Dexmedetomidine EVER

Pharma
Medical & Product
Knowledge
Raymond Gorgui
1) Anesthesia

2
ANAESTHESIA Intravenous
as
thiopental
propofol
ketalar
General
Inhalational
as
halothane
Anesthesia isoflurane
sevoflurane
Local
as
Regional spinal
epidural
nerve3block
General anesthesia: a reversible state of central nervous
system depression resulting in loss of response and
perceptions of external stimuli.

For patients undergoing surgical and other medical

procedures anesthesia provides these benefits:
 Sedation and reduction of anxiety
 Lack of awareness and amnesia
 Skeletal muscle relaxation
 Suppression of undesirable reflexes
 Analgesia

Because no single agent can provide all those benefits,

several drugs are used in combination to produce
optimal anesthesia.

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 Preanesthetic Medications
• Serve to calm the patient, relieve the pain and protect
against undesirable effects of anesthetics or the surgical
procedure
▫ Antacids (neutralize stomach acidity).
▫ H2 blockers like famotidine (Reduce gastric acidity).
▫ Anticholinergics like glycopyrrolate (Prevent bradycardia and
secretion of fluids).
▫ Antiemetics like ondansetron (Prevent aspiration of stomach
contents and postsurgical nausea and vomiting).
▫ Antihistamine like diphenhydramine (Prevent allergic reactions).
▫ Benzodiazepines like diazepam (Relieve anxiety).
▫ Opioids like fentanyl (Provide analgesia).
▫ Neuromuscular blockers (Facilitate intubation and relaxation).

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◦ Neuromuscular blockers
🞄Pancuronium
🞄Succinylcholine

⦁ Facilitate intubation of the trachea and

suppress muscle tone to the degree required
for surgery

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Choice of anesthetic drugs are made to provide safe and
efficient anesthesia based on the nature of the surgical
or diagnostic procedures and patient’s physiologic,
pathologic and pharmacologic state

(One Size Can’t FIT all.)

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• Two factors are important
1. Status of organ system
🞄 Cardiovascular system
🞄 Respiratory system
🞄 Liver and kidney
🞄 Nervous system
🞄 Pregnancy
2. Concomitant use of drugs
🞄 Multiple adjunct agents
🞄 Nonanesthetic drugs

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⦁ Cardiovascular system:
▫ Anesthetic agents suppress cardiovascular
functions.
▫ Ischemic injury to tissues may follow reduced
perfusion pressure if a hypotensive episode occurs
during anesthesia, treatment with vasoactive
substances may be necessary
▫ Some anesthetics like halothane sensitize the heart
to arrhythmogenic effects of sympathomimetics

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⦁ Respiratory system
▫ Asthma may complicate control of inhalation
anesthetic
▫ Inhaled anesthetics depress the respiratory system
▫ IV anesthetics and opioids suppress respiration
▫ These effects may influence the ability to provide
adequate ventilation and oxygenation

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⦁ Liver and kidneys
◦ Affect distribution and clearance of anesthetics, and might
be affected by anesthetic toxic effects
◦ Their physiologic must be considered
⦁ Nervous system
◦ Presence of neurologic disorders like epilepsy, myasthenia
gravis, problems in cerebral circulation can interact with
anesthesia.
⦁ Pregnancy
◦ Effects of anesthetic agents on the fetus
🞄 Nitric oxide causes aplastic anemia in the unborn child
🞄 Benzodiazepines might cause oral clefts in the fetus
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 ⦁ Multiple adjunct agents
◦ Multiple agents are administered preanesthesia, these
agents facilitate induction of anesthesia and lower the
needed dose of anesthetics
◦ They may enhance adverse effects of anesthesia like
hypoventilation

⦁ Concomitant use of additional non-anesthetic

drugs:
◦ Example: Opioid abusers may be intolerant to opioids

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 ⦁ Induction: the period of time from the onset of
administration of the potent anesthetic to the development
of effective surgical anesthesia in the patient.
▫ Depends on how fast effective concentration of the drug
reaches the brain
⦁ Maintenance of anesthesia: providing a sustained
surgical anesthesia
⦁ Recovery: the time from discontinuation of
administration of anesthesia until consciousness and
protective physiologic reflexes are regained
▫ Depends on how fast the drug leaves the brain

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Stages of anesthesia

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• Depth of anesthesia is the
degree to which the CNS is
depressed
• Useful parameter for
individualizing anesthesia

▫ Stage I Analgesia

▫ Stage II Excitement

▫ Stage III Surgical anesthesia

▫ Stage IV Medullary paralysis

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⦁ General anesthesia (GA) in adults is normally induced
with an IV anesthetic like propofol
⦁ At that time, additional inhalation and/or IV anesthetic
drugs may be given to produce the desired depth of
surgical anesthesia (Dexmedetomidine)
⦁ Often includes coadministration of an IV skeletal
muscle relaxant such as rocuronium, vecuronium, or
succinylcholine to facilitate intubation and muscle
relaxation
⦁ For children without IV access, inhalation induction is
used such as halothane or sevoflurane, to induce
general anesthesia

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⦁ Maintenance is the period during which the
patient is surgically anesthetized
⦁ Patient’s vital signs and response to various
stimuli are monitored continuously throughout
the surgical procedure Opioids such as fentanyl
- Remifentanil are often used for pain relief
⦁ IV infusions of various drugs may also be used

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⦁ Postoperatively, the anesthetic admixture is
withdrawn, and the patient is monitored for
the return of consciousness
⦁ If skeletal muscle relaxants have not been fully
metabolized, reversal agents may be used
⦁ The anesthesiologist continues to monitor the
patient for full recovery, with normal
physiologic functions

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▫ Stage I Analgesia
🞄Loss of pain sensation
🞄Drowsiness
🞄Amnesia and reduced awareness of pain

▫ Stage II Excitement
🞄Delirium
🞄Rise and irregularity in blood pressure and respiration
🞄Risk of laryngospasm
🞄To shorten this period a rapid acting anesthetic like
propofol is administered IV before inhaled anesthetic

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▫ Stage III Surgical anesthesia
🞄Loss of muscle tone and reflexes
🞄Ideal stage for surgery
🞄Requires careful monitoring

▫ Stage IV Medullary paralysis

🞄Severe depression of the respiratory and vasomotor
centers
🞄Death can occur unless respiration and circulation are
maintained

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⦁ Potent general anesthetics are delivered via
inhalation or IV injection
◦ Inhaled general anesthetics
◦ Intravenous general anesthetics

⦁ Local anesthetics

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⦁ Desflurane
⦁ Halothane
⦁ Isoflurane
⦁ Sevoflurane
⦁ Nitrous oxide

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⦁ Used for maintenance of anesthesia after
administration of an IV agent
⦁ The depth of anesthesia can be altered rapidly
by changing inhaled concentration of the drug
⦁ Narrow therapeutic index (from 2 -4)
⦁ The difference between the dose causing no
effect, surgical anesthesia and severe cardiac
and respiratory depression is small
⦁ No antagonists exist

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⦁ Potency of inhaled anesthetic is defined as
the minimum alveolar concentration (MAC)
⦁ MAC: the concentration of anesthetic gas
needed to eliminate movement among
50% of patients
⦁ Expressed as the percentage of gas in a
mixture required to achieve the effect
⦁ The smaller MAC is the more potent the
drug
⦁ Nitrous oxide alone cannot produce
complete anesthesia

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⦁ The more the blood solubility, the
more the anesthetic dissolves in the
blood and the longer the induction
and recovery time needed and slower
changes in the depth of anesthesia
occur as we change the concentration
of inhaled drug
⦁ Halothane> isoflurane>
sevoflurane>nitrous oxide >desflurane

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⦁ Cardiac output affects the removal of anesthetic to
peripheral tissues (not the site of action)
⦁ The higher the cardiac output, the more the
anesthetic is removed, the slower the induction
time

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⦁ Mechanism of action
◦ No specific receptor has been identified as the locus
cerueles of general anesthetic action
◦ Anesthetics increase the sensitivity of GABA receptors to
the neurotransmitter GABA prolonging the inhibitory
chloride ion current after GABA release, reducing the
postsynaptic neurons excitability
◦ Anesthetics increase the activity of the inhibitory glycine
receptors in the spinal motor neuron
◦ Anesthetics block excitatory postsynaptic nicotinic
Receptors.
◦ The mechanism by which the anesthetics perform these
modulatory roles is not understood

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⦁ Potent anesthetic, weak analgesic.

⦁ Administered with nitrous oxide, opioids or local

anesthetics

⦁ Being replaced by other agents due to its adverse

effects

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⦁ Adverse effects
◦ Cardiac effects: Vagomimetic effects, bradycardia, can
cause cardiac arrhythmias
◦ Malignant hyperthermia:
🞄Rare and life threatening condition
🞄Uncontrolled increase in skeletal muscle oxidative
metabolism, which overwhelms the body’s capacity to
supply oxygen, remove carbon dioxide, and regulate
body temperature
🞄If untreated would cause circulatory collapse and
death
🞄Treatment: Dantrolene (SMR) administration

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⦁ Undergoes little metabolism, not toxic to the liver
or kidney

⦁ Does not induce cardiac arrhythmias

⦁ Produces dose-dependent hypotension due to

peripheral vasodilation

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⦁ Provides very rapid onset and recovery due to its
low blood solubility, the lowest of all the volatile
anesthetics
⦁ Popular anesthetic for outpatient surgery

⦁ Irritating to the airway and can cause

laryngospasm, coughing, and excessive
secretions,
⦁ Degradation is minimal, tissue toxicity is rare

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⦁ Less irritant, allowing rapid induction without
irritating the airway, making it suitable for
inhalation induction in pediatric patients

⦁ Replacing halothane for this purpose

⦁ Metabolized by the liver, and compounds formed

in the anesthesia circuit may be nephrotoxic

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⦁ Non-irritating and a potent analgesic but a weak general anesthetic

⦁ Nitrous oxide is frequently employed at concentrations of 30–50% in

combination with oxygen for analgesia, particularly in dental surgery.

⦁ Nitrous oxide at 80 percent (without adjunct agents) cannot produce

surgical anesthesia

⦁ Combined with other, more potent agents to attain pain-free anesthesia

⦁ Mechanism of action is unresolved, might involve activity on GABAA and

NMDA receptors

⦁ Least hepatotoxic of all inhaled anesthetics

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⦁ Used in situations that require short duration
anesthesia (outpatient surgery)
⦁ Primarily used as adjuncts to inhalationals
⦁ Administered first
⦁ Rapidly induce unconsciousness
⦁ In lower doses, they may be used to provide
sedation

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Induction
⦁ After entering the blood stream, a percentage of the drug
binds to the plasma proteins, and the rest remains
unbound (free)
⦁ The drug is carried by venous blood to the heart
⦁ The majority of the CO (70%) flows to the brain, liver, and
kidney
⦁ Once the drug has penetrated the CNS tissue, it exerts its
effects
⦁The exact mechanism of action of IV anesthetics is unknown
Recovery
⦁ Recovery from IV anesthetics is due to redistribution from
sites in the CNS

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⦁ Propofol
⦁ Barbiturates
⦁ Benzodiazepines
⦁ Opioids
⦁ Ketamine

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⦁ IV sedative/hypnotic used in the induction or
maintenance of anesthesia
⦁ Widely used and has replaced thiopental as first choice
for anesthesia induction and sedation, because it does
not cause postanesthetic nausea and vomiting
⦁ The induction of anesthesia occurs within 30–40
seconds of administration
⦁ Supplementation with narcotics for analgesia is
required.
⦁ Propofol decreases blood pressure without depressing
the myocardium
⦁ It also reduces intracranial pressure due to systemic
vasodilation

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Like most intravenous anesthetics, Propofol works
by increasing GABA-mediated inhibatory tone in
the CNS. Propofol decreases the rate of
dissociation of the GABA from the receptor,
thereby increasing the duration of the GABA-
activated opening of the chloride channel with
resulting hyperpolarization of cell membranes.

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⦁ The barbiturates are not significantly analgesic, require
some type of supplementary analgesic administration
during anesthesia to avoid objectionable changes in
blood pressure and autonomic function.

⦁ Can cause apnea, coughing, chest wall spasm,

laryngospasm, and bronchospasm

⦁ Thiopental
◦ Potent anesthetic but a weak analgesic
◦ Ultrashort-acting barbiturate
◦ Has minor effects on the cardiovascular system, but it may
contribute to severe hypotension in patients with hypovolemia
or shock.
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⦁ Used in conjunction with anesthetics to sedate the patient
🞂 Midazolam
🞄 Diazepam
🞄 Lorazepam
🞄 Facilitate amnesia while causing sedation
🞄 Enhance the inhibitory effects of various
neurotransmitters, particularly GABA
⦁ Minimal cardiovascular depressant effect
⦁ Potential respiratory depressants
🞄 Can induce a temporary form of anterograde amnesia in
which the patient retains memory of past events, but new
information is not transferred into long-term memory
◦ Important treatment information should be repeated to the
patient after the effects of the drug have worn off

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⦁ Commonly used with anesthetics due to their analgesic property
⦁ The choice of opioid used perioperatively is based primarily
on the duration of action needed
⦁ Fentanyl, remifentanil
◦ Induce analgesia more rapidly than morphine.
◦ Administered intravenously, epidurally, intrathecally
⦁ Not good amnesics
⦁ Can cause hypotension, respiratory depression, muscle
rigidity and postanesthetic nausea and vomiting
⦁ Opioid effects can be antagonized by naloxone.

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⦁ A short-acting nonbarbiturate anesthetic
⦁ Used for short procedures
⦁ Induces a dissociated state in which the patient is
unconscious (but may appear to be awake) and does
not feel pain
⦁ This dissociative anesthesia provides sedation,
amnesia, and immobility
⦁ Interacts with the N-methyl-D-aspartate
receptor(NMDA)
⦁ Stimulates the central sympathetic outflow, which, in
turn, causes stimulation of the heart with increased
blood pressure and CO
◦ Beneficial in patients with hypovolemic or cardiogenic shock
and in patients with asthma)
◦ Not used in hypertensive or stroke patients
⦁ Causes post-operative hallucinations
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⦁ Used to stop reflexes to facilitate tracheal
intubation, and to provide muscle relaxation as
needed for certain types of surgery
⦁ Mechanism of action is blockade of the nicotinic
acetylcholine receptors in the neuromuscular
junction
⦁ Include pancuronium, rocuronium,
succinylcholine, and vecuronium

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Regional & Local

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⦁ Amides (lidocaine) and esters (procaine)
⦁ Cause loss of sensation and, in higher
concentrations, motor activity in a limited area of
the body
⦁ Applied or injected to block nerve conduction of
sensory impulses from the periphery to the CNS

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⦁ Mechanism:
◦ Local anesthesia is induced when propagation of
action potentials is prevented, so that sensation
cannot be transmitted from the source of
stimulation to the brain
◦ Work by blocking sodium ion channels to prevent
the transient increase in permeability of the nerve
membrane to sodium that is required for an action
potential to occur

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⦁ Lidocaine
⦁ Bupivacaine
⦁ Procaine
⦁ Ropivacaine
⦁ Tetracaine
⦁ Mepivacaine
◦ Not used in obstetric anesthesia due to its increased
toxicity to the neonate

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⦁ Local anesthetics cause vasodilation, which
leads to rapid diffusion away from the site of
action and results in a short duration of action

⦁ Adding the vasoconstrictor epinephrine to the

local anesthetic, the rate of local anesthetic
diffusion and absorption is decreased

⦁ This both minimizes systemic toxicity and

increases the duration of action

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⦁ They are applied directly to the skin or mucous
membranes
⦁ Benzocaine is the major drug in this group
⦁ Lidocaine and tetracaine ca be used topically
⦁ They are used to relieve or prevent pain from minor
burns, irritation, itching
⦁ They are also used to numb an area before an
injection is given.
⦁ Expected adverse effects involve skin irritation and
hypersensitivity reactions

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2) Dexmedetomidine
Medical Knowledge.

55
56
 Adrenergic Receptors
• Alpha (α) alpha1
A
alpha2
& B

beta1
• Beta (β)
beta2
• Alquist RP.A study of adrenergic receptors. Am j physiol.1948; 153: 586-589
• Langer SZ. Pre Synaptic regulation of catecholamine release. Biochem Pharmacol
57
1974; 23: 1793-1800
 Adrenergic Receptors : alpha 2
• pre
• post &
• Extra
synaptic sites of sympathetic terminals

Only the pre-synaptic type of alpha2

receptors are of clinical importance
Drew GM, Whiting SB. Evidence for two distinct types of post synaptic alpha adrenoceptors in vascular smooth
muscle in vivo. Br J Pharmacol. 1979; 67: 207-215
58
Adrenergic Receptors : alpha 2
• regulate the release of nor-adrenaline and
adenosine tri phosphate (ATP), through
negative feedback mechanism.
• located in central nervous system,
peripheral nerves, vascular smooth
muscles, platelets and various splanchnic
organs like, liver, kidney, pancreas and
eye.
• Gertler R, Brown H, Mitchell D and Silvius E. Dexmedetomidine: a novel- sedative – analgesic
agent. Proc (Baylor Univ med Cent) 2001;14(1): 13-21 www.baylorhealth.com
59
 Adrenergic Receptors : alpha 2
• Mechanism of action: by modulation of
ion channels causing hyperpolarization of
cell membrane, and suppression of entry
of calcium ions at nerve terminals.
• Suppress, both neuronal firing and
release of neurotransmitter, nor-
adrenaline.
• useful mechanisms of action of the drugs
which act as alpha2 adrenergic agonists
•Cotechhia S. Kobilka BK, et al. Multiple secondary messenger pathways of alpha adrenergic receptor subtypes expressed in
eukaryotic cells. J Biochem 1990; 103: 163-224
61 Acta. 1990;1031:
• Birnbaum L. Abramowitz J, Brown AM. Receptor – effector coupling by G- proteins. Biochem Biophys
163-224
 Dexmedetomidine
 MOA

62
 MOA

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64
alpha 2 Adrenergic Receptor Agonists

• Imidazole class of drugs

• Older drugs : xylazine
detomidine
medetomidine
in veterinary medicine!

• Clarke KW, Hall LW.“Xylazine” a new sedative for horse and cattle. Vet rec1969; 85: 512-517
• Tamsent A, Gordh T. Epidural clonidine produces analgesia, Lancet1984; 2:231-232
65
alpha 2 Adrenergic Receptor Agonists

Clonidine

66
 Clonidine
• first of these drugs for human use
• Introduced as a nasal decongestant
• ‘side-effects’ : prolonged sedation and
severe hypotension.
• It was named as ‚Potent centrally acting
anti-hypertensive agent‛
• Was available only as oral preparation
• Parenteral clonidine: Newer applications
• Various routes: Intravenous, Neuraxially,
regional blocks,etc. 67
Dexmedetomidine

68
alpha 2 Adrenergic ReceptorAgonists

Dexmedetomidine
What is so special about it?

69
 Dexmedetomidine
• a D – enantiomer of medetomidine
• New Entrant in this class
• approved in 1999 by FDA for clinical
application in humans
• Structure:

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 Actions
• Central
Sedation, anxiolysis and analgesia
(Controlled Cooperative Sedation)
Bradycardia and hypotension
• Peripheral
Decreased GI secretions, inclusive of saliva
Decreased GI motility
Inhibition of rennin-Angiotensin (RA) system and
decreased release of rennin
Increased Glomerular Filtration Rate (GFR),
Increased excretion of Na, water and thus diuresis
Decreased intra-ocular pressure
Decreased insulin release
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Actions

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 MECHANISM
CLINICAL CNS EFFECTS

• at supra-spinal level as well as at spinal level

Supra-spinal: Locus coeruleus:
– Brainstem center - modulates wakefulness
– Major site for hypnotic actions (sedation,
anxiolysis)

73
 MECHANISM
CLINICAL CNS EFFECTS
• Spinal: Spinal cord
 Binding to 2 receptors analgesia At
Substantia gelatinosa (Lamina II),
 closing the gate at the dorsal horn to
stimuli coming from Aδ and C fibers
 Inhibit release of nociceptive humoral
transmitters like Substance P

release of substance P

•Kuraishi Y, Hirota N, Sato Y, et al Noradrenergic inhibition of the release of Substance P from the primary afferents in the rabbit spinal cord
dorsal horn. Brain res.1985; 309: 177-182
74
 CELLULAR MECHANISM

Ca++
Ca++ – Decrease in action
potential due to
Ca++ hyperpolarization

2A

2AR

Go Gk K+
– K+
+
K+
Decrease in
influx of Ca++

75
 CNS ACTIONS
• Sedation – central,Negative Feed back
• Analgesia – spinal cord, Substance P

Dexmedetomidine

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 CNS ACTIONS
• Sedation, resembles the physiologic sleep
with less prominent respiratory depression
• Action is supposed to be mediated through
α2A subset of receptors and is very specific
for dexmedetomidine as compared to
clonidine
• Are easily arousable and additional sedative/
adjuvant is not needed to maintain the
sedation
•Hunter JC, Fontana DJ, Hedley LR et al. Assessment of the role of alpha 2 adrenoceptor subtypes in anti nociceptive , sedative and
hypothermic action of dexmedetomidine in transgenic mice Br J Pharmacol1997; 122: 1339-1344

•Venn RM, Bradshaw CJ, Spencer R et al. Preliminary UK experience of dexmedetomidine, a novel agent for post operative sedation
in intensive care unit. Anaesthesia 199; 54:1136-1142 77
 Actions on Cardio-Vascular system

• Totally devoid of any direct effects on

myocardium
• transient increase in BP : attributable to
peripheral vasoconstriction due to
stimulation of α2B adrenoreceptors in
peripheral vascular smooth muscles.
• significant bradycardia & Hypotension
Secondary to central inhibitory α2A agonist
effect
• all these effects can be offset or overcome
with use of atropine, ephedrine or volume
loading 78
 PHARMACOKINETICS
 Distribution: Rapid (steady-state volume of distribution:
118 L)
 Onset of action (IV route): 10-15 minutes
 Tmax (time needed to reach peak concentrations): 1
hour (after continuous IV infusion)
 Protein binding: 94% (serum Albumin & α1-glycoprotein)
 Follows linear or zero-order kinetics (a constant amount
of the drug is eliminated per hour)
 Elimination half-life (t ½ β): between 2.0 and 2.5 hours
 Metabolism: Liver through glucuronide conjugation and
biotransformation (by cytochrome P450 enzyme system)
 Excretion: 95% urinary & 4% fecal

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PHARMACOKINETICS

80
Biotransformation and Excretion
• Through liver with minimal unchanged
fraction
• 95% of this metabolized portion is excreted
through kidney
• metabolites do not have any significant
pharmacological activity
• Thus liver dysfunction may adversely affect
the clearance of drug
• Impaired renal dysfunction is not known to
change the pharmacokinetics of the drug
•Gertler R, Brown H, Mitchell D and Silvius E Dexmedetomidine: a novel- sedative – analgesic agent.
Proc (Baylor Univ med Cent) 2001;14(1): 13-21 www.baylorhealth.com

81
 Clinical Administration
• Onset of 10-15 minutes as compared to that
of midazolam 3-5 minutes and that of
propofol 30-50 seconds
• Duration of analgesic action of about 4
hours as compared to that of Fentanyl up
to 60-80 minutes
• Offset of sedative action in 5 minutes, while
midazolam has about 2 to 6 hours and
propofol has 3-8 minutes.

82
 Indications
• A pre-anaesthetic medication and as a
psychosedation in short outpatient surgical
procedures.
• found to attenuate the stress induced
sympatho adrenal responses to
laryngoscopy, endotracheal intubation,
surgical stimulation and provide overall
increased hemodynamic stability & as an
adjuvant to other anaesthetic agents,
including inhalational agents like isoflurane.
83
 Indications

• an intra-operative analgesic in GA as an
alternative to opioids
• as a post-operative analgesic
• More so used as a sole sedative and analgesic
combined in Critically ill patients on Ventilator

Scheinin B, Lindgren L, Bandel T, Scheinin H, Scheinin M. Dexmedomidine attenuates sympatho adrenal responses to
tracheal intubation and reduces need for thiopentone and peri-operative fentanyl Br J Anaesth 1992; 68: 126-131

Menda F, Koner O, Sayin M, Ture H et al. Dexmedetomidine as an adjunct to anaesthetic induction to attenuate
84
hemodynamic response to endotracheal intubation in patients undergoing fast track CABG. Ann Can J Anaesth 2010’
13: 16-21
 Indications
• It has been found to provide neuro-
protective effect by decreasing cerebral
blood flow without increasing either with
cerebral metabolic rate (CMRO2) or intra
cranial pressure (ICP)
• sole sedating agent with local anesthetic
agents in a high risk patient
• used as anti-shivering and for
thermoregulation
•Zornov MH, Maze M, Dyek JB. Shafer SL. Dexmedetomidine decreases cerebral blood flow velocity in humans J
Cereb Blood Flow Metab 1993; 13: 350-352
85 for axillo-femoral
•Rich JM. Dexmedetomidine as a sole sedating agent with local anesthesia in a high risk patient
bypass graft: a case report. AANAJournal2005;73:357-360
Antidote :alpha 2 Adrenergic
Receptor Antagonist

Atipamezole and
Yohimbine
• Effectively reverses Psychomotor side-
effects
• Reverses Sedation & Sympatholysis
• ReversesAnalgesia
• t ½ is 1 ½ - 2 hours.
86
 Dexmedetomidine & Sedation
(Literature Review)
Dexmedetomidine vs Midazolam for
Sedation of Critically Ill Patients: A
Randomized Trial (Richard R. Riker, MD et. al ;
JAMA, February 4, 2009—Vol 301, No. 5)

At comparable sedation levels,

Dexmedetomidine- treated
patients spent less time on the
ventilator, experienced
Less delirium, and developed
tachycardia and hypertension.
The most notable adverse effect of 87
Dexmedetomidine was bradycardia
 Dexmedetomidine & Sedation
(Literature Review)
Dexmedetomidine as a Sedative Agent in
Critically Ill Patients: A Meta-Analysis of
Randomized Controlled Trials (Laura Pasin et. al ; PLOS
ONE, December 2013, Volume 8, Issue 12, e82913)

Dexmedetomidine could help to ICU stay and time to

extubation, in critically ill patients.

(3,648 patients)
88
 Dexmedetomidine & Sedation
(Literature Review)
Dexmedetomidine: a
unique clinical profile in
ICU sedation (Steve Chaplin;
FUTURE PRESCRIBER Vol 13(3) )

Dexmedetomidine shorten the

median duration of
mechanical ventilation
compared with midazolam,
but not propofol.
Dexmedetomidine also shortenthe median time to
extubation compared with both agents 89
 Dexmedetomidine & Sedation
(Literature Review)
Sedation with dexmedetomidine in the intensive
care setting (Anthony T et. al; GerlachOpen Access Emergency Medicine
2011:3 77–85)

Dexmedetomidine is an α-agonist that does not

produce respiratory depression and is an option for
sedation in ICU patients.

However, it is associated with hemodynamic side

effects, including clinically significant bradycardia.
90
 Dexmedetomidine & Sedation
(Literature Review)
Comparison between
dexmedetomidine and propofol
for sedation in the intaensive care
unit: patient and clinician
perceptions (R. M. Venn et. al; British
Journal of Anesthesia)

An equivalent depth of sedation

between dex and propofol in the
ICU was achieved and
dexmedetomidine could
opioid requirement by 50% 91
 Opioid Sparing Role of Dexmedetomidine that
reduced the need for opioids without
compromising patient comfort in the
ICU(Randomized open label multicentral controlled trials of 295 adults undergoing
CABG)

39% of 28% of
Patients Patients
didn’t required 72% of
63 % of
require Morphine Patients
Patients
Morphine didn’t
required
require
Morphine
Morphine

Propofol based sedation

92
.
7.Herr et al , J Cardiothorac Vasc Anesth, 2003 Oct;17(5):576-84
 Dexmedetomidine & Delirium
Randomized clinical trial of intraoperative
Dexmedetomidine to prevent delirium in the
elderly undergoing major non-cardiac surgery 8

Intraoperative Dexmedetomidine halved the risk of delirium in the

elderly after major non‐cardiac surgery93
8.C.-J. Li, B.-J. Wang, D.-L. Mu, J. Hu, C. Guo, X.-Y. Liet al. BJS2020;107: e123–e132
 Dexmedetomidine & Delirium

Dexmedetomidine has been described to be effective in

treating four patients with agitation and hyperadrenergic
states refractory to haloperidol.

Dexmedetomidine may be of great benefit in treating and

preventing agitation and delirium in perioperative and
ICU patient care

Dexmedetomidine may be of great benefit in treating and

preventing agitation and delirium in perioperative and
ICU patient care
94
From Previous Trials :Delirium
Percentage Comparison

95
Dexmedetomidine & Sedation
(Literature Review)
Management of ICU –related agitation and
delirium with Dexmedotimidine(Hashemian, topics in
thoracic surgery 2012, ISBN: 978-953-51-0010-2)

96
97
98
 Agitated patient PAD

Pain Anxiety Delirium

In a studies it was found once a analgesic was given more

than 60% of patients do not require sedation. We suggest
that analgesia-first sedation be used With adult ICU patients

99
 PAD Guideline 2013 &
Dexmedetomidine PAD

PAD 2013 Says:

We suggest that in adult ICU patients with delirium

unrelated to alcohol or benzodiazepine
withdrawal, continuous i.v. infusions of
Dexmedetomidine rather than benzodiazepine
infusions be administered for sedation to reduce the
duration of delirium in these patients. (+2B)

100
 Dexmedetomidine & AWS
Concerns in AWS:

1. Agitation and autonomic hyperactivity control is

essential in severeAWS

2. Benzodiazepine monotherapy may be insufficient

for control of AWS

101
 Dexmedetomidine & AWS

Potential Benefits of Dexmedetomidine:

1. Provides sedation and less autonomic activity

2. No effect on respiratory function

102
 Review of Dexmedetomidine for severe
AWS
Clinical outcomes and efficacy
Case series comparing pre- and post-Dexmedetomidine
show rapid response :
1. Improved CIWA-Ar score
2. in blood pressure and heart rate
3. in benzodiazepines and haloperidol usage
Proposed benefits: Avoid mechanical ventilation and
facilitate extubation

Safety
Hypotension and bradycardia most common adverse
effects 103
 Dexmedetomidine & Seizure
Anticonvulsant Data:

An animal study(Rats) has shown that

Dexmedetomidine decreases the CNS toxicity of
bupivacaine and by
Decreasing theconvulsive dose and threshold
plasma concentrations for convulsions

Another animal study(Rats) suggest that

Dexmedetomidine decrease the cocaine-induced
seizure threshold possibly via a mechanism related to
the attenuation of the extracellular dopaminergic
neurotransmitter response to cocaine. 104
 Dexmedetomidine & Cardiovascular
System
Dexmedetomidine may decrease the risk of
ventricular tachycardia and hyperglycemia.
Thus, Dexmedetomidine could be a safe and
efficacious sedative agent in cardiac surgical
patients.

Perioperative Dexmedetomidine use was associated

with a low rate in postoperative mortality up to 1
year and incidence of postoperative complications
and delirium in patients undergoing cardiac surgery
105
 Dexmedetomidine in procedural
sedation

1 Awake fibreoptic 2 Cataract surgery 3 Colonoscopy

Intubation

4 Upper Endoscopy 5 Post operative Bronchoscopy 6 Neuro and Vascular Surgery

106
 MULTI MODAL
AN ALGESI
A (MMA)
The rationale for multimodal analgesia is
achievement of sufficient analgesia due to
additive or synergistic effects between different
analgesics, with concomitant reduction of side
effects, due to resulting lower doses of analgesics
and differences in side-effect profiles.

1. Kehlet H et al. Anesth Analg 1993;77:1048-56. 107

 “Real World”: Multimodal Analgesia
• Reduced doses
Opioids
• Improved pain relief
• Reduce severity
Potentiation of AEs

• Earlier discharge
Non opioids :α2 agonists
NSAIDs, coxibs, • Decreased costs
paracetamol,
nerve blocks

Kehlet et al. Anesth Analg. 1993;77:1048-1056 (B).

 Preventive Multimodal Analgesia

• Significant improvement in
– Pain reduction

– Opioid use

– Opioid-related AEs

– Recovery or day ward length of stay

– Unplanned admission to the hospital

109
Reuben et al. Acute Pain. 2004;6:87-93.
 Multimodal analgesia should consist of….
Combination of Agents

• Newer ‘Novel’ Centrally acting I. V.Non-Opioid agents

2-agonists

Parenteral Paracetamol
NSAIDs, COX-2 selective inhibitors (coxibs)
Ketamine , Tramadol, Neostigmine
Gabapentin / Pregabalin
• Opioids
• Local anaesthetics: local anaesthetic block
– Local infiltration
– Local nerve block
– Plexus nerve block
– Neuraxial block
110
 Proposed Protocols MMA- I
• Pre-medication/ Analgesia with Dexmedetomidine
• Dose: 1 µg/ kg I.V. for 10 minutes
• Induce with small dose of Propofol
• Rocuroneum for Intubation/ Maintenance
• Inhalational iso or sevoflurane
• Near end of surgery I.V. Paracetamol- 15mg/ kg- upto
1g max.
• Continue every 4-6 hourly , till NBM status, switch to
oral NSAID/COXIB
• Dexmedetomidine infusion: Post operative or ICU
sedation/analgesia in ventilated patients: Dex. 0.5
µg/kg/hr infusion
111
 Proposed Protocols MMA- II
• Neuraxial Blockade with 0.75% ropivacaine;
3 ml intra-thecal or 12-15 ml epidural
• Sedation with Dexmedetomidine : 0.2 to 0.7
µg/kg/hr.
• Post-op analgesia with : either epidural with
or without adjuvant; like clonidine 75µg,
midazolam 0.5 mg, fentanyl 25-50 µg
• I V Paracetamol &/ or Dexmedetomidine
112
 Summarizing
• Alpha2 adrenoceptor agonists are very unique
class of drugs
• imidazole group
• latest entrant: Dexmedetomidine
• mimics many of the actions of mythical
‘ideal’sedative/analgesic agent
• wide spectrum of actions for the entire peri-
operative period and then beyond that, into
the critical care services/ as a part of Multi-
ModalAnalgesia 113
 Conclusion
• Dexmedetomidine is revolutionizing, the intra-
venous anaesthesia
• Changing pre-operative sedation, pre-
anaesthetic anxiolytic medication and even the
day care procedures like conscious sedation
• changing our viewpoint of providing intra and
post- operative analgesia, without any potential
and significant side-effects of existing agents
employed for this purpose.

114
 Conclusion
• In critical care setting as a sedative/ analgesic,
without much deleterious effects, morbidity
and dependence of the patients on the
ventilators.
• All these indications with a high safety
profile makes it a promising, desirable and
dependable drug.

115
 Take Home Message!
6 Final Points

1. Dexmedetomidine has a mechanism of action

that is different from that of benzodiazepines
and Propofol. It has greater selectivity for
alpha-2 receptors than Clonidine, suggesting
the potential for a lower risk of
hemodynamic adverse events.
116
 Take Home Message!
6 Final Points
2. The nature of the sedation induced by
Dexmedetomidine is different to that of
established agents, although the depth of the
sedation is comparable between the agents.
Patients being treated with Dexmedetomidine
are responsive to stimuli, and in clinical
trials, nurses noted better co-operation and
communication with patients treated with
Dexmedetomidine compared with Midazolam
and Propofol.
117
 Take Home Message!
6 Final Points

3. Importantly, delirium is less frequent with

Dexmedetomidine treatment than midazolam
and propofol, and the time to extubation is
shorter than with either midazolam or propofol.

118
 Take Home Message!
6 Final Points

4. Dexmedetomidine is not believed to cause

respiratory depression.

119
 Take Home Message!
6 Final Points
5. Consistent with its pharmacology, cardiovascular
adverse events are the most commonly reported
in clinical trials.

However, in clinical trials, the overall frequency of

discontinuation due to adverse events was similar
for Dexmedetomidine, Midazolam and Propofol.

120
 Take Home Message!
6 Final Points

6. In clinical trials, Dexmedetomidine was

noninferior to other sedating agents and
offered a different quality of sedation to
others.

121
Dexmedetomidine – Market