Clonidine

The ‘wonder drug’- most misunderstood!

ConsultantDepartment of Anesthesiology

&Intensive care

Public Hospital Authority’s Rand Memorial HospitalFreeport, Grand Bahama

The Bahamas

Dr. M. M. PANDITRAO

Chemical Structure

2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride

α2 Adrenoceptor Agonist -Clonidine

Agonist to postsynaptic α2 adrenoceptors in brain, stimulation suppresses sympathetic outflow.

High dose activates peripheral presynaptic autoreceptors on adrenergic nerve endings mediating negative feedback suppression of noradrenaline release.

Clonidine reduces blood pressure.

Overdose stimulates peripheral postsynaptic α1 adrenoceptors & cause hypertension by vasoconstriction.

Abrupt or gradual withdrawal causes rebound hypertension.

Treatment is to reinstitute clonidine.

Never use Clonidine with β- adrenoceptorblockers.

Mechanism of Analgesia

Clonidine attenuates the opioid withdrawal syndrome.

“Indicating interaction with intrinsic

Opioid System”

Mechanism of Analgesia (Contd.)

Clonidine induced Analgesia is mediated by an agonist effect at:

α2

adrenoceptors or Imidazoline

receptors

resulting in: ►

Mechanism of Analgesia (Contd.)

Peripheral & central suppression of sympathetic transmitter release

Pre-synaptic inhibtion of nociceptive afferents

Post-synaptic inhibition of spinal cord neurones

Facilitating the Brain-stem pain modulating system

Pharmacokinetics

Well absorbed orally Nearly 100% bioavailableThe mean half life of the drug in plasma is about 12 hoursIt is excreted in an unchanged form by the kidneyThree or four days are required to achieve steady state concentrations Onset may be rapid (a few hours) or delayed for as long as 2 days and subsides over 2-3 days

Pharmacokinetics (Contd.)

Epidurally: 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

Adverse effects

Dry mouth SedationBradycardia Sexual disfunction20% of patients develop a contact dermatitis to the transdermal delivery systemWithdrawal syndrome and potentially life threatening rebound hypertension

Precautions & Warnings

Withdrawal causes rebound hypertension

Caution needed in Cerebrovascular & coronary insufficiency

Sedation is common with neuraxial route

Like other antihypertensives, in CHF pts. ‘high level monitoring’ needed

Very little amount of Clonidine removed by dialysis, so ‘high level monitoring’ needed in CRF patients

Drug Interactions

Non selective adrenergic blockers

Diuretics, Vasodilators & adrenergic blockers

NSAIDs

Therapeutic usesThe major use of clonidine is in the treatment of hypertension.

Clonidine is useful in the management of 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 LAAs / GA

Therapeutic uses (Contd.)

Has been successfully used to relieve the Myo-spasms and hypertonia in spinal cord injury patients

To improve the gastroparesis and ch. Diarrhea secondary to Diabetes mellitus

To relieve “Hot Flushes” associated with menopausal hormonal disturbances both in males as well as females

Clonidine in Regional Anaesthesia

Published Reports of Pts. Receiving Clonidine for Regional Anaesthesia

Effect of route of administration on duration of analgesia from a small dose of clonidine by Intra- Muscular, Epidural,

Placebo & Spinal Routes

Cholinergic interaction in spinal α 2 -adrenergic analgesia

Descending noradrenergic pathways release norepinephrine (NE), to cause analgesia directly and to stimulate acetylcholine (ACh) release, to produce analgesia (left). This is consistent with an increase in cerebrospinal fluid (CSF) acetylcholine after epidural clonidine injection (right, above) and with neostigmine's potentiation of clonidine analgesia in humans (right, below).

Sites of hemodynamic actions of

α 2 -adrenergic agonists

α -Adrenergic agonists

produce sympatholysis and reduced BP by actions in the periphery, brainstem, and spinal cord, effects opposed by direct vasoconstriction from α 2 -adrenergic agonists in the periphery. As a result of the spinal sympatholytic site of action, epidural clonidine reduces blood pressure more when injected in the thoracic than in the cervical or lumbar space

Effect of Addition of Epidural Clonidine to Bupivacaine for

Labour Analgesia

Clonidine added to mepivacaine for brachial

plexus block

In 190 patients from 3 controlled studies receiving 40 ml 1% mepivacaine for brachial plexus block, clonidine produced dose-dependent increases in duration of anesthesia (open circles) and analgesia (solid circles). Data from each study are connected by lines.

Summary of Clinical Experience with Clonidine for Regional Anesthesia

Conclusion

α -Adrenergic agonistsParenteral PreparationUnique PharmacologyMultiple IndicationsGood safety ProfileAdequate Clinical experience

“So It is going to stay & Prosper”