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Dexmedetomidine
1.
2.
3. DR. SAI DIVYA.V
JNR. CONSULTANT,MRNH
DEPARTMENT OF
ANESTHESIOLOGY.
DEXMEDETOMIDINE
4. HISTORY
It was introduced in clinical practice in the
United States in 1999 and approved by the
FDA only as a short-term (<24 hours)
sedative for mechanically ventilated adult
ICU patients.
• Dexmedetomidine is a more selective α2
agonist with a 1600 greater selectivity for
the α2 receptor compared with the α1
receptor.
7. Dexmedetomidine is the s-enantiomer of
medetomidine.(which was formerly used in
veternary medicine)
It shows a high ratio of specificity for the
α2 receptor (α2/α1 1600 : 1) compared with
clonidine (α2/α1 200 : 1), making it a
complete α2 agonist.
Dexmedetomidine belongs to the
imidazole subclass of α2 receptor
agonists, similar to clonidine.
It is freely soluble in water and has a pKa
of 7.1
Available as clear isotonic solution of
100mcg/ml with 9mg of NaCl
8. METABOLISM AND
PHARMACOKINETICS
• it undergoes almost complete biotransformation
with very little unchanged form in urine and feces
• biotransformation involves bith direct
glucorinidation and cytochrome p 450 mediated
metabolism
• major metabolic pathways are direct N -
glucoronidation to inactive
metabolites,hydroxylation and N- methylation.
• 94% protein bound
• concentration ratio between whole blood and
plasma is 0.66.
• clearence varies with hepatic impairment but
9. Metabolism and
Pharmacokinetics
Dexmedetomidine has profound effects on
cardiovascular variables and may alter its own
pharmacokinetics.
Dexmedetomidine displays nonlinear
pharmacokinetics.
Its pharmacokinetics in volunteers is best described
by a
three-compartment model .
These pharmacokinetic parameters apparently are
unaltered by age or weight or renal failure, but
clearance is a function of height.
The elimination half-life of dexmedetomidine is 2 to 3
hours,
with a context-sensitive half-time ranging from 4
minutes after a 10-minute infusion to 250 minutes after
an 8-hour infusion
10. in patients with severe renal disease the sedative
effect is stronger as a result of lower degree of
protein binding
no clinically relevant cytochrome p 450 mediated
drug interactions have been found
11. PHARMACOLOGY
Dexmedetomidine is a nonselective α2 agonist.
Alpha2 adrenoreceptors are membrane-spanning G proteins.
Intracellular pathways include inhibition of adenylate cyclase and
modulation of ion channels.
Three subtypes of α2 adrenoreceptors have been described in
humans: α2A, α2B, and α2C
Postsynaptic located α2 adrenoreceptors in peripheral blood
vessels produce vasoconstriction,
whereas presynaptic α2 adrenoreceptors inhibit the release of
norepinephrine, potentially attenuating the vasoconstriction.
The overall response to α2 adrenoreceptors agonists is related to
the stimulation of α2 adrenoreceptors located in the CNS and
spinal cord.
These receptors are involved in the sympatholysis, sedation, and
antinociception effects of α2 adrenoreceptors.
13. INDICATIONS As a premedicant.
for monitored anesthesia care.
Sedation in pediatric patients.
Pre medicant in ophthalmic surgery.
For maintenance of anesthesia.
awake craniotomies with functional testing and
electrocorticography.
anesthetic adjunct or sedative agent for patients who are
susceptible to narcotic-induced respiratory depression or sleep
apnea.
15. SEDATION
ACTION ON ALPHA 2 RECEPTORS IN LOCUS
COERULEUS
Analgesic action by acting on receptors at Lc
and at spinal cord
Decreased action of projections of LC to
VLPO nucleus
So there is release of GABA and galantin
release in tuberomamillary nucleus
Sedative effect through endogenous sleep
promoting pathways thus generating natural
sleep pathways
16. patients have been described as being very easy
to wake up and having the ability to follow
commands and cooperate while being intubated.
this allows for “daily wake up “ tests to be done in
a safe fashion.
the number of patients experiencing delirium in
the ICU is significantly lower compared with
propofol or lorzepam or with midazolam.
17. Analgesia
The primary site of analgesic action is thought to be the spinal
cord.
primarily mediated through alpha 2c and 2a receptors in dorsal
horn.
anaalgesia is due to inhibition of pronociceptive transmitters like
substance p and glutamate
Systemic use of dexmedetomidine shows narcotic sparing.
systemic analgesic effects have been attributed to the
confounding sedative effects.
The analgesic effect of dexmedetomidine has been compared with
remifentanil, dexmedetomidine was less effective in reducing pain
than remifentanil.
18. `
advantageous in patients who are prone to
postopertaive hypoventialtion
dexmed also reduces the MAC of inhaled
anasthetics.
19. Central Nervous System
Protection and Other Central
Nervous System Effects
reduces cerebral necrosis and improves
neurologic outcome.
dexmedetomidine reduced the intracerebral
catecholamine outflow during injury and resulted
in less neural tissue damage with better
neurologic outcome.
The neuroprotection may be attributed to
modulation of pro apoptotic and antiapoptotic
proteins.
reduction of the excitatory neurotransmitter
glutamate .
20. has a major role in neuro physiological monitoring
cortical evoked potential amplitudes abd latencies
were minimally affected when used
intraoperatively
21. Effects on the Respiratory
System
reduces minute ventilation.
but retains the slope of the ventilatory response to
increasing carbon dioxide.
no change in arterial oxygenation or pH.
Dexmedetomidine also exhibited a hypercarbic
arousal phenomenon, which has been described
during normal sleep and is a safety feature.
22. Effects on the Cardiovascular
System
decreased heart rate, decreased systemic vascular resistance
and indirectly decreased myocardial contractility, cardiac output,
and systemic blood pressure.
• The hemodynamic effects of a bolus of dexmedetomidine have
shown a biphasic response.
The incidence of hypotension and bradycardia may be related to
the administration of a loading dose.
Omitting the loading dose or not giving more than 0.4 µg/kg
reduces the incidence of hypotension, or makes it less
pronounced.
Giving the loading dose over 20 minutes also minimizes the
transient hypertension.
Generally, these episodes resolved spontaneously or were
readily treated without adverse outcome by anticholinergics.
23. INTENSIVE CARE UNIT
Dexmedetomidine has advantages over propofol for sedation in
mechanically ventilated postoperative patients.
Heart rate was slower in the dexmedetomidine group, whereas
MAP was similar.
The PaO2/FIO2 ratio was significantly higher in the
dexmedetomidine group.
Time to extubation after discontinuation of the infusion was
similar at 28 minutes.
Patients receiving dexmedetomidine seemed to have greater
recall of their stay in the ICU, but all described this as pleasant
overall.
Several other studies have confirmed the decreased requirement
for opioids (>50%) when dexmedetomidine is used for sedation
compared with propofol or benzodiazepines.
24. For sedation in the ICU, loading doses of 0.5
to 1 µg/kg have been used.
Omitting the bolus or giving the lower dose
has been associated with fewer episodes of
severe bradycardia and other hemodynamic
perturbations.
Infusion rates of 0.1 to 1 µg/kg/hr are
generally needed to maintain adequate
sedation.
Delirium in the ICU is a risk factor for
increased length of stay and increased
25. AS ADJUVANTS
frequently used as a adjuvant in central or
peripheral neural blockade.
as a adjuvant in the range of o.5 mcg/kg to
1mcg/kg
many studies showed the intensification and
foremost prolongation of sensory blockade
26. other uses
as premedicant in the doses of 0.33 to
0.67mcg/kg
used to reduce the laryngoscopy response
used as a total IV anaesthesia , given in the dose
range of about 10 times the dose for sedation
employed for addiction treatment- rapid opiod
detoxification ,cocaine
withdrawal,benzodiazepine and opioid tolerance
useful adjumct in awake fiberoptic intubation
