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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 com- pounds 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 post- operative 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
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