rate is required in the elderly.[31]
In general, age does not significantly affect the pharmacodynamics of muscle relaxants. However, the duration of action may be prolonged if the drug depends on liver or renal metabolism. One would expect that pancuronium clearance would decrease in the elderly because of its dependence on renal excretion. However, changes in pancuronium clearance with aging are controversial.[33] [34] Atracurium depends to a small extent on hepatic metabolism and excretion, and its elimination half-life is prolonged in the elderly. However, clearance is unchanged with age, thus suggesting that alternative pathways of elimination (ester hydrolysis and Hofmann elimination) assume importance in the elderly.[35] Cisatracurium undergoes Hofmann degradation and is unaffected by age. Plasma clearance of vecuronium is lower in the elderly. [34] The age-related prolonged duration of action of vecuronium may reflect decreases in renal or hepatic reserve.[36]
Age has no effect on the duration of motor blockade with bupivacaine spinal anesthesia.[37] However, the duration of analgesia may be prolonged with age, depending on the baricity of the bupivacaine solution.[37] [38] Effects of age on duration of epidural anesthesia have not been demonstrated with 0.5% bupivicaine.[39] When using 0.75% ropivacaine for peripheral nerve block, age is a major factor in determining the duration of motor and sensory blockade.[40]
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