Dexmed : α2 – Agonists

Adrenergic Receptors

Initially, α-adrenergic receptors were distinguished from β-adrenergic receptors by their

greater response to epinephrine and norepinephrine than to isoproterenol. The

development of α and β antagonists further supported the existence of separate α

receptors. Traditionally, adrenergic receptors have been classified as α or β and more

recently as α1, α2, β1, or β2 based on responses to specific drugs3.

Physiology of the Αlpha2 Receptor

α2 adrenergic receptors are primarily located on the presynaptic membrane and modulate release

of norepinephrine, whereas postsynaptic α1 adrenergic receptors mediate smooth muscle

vasoconstriction . α2 receptors are found in the peripheral nervous system, in the CNS, and in a

variety of organs, including platelets, liver, pancreas, kidney, and eyes, where specific physiologic

functions have been identified. Of late, the predominant α 2 receptor of the human spinal cord

was also identified and was named as the α2a subtype3.

Responses mediated by α2-adrenergic receptors

Activation of the receptors in the brain and spinal cord inhibits neuronal firing, causing

hypotension, bradycardia, sedation, and analgesia. The responses to activation of the

receptors in other areas include decreased salivation, decreased secretion, and decreased

bowel motility in the gastrointestinal tract; contraction of vascular and other smooth

muscle; inhibition of renin release, increased glomerular filtration, and increased secretion

of sodium and water in the kidney; decreased intraocular pressure; and decreased insulin

release from the pancreas 2,21.

.

Responses mediated by α2-adrenergic receptors2

Pharmacology of Dexmedetomidine

Dexmedetomidine is the d-enantiomer of medetomidine, a substance that has been used

for sedation and analgesia in veterinary medicine for many years. It belongs to the

imidazole subclass of α2 receptor agonists, similar to clonidine. It is freely soluble in

water.

Chemical structure

Mechanism of action

Presynaptic α2 receptors regulate the release of norepinephrine and adenosine triphosphate

through a negative feedback mechanism. In general, presynaptic activation of the α2

adrenoceptor inhibits the release of norepinephrine, terminating the propagation of pain

signals while postsynaptic activation of α2 adrenoceptors in the central nervous system

(CNS) inhibits sympathetic activity and thus can decrease blood pressure and heart rate.

Combined, these effects can produce analgesia, sedation, and anxiolysis thus avoiding

some of the side effects of multiagent therapies21.

Mechanism of

action21.

The mechanism of the analgesic effects

A number of sites, both supraspinal and spinal, modulate the transmission of nociceptive

signals in the CNS. In addition to dexmedetomidine's action in the locus coeruleus of

the brain stem, it has been shown to stimulate α2 receptors directly in the spinal cord,

thus inhibiting the firing of nociceptive neurons. Even peripheral α2 adrenoceptors may

mediate antinociception16.

The mechanism of the hypnotic and sedative effects

One of the highest densities of α2 receptors has been detected in the locus coeruleus, the

predominant noradrenergic nucleus in the brain and an important modulator of vigilance.

The hypnotic and sedative effects of dexmedetomidine have been attributed to the

endogenous sleep-promoting pathways16.

Mechanisms of the analgesic effects of alpha 2 agonists

and other commonly used analgesics.

Pharmacological actions

Cardiovascular System

A biphasic cardiovascular response has been described after the application of

dexmedetomidine. The administration of a bolus of 1 μg/kg dexmedetomidine initially

results in a transient increase of the blood pressure and a reflex decrease in heart rate,

especially in younger, healthy patients. The initial increase in blood pressure is probably

due to the vasoconstrictive effects of dexmedetomidine when stimulating peripheral α2

receptors. The initial response lasts for 5 to 10 minutes and is followed by a decrease

in blood pressure of approximately 10% to 20% below baseline and a stabilization of the

heart rate, also below baseline values; both of these effects are caused by the inhibition

of the central sympathetic outflow overriding the direct stimulating effects21.

Central Nervous System

1. Sedation

The quality of sedation produced by dexmedetomidine is different from that produced by

other sedatives acting through the GABA systems. They act through the endogenous sleep

promoting pathways. Patients have been described as being very easy to wake up and

having the ability to follow commands and cooperate while being tracheally intubated 9.

Despite sound levels of sedation, there is limited respiratory depression, providing wide

safety margins22.

2. Analgesia

The primary site of analgesic action is thought to be the spinal cord. It is also shown to

have an analgesic effect when injected via the intrathecal or epidural route.

Dexmedetomidine also inhibits the release of substance P from the dorsal horn of the

spinal cord, leading to primary analgesic effects23.

3. Central Nervous System Protection and Other Central Nervous System Effects

Dexmedetomidine in animal models of incomplete cerebral ischemia and reperfusion

reduces cerebral necrosis and improves neurologic outcome. It is shown to reduce the

intracerebral catecholamine outflow during injury resulting in less neural tissue damage

with better neurologic outcome24.

Respiratory System

Although dexmedetomidine produces sedative, analgesic and anxiolytic affects, unlike

other sedatives, it provides respiratory stability and does not cause ventilatory depression.

The changes in ventilation appear similar to those observed during natural sleep. It

exhibits a hypercarbic arousal phenomenon similar to that in normal sleep. Intravenous or

inhaled dexmedetomidine has been implicated in blocking histamine induced

bronchoconstriction in dogs16,25.

Renal System

It is shown to result in diuresis and natriuresis, possibly through an ability to reduce

efferent sympathetic outflow of the renal nerve. It decreases the secretion of vasopressin

and increases the release of atrial natriuretic peptide7,16.

Endocrine System

Action of dexmedetomidine on endocrine system is mainly related to its action on

sympathetic outflow and the decrease of catecholamines. This attenuates the responses to

stress by inhibiting the secretion of adrenocorticotropic hormone (ACTH) and cortisol. In

addition, stimulation of α2 adrenoceptor agonists located on cells of the Islet of

langerhans can temporally cause direct inhibition of insulin release with concomitant

detectable clinical hyperglycemia16.

Preparation and dosage

Available

in 1 or 2 ml vials as dexmedetomidine hydrochloride ; 1ml equivalent to 100 mcg of

dexmedetomidine.

Dexmedetomidine must be diluted in 0.9% normal saline prior to injection. To prepare

the solution, dilute 2 ml in 48 ml or 1 ml in 24 ml of normal saline solution to a total

of 50 ml to make a concentration of 4 µg/ ml.

Dexmedetomidine should be administered through a controlled infusion device.

Dosing should be individualised and titrated to the desired clinical effect.

It is not indicated for infusions lasting more than 24 hrs.

Dexmedetomidine is generally initiated with a loading infusion of 1 μg/kg over 10 min

followed by a maintainence infusion of 0.2 - 0.7 μg/hour. The rate should be adjusted to

maintain the desired level of response.

Pharmacokinetics

Dexmedetomidine is rapidly distributed and extensively metabolized in the liver and

excreted in urine and feces. It undergoes conjugation (41%), n-methylation (21%), or

hydroxylation followed by conjugation. Dexmedetomidine is 94% protein bound, and its

concentration ratio between whole blood and plasma is 0.66. Dexmedetomidine has

profound effects on cardiovascular variables and may alter its own pharmacokinetics.

With large doses, there is marked vasoconstriction, which probably reduces the drug's

volume of distribution. In essence, dexmedetomidine displays nonlinear

pharmacokinetics16,26.

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. Postoperative patients sedated with dexmedetomidine display similar

pharmacokinetics to the pharmacokinetics seen in healthy volunteers27 .

The steady-state volume of distribution is 118 L, and the distribution phase is rapid,

with a half-life of distribution of approximately 6 minutes28 .

Therapeutic uses

1. Intensive Care Unit

i. For sedation in mechanically ventilated patients in loading doses of 0.5 to 1

µg/kg and infusion rates of 0.2 to 0.7 µg/kg/hr.

ii. For weaning patients from the ventilator: the unique characteristics of

dexmedetomidine in providing adequate sedation with minimal respiratory

depression allows for easy weaning29.

iii. To facilitate daily “wake up” tests in mechanically ventilated patients30 .

iv. For treatment of alcohol and drug withdrawal: Dexmedetomidine has been

successfully used in the treatment of withdrawal of narcotics, benzodiazepines,

alcohol, and recreational drugs. It is shown to control withdrawal behaviour and

allows for successful detoxification16 .

2. Anesthesia

i. As a premedicant : to attenuate sympathetic activation during induction of

anesthesia and to provide a more stable hemodynamic profile16,19,24 . Apart from

the intravenous route, it can be given as intramuscular injection in doses of 2.5

µg/kg.26 Administration of intranasal dexmedetomidine at 0.5 or 1 mcg/kg has also

been proved to produce adequate sedation31 .

ii. Sedation for monitored anesthesia care: It has been successfully used in patients

receiving local anesthesia or regional block. Dexmedetomidine has also been

reported to provide successful sedation in paediatric patients undergoing MRI

scans32,33 .

iii. Maintenance of anesthesia: It promotes hemodynamic stability and decreases the

doses of anesthetics and analgesics23 .

iv. Awake fiberoptic intubation: The use of dexmedetomidine when securing the

airway with a fiberoptic intubation is shown to be well tolerated with no

hemodynamic compromise or respiratory depression16.

v. As anesthetic adjunct or sedative agent in patients susceptible to narcotic induced

respiratory depression or sleep apnea. It has been successfully used in patients

undergoing transesophageal echocardiography examination16 .

Drug interactions

A reduction in dosage of all an.esthetics, sedatives, hypnotics and opioids is seen. Care

should be taken when used in concurrence with drugs causing bradycardia like beta

blockers, vecuronium, fentanyl and neostigmine.

Side effects

i. Hypotension, hypertension, nausea, bradycardia, atrial fibrillation, and hypoxia

ii. Overdose may cause first-degree or second-degree atrioventricular block.

Most of the adverse events associated with dexmedetomidine use occur during or briefly

after loading of the drug. By omitting or reducing the loading dose, adverse effects can

be reduced.

Atipamezole, a selective α2 antagonist, at 50 µg/kg was effective in reversing the

sedation of dexmedetomidine (2 µg/kg intramuscularly), when used to provide sedation

for brief operative procedures. This reversal of effects results in more rapid recovery

than occurred after equisedative doses of midazolam34.