DEXMED- ALPHA 2 AGONIST

1. Dr. ZIKRULLAH

2. Introduction
 Alpha 2 agonists are increasingly being used in
anaesthesia as they not only decrease sympathetic
tone and attenuate the stress response to anaesthesia
and surgery but also cause sedation and analgesia.
 They are also used as adjuvants during regional
anaesthesia.
 Clonidine ,which was initially introduced as anti
hypertensive ,is the most commonly used alpha 2
agonists by anaesthesiologist.

3.  Dexmedetomidine is the most recent agent found in
this group approved by FDA in 1999 for use in
humans for analgesia and sedation.
 It is a dextro-isomer and pharmacologically active
component of medetomidine , which has been used
for many years in vetenary practice for its its
hypnotic, sedative and analgesic effects.

4. SYSTEMIC NAME
 (S)-4-[1-(2,3-dimethylphenyl)ethyl]-3H-imidazole
EMPERICAL FORMULA
 C13H16N2•HCl
STRUCTURAL FORMULA

5. MECHANISM OF ACTION
 Dexmedetomidine is a highly selective, specific , and
potent alpha 2 adrenergic agonist.
 Alpha 2 : alpha 1 ~ 1600 : 1
 Alpha 2 receptors has 3 subtypes-
subtype A - CNS- Responsible for the sedative,
analgesic and sympatholytic
effect.
subtype B - Peripheral vasculature - Responsible
for the short-term hypertensive
response.
subtype C - CNS - Responsible for the anxiolytic
effect.

6. Site of alpha 2 receptors
Pontine locus ceruleus
 Important modulator of vigilance.
 Presynaptic activation of the alpha2-A inhibits the
release of norepinephrine results in the sedative and
hypnotic effects .
 Locus Ceruleus is the site of origin for the descending
medullospinal noradrenergic pathway, an important
modulator of nociceptive neurotransmission.
Stimulation of the alpha2-adrenoceptors in this area
terminates the propagation of pain signals leading to
analgesia.

7. CONT..
Medullary vasomotor center
 Post synaptic activation of alpha 2 receptor results in
decrease in sympathetic nervous system outflow from
CNS to peripheral tissue.
Substantia gelatinosa of the spinal cord
 Stimulation of alpha2-receptors leads to inhibition of
nociceptive neurons firing and the release of substance P.
Peripheral sympathetic nervous system nerve ending
Analgesic action by preventing NE release.
Blood vessels-
 Mediate vasoconstriction.

9. Pharmacokinetics
 Protein binding - > 90 %
 Distribution half life-- 6-8 minutes
 Elimination Half life - 2-3 hrs
 Metabolism - Hepatic metabolism
(glucuronidation and
Cytochrome p450
metabolism )
 Excretion - by kidney

10. formulation
 Only parenteral preperations are available.
 Administered as loading dose followed by
continuous infusion
 Administered by using a controlled infusion
device.
 Must be diluted in 0.9% sodium chloride
solution to achieve required concentration
(4 mcg/mL) prior to administration.

11. PHARMACODYNAMICS
CENTRAL NERVOUS SYSTEM
 Cause sedation by decreasing sympathetic nervous
system activity and the level of arousal.
 Result is calm patient,can be aroused readily to
full consciousnes and less likely to be disoriented
or uncooperative.
 Unlike other sedative does not cause clouding of
consciousnes, depression of ventilation , agitation
or delirium.

12. Cont..
CARDIOVASCULAR SYSTEM
 It has a biphasic cardiovascular response.
 The bolus dose results in transient increase in
blood pressure and reflex decrease in heart rate.
This is attributed to stimulation of peripheral alpha
adrenoceptors of muscles.
 Infusion results in decrease in heart rate and blood
pressure below baseline caused by inhibition of
central sympathetic outflow.
 Dexmedetomidine produces vasoconstriction in
denervated arteries and therefore its use in patients
with microvascular free flaps and cerebrovascular
disease should be avoided.

13. Cont..
RESPIRATORY SYSTEM
 Does not cause depression of ventilation.
RENAL SYSTEM-
 Diuresis due to inhibition of ADH release and
antagonism of ADH tubular effects.
High dose infusion can lead to loss of muscle tone
with potential for airway obstruction in non
intubated patients..

14. Other effects
Activation of alpha2-adrenoceptors in other areas
results in-
 decreased salivation
 decreased secretion
 decreased bowel motility in the gastrointestinal
tract.
 decreased insulin release from the pancreas.
 decreased intraocular pressure.
 decreased platelet aggregation ..
 decreased shivering threshold by 2°C.

15. CLINICAL USES AND DOSES
 As premedication.
 As an anesthetic adjunct for general and regional
anesthesia .
 As postoperative sedative and analgesic.
 In ICU for sedation
 Other uses-
 To attenuate the cardiostimulatory and post-
anaesthetic delirium effects of ketamine .
 Perioperative hypothermia
 Treatment for shivering.
 Treatment of cardiovascular manifestation of
cocaine intoxication

16. As premedication
 Dose is 0.33 to 0.67 mcg/kg IV given 15 minutes before
surgery.
 It possesses anxiolytic , sedative , analgesic ,antisialogogue and
sympatholytic properties.
 Attenuates hemodynamic response to tracheal intubation .
 Decreases perioperative requirements for inhaled anaesthetics
and opiods .
 Decreases oxygen consumption intraoperatively by 8% and
postoperatively by 17%
 Indications - patients susceptible to preoperative and
perioperative stress, drug addicts and alcoholics, chronic opioid
users and hyertensive patients

17. As an adjunct to general anaesthesia
 Increase hemodynamic stability because of attenuation of
the stress-induced sympathoadrenal responses to
intubation, during surgery and during emergence from
anesthesia.
 Reduction in requirements of inhalational or IV
anaesthetic agent for maintenance of anesthesia.
 Produces intraoperative and postoperative opioid-
sparing effect.
 Reduced need for pain medication in the PACU, thereby
reducing the length of stay.
 Reduces the shivering threshold and is associated with a
lower incidence of shivering.
 Used in the dose 0.2 to 0.7 mcg/kg/hr as continuous
infusion after 1mcg/kg loading dose.

18. As an adjunct to regional anaesthesia
 The faster onset of action of local anaesthetics.
 Rapid establishment of both sensory and motor blockade.
 Prolonged duration of analgesia into the post-operative
period.
 Dose-sparing action of local anaesthetics.
 Stable cardiovascular parameters.
 Good sedation and anxiolysis level during surgery
 Dose in spinal anaesthesia - 3 -15 mcg
 Dose in epidural anaesthesia - 1- 1.5 mcg/ml
 0.5 μg/kg dexmedetomidine to lidocaine for IVRA
improves quality of anesthesia and improves
intraoperative-postoperative analgesia without causing
side effects

19. Use in the postoperative period
 In addition to its sympatholytic effects, analgesic
effects and decreased rate of shivering, the
preservation of respiratory function allows the
continuation of the dexmedetomidine infusion in the
extubated, spontaneously breathing patient.
 Beneficial in reducing high rates of early
postoperative ischemic events in high-risk patients
undergoing non-cardiac surgery.

20. In Monitored Anaesthesia Care
 Ideal agent for MAC.
 Arousable sedation with ease of orientation,
anxiolysis, mild analgesia, lack of respiratory
depression and hemodynamic stability .
 lack of amnesia and poor controllability because of
its slow onset and offset
 Indication-
 Awake craniotomy/ carotid endarterectomy
 Sedation in difficult airway patients during fiberoptic
intubation and lumbar laminectomy surgery in the
prone-chest position under spinal anesthesia.

21. As a sole agent for total intravenous anesthesia
(TIVA).
 Infusion in increasing doses (up to 10 μg/kg/h) until
general anesthesia is attained.
 This new, off-label use of dexmedetomidine is based
on its known properties to provide sedation, analgesia
while avoiding respiratory depression.

22. In ICU
 Used for it's sedative, anxiolytic, and analgesic
properties without any respiratory depression .
 Loading dose of 1mcg/kg over 10 mins ,followed by a
maintenance infusion of 0.2 to 0.7mcg/kg/hr.
 No need to discontinue prior to extubation. Continue
infusion in mechanically ventilated patients prior to
extubation, during extubation, and postextubation.
 Short term (< 24 hrs) sedation of mechanically
ventilated patients.
 To prevent drug withdrawal syndrome following long
term sedation of benzodiazepines.

23. SIDE EFFECTS
 Hypertension (Transient , after loading dose)
 Nausea
 Dry mouth
 Bradycardia
 Systemic hypotention
 Atrial fibrillation
 Overdose may cause 1st deg/2nd deg AV block
 There is a risk for agitation and “sympathetic
rebound” following drug withdrawal , To
minimize this risk, dexmetomidine infusions
should not be continued for longer than 24 hours.

24. CAUTION-
Should be taken in patients
 With pre-existing bradycardia and conduction
problems.
 With reduced ventricular functions(ejection
fraction<30 %).
 Hypovolemic or hypotensive patients.
 Patients of diabetes , chronic hypertention and
elderly.
 With other vasodilators or negative
chronotropic agents due to additive
pharmacodynamic effects.

25. DRUG INTERACTIONS
General
 Weak inhibiting effect on cytochrome p450
Anaesthetics/sedatives/hypnotics/opioids
 Co-administration of Dex. With anaesthetics
(sevoflurane, isoflurane, propofol, alfentanyl
and midazolam ) lead to enhancement of there
effects.

26. Cont..
 No pharmacokinetic interactions have been
demonstrated.
 However due to possible pharmacodynamic
interactions ,when coadministered with dex, a
reduction in dosage of concomitant anaesthetic
, sedative,hypnotic or opioid may be required
Neuromuscular blockers:
 No clinically significant interaction has been
reported

27. Cont..
PREGNANCY
 Teratogenic effects. Pregnancy category c.
 Placental transfer Was observed when radiolabeled
dex.was administered subcutaneously to pregnant rats.
 There are no adequate and well controlled studies in
pregnant woman.
 Dex should be used during the pregnancy only if the
potential benefits justify the potential risk to fetus

28. Cont..
NURSING MOTHERS:
 It is not known whether Dex is excreted in human
milk.
 Radiolabeled Dex administered subcutaneously to
lactating female rats was excreted in milk.
 Caution should be exercised.
PEDIATRICS:
 There have been no clinical studies to establish the
safety and efficacy of Dex in pediatric patients.
 Dex is not recommened for use in pediatric patients

29. Cont..
GERIATRICS
 In patients greater than 65 years of age a higher
incidence of bradycardia and hypotension was
observed following administration of Dex. Therefor
dose reduction may be considered in patients over 65
yrs .
 Dexmedetomidine is known to be substantially
excreted by the kidney and the risk of adverse
reactions to this drug may be greater in patients with
impaired renal functions.

30. conclusion
 Dexedetomidine is used to optimize anesthesia via:
 Sedation, analgesia +  sympathetic activity
 Attenuation of stress response +  HR
 Smooth emergence + tracheal extubation
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