Alpha-2 Adrenergic Agonists R15

REFRESHER COURSE OUTLINE R13

Takahiko Kamibayashi MD, Alpha-2 adrenergic Katsumi Harasawa MD, Mervyn Maze MB CHB MKCP agonists

INCE the first reports on the utility of a 2 those having difficulty swallowing, or those who are adrenergic agonists, less than a decade ago, the unable to absorb drugs through the gastrointestinal clinical application of this class of compound tract. Clonidine is now being used by the rectal route of S continues to expand. Initially, reports concen- administration in children with 95% bioavailability and trated on the anaesthetic-sparing actions of a2 adrener- unchanged pharmacokinetic variables, s gic agonists. Now, their efficacy in pain management, Medetomidine, 4(5)- [ 1-2,3-dimethylphenyl[ ethyl] regional anaesthesia, and organ protection are coming imidazole], is the prototype of the novel superselective to the fore. Furthermore, there are a plethora of stud- a2 agonists. It is an order of magnitude more selective ies addressing the manner by which a 2 agonists can than clonidine and is a full agonist at this class of enhance the safety of other anaesthetic agents, as well as receptor. 6 Medetomidine is extremely potent and is suggestions on how to improve the therapeutic window active at low nanomolar concentrations and has been of its own administration. Here, we have concentrated widely used in veterinary practice in Europe. Since the on clinical studies but have included a short section on D-enantiomer of this racemate is the active ingredient, interesting preclinical studies which may be extrapolat- dexmedetomidine has been developed for clinical use. ed to the clinical arena. The pharmacokinetic profile is more favourable for Adrenergic receptors have been differentiated into perioperative use than is clonidine because of its much and t3 based on the rank order of potency of various shorter half life of approximately two hours. 7 Phase III natural and synthetic catecholamines in different phys- studies with this compound are currently being con- iological preparations. 1 Subsequently, the ct adreno- ducted in North America, Europe and Japan to inves- ceptors were separated into two subtypes, a 2 and a~, tigate its perioperative utility. depending on their sensitivity to the a2-selective Some of the ligands have an imidazole ring which antagonist yohimbine or the 0~1 selective antagonist facilitates binding to nonadrenergic imidazole-prefer- prazosin. 2 Activation of ct1 adrenoceptors can func- ring receptors s,9 as well as to the a 2 adrenoceptor. The tionally antagonize a2-mediated CNS responses so it is cardiovascular properties of g2 ligands may vary consid- critical to use compounds with high selectivity for the erably depending on whether the imidazole-preferring g2 adrenoceptor. receptor is also activated. 1~ Other imidazoline compounds which have been investigated for their a2 ago- Applied pharmacology nist properties include tizanidine 11 and mivazerol. 12 Clonidine, an imidazole compound, is a selective partial agonist for a2-adrenoceptors with a ratio of approxi- Premedical:ion mately 200:1 (r Clonidine is rapidly and almost Since sedation, anxiolysis and antisialogogue action completely absorbed after oral administration and are attractive attributes in a premedication agent, reaches a peak plasma level within 60-90 min by this administration of a 2 agonists suits this purpose well. route. Clonidine can also be delivered via a time-release Another benefit of a 2 agonists for premedication is transdermal patch although it takes a minimum of two their ability to potentiate the anaesthetic action of days for therapeutic levels to be achieved by this route. 3 other agents and to reduce anaesthetic requirements The elimination half-life of donidine is between 8-12 during surgery. This effect is universally observed hr with -~50% of the drug being metabolized in the liver regardless of the type of anaesthetic, intravenous, to inactive metabolites while the rest is excreted volatile or regional blockade. Conversely, require- unchanged in the kidney. A single dose of 0.3 mg cloni- ments for neuromuscular blocking agents remain dine has the same pharmacokinetic and pharmacody- tmaffected by pretreatment with a 2 agonists. 13 namic profile whether administered po or sl. 4 Therefore, The successful application of a 2 agonists to patients the sl route can be predictably used in fasting patients, at the extremes of life is now established. 14,~s The

From the Anesthesiology Service Veterans Affairs Palo Alto Health Care Services, Palo Alto, CA 94304; and Department of Anesthesia, Stanford University, Stanford, CA 94305.

CAN J ANAESTH 1997 / 44:5 / pp R13-R18 R14 CANADIAN JOURNAL OF ANAESTHESIA elderly patient population appears to be one that is five opioid analgesic requirements are diminished. 27 The most likely to benefit from the sympatholytic effects of onset time required to surgical anaesthesia is unaffected the drug because of the prevalence of coronary artery by donidine but the duration of spinal and epidural disease and hypertension. ~6,17 In patients between anaesthesia was increased more than two-fold.28 4-12 yr, the combination of 4 lag.kg -1 clonidine and From the data included in these studies, it is now 30 pag.kg-1 atropine orally, 105 rain before coming to possible to enhance, both qualitatively and quantita- the OR, was more effective than diazepam at promot- tively, conduction blockade with tz2 agonists by vari- ing anxiolysis and sedation, is ous routes of administration. Unfortunately, we are Clonidine significantly attenuated the rapid increases still no closer to understanding the mechanism for in blood pressure and heart rate during the transition these local anaesthetic enhancing qualifies. between low and high doses ofdesflurane) s09 Similarly, the sympathoexcitatory response to 1.0 mg.kg-1 keta- General anaesthesia mine, iv, was attenuated by 5 !ag.kg-1 clonidine, po, as Although a2 agonists have been recognized to possess evidenced by the smaller increment in blood pressure. 2~ potent analgesic and sedative effects, these agents have Clonidine premedication also blunted hypertension, not been used as sole anaesthetic agents. The combina- tachycardia as well as increments in plasma cate- tion of oral and transdermal clonidine (which main- cholamine concentrations during stepwise increase in tained the plasma concentration of clonidine at isoflurane concentration by mask anaesthesia. 21 therapeutic levels) provided lower anaesthetic require- Several recent studies have reported on the use of ments, greater haemodynamic stability, more rapid premedication dose of clonidine in patients with coro- recovery from anaesthesia and less postoperative nary artery disease. Clonidine, 5 ~ag.kg-~ decreased requirement for supplemental morphine for pain con- intraoperative sufentanil use and lowered cate- trol in patients undergoing lower abdominal surg- cholamine response while maintaining haemodynamic eries. 29 An issue which has been raised repeatedly is that stability in coronary artery bypass graft surgery. 22 To a2 agonists may decrease the anaesthetic requirements determine whether the addition of clonidine to a stan- not by a direct anaesthetic action but through their abil- dardized general anaesthetic could safely provide post- ity to alter the haemodynamic responses which are used operative sympatholysis for patients with known or to titrate the anaesthetic dose. Gabriel and his col- suspected coronary artery disease, Ellis and col- leagues s~ showed that in the presence of clonidine, the leagues 23 randomly allocated patients undergoing EEG spectral indices reflected a deeper anaesthetic state elective major noncardiac surgery to receive either despite the fact the end-expiratory isofluranc concen- placebo or clonidine by a combination of oral and tration was reduced by 50%. Preliminary results involv- transdermal routes. Clonidine reduced enflurane ing MAC studies in both volunteers and surgical requirements, intraoperative tachycardia, and myocar- patients support the contention that these agents have dial ischaemia. Lastly, a relative "renal-sparing" effect a primary anaesthetic action. was noted in CABG surgery patients who received Clonidine, 4 ~g-kg-1 iv, blocks the haemodynamic clonidine, 4 }ag.kgq, before induction. 24 and catecholamine responses to laryngeal stimulation in From these studies, it is apparent that % agonists patients undergoing coronary artery bypass graft are being used for more specific indications and by a surgery, s~ Puig's group examined the effect of epidural variety of routes for its sympatholytic effect. The need clonidine on fentanyl requirements in patients undergo- to pre-empt sympathoexcitatory responses in sicker ing general anaesthesia with a "nitrous-narcotic" tech- patients undergoing general anaesthesia will likely nique for abdominal hysterectomy. 32 Epidural clonidine become an important indication for the clinical uses of decreased fentanyl requirements, improved cardiovascu- this class of drugs. lar stability, reduced pain intensity and the need for postoperative analgesia in the recovery room. Regional anaesthesia Data from these studies continue to stress the anaes- Oral clonidine, 75-300 lag, dose-dependently prolongs thetic-sparing qualifies of the ~2 agonists in patients spinal anaesthesia with hyperbaric tetracaine in patients undergoing general anaesthesia. Whether the use of undergoing gynaecological and urological surgery. 2s lower concentrations of the other anaesthetics will be When compared with intrathecal fentanyl, oral clonidine associated with a better outcome is not addressed. (200 ~ag), shortened the onset time of tetracaine senso- However, it is anticipated that with lower doses of "fixed ry block and prolonged the duration of sensory and agents" faster emergence from general anaesthesia may motor block. 26 Although severe hypotension and/or be anticipated with a commensurate decrease in time in bradycardia are slightly more likely to occur, postopera- the post-anaesthesia care unit. Kamibayashi: ALPHA-2 ADRENERGIC AGONISTS R15

Postoperative pain provide very durable analgesia with fewer side-effects In a study involving post-caesarean section patients, than if either were used alone. Capogna et al. 3a showed a dose-dependent increase in the duration of epidural morphine/local anaesthetic Postoperative - miscellaneous analgesia when clonidine (75 or 150 pg) was included Perioperative infusion of clonidine increases anabolic in the mixture. Also, the need for redosing was dimin- growth hormone levels 39 and this may have a positive ished in the patients who received clonidine. In a fur- effect on nitrogen wasting. Mertes et al. 4~ demon- ther study involving caesarean section patients the strated that nitrogen balance was well maintained in addition of either clonidine or epinephrine (which also alcoholics undergoing radical cancer surgery when activates ct2 adrenergic receptors) to epidural sufen- they were given clonidine perioperatively: an age- tanil decreased the number of administrations of matched (non-alcoholic) group of cancer surgery sufentanil by PCA. s4 patients served as controls. Patients undergoing gastrectomy with a combined Treatment of uncontrolled shivering in patients in general/epidural technique received epidural mor- labour receiving epidural analgesia often consists of phine with or without clonidine (3 lag.kg -l) for post- administration of meperidine. Mercadante et al. 41 operative analgesia, ss The cumulative number of demonstrated that clonidine (0.15 mg iv) was as effec- supplemental systemic morphine injections via PCA tive as the standard therapy for shivering during was less in patients who had received clonidine each labour. In a large double-blind study the prophylactic hour for 24 hr after surgery (P < 0.05) while the VAS use of clonidine, 4 pg.kg-~, iv, immediately after for pain was lower. In the clonidine-treated patients, induction of general anaesthesia, reduced the inci- sedation scores were higher, and mean blood pressures dence, severity and duration of postoperative shivering were lower. without changing the incidence of sedation. 42 Bernard's group 36 compared the analgesic efficacy, The use of ~2 agonists in the immediate emergence arterial blood gases, and pharmacokinetic variables of and early postoperative period appears to hold out an iv infusion of fentanyl 75 pg.hr -1 and a mixture of great promise. This class of compound may represent fentanyl 25 pg-hr -l plus clonidine 0.3 pg.hr q after the first of its kind to provide such a positive effect on surgery. Pain relief, sedation, and supplemental keto- nitrogen balance. If this is corroborated, the utility of profen requirements were similar in both groups. ~2 agonists in the severely ill intensive care unit patient There were 106 episodes of arterial desaturation may become de rigeur. (<90% for >20 sec) in four of the patients in the fentanyl group compared with none in the clonidine-fen- Chronic pain tanyl group. Mean arterial blood pressure, plasma In an "enrichment" study design, transdermal cloni- clearance, and the elimination rate constant of fen- dine could decreased pain in subjects with diabetic tanyl were lower in the clonidine-fentanyl group than neuropathy. 43 Since phentolamine was ineffective, in the fentanyl group. even in the most responsive patients, the mechanism In an interesting study, Rockemann et al. s7 compared for the clonidine response appears to be separate from the analgesic effects of epidural clonidine (8 pg.kgq) its sympatholytic action. Anecdotally, it has been alone, with a lower dose (4 ~ag.kg-1) in combination with noted in a patient suffering from pharyngeal cancer morphine (2 mg), or morphine (50 pg-kgq) alone in pain, that the addition of clonidine to intracere- patients undergoing pancreatectomy. Patients who broventricular doses of morphine enhanced the effica- received epidural solutions containing clonidine had an cy of the opioid. 44 Similarly, in a patient suffering from earlier onset and a longer duration of analgesia than intractable pain following spinal cord injury, the addi- when morphine alone was used. Haemodynamicaly, the tion of clonidine resulted in rapid improvement. 4s clonidine-treated patients had a rate-depedent decrease While these studies continue to hold out hope, the in cardiac output. full potential of ~2 agonists for chronic pain states has Recently, it was demonstrated that the pre-opera- not been rigorously tested. What is needed are studies tive administration of clonidine, 4 pg.kg -1, decreased that demonstrate that the analgesic effects are durable postoperative pain and analgesic requirements in a and without long-term complications. paediatric population, ss The efficacy of ~2 agonists, alone, for postsurgical analgesia has yet to be shown in Complications surgical patients other than in patients receiving quite An extension of the pharmacological properties of ~2 high doses or in parturients. In other settings, the agonists is the development of bradycardia and combination of a 2 agonists with opioids appears to hypotension, s,46,47 Bradycardia can be pre-empted by R16 CANADIAN JOURNAL OF ANAESTHESIA

the prophylactic use of an anticholinergic agent venous and intramuscular dexmedetomidine hydrochlo- (atropine or glycopyrrolate) although the increment in ride in adult human volunteers. Anesthesiology 1993; heart rate which can occur in response to anticholiner- 78: 813-20. gics is reduced in both adults and children. 4s Conversely, 8 ErnsbergerP, MeeleyMP, Mann JJ, Reis DJ. Clonidine hypotension responds in an exaggerated fashion to treat- binds to imidazole binding sites as well as alpha 2-adreno- ment with ephedrine. 49 The pressor response to ceptors in the ventrolateral medulla. Eur J Pharmacol phenylephrine is enhanced following oral clonidine and, 1987; 134: 1-13. thus, restoration of blood pressure can be achieved effec- 9 Zonnenchein R, Diamant S, Atlas D. Imidazoline tively by either ephedrine or phenylephrine, s~ receptors in rat liver cells: a novel receptor or a subtype of alpha 2-adrenoceptors? Eur J Pharmacol 1990; 190: Conclusion 203-15. The use of ct2 agonists, either alone or in combination, 10 Tibirica E, Feldman J, Mermet D, Gonon F, Bousquet P. is becoming widespread in anaesthesia. The original A imidazoline-specific mechanism for the hypotensive enthusiasm for this class of compound for its plethora effect of clonidine: a study with yohimbine and idazox- of beneficial effects appears to have been justified an. J Pharmacol Exp Ther 1991; 256: 606-13. based on the more recent clinical studies reported 11 Miettunen TJ, Kanto JI-I, Salonen MA, Scheinin M. The here. In the next decade, the field will continue to sedative and sympatholytic effects of oral tizanidine in evolve with the clinical introduction of the second healthy volunteers. Anesth Analg 1996; 82: 817-20. generation of ~2 agonists, notably dexmedetomidine 12 Noyer M, de Laveleye F, Vauquelin G, GobertJ, Wulfert which is a more selective, specific and efficacious com- E. Mivazerol, a novel compound with high specificity pound than the prototype, clonidine. Furthermore, for alpha 2 adrenergic receptors: binding studies on formulations allowing several different routes of different human and rat membrane preparations. administration, ranging from transdermal to neuraxi- Neurochemistry International, 1994; 24: 221-9. al, will further extend its clinical utility. 13 Takahashi H, Nishikawa T. Oral clonidine does not alter vecuronium neuromuscular blockade in anaes- Acknowledgements thetized patients. Can J Anaesth 1995; 42: 511-5. The authors gratefully acknowledge the support of the 14 Filos KS, Patroni O, Goudas LC, Bosas O, Kassarans A, Uehara Foundation (T.K.), the National Institutes of Gartaganis S. A dose-response study oforaUy adminis- Health (M.M.) and the Department of Veterans tered clonidine as premedication in the elderly: evaluat- Affairs (M.M.). ing hemodynamic safety. Anesth Analg 1993; 77: 1185-92. References 15 Mikawa K, Maekawa lq, Nishina K, Takao Y, Yaku H, 1 Ahlquist PR. A study of the adrenotropic receptors. Obara H. Efficacy of oral clonidine premedication in Am J Physiol 1948; 153: 586-600. children. Anesthesiology 1993; 79: 926-31. 2 Bylund DB, U'Pritchard DC. Characterization of 16 Ghignone M, Noe C, Calvillo O, Quintin L. Anesthesia alpha-1 and alpha-2 adrenergic receptors. Int Rev for ophthalmic surgery in the elderly: the effects of Neurobiol 1983; 24: 343-431. clonidine on intraocular pressure, perioperative hemo- 3 Toon S, Hopkins KJ, Aarons Io Rowland M. Rate and dynamics, and anesthesia requirement. Anesthesiology extent of absorption of clonidine fi'om a transdermal 1988; 68: 707-16. therapeutic system. J Pharm Pharmacol 1989; 41: 17-21. 17 Kumar A, Bose S, Bhattacharya A, Tandon OP, Kundra 4 Cunningham FE, Baughman VL, Peters,[, Laurito CE. P. Oral clonidine premedication for elderly patients Comparative pharmacokinetics of oral versus sublingual undergoing intraocular surgery. Acta Anaesthesiol clonidine. J Clin Anesth 1994; 6: 430-3. Scand 1992; 36: 159-64. 5 Lonnqvist PA, Bergendahl HTG, Eksborg S. 18 Devcic A, Muzi M, Ebert TJ. The effects of donidine Pharmacokinetics of clonidine after rectal administra- on desflurane-mediated sympathoexcitation in humans. tion in children. Anesthesiology 1994; 81: 1097-101. Anesth Analg 1995; 80: 773-9. 6 Scheinin H, Virtanen R, MacDonald E, Lammintausta 19 WeiskopfRB, Eger EI II, Noorani M, Daniel M. R, Scheinin M. Medetomidine - a novel alpha 2- Fentanyl, esmolol, and clonidine blunt the transient adrenoceptor agonist: a review of its pharmacodynamic cardiovascular stimulation induced by desflurane in effects. Prog Neuropsychopharmacol Biol Psychiatry humans. Anesthesiology 1994; 81: 1350-5. 1989; 13: 635-51. 20 Tanaka M, Nishikawa T. Oral clonidine premedication 7 DyckJB, Maze M, Haack C, Vuorilehto Io Sharer SL. The attenuates the hypertensive response to ketamine. Br J pharmacokinetics and hemodynamic effects of intra- Anaesth 1994; 73: 758-62. Kamibayashi: ALPHA-2 ADRENERGIC AGONISTS R].7

21 Tanaka S, Tsuchida H, Namba H, l~amiki A. Clonidine 34 Vercauteren MP, Vandeput DM, Meert TF, Adriaensen and lidocaine inhibition of isoflurane-induced tachycar- HA. Patient-controlled epidural analgesia with sufen- dia in humans. Anesthesiology 1994; 81: 1341-9. tanil following Caesarean section: the effect of adrena- 22 Howie MB, Hiestand DC, Jopling M~, Romanelli VA, line and clonidine admixture. Anaesthesia 1994; 49: Kelly WB, McSweeney TD. Effect of oral clonidine pre- 767-71. medication on anesthetic requirement, hormonal 35 Anzai Y, Nishikawa T. Thoracic epidural clonidine and response, hemodynamics, and recovery in coronary morphine for postoperative pain relief. Can J Anaesth artery bypass graft surgery patients. J Clin Anesth 1995; 42: 292-7. 1996; 8: 263-72. 36 Bernard JM, Lagarde D, Souron R. Balanced postoper- 23 Ellis JE, Drijvers G, Pedlow S, et al. Premedicafion with ative analgesia: effect of intravenous clonidine on blood oral and transdermal clonidine provides safe and effica- gases and pharmacokinetics of intravenous fentanyl. cious postoperative sympatholysis. Anesth Analg 1994; Anesth Analg 1994; 79: 1126-32. 79: 1133--40. 37 Rockemann MG, Seeling W, Brinkmann A, et al. 24 Kulka PJ, Tryba M, Zenz M. Preoperative alpha2- Analgesic and hemodynamic effects of epidural cloni- adrenergic receptor agonists prevent the deterioration dine, clonidine/morphine, and morphine after pancre- of renal fimction after cardiac surgery: results of a ran- atic surgery - a double-blind study. Anesth Analg domized, controlled trial. Crit Care Med 1996; 24: 1995; 80: 869-74. 947-52. 38 Mikawa K, Nishina K, Maekawa N, Obara H. Oral 25 Ota K, Naraiki A, Iwasaki H, Takahashi I. Dose-relat- clonidine premedication reduces postoperative pain in ed prolongation of tetracaine spinal anesthesia by oral children. Anesth Analg 1996; 82: 225-30. clonidine in humans. Anesth Analg 1994; 79: 1121-5. 39 De Kock M, Merello I o Pendeville P, Maiter D, Scholtes 26 Singh H, Liu J, Gaines GY, White PF. Effect of oral JL. Effects of intravenous donidine on the secretion of clonidine and intrathecal fentanyl on tetracaine spinal growth hormone in the perioperative period. Acta block. Anesth Analg 1994; 79: 1113-6. Anaesthesiol Belg 1994; 45: 167-74. 27 Niemi L. Effects of intrathecal clonidine on duration of 40 Mertes iV, Goeters C, Kuhmann M~ Zander JF. bupivacaine spinal anaesthesia, haemodynamics, and Postoperative alpha 2-adrenergic stimulation attenuates postoperative analgesia in patients undergoing knee protein catabolism. Anesth Analg 1996; 82: 258-63. arthroscopy. Acta Anaesthesiol Scand 1994; 38: 724-8. 41 Mercadante S, De Michele P, Letterio G, Pignataro A, 28 Klimscha W, Chiari A, Krafft P, et al. Hemodynamic Sapio M, Villari P. Effect of clonidine on postpartum and analgesic effects ofclonidine added repetitively to shivering after epidural analgesia: a randomized, con- continuous epidural and spinal blocks. Anesth Analg trolled, double-blind study. J Pain Symptom Manage 1995; 80: 322-7. 1994; 9: 294-7. 29 Segal IS, Jarls DJ, Duncan SR, White PF, Maze M. 42 Vanderstappen I, Vandermeersch E, Vanacker B, Clinical efficacy of oral-transdermal clonidine combina- Martheussen M, Herijgers P, Van Aken H. The effect of tions during the perioperative period. Anesthesiology prophylactic clonidine on postoperative shivering. A 1991; 74: 220-5. large prospective double-blind study. Anaesthesia 1996; 30 Gabriel AH, Faryniak B, Sojka G, Czech T, Freye E, 51: 351-5. Spiss CK. Clonidine: an adjunct in isoflurane N20/O2 43 Byas-Smith MG, Max MB, Muir], Kingman A. relaxant anaesthesia. Effects on EEG power spectra, Transdermal clonidine compared to placebo in painful somatosensory and auditory evoked potentials. diabetic neuropathy using a two-stage 'enriched enroll- Anaesthesia 1995; 50: 290-6. ment' design. Pain 1995; 60: 267-74. 31 Kulka PJ, Tryba M, Zenz M. Dose-response effects of 44 Loriferne JF, Souchal Delaeour I, Rostaing S, N'Guyen intravenous clonidine on stress response during induc- JP, Bonnet F. Combined intraventricular morphine and tion of anesthesia in coronary artery bypass graft clonidine administration for cephalic cancer pain relief. patients. Anesth Analg 1995; 80: 263-8. (French) Ann Fr Anesth Reanim 1995; 14: 233-6. 32 Murga G, Samso E, VallesJ, Casanovas P, Puig MM. 45 SiddaU PJ, Gray M~ Rutkowski S, Cousins MJ. Intrathecal The effect of clonidine on intra-operative requirements morphine and clonidine in the management of spinal of fentanyl during combined epidural/general anaes- cord injury pain: a case report. Pain 1994; 59: 147-8. thesia. Anaesthesia 1994; 49: 999-1002. 46 Carabine UA, Wright PMC, MooreJ. Preanaesthetic 33 Capogna G, Celleno D, Zangrillo A, Costantino P, medication with clonidine: a dose-response study. Br J Foresta S. Addition of clonidine to epidural morphine Anaesth 1991; 67: 79-83. enhances postoperative analgesia after cesarean delivery. 47 Aantaa R, Kanto J, Scheinin M. Intramuscular Reg Anesth 1995; 20: 57-61. dexmedetomidine, a novel alpha 2-adrenoceptor agonist, R18 CANADIAN JOURNAL OF ANAESTHESIA

as premedication for minor gynaecological surgery. Acta Anaesthesiol Scand 1991; 35: 283-8. 48 Nishikawa T, Dohi S. Oral clonidine blunts the heart rate response to intravenous atropine in humans. Anesthesiology 1991; 75: 217-22. 49 Nishikawa T, Kimura T, Taguchi lq, Dohi S. Oral donidine preanesthetic medication augments the pressor responses to intravenous ephedrine in awake or anes- thetized patients. Anesthesiology 1991; 74: 705-10. 50 Inomata S, Nishikawa T, Kihara S, Akiyoshi Y. Enhancement of pressor response to intravenous phenylephrine following oral donidine medication in awake and anaesthetized patients. Can J Anaesth 1995; 42: 119-25. CONI~1~ILENCE D'ACTUALISATION 1L19

Takahiko Kamibayashi MD, Les agonistes alpha-2 Katsumi Harasawa MD, Mervyn Maze MB CHB MRCP adr nergiques

D EPUIS la publication des premiers comptes dine ale m~me profil pharmacocin&ique et pharma- rendus sur l'utilit~ des agonistes adr~n- codynamiqueA La voie sublinguale peut donc &re ergiques il y a tme dizaine d'ann&s,, les utilis& efficacement chez les patients ~ jeun, ceux qui applications cliniques de cette classe de ont de la difficult6 ~ avaler ou ceux qui sont incapables produits ne cessent de se multiplier. Initialement, on d'absorber des m~dicaments par le tractus gastro- s'int~ressait ~ l'activit~ d'~pargne anesth&ique des ago- intestinal. La clonidine est maintenant utilis& par voie nistes 0~2-adr~nergiques. Maintenant, on met de l'avant rectale chez les enfants avec une biodisponibilit6 de leur efficacit~ pour la gestion de la douleur, l'anesth~sie 95% et des variables pharmacocin&ique inchang&s, s r~gionale et la protection des organes. En outre, un La m~d&omidine, 4(5 )- 1-1,3 -dim&hylph~ny([&hyl ] grand nombre de chercheurs ont &udi~ comment les imidazole) repr6sente le prototype des nouveaux ago- agonistes ~-adr~nergiques am~lioraient la s&urit~ des nistes hypers61ectifs g2" Elle est plus s61ective que la agents anesth&iques et ont sugg~r~ des faqons clonidine et un agoniste complet de cette classe de d'am~liorer les effets th~rapeutiques de leur administra- r&epteurs. 6 La m6d&omidine est extr~mement puis- tion. Pour cet entretien, nous pr~senterons les r~sultats sante et active ~ de faibles concentrations nanomolaires; des &udes cliniques pertinentes auxquels nous avons elle a 6t6 abondamment utilis& en pratique v&6rinaire aussi incorpor~ une courte section sur des &udes pr& en Europe. Comme le D-6nantiom~re de ce rac6mate cliniques int~ressantes qui pourraient ~tre extrapol&s constitue l'ingr~dient actif, c'est la dexm6d&omidine la clinique. qui a &6 d&elopp& pour usage clinique. La dexm6d& On a classifi~ les r&epteurs adr~nergiques en r&ep- tomidine a un profti pharmacocin&ique plus favorable teur ~ ou fl en fonction de la puissance relative de l'utilisation p&iop6ratoire que la donidine parce que sa cat&holamines naturelles ou synth~tiques dans dif- demi-vie est plus courte d'environ deux heures. 7 Des f~rentes preparations physiologiques. * Par la suite, les &udes de Phase III sur ce produit sont pr~sentement en adr~nor&epteurs ~ ont &~ s~par& en deux sous- cours en Am&ique du Nord, en Europe et au Japon groupes ~2 et ~ selon leur sensibilit~ ~ l'antagoniste pour rechercher s'il a des avantages ~ la p&iode p&i- selectif ~2 yohim'bine ou l'antagoniste s~lectif ~1 pra- op~ratoire. zosin. 2 L'activation des adr~nor&epteurs ~ peut Quelques-uns des ligands ont tm anneau imidazole inhiber fonctionnellement les r~ponses du syst~me qui favorise sa liaison avec des r&epteurs non adr& nerveux central ~ m~diation ~2; il est donc primordial nergiques $ affinit~ pr6f6rentielle pour l'imidazole s,9 d'utiliser des compos~s qui ont une haute s~lectivit~ aussi bien qu'avec des adr~nor&epteurs 0c2. Les pro- pour l'adr~nor&epteur ~2. pri&6s cardio-vasculaires des ligands r peuvent varier consid6rablement si le r&epteur ~ affinit6 pr6f~ren- Pharmacologie appliqu~.e tielle imidazole est aussi activ6.11 Les autres compos& La clonidine, un imidazole, est un agoniste s~lectif imidazole &udi& pour leurs propri&6s agonistes ~2 partiel pour les adr~nor&epteurs ~2 avec un rapport sont la tizanidine et le mivaz6rol. ~ approximatif de 200:1 ~2:t~l. La clonidine est absorb& rapidement et presque compl&ement apr~s son Pr~m~dication administration orale et atteint un pic plasmatique dans Parce qu'ils ont des propri&6s s6datives, anxioly- les 60-90 minutes suivantes. La clonidine peut aussi tiques et antisialog~nes, les agonistes ~2 poss~dent les &re d~livr& avec des timbres transdermiques mais, attributs d'une bonne pr6m~dication. En outre, les par cette voie, au moins deux jours sont n&essaire agonistes ~2 en pr6m~dication potentialisent Faction pour arriver ~ des niveaux th&apeutiques, s La demi- des anesth6siques et diminuent les besoins en vie d'~limination de la clonidine se situe entre 8-12 anesth&ie pendant la chirurgie. Cet effet est observ~ heures avec =50% du produit m&abolis~ par le foie en universellement quel que soit le type d'anesth&ique, m&abolites actifs alors que le reste est excr&~ intraveineux, volatil ou local. A l'inverse, les besoins inchang~ par le rein. Que son administration soit orale en relaxant neuromusculaire ne sont pas affect& par ou sublinguale, une dose unique de 0,3 mg de cloni- un pr&raitement aux agonistes ~2. ~3

CAN J ANAESTH 1997 / 44:5 / pp R19-R22 R20 CANADIAN JOURNAL OF ANAESTHESIA

L'efficacit6 de l'administration des agonistes ct2 Anesth~sie r~gionale des patients qui se situent aux extremes de l'~ge est Chez des patient(e)s soumis(es) ~ une chirurgie gyn& maintenant &ablie. ~,~s Les personnes ~gtes semblent cologique ou urologique, la clonidine orale (75-300 lag) &re ceux qui sont les plus susceptibles de btn~ficier prolonge l'anesthEsie rachidienne ~ la t&raca~e hyper- de l'action sympatholytique du produit ~ cause de la bare proportionneUement ~ la dose.2s Compar& au fen- pr&alence d'insuffisance corona]re et d'hypertension tanyl sous-arachno'fdien, la donidine orale (200 lag) a chez eux. I6,17 Chez des patients ~gts de 4-12 ans, la r~duit la p&iode de latence du bloc sensitif~i la t&racaine combinaison de 4 mg.kg q de clonidine et de 30 et prolong~ la dur& du bloc sensitifet moteur. 26 Malgr~ mg.kg -~ d'atropine par la voie orale 105 minutes la possibilit~ un peu plus ~lev& d'hypotension impor- avant leur arriv~ en salle d'op6ration a &6 plus effi- tante et de bradycardie, les besoins en morphinique pour cace que le diaztpam pour procurer l'anxiolyse et la analgEsie postop~ratoire ont diminu~. 27 La p~riode de stdation) s latence pr&~dant l'anesthEsie chirurgicale n'&ait pas La clonidine a atttnu~ considtrablement l'augmen- affect& par la clonidine mais la dur& de l'anesthEsie ration rapide de la pression art&ielle et de la frtquence rachidienne et p&idurale doublait. 2s cardiaque pendant la transition entre faibles et hautes A partir des donn&s obtenues dans ces &udes, il concentrations de desflurane: s:9 De faqon identique, est maintenant possible d'am~liorer l'anesth~sie la rtponse sympathicoexcitatrice h 1,0 mg.kg -I de kt- r~gionale avec des agonistes ~2 administr~s par dif- tamine intraveineuse a 6t~ r~duite par 5 lag.kg -I de f~rentes voies. Malheureusement, nous ne connaissons clonidine per os comme le montrait une augmentation pas encore le m&anisme de cette action. moins marqu& de la pression art~rielle. ~~ La prtmtdication ~ la clonidine atttnuait l'hypertension, la tachy- Anesth~sie g~n~rale cardie aussi bien que l'augmentation progressive de la Malgr~ leurs propri&Es analg&iques et stdatives recon- cat&holamine plasmatique lorsqu'on augmentait par nues, les agonistes a 2 ne sont pas utilisEs seuls pour pro- paliers la concentration de l'isoflurane pendant duire l'anesthtsie. La combinaison orale et transdermique l'anesthEsie au masque3 I de clonidine (qui permet de maintenir la concentration Plusieurs &udes r&entes ont rapport6 l'utilisation plasmatique de clonidine/i des niveaux thtrapeutiques) a de la clonidine en prtmtdication chez des insuffisants diminu6 le besoin d'anesth&ique, procur6 une plus coronariens hospitalisEs. La clonidine 5 lag-kgq dimi- grande stabilit~ htmodynamique, un r&eil plus rapide et nuait le besoin de sufentanil peroptratoire et la r~ponse a diminu6 le besoin postop&atoire de morphine suppl& des cat&holamines tout en maintenant une bonne sta- mentaire chez des patients soumis ~ des interventions bilit6 htmodynamique pendant la chirurgie de revas- abdominales basses. 29 On s'est souvent demand6 s'il &ait cularisation myocardique. 2z Pour d&erminer si l'ajout possible que les agonistes ~2 ne diminuent pas les besoins de clonidine ~ une anesthEsie gtntrale standard pou- anesthEsiques par une action anesthEsique directe mais vait procurer une sympathicolyse postoptratoire effi- pluttt par leur capacit6 de modifier les rtactions h~mo- cace /t l'insuffisant coronarien coronaire connu ou dynamiques qui sont ufilis&s pour 6valuer l'effet de la suspectt, Ellis et al. ~ ont rtparti altatoirement des concentration anesthEsique. Gabriel et al. s~ ont montr~ patients soumis h une chirurgie non cardiaque majeure qu'en presence de donidine, l'analyse spectrale de I~EG et non urgente pour recevoir soit un placebo soit la refl&ait une anesthEsie plus profonde malgr6 une r~duc- clonidine dans une combinaison de voies orale et lion de la concentration ttl&expiratoire d'isoflurane de transdermique. La clonidine a diminu6 le besoin en 50%. Des &udes pr~liminaires sur le MAC r~alis&s ~ la enflurane, la tachycardie perop&atoire et l'ischtmie fois chez des volontaires et chez des patients supportent myocardique. Finalement, un effet d'tpargne rtnal l'hypoth~se selon laquelle ces agents exercent une action relatif a ~t~ not6 pendant le pontage coronaire chez anesthEsique directe. des patients qui recevaient de la clonidine 4 lag.kg -~ La clonidine (4 lag.kg q i.v.) bloque les r~ponses avant l'induction. 2~ h~modynamiques et la libtration de cat&holamines ~k partir de ces &udes, on peut constater main- provoqu&s par la stimulation laryng& chez des tenant que les agonistes ~ sont utilis& par difftrentes patients soumis ~ une chirurgie de revascularisation voies d'administration pour des indications plus sp&i- myocardique. 31 Le groupe de Puig a &udi6 l'influence de fiques et pour leur activit6 sympathicolytique. La la clonidine p&idurale sur les besoins en fentanyl de n&essit6 de pr~venir les rtponses sympathicoexcita- patientes sous anesthEsie gtn&ale au prototype d'a- toires chez les grands malades sous anesth&ie gtntrale zote/morphinique optr&s pour une hysttrectomie deviendra vraisemblablement une indication impor- abdominale. La clonidine ptridurale a diminu~ les tante de cette cattgorie de mtdicaments. besoins de fentanyl, amtlior6 la stabilit6 cardio-vasculaire, Kamibayashi: LES AGONISTES ALPHA-2 ADR~NERGIQUES R21 diminu6 l'intensit6 de la douleur et le besoin d'analgrsie analg&ie qui d~butait plus t6t et durait plus postoprratoire ~ la salle de r&eil longtemps que lorsque la morphine seule &ait utilis&. Les donn&s foumies par ces &udes mettent en Du point de vue h~modynamique, la clonidine pro- lumi&e les qualitrs d'rpargne anesthrsique des agonistes duisait une baisse du dtbit cardiaque proportionnelle ~. chez les patients soumis ~ une anesthrsie g~n&ale. On la baisse de la frtquence. n'a toutefois pas 6mdi6 si le fait qu'ils soient combinrs R&emment, on a dtmontr~ que l'administration des concentrations plus faibles d'anesthrsiques e.st asso- prtop&atoire de clonidine (4 lag.kg -1) diminuait la ci6 ~ de meilleurs r&ultats. Cependant, on anticipe douleur postoptratoire et les besoins analg~siques qu'avec des concentrations moins 61ev&s d'un agent chez les enfants. 3s L'efficacit6 des agonistes ~2 seuls donnr, le patient se r&eillera plus rapidement et administr& pour l'analgtsie postop&atoire n'a pas 6t6 srjournera moins longtemps ~ l'unit6 de soins dtmontr& chez des patients qui en recevaient de tr& postanesth~siques. hautes doses ainsi que chez des parturientes. Sous d'autres conditions, la combinaison d'agonistes Douleur postoprratoire et2/morphinique semble procurer une analg&ie tr~s Apr~s la crsarienne, Capogna et aL ss ont constat6 une durable avec moins d'effets secondaires que chacun augmentation dose drpendante de la dur& de l'anal- des deux produits utilis6 stpar~ment. g&ie p&idurale morphine/anesthrsique local quand la clonidine (75-150 ~ag) &ait ajout& au mrlange. La Effets postoprratoires divers clonidine diminuait aussi la n&essit~ de rrajuster les Une perfusion p&ioprratoire de clonidine augmente la doses. Au cours d'une &ude ult&ieure r~alis& chez des concentration de l'hormone anabolique de croissance 39 accouch&s par crsarienne, l'ajout de clonidine ou et ceci peut avoir un effet positif sur la drperdition d'rpin~phrine (qui active aussi les r&epteurs ~z-adr& azot&. Mertes et al. 4~ ont d~montr6 que l'rquilibre nergique) au sufentanil p&idural a diminu6 le nombre azot6 se maintenait chez des alcooliques oprrrs pour des injections de sufentanil par PCA. s4 une chirurgie radicale nroplasique quand on leur Des gastrectomis~ sous anesthrsie g~n&ale corn- administrait de la clonidine p&iop&atoire: un groupe bin& ~ une prridurale ont requ de la morphine appari6 pour l'~ge (cancrreux non alcooliques) servait prridurale avec ou sans clonidine (3 ~ag.kg-* ) pour de contr61e. l'analgrsie postoprratoire, ss Les patients qui avaient Pour traiter les frissons chez les parturientes pen- reffu la clonidine ~ toutes les heures pendant 24 heures dant le travail sous analg&ie prridurale, on administre apr~s la chirurgie recevaient moins d'injections sup- souvent de la mrprridine. Mercadante et al. 4x ont plrmentaires de morphine par PCA (P < 0,05) alors drmontr~ que la clonidine (0,15 mg iv) &ait aussi effi- que leur score sur I'EVA de la douleur &ait infrrieur. cace que le traitement standard pendant le travail. Une Le groupe de Bernard s6 a compar~ l'efficacit6 anal- vaste &ude prospective ~ double insu sur l'usage pro- gtsique, la gazom&rie et les variables pharmacocin& phylactique de la clonidine (4 lag-kg-1 iv) administr& tiques d'une perfusion intraveineuse de fentanyl immrdiatement apr& l'induction de l'anesth&ie 75 pg.h -1 avec un mtlange de fentanyl de 25 ~ag.hq et grnrrale a montr~ qu'eUe rrduisait l'incidence, la gra- de clonidine 0,3 lag.h -~ aprts la chirurgie. Le soulage- vit6 et la dur& du frissonnement postoprratoire sans ment de la douleur, la stdation et les besoms suppl& modifier la srdation. 42 mentaires de k&oprofen &aient identiques dans les L'utilisation d'agonistes a 2 en urgence et A la prri- deux groupes. II y a eu 106 6pisodes de dtsaturation ode postop&atoire immrdiate est pleine de promes- art&idle (<90% pour >20 sec) chez quatre des patients ses. Ces produits semblent avoir un effet favorable dans le groupe fentanyl compar6 avec aucun dans le unique sur l'rquilibre azot~. S'il est corroborr, l'em- groupe clonidine-fentanyl. La pression art&idle ploi des agonistes ~2 deviendra la r~gle chez des moyenne, la clairance plasmatique et la constante patients en phase critique ~ l'unit6 de soins intensifs. d'61imination du fentanyl &aient inftrieures dans le groupe clonidine-fentanyl A celles du groupe fentanyl. Douleur chronique Dans d'une &ude inttressante, Rockemann et aL s7 Une &ude a montr6 que la clonidine transdermique ont compar6 les effets analg&iques de l'tpidurale A la pouvait diminuer la douleur chez des sujets atteints de clonidine (8 lag&g -x) settle avec une dose inf&ieure neuropathie diab&ique. 43 Comme la phentolamine &ait (4 }ag.kgq) associ&/t la morphine (2 mg) ou fa la mor- inefficace m~me chez les patients les plus aptes ~ rrpon- phine (50 lug.kg-~) seule chez des patients soumis Aune dre ~ ce traitement, le m&anisme de la rrponse $ la pancrtatectomie. Les patients qui recevaient les solu- clonidine semble indrpendant de son activit6 sympa- tions p&idurales contenant de la clonidine avaient tree thicolytique. De faqon anecdotique, on a observ6 chez R22 CANADIAN JOURNAL OF ANAESTHESIA un patient souffrant d'une pharyngodynie d'origine canc6reuse que l'ajout de clonidine aux doses ventricu- laires intrac~r~brales de morphine augmentait l'efficacit~ de ce morphinique.~ Identiquement, l'addition de douidine a soulag6 rapidement tm patient souffrant de douleur r6fractaire ~ la suite d'une 16sion m6dullaire. 4s M6me si ces &udes sont prometteuses, le plein potentiel des agonistes r 2 pour le traitement des &ats douloureux chroniques n'a pas &6 6valu6 rigoureuse- ment. Nous avons besoin d'&udes qui d6montrent que les effets analg6siques sont durables et, ~ long terme, sans complications.

Complications La bradycardie et l'hypotension repr&entent la suite logique des propri&6s pharmacologiques des agonistes ~2. 3,46,47 On peut pr&enir la bradycardie par l'administration pr6alable d'un agent anticholinergique (Fat- ropine ou le glycopyrrolate) quoique l'augmentation de la fr6quence cardiaque qui peut survenir en r6ponse aux anticholinergiques est diminu& ~ la fois chez les adultes et chez les enfants. 4s Au contraire, l'hypotension r6pond de fa~on exag&& ~ l'administration d'~ph~drine.49 La r6ponse vasopressive ~ la ph6nyl6phrine est exag6r& apr~s l'administration de clonidine orale et on peut donc ainsi r&ablir la pression art&ieUe efficacement avec soit l'~ph6drine soit la ph6nyl6phrine, s~

Conclusion En anesth6sie, l'utilisation des agonistes ~2, seuls ou en association se r6pand rapidement. En vertu des nom- breux avantages que les agonistes ~2 procurent, l'ent- housiasme initial d6montr6 envers cette classe de compos& semble justifi6 sur la base des plus r&entes &udes cliniques que nous avons rapport&s. La prochaine d&ennie verra se continuer cette &olution avec l'introduction en clinique de la deuxi~me g6n6ra- tion des agonistes ~2, en particulier de la dexm6d&omidine qui est plus s~lecdve, plus sp&ifique et plus efficace que son prototype, la donodine. En outre, les cliniciens trouveront d'autres indications pour ces produits grace des pr6parations adapt&s aux diff6rents modes d'administration, de la voie transdermique h celle du syst~me nerveux central.

R~f~rences (Voir page R16)