Clonidine:The Wonder Drug- Most Misunderstood

Prof. Panditrao explains the whole new spectrum of pharmacological actions/ indications/ contra indications/ of Clonidine when used parenterally.

1. Clonidine The ‘wonder drug’- most misunderstood!

2. Consultant Department of Anesthesiology & Intensive care Public Hospital Authority’s Rand Memorial Hospital Freeport, Grand Bahama The Bahamas Dr. M. M. PANDITRAO

3. Chemical Structure 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride

4. α 2 Adrenoceptor Agonist - Clonidine Agonist to postsynaptic α 2 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.

5. Overdose stimulates peripheral postsynaptic α 1 adrenoceptors & cause hypertension by vasoconstriction. Abrupt or gradual withdrawal causes rebound hypertension.

6. Treatment is to reinstitute clonidine. Never use Clonidine with β - adrenoceptorblockers.

7. Mechanism of Analgesia Clonidine attenuates the opioid withdrawal syndrome. “Indicating interaction with intrinsic Opioid System”

8. Mechanism of Analgesia (Contd.) Clonidine induced Analgesia is mediated by an agonist effect at: α 2 adrenoceptors or Imidazoline receptors resulting in: ►

9. 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

10. Pharmacokinetics Well absorbed orally Nearly 100% bioavailable The mean half life of the drug in plasma is about 12 hours It is excreted in an unchanged form by the kidney Three 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

11. 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

12. Adverse effects Dry mouth Sedation Bradycardia Sexual disfunction 20% of patients develop a contact dermatitis to the transdermal delivery system Withdrawal syndrome and potentially life threatening rebound hypertension

13. 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

14. Drug Interactions Non selective adrenergic blockers Diuretics, Vasodilators & adrenergic blockers NSAIDs

15. Therapeutic uses The 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

16. 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

17. Clonidine in Regional Anaesthesia Published Reports of Pts. Receiving Clonidine for Regional Anaesthesia

18. Effect of route of administration on duration of analgesia from a small dose of clonidine by Intra- Muscular, Epidural, Placebo & Spinal Routes

19. 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).

20. 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

21. Effect of Addition of Epidural Clonidine to Bupivacaine for Labour Analgesia

22. 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 .

23. Summary of Clinical Experience with Clonidine for Regional Anesthesia

24. Conclusion α -Adrenergic agonists Parenteral Preparation Unique Pharmacology Multiple Indications Good safety Profile Adequate Clinical experience “So It is going to stay & Prosper”

25. Thank You