A totally “ New Drug ”designed for the perioperative period !

Properties

• Anxiolysis• Sedation /MAC-sparing effect• Intra-operative hemodynamic stability• Myocardial protection (Am J Med 2003; 114: 742-752)

• Analgesia/anti-hyperalgesia• Spasmolytic (viscero-analgesia)• Positive interaction with the stress- induced immune

response (human) (Wu et al., anesth analg 2004)

A totally “ New Drug ”designed for the perioperative period !

Properties

• Prevention and treatment of PO shivering• Protection of renal function ( human)• CNS protection ( animal)• Anti-emetic• Promotes learning and memory in elderly ( animal)• Anti-epileptic• Anabolic properties (GH secretion)• Anti-withdrawal (benzodiazepine, nicotine, morphine, cocaine, alcoo l,..)

• …….

A totally “ New Drug ”designed for the perioperative period !

Routes

• Per os• IV (!! Not available in most of the countries)

• IM• Epidural• Intrathecal• Intra-articular• Local• Topic• ….

A totally “ New Drug ”designed for the perioperative period !

Safety

• Tested in animals ++++ (basis of veterinary anesthes ia)• Used in humans from +/- 40 years (including during

pregnancy)• Overdose ….

• Active in 20 min for …6-8 hours !!!

• Cheap !!!

Clonidine (CatapressanR)

1962imidazolin analogue of Norepinephrine

αααα2-adrenergic receptor agonist

���� Nasal decongestant …antihypertensive ….Anesthetic …….Analgesic ……

+/= 1200 papers/years (from 2000)

Westfall TC, Westfall DP. Neurotransmission: The a utonomic and somatic motor nervous systems (Chapter 8). In: Goodman and Gilman’s The Pharmacological Basis of T herapeutics, 12th edition. Editor Laurence L Brunt on. The McGraw-Hill Companies, Inc. 2011

– 2A � sédation, hypnose, analgésie, sympatholyse,neuroprotection– 2B � effets hémodynamiques Anti-frisson, analgésie, vasoconstriction périphérique– 2C �Effet sur la réflexion, perception sensorielle, humeur, activité locomotrice, tonus

adrénergique de la médullosurrénale

Aujourd ’hui !Utilisation « Anesthésiologique »

• 2 grands principes !• 3 motivations cliniques

- 1 « MAC-sparing » effect- 2 analg ésie- 3 stabilité hémodynamique ou

protection myocardique

Principe 1 !

La clonidine =

Un médicament du Système Nerveux Sympathique

L’administrer équivaut à promouvoir un système qui va moduler une activité adrénergique stimulée !

(frein physiologique de l’ αααα1)

Ceci va déterminer l’indication et la dose (âge!)(l’exemple du sevrage)

the Role of sympathetic nervous system and hypothalamo-pituitary-adrenal axis

is to maintain basal and stress Homeostasis

• The coordinated physiological reactions which maintain most of the steady

states in the body are so complex, and are so peculiar to the living organism,

that it has been suggested (Cannon, 1929) that a specific designation for these

states be employed — homeostasis.[3]

SNC: le Locus Coeruleus

The locus coeruleus ?

The projections of this nucleus reach far and wide, innervating the spinal cord, the brain stem, cerebellum, hypothalamus, the thalamic relay nuclei, the amygdala, the basal telencephalon, and the cortex.

The norepinephrine from the LC has an excitatory effect on most of the brain, mediating arousal and priming the brain’s neurons to be activated by stimuli . (anatomic location of anxiety)

A single noradrenergic neuron can innervate the entire cerebral cortex via its branches

Principe 2 !

• La voie d’administration influence l’effet pharmacologique.

• Différentes doses sont nécessaires pour

différents effets .

Applications cliniques des agonistes αααα2-adrénergiques

n = 1

• Anxiolyse ! (prémédication)• Sédation/hypnose ?• Epargne en Anesth ésiques

- halogénés/ propofol : -40% !!!!- benzodiazepines: - +/- 80% !!!!!!!!

Doses +/- 4µg/kg

Nelson et al.: Anesthesiology 2003; 98: 428-36

Huupponen et al.: Acta Anaesthesiol Scand 2008; 52: 289-94

Sedation similar to sleep

• In experimental studies, dexmedetomidine activates endogenous nonrapid eye movement (NREM) sleep-promoting pathways

• In humans, dexmedetomidine produces a state closely resembling physiological normal stage 2 NREM sleep

La Sédation induite par la Dexmédétomidine est similaire au Sommeil Naturel !!!

Nelson et al. Anesthesiology 2003;98:428-36;Huupponen et al Acta Anaesthesiol Scand. 2008;52:289-94

Riker et al. JAMA 301, 2009: 489-99

Pandharipande et al: JAMA 2007, 298, 2644-53

Dexmédétomidine and DeliriumPatients in the ICU !

Survival !!

MENDS: Pandharipande et al. JAMA 2007

Applications cliniques des agonistes αααα2-adrénergiques

n = 2

Les différents effets analg ésiques !

1- potentiation2- effet analg ésique intrins èque

Intrathecal Clonidine (G3)Area of Hyperalgesia(von Frey hairs)

(Anesth Analg 2005)

72 HOURS POST OP

0

50

100

150

200

250

G1 G2 G3

cm²

A Meta-analysis of

Clonidine as an Analgesic(1984-1995: 2116 patients)

Anesthesiology 1996;85: 655-74Eisenach J, De Kock M, Klimsha W.

« Clonidine appears to offer unique advantages over existing agents in the treatment of certain pain conditions. Clonidine added to local anesthetics for epidural, spinal or peripheral blocks, prolongs and intensifies anesthesia for surgery. Postoperatively, a combination of epidural clonidine with opiates offers the advantage of reduced dose of each component with correspondingly fewer side effects ……. »

Site analg ésique « préférentiel »

• Récepteurs situ és au niveau des cornes postérieures

de la moelle épinièremais ……

• Récepteurs au niveau desnerfs p ériph ériques sensoriels

(réaction inflammatoire)

Quid de l ’action analgésique centrale ??

Mervin Maze: Anesthesiology 1996« Le locus Coeruleus et les noyaux

noradrénergiques adjacents (A5 et A7) exercent un effet inhibiteur sur les récepteurs αααα2-adrénergiques spinaux . Si les recepteurs centraux αααα2 (LC) sont stimulés, il y a suppression du contrôle inhibiteur sur les αααα2 spinaux »

La Clonidine et les Opiacés

• Les agonistes αααα2-adrénergiques sont les alliés physiologiques des opiac és endog ènes pour l ’analg ésie!!!!!

!

Protecteur des opiac és

1 moyens asp écifiques :Diminuer la quantité d’opiacés donn ée

pendant l’anesth ésie !clonidine

2 moyens sp écifiques :• Ketamine, Mg++ (NMDA antagoniste)• AINS• Anesthésiques locaux• Naloxone ?!!• gabapentine (ampa/kainate antagoniste)• Antioxidants……

αααα2-Adrenergic Agonists and Local Anesthetics

• Clonidine added to local anesthetics for epidural, spinal or peripheral blocks, prolongs and intensifies anesthesia for surgery. ( Eisenach 1996 )

• Clonidine protects against bupivacaine-induced cardiac and neurotoxicity (de La Coussaye 1992, dekock 1996)

Applications cliniques des agonistes αααα2-adrénergiques

n = 3

Protection Myocardique et

Stabilité Hémodynamique

The Problem !

Surgery induces a marked and long -lastingstimulation

of the sympathetic nervous system

The balance between myocardial oxygen supply and demand may be compromized

+ hypercoagulation, overshooting inflammatory reaction and endothelial dysfunction!!!

The Problem !

• 30.000.000 surgical patients with or at risk of coronary artery disease !!

• Every tenth suffers a serious adverse peri-operative cardiac event

(Mangano et al. Anesthesiology 1990, New Eng J Med 1 995)• perioperative myocardial ischemia:

risk x 9 of severe cardiac complications! (Mangano et al. New Eng J Med 1990 )

• severe effect on long term survival rate !

Cardio -protective effects of Clonidine in humans

in non surgical patients: Clonidine

- alleviates angina pectorisCeremuzynski et al : Eur J Cardiol 1979

Zochowski et al : Int J Cardiol 1984

- improves exercice toleranceCocco et al : Eur J Cardiol 1979

Thomas et al : J Cardiovascul Pharmacology 1986

Cardio -protective effects of Clonidinein humans

Effects of sympatho-inhibition in chronic heart failure

Lang et al : Circulation 1996Zang et al : International J Cardiology 2000

Cardio -protective effects of Clonidinein the peri-operative period

a meta-analysis by Nishina et al. (Anesthesiology 2002)

« Clonidine given pre- or intraoperatively reduces myocardial ischemic episodes in patients with coronary arterial disease and in those at risk for this disease ….. »

Cardio -protective effects of Clonidinein the peri-operative period

Mechanisms

• sympathetic modulation• Prevention of ischemic ventricular tachycardia of

Purkinje origin (Arnar et al : Am J Physiol Heart Circ Physiol 2001 )

• Reperfusion injury (glutamate) (Bickler et al: Neuropharmacology 1996, Chao et al :Brain Res 2001 )

• Reduces PO hyperfibrinogemia and inhibits epinephrine-induced platelet aggregation

(Rosenfeld et al : Anesthesiology 1993 )

Hemodynamic Side -Effects ofClonidine

• «…...Clonidine does not increase bradycardia »Nishina et al : Anesthesiology 2002

• « ...severe hemodynamic impairement during rewarming requiring more vasoactive drugs and inotropics »Abi-Jaoude et al: J Cardiothoracic and Vascular An esthesia 1993

?????

Side Effects

Clonidine – induced- Hypotension ?- Bradycardia ?

Loss of important hemodynamic parameters !!!

Perioperative hypotension!Criteria ?

• Hypertensive patients during physiological sleep: 74/40mmHg

• Beta-blockers: 100/40 mm Hg• Lack of gravity ????• General anesthesia: >90 mmHg SABP or - 20%

baseline (HR > 40 )

• Clonidine ???

αααα2-Adrenergic induced hypotension !

Reactivity of the Sympathetic Nervous System to Stimuli (i.e) Hypotension

• animals experimentations (in vivo, in vitro) rats, cat s, dogs, diving ducks…… .

• « All the findings are compatible with the belief that αααα2-adrenergic agonists depress base-line sympathetic act ivity but that clonidine leaves, at least partially, unaf fected the response to environmental or circulatory challenges such as hypotension »

(Quintin L and Ghignone M Balliéres ’Clinical Anesthe siology 2000 )

After clonidine administration,The vasomotor baroreflex is largely

intact despite central sympatho -inhibition

Beware conduction disturbances:BAV 2 ….. BAV 3…

In Conclusion ,

old drugs are not necessarily drugs of the past…..