Alpa 2 Agonists:

Clonidine and Dexmedetomidine

Dr.Astha Shrestha
1st Year Resident
Dept. of Anaesthesiology
8th June 2021
 Introduction
• Alpha 2 receptor: inhibitory G- protein coupled
receptor that binds norepinephrine

• present in both the CNS and sympathetic ANS

• Within sympathetic fibers ,uniquely found on the

presynaptic terminals of postganglionic
•3 pharmacological subtypes,
α- 2A, α-2B, and α-2C.

•α-2A and -2C subtypes are

found mainly in the central
nervous system.

•Stimulation of these
receptor subtypes inhibits
norepinephrine release

•may be responsible for

sedation, analgesia.
 Agonist effects at α2 receptors
• Alpha 2A (pre synaptic) - sedation, hypnosis, analgesia,
sympatholytic, neuroprotection and inhibition of insulin
secretion.

• Alpha 2B (post synaptic) - suppresses shivering centrally,

promotes analgesia at spinal cord sites, and induces
vasoconstriction in peripheral arteries.

• Alpha 2C - modulation of cognition, sensory processing and

regulation of epinephrine outflow from the adrenal medulla.
 Alpha 2 agonist

• Dexmedetomidine

• Clonidine
 Dexmedetomidine
• Highly specific and selective α2-adrenergic agonist with
α2 to α1 ratio of 1,600:1

• sedative, anxiolytic, and analgesic effects.

• Lipophylic ,α-methylol derivative

• Pharmacologically active dextro-isomer of medetomidine.

• Approved by FDA at the end of 1999 for use in humans as a

short-term medication (<24 hours) for analgesia and sedation
in the intensive care unit (ICU).
Dexmedetomidine is 8 times more selective
than Clonidine
Alpha-Adrenoceptor Agonists
α2:α1 = 1600:1 vs 200:1 α1 • Norepinephrine
• Epinephrine
• Dopamine
• Tizanidine
• Clonidine
• Mivazerol
• Guanfacine
• Guanabenz
• Medetomidine
• Dexmedetomidine
α2
MECHANISM OF ACTION
• Primary analgesic effects
and potentiation of opioid-
induced analgesia result
from the activation of α2-
adrenergic receptors in the
dorsal horn of the spinal
cord.
• Inhibition of substance P
release.
 Pharmacokinetics
• Route: Intravenous infusion (recommended route)
Loading: 1mcg/kg over 10 min
Maintenance: 0.2-0.7 mcg/kg/hr
• Half Life : Short distribution half-life (5 min): Rapid onset of
sedation
Short elimination half-life (2 hr): Facilitates clearance

• Intramuscular (2mcg/kg):Peak plasma conc 13±18 min

(variable)
70% bioavailability
• Enteral: Buccal -  80% bioavailability
Gastric -  16-20% bioavailability

• Intranasal (1mcg/kg) has been used for preoperative

anxiolysis, with an onset of 25 minutes and duration of 85
minutes

• Context sensitive half life – less than 5 min

• Protein binding: 94%
• There are no active or toxic metabolites.
• Hepatic metabolism with limited unchanged.
• Excreted : urine or stool
• Hepatic clearance may be ↓ by as much as 50% of
normal with severe liver disease.
• Pka is not significantly altered in patients with severe
renal impairment, but patients remained sedated for
longer than normal controls, suggesting an enhanced
pharmacodynamics effect.
• Dosages should be ↓ in the presence of either hepatic or
renal disease.
 Infants (1 to 24 months):
• Appear to clear dexmedetomidine more quickly than
adults or older children → (median clearance of
27.2mL/kg/min).
• Need larger initial doses of dexmedetomidine than
the older children to reach a certain plasma
concentration → (young children have a larger
volume of distribution of the drug).
• Similar rates of infusion can be used to maintain a
steady-state concentration of dexmedetomidine in
plasma → (total plasma clearance of
dexmedetomidine is independent of age).
 Effects On System
CVS
• Hypotension and bradycardia(sympathetic inhibition)
– presence of comorbid cardiac disease
– when administered with other medications that
possess negative chronotropic effects
– during vagotonic procedures (laryngoscopy) or
following large or rapid bolus doses.
• High-dose boluses may result in a biphasic response
– with bradycardia and hypertension consequent to
initial stimulation of peripheral alpha-2B vascular
receptors,
– followed by central sympatholysis and a decline in
blood pressure.

Respiratory
• At clinically effective doses, dexmedetomidine causes
minimal respiratory depression.
CNS
Anxiolysis and Sedation:
• Through activation of α2-adrenergic in the locus
coeruleus.
• Enhances cognitive performance

Analgesia
• Significant analgesic effects, reduces opioid
requirements by 30 to 50%.
ICP and CPP:
• Slight decrease in the mean for ICP and a slight
corresponding increase in CPP.

CBF and CMRO 2:

• Dose-related reduction in both CBF and CMR in
healthy subjects.
• The anticipated adverse effects on the cerebral
oxygen supply– demand relation, i.e., the CBF/CMR
ratio, were not apparent during either normocapnia
or hypocapnia.
Effect on EEG
• during dexmedetomidine sedation resembled stage II
NREM sleep.
• Spike frequency increased by 47% during sedation but
no new spike foci or seizures were observed.

Effect on Evoked Potentials

• Use of dexmedetomidine as an anesthetic adjunct at
target plasma concentrations up to 0.6 ng/ml does not
change somatosensory or motor evoked potential
responses during complex spine surgery by any
clinically significant amount.
Neuroprotection
• Decreases the peripheral catecholamine levels thus
balancing the ratio between cerebral oxygen supply &
demand and improving the perfusion in the ischemic
penumbra.

• Inhibits isoflurane induced capsase-3 expression in

hippocampal slice cultures suggesting that
dexmedetomidine may be an important adjunct to
prevent isoflurane-induced neurotoxicity in the
growing brain.
Endocrine System
• decrease catecholamine release
• decrease insulin release from pancreas

Renal system
• Diuresis , increase GFR, inhibition of Renin release ,
Natriuresis
Eye – Decrease IOP

GIT- decrease secretions, GI motility, salivation

• Anti shivering –CNS based thermoregulatory
inhibition(alpha2)
 Side Effects
Most common adverse effects :
– Hypotension
– Bradycardia
– Dry mouth
Transient hypertension may be seen during a loading
dose (rapid infusion)
Central nervous system side effects:
– Ineffective sedation and/or analgesia
– Paradoxical agitation
– Proconvulsant effect (animal study).
 Precautions
Avoid in patients with:
• Low BP/ Shock not responding to vasopressors.
• SBP < 90mmHg or a mean BP < 60 mmHg inspite of
significant vasopressor support:
– (Vasopressin > 2 U/hr Noradrenaline or Adrenaline > 0.2
μg/kg/min or Dobutamine > 10 μg/kg/min)
• HR<55 BPM, not induced by beta-blocker.
• Uncorrected hypovolemia.
• Conduction defects:
– Severe ventricular dysfunction
– High grade AV block in the absence of pacemaker
 Indications
ICU sedation
– Intubated and mechanically ventilated patients in ICU.
– Loading dose: 1mcg/kg over 10 minutes
– Maintenance dose: 0.2-0.7 mcg/kg/hr
(Burns,Trauma, Alcohol withdrawal, Delirium, Seizure)
Procedural sedation
– Non-intubated patients prior to and/or during surgical
and other procedure.
– Loading dose: 1 mcg/kg over 10 minutes
– Maintenance dose: initiated at 0.6 mcg/kg/hr and then
titrated between 0.2-1 mcg/kg/hr (UGI endoscopy,
Clonoscopy, MRI, ERCP)
As Anesthetic Adjuvant
– Adjunct to general & regional (IVRA) anesthesia
– Supplement to regional block in patients
undergoing carotid endarterectomy or during
awake craniotomy / fiberoptic intubation.
• To control agitation in patients receiving noninvasive
ventilatory support.
• To treat shivering.
• To minimize withdrawal phenomena in patients who
have received long-term BDZ and Opioids during their
hospitalization.
• Single I.V. dose of Dexmedetomidine 0.6 mcg/kg decrease
IOP by 34%
 Clonidine
• A selective partial agonist for α2 adrenoreceptors, with a ratio
of approximately 200:1 (α2 to α1).
• Uses : for treatment of hypertension
• 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride
 Mechanism Of Action
• Clonidine treats high blood pressure by
stimulating α2 receptors in the brain ,inhibiting
the release of norepinephrine (NE).

• Decreases peripheral vascular resistance.

• specificity towards the presynaptic α2 receptors

in the vasomotor center in the brainstem.
• Overdose stimulates peripheral postsynaptic α1
adrenoceptors & cause hypertension by vasoconstriction.

• Abrupt or gradual withdrawal causes rebound hypertension.

• Treatment is to reinstitute clonidine.

MOA for Analgesia
•Clonidine induced Analgesia is mediated by an agonist
effect at : α2 adrenoceptors Or Imidazoline receptors ( I1 )

– Peripheral & central suppression of sympathetic

transmitter release.
– Pre-synaptic inhibition of nociceptive afferents.
– Post-synaptic inhibition of spinal cord neurons.
– Facilitating the Brain-stem pain modulating
system.
 Pharmacokinetics
• Bioavailability: Immediate release (75-85%)
Transdermal (60-70%)

• Protein bound: 20-40%

• Duration: 6-10 hr.

• Metabolism in Liver.

• Elimination Half-life: 12-16 hr.

• Excretion: Urine.
Epidural :
– Absorbed into CSF, peak within 30-60 min,
excellent correlation between Analgesia & CSF
levels.
– Peak blood levels within 10 min.
– Poor correlation between Analgesia & blood levels
– Metabolism-minimal: p-hydroxyclonidine
– Excretion- majority unchanged: Urine

• I.V/ I.M./Intrathecally : mimics epidural route

 Uses
• Major use in hypertension.

• withdrawal symptoms seen in addicts after

withdrawal from opiates, alcohol, and tobacco.
• due to its ability to suppress
sympathomimetic symptoms of withdrawal.

• Low dose Clonidine (50-100µg/dl) is used in

migraine prophylaxis and chorea.
• As an analgesic and adjuvant to LA/ GA
– large doses of clonidine alone
administered intrathecally (as much as
450 μg) or epidurally (1 to 2 μg/kg/hour)
to control intraoperative and
postoperative pain.
•Has been successfully used to relieve the Myo-spasms
and hypertonia in spinal cord injury patients.

•To improve the gastroparesis and chronic diarrhea

secondary to Diabetes mellitus.

•To relieve “Hot Flushes” associated with

menopausal hormonal disturbances both in males as
well as females.
 Side Effects
•Dry mouth (Xerostomia)
•Sedation ,
•Somnolence
•Orthostatic hypotension
•Bradycardia
•Hypotension
•Erectile dysfunctions
•20% of patients develop a contact dermatitis to the
transdermal delivery system.
•Withdrawal syndrome and potentially life threatening
rebound hypertension.
• Constipation
 Precautions
•Withdrawal causes rebound hypertension
•Caution needed in Cerebrovascular & coronary
insufficiency
•Sedation is common with neuraxial route.
•With other anti hypertensives, in CHF – monitoring
needed
•Very little amount of Clonidine removed by dialysis-
cautions needed in CRF patients.
•Category C by FDA – avoid in pregnancy and lactation.
•Never use Clonidine with β- adrenoceptor blockers.
Drug interactions

•Non selective adrenergic blockers.

•Diuretics, Vasodilators & adrenergic blockers

•NSAIDs
Dexmedetomidine Clonidine
Developed in 1980s Developed in 1960s
Full agonist at alpha2 receptors with Partial a gonist at alpha2 receptors with
1600:1 and 8 times more specific 200:1

90% reduction in inhalational anesthetic 50% reduction in inhalational anesthetic

requirement to maintain 1 MAC requirement to maintain 1 MAC

Plasma Half life:2-2.5 hrs Plasma Half life:9-12 hrs

Protein binding 94% Protein binding: 50%
Elimination Half life: 2 hrs Elimination Half life: 8 hrs

Distribution half life 5mins Distribution half life 10 mins

 References
• Stoelting’s Pharmacology and Physiology in Anesthesia
practice 5th E
• Clinical Anesthesiology by Paul G Barash 8th E
• Miller’s Anesthesia IE
Thank You!