Page 471 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 25 General Anesthetics 457

in the early postoperative period may be useful to produce anal- may result from unopposed vagal stimulation. The response to
gesia or reduce opioid tolerance and opioid-induced hyperalgesia. anticholinergic drugs is unchanged.
The use of ketamine has always been limited by its unpleasant
psychotomimetic side effects, but its unique features make it a C. Respiratory Effects
very valuable alternative in certain settings, mostly because of The effects of dexmedetomidine on the respiratory system are a
the potent analgesia with minimal respiratory depression. Most small to moderate decrease in tidal volume and very little change
recently, it has become popular as an adjunct administered at sub- in the respiratory rate. The ventilatory response to carbon dioxide
analgesic doses to limit or reverse opioid tolerance. is unchanged. Although the respiratory effects are mild, upper
airway obstruction as a result of sedation is possible. In addition,
DEXMEDETOMIDINE dexmedetomidine has a synergistic sedative effect when combined
with other sedative-hypnotics.
Dexmedetomidine is a highly selective α -adrenergic agonist. Rec-
2
ognition of the usefulness of α agonists is based on observations Clinical Uses & Dosage
2
of decreased anesthetic requirements in patients receiving chronic Dexmedetomidine is principally used for the short-term seda-
clonidine therapy. The effects of dexmedetomidine can be antago- tion of intubated and ventilated patients in an ICU setting.
nized with α -antagonist drugs. Dexmedetomidine is the active In the operating room, dexmedetomidine may be used as an
2
S-enantiomer of medetomidine, a highly selective α -adrenergic adjunct to general anesthesia or to provide sedation, eg, dur-
2
agonist imidazole derivative that is used in veterinary medicine. ing awake fiberoptic tracheal intubation or regional anesthesia.
Dexmedetomidine is water soluble and available as a parenteral When administered during general anesthesia, dexmedetomi-
formulation. dine (0.5–1 mcg/kg loading dose over 10–15 minutes, followed
by an infusion of 0.2–0.7 mcg/kg/h) decreases the dose require-
Pharmacokinetics ments for inhaled and injected anesthetics. Awakening and
Dexmedetomidine undergoes rapid hepatic metabolism involv- the transition to the postoperative setting may benefit from
ing N-methylation and hydroxylation, followed by conjugation. dexmedetomidine-produced sedative and analgesic effects with-
Metabolites are excreted in the urine and bile. Clearance is high, out respiratory depression.
and the elimination half-time is short (Table 25–2). However,
there is a significant increase in the context-sensitive half-time OPIOID ANALGESICS IN ANESTHESIA
from 4 minutes after a 10-minute infusion to 250 minutes after
an 8-hour infusion. Opioids are analgesic agents and are distinct from general anes-
thetics and hypnotics. Even when high doses of opioid analge-
Organ System Effects sics are administered, recall cannot be prevented reliably unless
hypnotic agents such as benzodiazepines are also used. Opioid
A. CNS Effects analgesics are routinely used to achieve postoperative analgesia
Dexmedetomidine produces its selective α -agonist effects through and intraoperatively as part of a balanced anesthesia regimen as
2
activation of CNS α receptors. Hypnosis presumably results from described earlier (see Intravenous Anesthetics). Their pharmacol-
2
stimulation of α receptors in the locus coeruleus, and the anal- ogy and clinical use are described in greater detail in Chapter 31.
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gesic effect originates at the level of the spinal cord. The sedative In addition to their use as part of a balanced anesthesia regimen,
effect produced by dexmedetomidine has a different quality than opioids in large doses have been used in combination with large
that produced by other intravenous anesthetics in that it more doses of benzodiazepines to achieve a general anesthetic state, par-
completely resembles a physiologic sleep state through activation ticularly in patients with limited circulatory reserve who undergo
of endogenous sleep pathways. Dexmedetomidine is likely to be cardiac surgery. When administered in large doses, potent opioids
associated with a decrease in cerebral blood flow without signifi- such as fentanyl can induce chest wall (and laryngeal) rigidity,
cant changes in ICP and CMRO . It has the potential to lead to thereby acutely impairing mechanical ventilation. Furthermore,
2
the development of tolerance and dependence. large doses of potent opioids may speed up the development of
tolerance and complicate postoperative pain management.
B. Cardiovascular Effects
Dexmedetomidine infusion results in moderate decreases in heart CURRENT CLINICAL PRACTICE
rate and systemic vascular resistance and, consequently, a decrease
in systemic blood pressure. A bolus injection may produce a The practice of clinical anesthesia requires integrating the phar-
transient increase in systemic blood pressure and pronounced macology and the known adverse effects of these potent drugs
decrease in heart rate, an effect that is probably mediated through with the pathophysiologic state of individual patients. Every
adrenoceptors. Bradycardia associated case tests the ability of the anesthesiologist to produce the depth
activation of peripheral α 2
with dexmedetomidine infusion may require treatment. Heart of anesthesia required to allow invasive surgery to proceed and
block, severe bradycardia, and asystole have been observed and to achieve this safely despite frequent major medical problems.