Resurgence in interest in 2-adrenergic agonists has been fuelled by the emergence of dexmedetomidine, the latest
2-agonist to be developed. Recently licensed in the USA, it has prompted many to re-examine more closely the workings of this fascinating class of drug and thereby its clinical applications. Clonidine, the prototype
2-agonist, was originally developed in the early 1970s for its potential use as a nasal decongestant. It rapidly found favour as a useful anti-hypertensive agent;1 however, with the advent of the ACE inhibitors and more selective ß-adrenergic antagonists, clonidine has been relegated to no better than a third line alternative for this purpose. It has, however, remained an intriguing compound that has been shown to be efficacious in a wide range of applications, from analgesia,2 sedation and reduction in post-operative shivering,3 to the control of symptoms during alcohol4 and nicotine5 withdrawal. In this issue of the journal, Hall and colleagues report their findings of a study specifically designed to quantify the dose response of low-dose clonidine in healthy volunteers with regard to sedation, analgesia and cognition.6
While much work has been published pertaining to the use of clonidine as an adjunct to anaesthesia and pain management, few reports address its specific use as a sedative unrelated to anaesthesia. Its use as a sedative/anxiolytic in the intensive care setting is now relatively commonplace, particularly after long-term sedation with opiates and/or benzodiazepines. Evidence does exist to show that clonidine is efficacious in the relief of withdrawal symptoms from these agents.7 8 However, reliable data on i.v dosing, sedative efficacy and the effect on outcome in the intensive care setting are lacking.
This paper, together with a recently published manuscript by the same group addressing the same questions for dexmedetomidine9, begins to fill the gaps although there are several reasons why data collected from young healthy volunteers cannot readily be extrapolated to patients in intensive care. First, there are two adverse effects that need to be considered. Bradycardia can be seen after acute administration of 2-agonists, an effect that is thought to be mediated by a centrally mediated reduction in sympathetic tone, together with an increase in vagal tone. In this paper, the loading dose of clonidine is given over a 15-min period, thereby lessening the risk of acute bradycardia. If there is a need to administer the drug faster, bradycardia can be pre-empted by the administration of an anticholinergic agent. Hall and colleagues point out that volunteers consistently complained of mouth dryness after clonidine administration and this could be potentially clinically significant in the intensive care setting. The addition of an anticholinergic (to avoid bradycardia) could compound this problem further. Second, as with nearly all drugs that are receptor agonists, one would expect to see desensitization after prolonged exposure to clonidine and its corollary, rebound. Indeed there have been reports of acute hypertensive crises occurring after the abrupt cessation of clonidine therapy.11 If clonidine infusions are used in intensive care for long periods it is to be expected that abrupt cessation of therapy would also have to be carefully monitored.
Third, in the intensive care setting, there are likely to be complex interactions with coincident administration of opioid and cholinergic receptor ligands making determination of the mechanisms between adrenoreceptor agonists and effect difficult. For example clonidine, at doses providing significant analgesia, has been shown to cause an increase in the release of acetylcholine from the dorsal horn of the spinal cord in sheep.11 Concurrent administration of neostigmine enhances this analgesic effect.12 Areas containing dense populations of 2-receptors have been demonstrated in the substantia gelatinosa of the human spinal cord,13 often in close association with µ-opioid receptors. Again,
2-agonist-mediated analgesia can be enhanced in the presence of µ-agonists.14 Will similar interactions and synergy occur supraspinally? The MAC-sparing effect of i.v. and oral clonidine has been well documented15 16 and as such again provides further evidence for their complex interactions with other CNS depressants.
Hall and colleagues have commented on the unique feature of rousability seen with low dose clonidine (and other 2-agonists9), whereby even apparently deeply sedated subjects (as evidenced by Bispectral Index (BIS) monitoring) can be fully aroused and show little or no impairment in psychomotor performance. Arousal can be defined as the state of physiological reactivity of a subject, ranging from sleep to panic. It has been suggested that a dual-level control mechanism exists with a passive low-level physiological arousal system being modulated by active cognition. Investigators studying the neural correlates underlying sedation (as opposed to anaesthesia) have focused on the mechanisms underlying arousal and attention (as opposed to anaesthesia or sedation). Arousal level is regulated by many neurotransmitter systems found in a wide variety of areas of the brain. Norepinephrine release affects both attention and arousal in a complex manner; it is speculated that noradrenergic systems are more involved with the active cognitive modulation of arousal. Smith and Nutt17 have described how, after administering clonidine to volunteers and asking them to perform a simple task many lapses of concentration were seen when the subjects were left quietly alone. These lapses of concentration were almost fully reversed by arousing noise and by idazoxan, an
2-antagonist, and may be illustrative of the differing modulatory effects of norepinephrine depending on the underlying arousal level of the subject. Pre-synaptic inhibition of norepinephrine release by
2-agonists leads to reduced levels of arousal. Idazoxan has been shown to speed up response times in certain situations and reverse the sedative effects of clonidine;18 externally stimulating the subject (for example with loud noise) has the same effect. It is speculated that arousing subjects causes increased release of central norepinephrine, thereby chemically antagonizing the effects of clonidine. Once the subject is left quietly alone, norepinephrine release decreases and the sedative effects of clonidine once again become apparent.
Coull and colleagues compared subjects performance of a simple task while sedated with diazepam or clonidine and found that in certain situations the subjects sedated with clonidine were both able to successfully complete the test task and in some cases their performance was enhanced (when compared with placebo).19 One theory behind this observation is that when the subject is aroused, they begin to focus their attention on the task at hand. Increased release of norepinephrine in areas of the brain specifically required to perform the task momentarily antagonizes the effect of clonidine. While in other areas of the brain the clonidine effect is still apparent, perhaps obtrunding the subjects response to distracting or unnecessary inputs. Another explanation may lie in the fact that the doseresponse curve of 2-agonists is complex. For example clonidine attenuates noradrenergic activity at low doses (because of the highly efficacious pre-synaptic action), but enhances activity at higher doses. It is thus clear that central
2-agonist sedation is not a result of a global reduction in cerebral activity. This is to be expected as the distribution of
2-receptors within the brain is not at all uniform, with areas such as the thalamus and locus coeruleus (an important modulator of vigilance) containing very high concentrations of noradrenergic neurones13 compared with other regions of the brain.
These studies raise a number of interesting issues regarding the depth and quality of sedation. The Ramsay score forms the basis of most commonly used sedation scoring systems, relying on the patients response to stimulation (verbal and/or tactile). If patients sedated with low doses of 2-agonists can be easily aroused to full consciousness from a state of deep sleep, it makes assessment of sedation using this system impossible. Hall and colleagues have used three methods of sedation assessment consecutively and all three scores mirror this phenomenon of rousability, including BIS values returning to almost baseline levels during arousal. The use of the BIS to monitor the level of sedation with other agents has been well validated, and it is interesting to see that similar results are produced under sedation with clonidine. Therefore, in order to assess the sedative state in patients receiving
2-agonists a new method of sedation assessment is needed. Indeed, are such patients really sedated, if they can be so fully aroused by external stimuli? In what situations would this feature be an advantage? Certainly there are scenarios in which this could be a distinct disadvantage, such as when patients are subjected to painful or unpleasant procedures. However, in situations where patient co-operation is desirable or needed, it may prove most useful. For example, sedated patients in the intensive care setting can be called upon to co-operate with the physiotherapist (by focusing on a task) and then fall back to sleep when left undisturbed.
A review on 2-agonists from last year20 describes the many benefits of clonidine use in anaesthetic practice. Why then is it not used more frequently? Clonidine is licensed, (and therefore only marketed), for the treatment of hypertension, migraine prophylaxis and menopausal flushing. Lack of familiarity, availability and fear of side effects are additional reasons. Clonidine has a spectrum of action that goes beyond the effects described in this paper, including a decrease in insulin release,21 inhibition of renin release22 and a decrease in intra-ocular pressure23 to name but a few. The activation of
1 receptors at higher concentrations widens its spectrum of activity. Establishing which of the three
2-adrenoceptor subtypes (
2a,
2b and
2c) are responsible for which effects, may lead to the development of novel agents that are selective for individual receptor subtypes. These can then be administered to achieve the desired effects without producing unwanted side effects. The newer
2-agonist, dexmedetomidine, being more highly specific for the
2-adrenoceptor, goes some way to achieving this ideal and is specifically licensed for use as a sedative agent in the USA. This paper provides a starting point for furthering our understanding of how, possibly clonidine, and probably new, specific
2-agonists can best be used in ways that ultimately could improve patient care.
M. E. P. Jones
M. Maze
Department of Academic Anaesthetics
Imperial College School of Medicine
Chelsea and Westminster Hospital
London SW10 9NH
UK
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