Pharmacology
Effects on the Central Nervous System
α2
-Agonists produce their sedative-hypnotic effect
by an action on α2
-receptors in the locus ceruleus and produce their
analgesic effect by an action on α2
-receptors within the locus ceruleus
and the spinal cord.[664]
An interesting observation
is that the quality of sedation produced by dexmedetomidine appears to be different
from that produced by other sedatives acting through the GABA systems. α2
-Agonists
act through the endogenous sleep-promoting pathways to exert their sedative effect.
They produce a decrease in activity of the projections of the locus ceruleus to
the ventrolateral preoptic nucleus. This action increases GABAergic and galanin
release in the tuberomammillary nucleus and as a result leads to a decrease in histamine
release in the cortical and subcortical projections.[665]
α2
-Agonists appear to inhibit ion conductance through L- or P-type
calcium channels and to facilitate conductance through voltage-gated calcium-activated
potassium channels.[666]
α2
-Agonists
have the advantage that their effects are readily reversible by α2
-adrenergic
antagonists (e.g., atipamezole).[667]
Like other
adrenergic receptors, α2
-agonists also produce tolerance after prolonged
administration.[668]
However, because dexmedetomidine
is approved for only short-term sedation, tolerance, dependence, or addiction does
not appear to be a problem. In contrast, dexmedetomidine has been used for rapid
opioid detoxification, cocaine withdrawal, and iatrogenic-induced benzodiazepine
and opioid tolerance after prolonged sedation.[669]
In animals, dexmedetomidine, unlike opioids, does not result in hyperalgesia or
allodynia after its withdrawal.[670]
Rats rendered
tolerant to morphine also show a decrease in efficacy of both the hypnotic and analgesic
effects of dexmedetomidine. As tolerance to opioids improves, recovery of the hypnotic
effect of dexmedetomidine is more rapid than recovery of its analgesic efficacy.
[671]
These data would tend to indicate a possible
cross-tolerance across receptors.
In animal models of incomplete cerebral ischemia and reperfusion,
dexmedetomidine reduces cerebral necrosis and improves neurologic outcome. In a
model of focal ischemia in rabbits, dexmedetomidine, administered at doses that reduced
the MAC of halothane by 50%, resulted in less cortical neuronal damage than when
halothane was administered alone at equi-effective MAC concentrations.[672]
Little is known of the effects of dexmedetomidine alone on ICP and CBF. In patients
after pituitary surgery, a target concentration of 600 ng/mL dexmedetomidine resulted
in no increase in lumbar CSF pressure.[673]
In
dogs in the presence of volatile anesthetics and dexmedetomidine, CBF was decreased
and oxygen consumption was maintained.[674]
[675]
CBF velocity, as measured by transcranial Doppler, decreased with increasing concentrations
of dexmedetomidine in parallel with decreasing mean arterial pressure and increasing
arterial carbon dioxide.[676]
In volunteers, both
low (402 to 530 pg/mL) and high concentrations (524 to 732 pg/mL) of dexmedetomidine
decreased global CBF by 30%. This decrease persisted for at least 30 minutes after
termination of the infusion.[677]
In a rat seizure
model, dexmedetomidine demonstrated significant proconvulsant action, which is consistent
with previous findings that inhibition of central noradrenergic transmission facilitates
seizure expression.[678]
This finding, however,
is in contrast to an anticonvulsant effect shown in rats after kainic acid-induced
seizures.[679]
As yet, there have been no reports
of seizures in humans. Dexmedetomidine is also able to reduce muscle rigidity after
high-dose opioid administration.[680]
In resting
volunteers, dexmedetomidine increased growth hormone secretion in a dose-dependent
manner, but it had no effect on other pituitary hormones.[681]
[682]
Dexmedetomidine ablates memory in a dose-dependent
manner. In concentrations used for clinical sedation (i.e., 0.7 ng/mL), recall of
picture cards is preserved. An increase to concentrations of 2 ng/mL dexmedetomidine
largely ablates both recall and recognition of a picture card.[683]
Effects on the Respiratory
System
In volunteers, dexmedetomidine at concentrations producing significant
sedation reduces minute ventilation but retains the slope of the ventilatory response
to increasing CO2
.[684]
The changes
in ventilation appeared to be very similar to those observed during natural sleep.
Ebert and coworkers infused dexmedetomidine up to concentrations of 15 ng/mL in
spontaneously breathing volunteers and showed no change in arterial oxygenation or
pH. At the very highest concentrations, PaCO2
increased by 20%. The respiratory rate increased with increasing concentration from
14 to 25 breaths/min.[683]
When dexmedetomidine
and propofol were titrated to equal sedative end points (BIS index of 85), both resulted
in no change in the respiratory rate.[685]
Doses
of 1 to 2 µg/kg of dexmedetomidine induce a mild increase in PaCO2
(45 mm Hg) and a rightward shift and depression of the carbon dioxide response curves.
The changes in respiration are mainly a decrease in tidal volume with little change
in respiratory frequency. When combined with alfentanil, dexmedetomidine enhances
analgesia without causing further respiratory depression.
Effects on the Cardiovascular System
The basic effects of α2
-agonists on the cardiovascular
system are a decreased heart rate, decreased systemic vascular resistance, and indirectly
decreased myocardial contractility, cardiac output, and systemic blood pressure.
By
Figure 10-26
Effects of increasing plasma concentrations of dexmedetomidine.
developing highly selective α-agonists, it had been hoped that some of these
adverse cardiovascular effects would be decreased and the desirable hypnotic-analgesic
properties maximized. The hemodynamic effects of a bolus of dexmedetomidine in humans
have shown a biphasic response. An acute intravenous injection of 2 µg/kg
resulted in an initial increase in blood pressure (22%) and decrease in heart rate
(27%) from baseline that occurred 5 minutes after injection. This initial increase
in blood pressure is probably due to the effect of dexmedetomidine on peripheral
α2
-receptors. The heart rate returned to baseline by 15 minutes,
and blood pressure gradually drifted down to approximately 15% below baseline by
1 hour. After an intramuscular injection of the same dose, the initial increase
in blood pressure was not seen, and both the heart rate and blood pressure remained
within 10% of baseline values.[686]
Ebert and colleagues
performed a very elegant study in volunteers in which a target-controlled infusion
system was used to provide increasing concentrations (0.7 to 15 ng/mL) of dexmedetomidine
( Fig. 10-26
).[683]
The lowest two concentrations produced a decrease in mean arterial pressure (13%)
followed by a progressive increase (12%). Increasing concentrations of dexmedetomidine
also produce progressive decreases in heart rate (maximum of 29%) and cardiac output
(35%).[683]
Infusion of dexmedetomidine in volunteers
has also been shown to result in a compensated reduction in systemic sympathetic
tone without changes in baroreflex sensitivity.
It also blunts the heart rate and the systemic sympathetic response to sweating but
is less effective in blunting the cardiac sympathetic response to shivering.[687]
In several studies involving both intramuscular and intravenous administration,
dexmedetomidine caused profound brady-cardia (<40 beats/min) and occasionally
sinus arrest/pause in a small percentage of patients. These episodes generally resolved
spontaneously or were readily treated by anticholinergics without adverse outcome.
It would be expected from its profile that dexmedetomidine would be beneficial to
ischemic myocardium. In animal models, dexmedetomidine demonstrated some beneficial
effects on the ischemic heart through decreased oxygen consumption and redistribution
of coronary flow from nonischemic zones to ischemic zones after acute brief occlusion.
[688]
Dexmedetomidine also decreased serum lactate
levels in a dog model of coronary ischemia with an associated decrease in heart rate
and measured catecholamines. In addition, it produced a 35% increase in the endocardial-epicardial
blood flow ratio.[689]
Other Effects
A frequently reported side effect of dexmedetomidine has been
dry mouth, which is due to a decrease in saliva production.[690]
