ALFA2 SU FISIO

REVIEW ARTICLE

Alpha-2 and imidazoline receptor agonists Their pharmacology and

therapeutic role

Z. P. Khan,1 C. N. Ferguson2 and R. M. Jones3

1 Lecturer, 2 Honorary Lecturer and 3 Professor, Department of Anaesthetics, Imperial College School of Medicine,St Mary’s Hospital, London W2 1NY, UK

SummaryClonidine has proved to be a clinically useful adjunct in clinical anaesthetic practice as well as inchronic pain therapy because it has both anaesthetic and analgesic-sparing activity. The moreselective alpha-2 adrenoceptor agonists, dexmedetomidine and mivazerol, may also have a role inproviding haemodynamic stability in patients who are at risk of peri-operative ischaemia. Theside-effects of hypotension and bradycardia have limited the routine use of alpha-2 adrenoceptoragonists. Investigations into the molecular pharmacology of alpha-2 adrenoceptors have elucidatedtheir role in the control of wakefulness, blood pressure and antinociception. We discuss thepharmacology of alpha-2 adrenoceptors and their therapeutic role in this review. The alpha-2adrenoceptor agonists are agonists at imidazoline receptors which are involved in central bloodpressure control. Selective imidazoline agonists are now available for clinical use as antihypertensiveagents and their pharmacology is discussed.

Keywords Receptors; alpha-2, imidazoline.

......................................................................................Correspondence to: Dr Z. P. Khan. Present address: Department ofAnaesthesia and Intensive Care, City Hospital NHS Trust, DudleyRoad, Birmingham B18 7QH, UKAccepted: 24 June 1998

The widespread use of alpha-2 adrenoceptor agonists inveterinary practice has provided extensive experience over20 years. In addition, alpha-2 adrenoceptor agonists havebeen used to a limited degree in clinical practice and theirmolecular pharmacology has been elucidated. This hasalso cast some light on the mechanisms of action of avariety of other drugs not directly associated with alpha-2adrenoceptors. Alpha-2 adrenoceptor agonists are notroutinely used by the majority of anaesthetists despite havingmany desirable effects, including anxiolysis, analgesia,sedation, anaesthetic-sparing and peri-operative haemo-dynamic-stabilising effects. Their potential thus remains tobe fully realised. This may be because there are no highlyspecific alpha-2 adrenoceptor agonists currently availablefor anaesthesia (clonidine has some alpha-1 activity) andthere is a possibility of undesirable haemodynamic effects

at certain doses. Indeed there is still debate as to whetherthese drugs offer real clinical benefits.

Clonidine, mivazerol and to a lesser extent dexmed-etomidine are not pure alpha-2 adrenoceptor agonists butare also able to combine with nonadrenergic imidazolinereceptors [1]. These receptors are binding sites specificallyrecognising the imidazoline or oxazoline chemical struc-ture and have been classified into I1 found in the brain, andI2 found in the brain, kidney and pancreas. Imidazoline-receptor stimulation mediates a central hypotensive andanti-arrhythmogenic action. It may be possible that someof the effects of alpha-2 adrenoceptor agonists are medi-ated by imidazoline receptors. Moxonidine and rilmeni-dine are the first orally active imidazoline receptor agoniststo be introduced into clinical practice. In this review wediscuss the clinical pharmacology of alpha-2 adrenoceptor

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agonists and reflect on their potential use in anaesthesia aswell as critical-care practice.

Molecular pharmacology

Receptor classificationHistoryIn 1948 Ahlquist challenged the view that adrenergicreceptors were either excitatory or inhibitory by differ-entiating adrenergic receptors into alpha and beta [2]. In1969, Paton and co-workers found that a subclass of alphaadrenoceptors located presynaptically regulated the release ofneurotransmitter [3]. This led to the subdivision of alphaadrenoceptors into postsynaptic alpha-1 and presynapticalpha-2 [4, 5]. However, this proved to be misleading withthe characterisation of alpha-2 adrenoceptors postsynapti-cally and extrasynaptically [6]. A functional classification ofalpha-2 adrenoceptors as inhibitory and alpha-1 as excita-tory also proved to be inaccurate, as not all alpha-2adrenoceptors are inhibitory [7]. Stimulation of alpha-1and alpha-2 adrenoceptors in vascular smooth muscleresults in vasoconstriction. Clearer characterisation ofalpha-1 and alpha-2 adrenoceptors on a pharmacologicalbasis followed the discovery of selective antagonists, pra-zosin being more potent at alpha-1 adrenoceptors andyohimbine being more potent at alpha-2 adrenoceptors [8].

Bylund and co-workers [215] defined three alpha-2isoreceptors; alpha-2a, alpha-2b and alpha-2c based ontheir affinity for alpha adrenoceptor ligands. The regionaldistribution of the isoreceptors has been demonstratedautoradiographically using radiolabelled probes. The genesresponsible for encoding alpha-2 adrenoceptors in thehuman platelet have been identified on chromosome 10[9] and the human kidney on chromosome 4 [10]. Furtheralpha-2 adrenoceptors have been cloned from geneslocated on chromosome 2 [11]. Therefore the alpha-2adrenoceptors can be further classified as alpha-2 C10,alpha-2 C4 and alpha-2 C2 and these correspond withalpha-2a, alpha-2c and alpha-2b, respectively. The threealpha-2 adrenoceptor subtypes bind alpha-2 agonists andantagonists with similar affinities.

Structure of alpha-2 adrenoceptorsThe alpha-2 adrenoceptor is a transmembrane receptor.This is an excitable protein which traverses the cell mem-brane and reacts selectively with extracellular ligands(endogenous hormones or exogenous molecules such asdrugs) to initiate a cascade of events leading to a physio-logical effect. The long chain of amino acids making upthe alpha-2 adrenoceptor protein contains hydrophobicand hydrophilic areas. It winds in and out of the cellmembrane, crossing the cell membrane seven times at thehydrophobic areas. The seven hydrophobic segments are

made up of 20–25 amino acids forming alpha helices thatare embedded in the membrane. The three alpha-2 recep-tor subtypes are 72–75% identical to each other withrespect to amino acid sequence in the membrane-spanningdomains. This sequence homology can be compared witha similarity between different adrenoceptors of 42–45%and alpha-2 and muscarinic receptors of 35%. This indi-cates that the transmembrane area of the receptors isimportant for selectivity of ligand binding. To bind aligand, a receptor must have charged counterbalancingions located within it, but the transmembrane region itselfis nonpolar. This apparent inconsistency can be explainedby the way the side-chain groups in critical amino acids arecharged and coalesce to form a binding pocket permittingaccess from the extracellular space for binding chargedligands. The third and fourth transmembrane domains aremost important [12] with more minor involvement fromthe sixth and seventh domains. It can be inferred that thesedomains are closely related in the three-dimensionalstructure of the molecule. The structure of the liganddetermines whether it has agonistic or antagonistic effectson the receptor. Mutation of amino acids in these regionsaffects the binding of agonists and antagonists and theirphysiological effects. The cytoplasmic aspect of the recep-tor protein forms a contact point for the G-proteinproviding a means of signal transduction and thereforerapid stimulation of the effector system.

G-proteinsAlpha-2 adrenoceptors are examples of G-protein-coupled receptors. G-proteins are ubiquitous transmem-brane signalling mediators [13]. They are proteins thatbind the guanine nucleotides, GDP (guanosine diphos-phate) and GTP (guanosine triphosphate). The adrenergicreceptors and opioid receptors are also coupled to G-pro-teins. Other receptors, which are also G-protein coupledinclude the following: adenosine (AI), acetylcholine (M2),GABAB, dopamine (D2) and histamine (H2). The G-pro-teins are composed of three polypeptide subunits desig-nated as alpha, beta and gamma in order of decreasingmolecular mass.

The G-proteins can be classified according to their actionon adenyl cyclase and the sensitivity of their alpha subunitto ribosylation by Bordetella pertussis toxin. The alpha-2adrenoceptors are coupled to pertussis-toxin-sensitiveG-proteins, Go which has no effect on adenylyl cyclase,and Gi which supports inhibition of adenylyl cyclase [14].Beta adrenoceptors are coupled to the G-protein Gs whichis not pertussis-toxin sensitive and stimulates the activationof adenylyl cyclase. In the inactive state, the G-protein isnot closely associated with the alpha-2 receptor and isbound to GDP. When an agonist binds to the receptor, thestructure of the receptor changes and it associates with the

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alpha subunit of the G-protein. This results in a reducedaffinity of the G-protein for GDP and in the presence ofmagnesium, it is replaced by GTP. The alpha subunit thenuncouples from the beta and gamma subunits and coupleswith the effector, resulting in a decrease in the affinity ofthe receptor for the agonist and the agonist leaves its receptorsite. The duration of binding of the agonist to the receptordetermines the amount of amplification of the intracellularresponse. The GTPase on the alpha subunit is then acti-vated and hydrolyses GTP to GDP, releasing an inorganicphosphate; the receptor then returns to the inactive state[15]. A number of effector mechanisms (see below) havebeen described: each alpha-2 receptor may stimulate morethan one effector mechanism and although each may notrepresent a pathway to a biological response, the physio-logical and clinical relevance remains to be elucidated.

Adenylyl cyclaseAn important consequence of alpha-2 adrenoceptor stimu-lation is the inhibition of adenylyl cyclase and this results indecreased formation of 30 50-cyclic adenosine monophos-phate (cAMP). This is an important regulator of manycellular functions by controlling the phosphorylation stateof regulatory proteins by cAMP-dependent protein kinase[16]. Although the inhibition of adenylyl cyclase is analmost universal effect of alpha-2 adrenoceptor activation,the decrease in intracellular cAMP cannot explain many ofthe physiological results.

Alternative effector mechanismsThese include activation of Gi-protein-gated potassiumion channels [17], causing hyperpolarisation of the neuronal

cell and so reducing the rate of firing of excitable cells inthe central nervous system [18]. The increase in potas-sium-ion conductance is calcium dependent in manysystems and the inhibition of adenylyl cyclase may alsoplay a permissive role. Alpha-2-adrenoceptor stimulationresulting in inhibition of neurotransmitter release ismediated through a decrease in calcium-ion conductance.The decrease in calcium-ion conductance involves directregulation of calcium entry by voltage-gated calcium ionchannels [19] and these may be coupled to a Go-protein[20]. Activation of alpha-2 adrenoceptors can also accele-rate sodium–hydrogen-ion exchange causing alkalinisationof the interior of platelets and stimulating an increase inphospholipase A2 activity resulting in increased formationof thromboxane A2 [21]. Alpha-2 receptors can modulatethe actions of phospholipase C that mediate the hydrolysisof phosphatidyl inositol biphosphate into diacyglyceroland inositol triphosphate (Fig. 1).

Distribution of alpha-2 adrenoceptorsPresynaptic alpha-2 adrenoceptors are present in sympa-thetic nerve endings and noradrenergic neurones in thecentral nervous system where they inhibit the release ofnoradrenaline [22]. Postsynaptic alpha-2 adrenoceptors existin a number of tissues where they have a distinct physio-logical function; these include the liver, pancreas, platelets,kidney, adipose tissue and the eye. The medullary dorsalmotor complex in the brain has a high density of alpha-2adrenoceptors and activation of these may be responsiblefor the hypertensive and bradycardic effects of alpha-2adrenoceptor agonists.

The locus coeruleus is a small neuronal nucleus located

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Figure 1 Diagrammatic representation of the structure of the alpha-2 adrenoceptor, G-proteins and possible effector mechanisms. Thealpha-2 adrenoceptor agonist binds to the alpha-2 adrenoceptor (a2 R). This results in coupling with G-proteins due to aconformational change in the receptor protein. The alpha-2 adrenoceptor inhibits adenylyl cyclase (Ac) through the inhibitory Gi

protein; transmembrane signalling is mediated by the replacement of guanosine diphosphate with guanosine triphosphate. The Gi

protein also activates the outward opening of a potassium (K�) channel, which results in hyperpolarisation. The Go protein is coupledin an inhibitory fashion to calcium ion (Ca2�) translocation and to the membrane-bound enzyme phospholipase C (Pc). The alpha-2adrenoceptor is coupled through yet another undetermined G-protein to hydrogen (H�) and sodium (Na�) ion exchange andphospholipase A2 (PA2).

bilaterally in the upper brainstem and is the largest nor-adrenergic cell group in the brain. The locus coeruleus isan important modulator of wakefulness and may be themajor site for the hypnotic action of alpha-2 adrenoceptoragonists mediated by alpha-2a adrenoceptors located there[23]. The locus coeruleus has a number of efferent con-nections. Cortical activity is influenced by the connectionwith the subthalamic relay nucleus and the thalamus vianoradrenergic fibres. Nociceptive transmission at a spinallevel is decreased via descending fibres in the dorsolateralfuniculus tracts. There are also efferent fibres to the reticu-lar formation with connections to the vasomotor centres[24]. There are afferent connections from the rostral ven-trolateral medullary nuclei. A high density of alpha-2adrenoceptors has also been demonstrated in the vagusnerve, intermediolateral cell column and the substantiagelatinosa. The dorsal horn of the spinal cord containsalpha-2a subtype adrenoceptors, while the primary sen-sory neurones contain both alpha-2a and alpha-2c sub-types of adrenoceptors.

Imidazoline receptor agonists

Blood pressure controlThe ventromedial (depressor) and the rostral-ventrolateral(pressor) areas of the medulla are responsible for the centralregulation of cardiovascular tone and blood pressure. Theyreceive afferent fibres from the carotid and aortic baro-receptors, which form the tractus solitarius via the nucleustractus solitarius. Variations in blood pressure are detectedby the carotid and aortic baroreceptors and their firing isaltered. This results in an increase or decrease in bothsympathetic outflow and vagal impulses to maintain bloodpressure. Sympathetic overactivity and decreased parasym-pathetic tone is present in human hypertension [25].

HistoryFirst generation centrally acting antihypertensives such asclonidine and a-methyl dopa were originally thought todecrease sympathetic tone by stimulating alpha-2 adreno-ceptors in the medulla. When substances with an imidazo-line or catecholamine structure were injected directly intothe medulla of anaesthetised animals only imidazolines hadhypotensive effects and there was no correlation betweentheir affinity for alpha-2 adrenoceptors and their hypo-tensive effects [26]. In the early 1980s, Bousquet et al. [27,28] proposed the existence of receptors specifically recog-nising the imidazoline or similar chemical structure andwhich were not adrenergic receptors. This was because thecentral hypotensive effects of clonidine-like drugs couldnot be explained by their alpha-2 receptor actions alone. Itwas suggested that these receptors might be found in thenucleus reticularis lateralis of the ventrolateral medulla, the

site of the hypotensive action of these drugs. In 1987,Ernsberger and co-workers [29] were the first to verify theexistence of specific imidazoline-binding sites in the ven-trolateral medulla which were insensitive to catecholamines.

Two subtypes of imidazoline receptor (I) have been iso-lated, I1 and I2. I1 receptors have a more restricted dis-tribution in the ventrolateral medulla [30]. They arethought to be G-protein linked although the signallingpathway remains to be fully elucidated. However, it islikely that activation of phospholipase A2 leading to therelease of arachidonic acid and the subsequent generationof prostaglandins plays a major role [31]. I1 receptors areinvolved in blood-pressure regulation. I2 receptors havebeen found in the liver, platelets, adipocytes, kidneys,adrenal medulla and brain, including the frontal cortex[32–36]. They have been implicated in neuroprotection inthe animal model of ischaemic infarction [37]. I2 receptorsare found mainly on the mitochondrial membrane and arenot G-protein linked [37]. Unlike the I1 receptors, I2receptors are not found on neuronal plasma membranes[38]. The imidazoline receptor protein has a molecularmass of 70 kDa but the exact amino acid sequence is notyet known. Several endogenous ligands for I receptors,collectively termed clonidine-displacing substances (CDSs),have been detected in tissues and serum. The only CDSwhose structure is known is agmatine. It is bioactive andwidely distributed and binds to alpha-2 adrenceptors andall classes of imidazoline receptors [39]. The exact role ofagmatine remains to be elucidated but its presence inspecific neuronal pathways, as well as in serum, suggeststhat it might be a novel neurotransmitter or hormone [40].

It has been suggested that imidazoline receptors play arole in the genesis of adrenaline-induced dysrhythmia underhalothane anaesthesia. Rilmenidine dose dependently inhi-bits adrenaline-induced dysrhythmias under halothaneanaesthesia in dogs [41]. This action was blocked bybilateral vagotomy and by pretreatment with a nonspecificalpha-2 adrenoceptor and imidazoline receptor antagonistidazoxan intracisternally. Pretreatment with rauwolscine,an alpha-2 adrenoceptor antagonist, also intracisternally,did not affect the anti-arrhythmic effect of rilmenidine.Therefore it can be said that activation of central imidazo-line receptors and vagal tone are critical to the anti-arrhythmic action of rilmenidine. Moxonidine, which isselective for the I1 receptor, increased the threshold foroubain-induced cardiac dysrhythmias in guinea pigs, thissuggests that the I1 subtype may be responsible for theanti-arrhythmic effects [42].

Agonists (Table 1)RilmenidineThe oxazoline, rilmenidine, has a structure similar to thatof imidazolines and is a centrally acting imidazoline receptor



agonist (Fig. 2). It is one of a new generation of centrallyacting antihypertensive agents. The safety and efficacy ofrilmenidine as a treatment for human hypertension hasbeen demonstrated in clinical trials [43]. It was found to beequally efficacious in elderly hypertensive patients [44] andthose who also suffered from diabetes [45], renal impair-ment [46] or left ventricular hypertrophy [47]. In animalstudies, rilmenidine has been shown to increase sodiumexcretion and urine flow rates [48]. It is comparable withatenolol [49] and hydrochlorothiazide [47] as a first lineantihypertensive. Both rilmenidine and idazoxan, an imi-dazoline receptor antagonist, have neuroprotective effectsin the animal model of ischaemic infarction. The precisenature of this is not known, but an interaction with theimidazoline I2 receptors on the mitochondrial membrane

of astrocytes in the cerebral cortex, causing a calcium sink,is one hypothesis.

Rilmenidine is rapidly absorbed after oral administra-tion, with a peak plasma concentration within 1.5–2 h. Itundergoes some oxazoline-ring hydrolysis and oxidation,but 65% of the dose is eliminated through the kidneysunchanged. Rilmenidine is 10% protein bound and itselimination half-life is 8 h. Unlike clonidine, there appearsto be no withdrawal syndrome following the cessation oftreatment [50].

MoxonidineA more potent and selective agonist for the imidazoline I1receptor is moxonidine. It is three times more selective forthe I1 receptor in the ventrolateral medulla than rilmeni-dine and has a 40–70 times greater affinity for I1 receptorsthan alpha-2 adrenoceptors. Clonidine is twice as potent asmoxonidine at the I1 receptor but has a similar affinity foralpha-2 and I receptors. Moxonidine acts by decreasingsystemic vascular resistance secondary to a reduction incentral sympathetic tone, reducing plasma catecholamineand renin levels [51]. Moxonidine may also increase sodiumand water excretion. It was shown to be as effective and welltolerated as atenolol [52], nifedipine [53], captopril [54]and prazosin [55] in controlling hypertension. After oraladministration, moxonidine is rapidly and almost completelyabsorbed. Maximum plasma concentration is achieved in1 h. It has a plasma half-life of 2 h and is 90–96% excretedby the kidneys, 51% as unchanged drug. A dose of 0.4 mgdaily will effectively lower the blood pressure over 24 h,although the dose should be reduced if there is renalimpairment.

The imidazoline receptor agonists have few of the adverseeffects of clonidine such as dry mouth, sedation, depressionand tiredness and can be given as a once-daily dose. Thehypotensive effects of these drugs can be antagonised byidazoxan and efaroxan which are antagonists at both imida-zoline receptors and alpha-2 adrenoceptors, but not by 2-MIa selective alpha-2 adrenoceptor antagonist [56–58].

Alpha-2 receptor agonists (Table 2)

Clonidine is an imidazoline and is the only alpha-2 adreno-ceptor agonist currently available for use in anaestheticpractice (Fig. 3). It is available as 100/250/300 mg tabletsfor oral administration, as a transdermal patch releasing100/200/300 mg over 24 h and in an injectable solutioncontaining 150 mg.mlÿ1 for intravenous, intramuscular,local and regional use. It is a partial agonist with analpha-2a-to-alpha-1 selectivity ratio of 39 [59]. Thealpha-2a-to-imidazoline selectivity ratio is 16. The adultoral dose is 100–600 mg administered 8 hourly; the corre-sponding intravenous dose is 150–300 mg, a dose of 150 mg



Table 1 Imidazoline receptor agonists in order of preference forimidazoline receptor.

MoxonidineRilmenidineClonidineDexmedetomidineMivazerol

Figure 2 The chemical structure of imidazoline agonistsmoxonidine and rilmenidine.

as been used epidurally. Methyldopa’s use is limited to thecontrol of blood pressure in pregnancy; it has a slow onsetof action because the active component is the metabolitemethylnoradrenaline.

Currently under investigation is dexmedetomidine, amore specific and shorter-acting alpha-2 adrenoceptoragonist with an alpha-2a-to-alpha-1 ratio of 1300 [59]and alpha-2a-to-imidazoline selectivity ratio of 32. Dex-medetomidine is a potent drug, at plasma concentrations

less than 1.0 ng.mlÿ1 it can produce profound physio-logical alterations. Dexmedetomidine is an isomer and theactive component of medetomidine. Although initiallydesigned to prevent myocardial ischaemia, mivazerol isan alpha-2 agonist which may have potential for peri-operative use; it has an alpha-2a-to-alpha-1 selectivityratio of 119 and an alpha-2a-to-imidazoline selectivityratio of 215, the specificity is between clonidine anddexmedetomidine [59].

Alpha-2 receptor antagonists (Table 3)

A drug which could cross the blood–brain barrier andselectively reverse the central effects of alpha-2 adreno-ceptors would be a useful adjunct to anaesthetic practice.Atipamezole, idazoxan and yohimbine are selective andcentrally acting alpha-2 adrenoceptor antagonists; all havebeen used in veterinary practice. Currently, the moreselective alpha-2 adrenoceptor antagonists are not availablefor clinical application. However, Karhuvaara and colleagues[60] gave atipamezole intravenously to human volunteers toreverse the effects of a preceding dose of dexmedetomidine.Atipamezole, the most selective of the alpha-2 adrenoceptorantagonists, was able to reverse the sedation and hypotensioncaused by dexmedetomidine.

Pharmacokinetics

Clonidine is lipid soluble and so has both rapid and com-plete absorption after oral administration, reaching a peakplasma level in 60–90 min. Time release transdermalpatches are also available; 2 days of administration arerequired before therapeutic plasma concentrations areachieved. Because of its high lipid solubility clonidinecrosses the blood–brain barrier and disappears rapidlyfrom the cerebrospinal fluid (CSF). The eliminationhalf-life after epidural injection of clonidine 150 mg is30 min. It is 20% bound to plasma proteins and the volumeof distribution is 1.7–2.5 l.kgÿ1. Clonidine is less than 50%metabolised in the liver to inactive metabolites, the remain-ing drug being excreted unchanged in the kidney; about



Table 2 Selective and nonselective alpha-2 adrenoceptor agonistsin order of preference for alpha-2 adrenoceptor.

Non-selective alpha-2adrenoceptor agonists

Selective alpha-2adrenoceptor agonists

Noradrenaline DexmedetomidineAdrenaline Mivazerol

Clonidinea-Methyldopa

Figure 3 The chemical structure of alpha-2 adrenoceptoragonists clonidine, dexmedetomidine and mivazerol.

Table 3 Selective and nonselective alpha-2 adrenoceptor anta-gonists in order of preference for alpha-2 adrenoceptor.

Non-selective alpha-2adrenoceptor antagonists

Selective alpha-2adrenoceptor antagonist

Phentolamine AtipamezoleTolazoline Idazoxan

YohimbineEfaroxanRauwolscine

20% is excreted in the faeces. The elimination half-life is ofthe order of 6–23 h and is prolonged if renal impairmentexists; the clearance is 1.9–4.3 ml.minÿ1.kgÿ1.

Dexmedetomidine has a volume of distribution of <200 land a systemic clearance of 0.5 l.minÿ1 after administra-tion of an intravenous infusion. Dexmedetomidine exhi-bits a concentration-dependent nonlinear pharmacokineticprofile [61]. At high concentrations following an intra-venous bolus, dexmedetomidine decreases the initial volumeof distribution and intercompartmental clearance due toits peripheral vasoconstrictive action. Dexmedetomidinebehaves in a biphasic manner, as the concentration declinesvasodilatation occurs due to its central effect. Therefore,dexmedetomidine should not be administered rapidly as itcan result in undesirable hypertension as well as alteredpharmacokinetics. The decline in the plasma concentra-tion of dexmedetomidine following the cessation of aninfusion is described by its context-sensitive half-life,which is similar to that of fentanyl. The intramuscularroute probably offers the better predictability as well asreasonably rapid onset, the peak plasma concentrationoccurring within 15 min.

Mivazerol given as a bolus dose followed by an infusionachieved a steady plasma concentration within 30 min ofthe initial dose. The plasma half-life is 4 h and it is <50%protein bound. About 40–45% is excreted unchanged bythe kidneys and about 20–25% undergoes conjugation inthe liver.

Pharmacodynamics

Central nervous system effectsWhen adrenaline has been administered intracerebroven-tricularly, so that the blood–brain barrier is avoided in anumber of mammals including man, sedation ranging fromsleep to surgical anaesthesia has been described [62–65].This effect may be mediated by postsynaptic alpha-2a sub-type adrenoceptors located in the locus coeruleus, causinga decrease in noradrenergic activity [66]. The use ofclonidine as an antihypertensive has been limited by itssedative effects, but offers advantages in anaesthetic prac-tice. When clonidine was given in a sufficient dose toproduce sleep, the EEG showed an increase in stage I and 2sleep and decrease in rapid eye movement sleep [67].Alpha-2 adrenoceptor agonists and benzodiazepines pro-duce comparable anxiolysis [68]. Clonidine at high dosescan be anxiogenic owing to alpha-1 [69], but paradoxicallyit has been used to treat panic disorders. Dexmedetomi-dine decreases cerebral blood flow in dogs during anaes-thesia with both halothane and isoflurane, without evidenceof global ischaemia occurring [70, 71]. It has little effect onintracranial pressure and in the animal models of brainischaemia has been shown to be neuroprotective [72]. The

analgesic and reduction in anaesthetic requirements ofalpha-2 adrenoceptor agonists are discussed later.

Cardiovascular system effectsThere are both alpha-1 and alpha-2 postjunctional recep-tors in the arterial and venous vasculature where they bothmediate vasoconstriction [73]. The alpha-1 and alpha-2adrenoceptors differ in their location and their utilisationof calcium. In the arterial vasculature, the alpha-1 adreno-ceptors are junctional and the alpha-2 adrenoceptors areextra-junctional, while the reverse is true of the venousvasculature. Alpha-1 adrenoceptor stimulation producesvasoconstriction by utilising intracellular calcium whilethe alpha-2-adrenoceptor-mediated vasoconstriction usesextracellular calcium [74]. This makes the alpha-2 adreno-ceptor agonist’s pressor response more sensitive to calciumantagonists [75]. Intravenous alpha-2 adrenoceptor agonistadministration leads to a decrease in heart rate and atransient increase in arterial blood pressure and systemicvascular resistance, but a decrease in cardiac output due tothe activation of postjunctional vascular alpha-2 adreno-ceptors. This is followed by a longer lasting decrease inheart rate and blood pressure due to a centrally mediateddecrease in sympathetic tone and an increase in vagalactivity. Neither the exact location nor the specific recep-tors responsible for the central hypotensive action ofalpha-2 adrenoceptor agonists are yet known. It seemsthat postsynaptic alpha-2 adrenoceptors and imidazolinereceptors in the brainstem are involved [76]. Clonidinelowers the ‘set point’ around which arterial blood pressureis regulated. It also increases the gain of the baroreceptorsystem, resulting in lower heart rates for a given increasein blood pressure, and broadens the range of heart-rateresponses to changes in blood pressure [77]. The brady-cardia commonly seen after administration of alpha-2adrenceptor agonists may be due to the central sympatho-lytic action of these drugs leaving vagal tone unopposed. Itmay also be due to presynaptic-mediated reduction ofnoradrenaline release or a direct vagomimetic action [78].Although bradycardia can be a problem with the admin-istration of alpha-2 adrenoceptor agonists, dexmedetomi-dine has been shown to protect against adrenaline-inducedarrhythmia during halothane anaesthesia in dogs [79]. Thisanti-arrhythmic action may be due to stimulation ofimidazoline receptors.

There are no known directly mediated alpha-2 adreno-ceptor effects on the myocardium. Alpha-2 adrenoceptorreduction in sympathetic tone and increase in parasym-pathetic tone results in a reduced heart rate, systemicmetabolism, myocardial contractility and systemic vascularresistance. These all result in a decrease in the myocardialoxygen requirements. This is may be why clonidine hasbeen successful in the treatment of angina pectoris [80].



The effect of alpha-2 adrenoceptor agonists on coronaryvasculature in humans is not yet known, as there is con-siderable interspecies variation in distribution and alpha-2adrenoceptor subtypes. It is known that the alpha-2adrenoceptors on the endothelium release nitric oxidewhen activated [81]. In swine this has been shown to bethe alpha-2a subtype [82]. It has been postulated thatthe stimulation of alpha-2 adrenoceptors may lead to apostsynaptic coronary vasoconstriction, which may becountered by a nitric-oxide-mediated coronary vasodila-tation [83].

Respiratory system effectsAlpha-2 adrenoceptors have a minimal effect on ventila-tion. In humans, clonidine in doses up to 300 mg, seems tocause a small reduction in resting minute ventilation and anincrease in expired carbon dioxide [84]. Dexmedetomi-dine has a biphasic effect on respiratory drive, with lowdoses decreasing and higher doses increasing resting ven-tilation in dogs [85]. Dexmedetomidine in doses up to2 mg.kgÿ1 caused mild ventilatory depression, but this wasnot significantly different from that seen with placebo [86].The locus coeruleus, described earlier, is an important sitefor the action of alpha-2 adrenoceptor agonists. The locuscoeruleus is involved in arousal reactions; suppression of itsactivity by alpha-2 adrenoceptor agonists can result in astate similar to sleep with mild respiratory depression.There is no significant effect on hypercapnic or hypoxicventilatory drive with alpha-2 adrenoceptor stimulation.The combination of alpha-2 adrenoceptor agonists withopioids does not lead to further ventilatory depression[87, 88].

Renal system effectsActivation of alpha-1 receptors in the kidney results in aredistribution of blood from the cortical to medullaryareas due to an increase in renal vascular resistance.Stimulation of alpha-2 adrenoceptors has a number ofeffects that promote diuresis and natriuresis. Theydecrease the secretion of vasopressin and antagonise itsaction on renal tubules [89]. Alpha-2 adrenoceptors arealso thought to inhibit the release of renin [90] andincrease the release of atrial natriuretic factor [91] inthe rat.

Neuroendocrine system effectsThe alpha-2 adrenoceptor agonists have a number of neuro-endocrine effects, mainly related to their inhibition ofsympathetic outflow and the decrease in plasma levels ofcirculating catecholamines [92]. Stimulation of alpha-2adrenoceptors located on the b cells of the islets of Lan-gerhans can temporarily cause direct inhibition of insulin

release [93]; clinical hyperglycaemia has not proved tobe a problem. Alpha-2 adrenoceptor antagonists have beenshown to increase insulin release. Alpha-2 receptor agon-ists also increase the release of growth hormone [94] andinhibit adipose tissue lipolysis. Clonidine can inhibit thesecretion of adrenocorticotropic hormone (ACTH) andcortisol during surgery [95].

Gastrointestinal system effectsAlpha-2 adrenoceptors regulate vagally mediated increasesin gastric and intestinal motility and secretions. It has beenpostulated that gastric cholinergic prejunctional alpha-2adrenoceptors inhibit gastric secretions during stress [96].Activation of alpha-2 adrenoceptors inhibits water secre-tion and increases net absorption in the large bowel; this isthe mechanism by which clonidine has been used tosuccessfully treat diarrhoea [97]. Stimulation of alpha-2adrenoceptors is known to reduce salivary secretions andmay lead to a dry mouth [98].

Platelet effectsSelective alpha-2 adrenoceptor agonists, as well as adrena-line, are known to stimulate platelet aggregation bystimulating alpha-2c receptors on platelets [99]. Highconcentrations of alpha-2 adrenoceptor agonists are requiredto cause platelet aggregation, as low concentrations ofthese drugs decrease plasma adrenaline concentration; thenet effect may be a reduction in platelet aggregation.Alpha-2 receptor stimulation also results in the release ofnitric oxide, a potent inhibitor of platelet aggregation[100]. Clonidine does not promote platelet aggregation;it also blocks adrenaline-induced platelet aggregation.

Drug and receptor interactions

Alpha-2 adrenoceptor agonists and opioids have somesimilar pharmacological effects. It is known that they havea similar distribution in the brain and that they functionthrough the activation of the same transduction and effectormechanisms, i.e. G-proteins and coupling to potassiumchannels. Therefore, if alpha-2 adrenoceptor agonists andopioids are administered together they may exhibit asynergistic action. It may also be possible to reduce theopioid dose and therefore decrease the respiratory andaddictive side-effects. Alpha-2 adrenoceptor agonists alsohave a synergistic action with benzodiazepines. The admin-istration of antagonists of either class of drug does not reversethe effects of the other, i.e. atipamezole and flumazenil[101]. The duration of the hypnotic action of dexmede-tomidine was increased by the administration of verapamil,a calcium channel blocker, the reverse effect was seen withthe administration of a calcium antagonist [102].



Therapeutic role in anaesthesia

Haemodynamic stability and peri-operativeischaemiaIt is one of the goals of anaesthesia, especially in thosepatients at risk of cardiac ischaemia during surgery, tomaintain myocardial oxygen balance. This can be achievedby attenuating sympathetically mediated hyperdynamicresponses to stimulation, while maintaining peri-operativecirculatory function. The ability of alpha-2 adrenoceptoragonists to modulate sympathetic tone leads to a desirablehaemodynamic profile, which may help to maintain themyocardial oxygen supply/demand ratio [103]. Kulka andcolleagues [104] reported that a minimum dose of 4 mg.kgÿ1 intravenous clonidine is required to significantlyattenuate the stress response to laryngosopy in patientsundergoing cardiac revascularisation surgery. In addition, asignificant reduction in peri-operative ischaemia wasdetected by monitoring critical ST depression in cardiacrevascularisation patients who received clonidine 5 mg.kgÿ1 [105]. De Kock and colleagues [106] reportedfewer adverse haemodynamic events in the 350 patientswho received intravenous clonidine 4 mg.kgÿ1 at induc-tion followed by 2mg.kgÿ1.hÿ1 infusion undergoing majorabdominal surgery compared with the 52 controls. Onlytwo episodes of severe hypotension and bradycardia wererecorded in the clonidine group. The same authors com-pared the haemodynamic stabilising effects of epiduralclonidine 4 mg.kgÿ1 at induction followed by an infusionof 1 mg.kgÿ1.hÿ1 with epidural sufentanil 0.5 mg.kgÿ1

followed by 0.2 mg.kgÿ1.hÿ1 in patients undergoing majorabdominal surgery with propofol and nitrous oxide anaes-thesia. Clonidine was more effective than sufentanil atestablishing stability at a reduced anaesthetic dose [107].

There is a ceiling to the haemodynamic stabilising effectsof opioids [108]; this may be overcome by combiningopioids with alpha-2 adrenoceptor agonists. Emergencefrom anaesthesia is a period associated with increasedsympathetic activity, tachycardia and hypertension. Ber-nard and colleagues [109] reported that clonidine pre-medication decreased the unwanted haemodynamic effectsseen during recovery from anaesthesia, therefore the use oflong-acting alpha-2 adrenoceptor agonists is particularlyuseful. Clonidine has been reported in a number of studiesto improve exercise tolerance in patients with anginapectoris [110, 111] and reduce exercise-induced myocar-dial ischaemia [112]. The hypertensive response to keta-mine is also attenuated by clonidine [113].

Talke and colleagues [114] reported that a target plasmaconcentration of dexmedetomidine of 0.45 ng.mlÿ1 admin-istered to patients with coronary artery disease undergoingvascular surgery resulted in less peri-operative ischaemiacompared with placebo.

In patients with stable angina undergoing an exercise-tolerance test, mivazerol reduced ischaemia and angina[115]. In a phase 2 multicentre clinical trial Mangano andco-workers [116] investigated the beneficial effects ofmivazerol on haemodynamic stability and myocardialischaemia in patients with coronary artery disease. Miva-zerol was given as a continuous infusion to 197 patientsintra-operatively and for 72 h postoperatively; 99 patientsreceived a dose of 0.75 mg.kgÿ1.hÿ1 and 98 received1.5 mg.kgÿ1.hÿ1. There were 103 placebo controls andall patients underwent noncardiac surgery. Mivazerol wasreported to decrease the incidence, and treatment for,tachycardia, hypertension and myocardial ischaemia. Thehigher dose of mivazerol was more effective than the lowerdose. There was no significant incidence of hypotension oradverse events, although there was an increase incidence ofbradycardia. Aanta & Kanto [117] highlighted the dangerthat a reduction in anaesthetic dose due to suppression ofhaemodynamic response to surgical stimulus, may lead toawareness.

Sedation and anxiolysisIt has long been known that clonidine causes sedation.During the first clinical trial of clonidine, a volunteer sleptfor 24 h following 1–2 mg intranasal clonidine, [118].Sedation, along with anxiolysis and an antisialogue effect,make alpha-2 adrenoceptor agonists useful premedicationdrugs. Clonidine has been used as a premedication in anumber of studies. Administered in doses of 100–300 mg,clonidine produced dose-related sedation [119]. A cloni-dine dose of 4 mg.kgÿ1 given as premedication to childrenresulted in sedation and anxiolysis [120]. The use ofclonidine as a premediction also has favourable haemo-dynamic consequences, attenuating the haemodynamicresponse to intubation and surgery [121]. Clonidine alsoreduces peri-operative plasma catecholamine concentra-tion [121].

Dexmedetomidine has similar effects to clonidine whenadministered for premedication. Its disadvantage is thatat present it can only be given as an intramuscular orintravenous injection. Dexmedetomidine administered atan intramuscular dose of 2.5 mg.kgÿ1 as a premedicationproduced sedation and anxiolysis comparable with a mid-azolam dose of 80 mg.kgÿ1 [122]. Both clonidine [123]and dexmedetomidine [124] have been shown to haveanxiolytic effects independent of sedation.

Anaesthetic requirementsMiller and colleagues [125] first demonstrated in 1968 thatmethyldopa and reserpine decreased the MAC of anaes-thetic agents, both drugs reducing central noradrenalineconcentration. However, Brodsky & Bravo [126] describedan acute postoperative hypertensive crisis following the



acute discontinuation of clonidine therapy pre-operatively.In 1978, Kaukinen and colleagues [127] reported that con-tinuing clonidine therapy peri-operatively in hypertensivepatients on long-term clonidine medication resulted in aless variable haemodynamic profile and no hypertensivecrisis. They also demonstrated that the administration ofclonidine subcutaneously for 3 days reduced the MAC ofhalothane by 15% in rabbits [128]. Bloor & Flacke [129]also reported an anaesthetic-sparing effect in dogs, theadministration of clonidine decreasing the MAC of halo-thane by a maximum of 50%. In addition the dose of thio-pentone required for induction of anaesthesia is reducedby clonidine premedication [130].

Because MAC is reduced by a maximum of 40% whennoradrenaline transmission is abolished totally [131] thereduction of MAC of 90% by selective alpha-2 adreno-ceptor agonists such as dexmedetomidine [132] suggestedadditional mechanisms may be responsible for the anaes-thetic action of alpha-2 adrenoceptor agonists. Flacke andcolleagues [121] studied the effects of clonidine in patientsundergoing coronary artery bypass surgery, comparingplacebo against clondine premedication of 200 or 300 mgorally with a second dose given via a nasogastric tube duringcardiopulmonary bypass. The clonidine-treated patientswere more sedated and required 40% less sufentanil thanplacebo patients. They had a lower heart rate and bloodpressure than placebo patients throughout the wholeoperative period. Post cardiopulmonary bypass, the clon-dine group had a higher cardiac output and lower systemicvascular resistance than the placebo group. Ghignone andcolleagues [133] showed a 45% reduction in fentanylrequirement in patients given a premedication of 5 mg.kgÿ1 of clonidine using EEG measurement of anaestheticdepth. The same dose also reduced the haemodynamicresponse to tracheal intubation [134]. In contrast, there arereports of no alfentanil sparing or haemodynamic stabilityfollowing clonidine premedication [135]. The opioid-sparing effect may not be a pure pharmacodynamic effectas clonidine has been reported to increase plasma alfen-tanil concentration by 60% [136] and dexmedetomidineis known to inhibit alfentanil microsomal liver meta-bolism [137].

Aho and colleagues [138] reported that the administrationof an infusion of dexmedetomidine in patients undergoingabdominal hysterectomy was able to reduce isofluranerequirements by 90%. Dexmedetomidine has also beenreported to be opioid- and barbiturate sparing [139].

AnalgesiaIn 1974, Paalzow [140] was the first to show the analgesiceffect of clonidine. He reported that clonidine increasedthe nociceptive threshold in mice and rats. Alpha-2 adreno-ceptor agonists have analgesic properties when given

parenterally, epidurally or intrathecally. Descending nor-adrenergic antinociceptive systems originating in thebrainstem contribute to pain control by suppressing thespinal centripetal transmission of nociceptive impulses[141, 142]. These pathways are activated by stimulationof the locus coeruleus [143] and dorsal raphe nucleus [144]and analgesia may be mediated by noradrenaline release[145]. Alpha-2 adrenoceptors, predominately the alpha-2asubtype, have been identified in the substantia gelatinosa ofthe dorsal horn of the spinal cord. Stimulation of thesealpha-2 adrenoceptors by intrathecal noradrenaline orspecific agonists inhibits the firing of nociceptive neuronesstimulated by peripheral Ad and C fibres [146]. Also,intrathecal noradrenaline inhibits the release of substanceP by primary afferents of the dorsal horn [147], andsuppresses the activity of wide dynamic range neuronesevoked by noxious stimulation [148]. Recent evidencesuggests that the antinociception produced by alpha-2adrenoceptor agonists may be due in part to acetylcholinerelease in the spinal cord [149, 150]. Because it has beensuggested that the spinal cord is the major site of analgesicaction of alpha-2 adrenoceptor agonists [151], the epiduraland intrathecal routes have been considered preferable tothe intravenous route.

Clonidine is relatively lipid soluble and after epiduraladministration is absorbed rapidly into the blood. Althoughthere is the possibility of cephalad spread this has not beenclearly demonstrated [152]. A central mechanism for theanalgesic action of alpha-2 adrenoceptor agonists has beendebated although there is evidence to suggest that there isno supraspinal mechanism. The analgesia produced byspinal clonidine persists after spinal transection [153]. Also,the direct administration of alpha-2 adrenoceptor agonistsinto the brainstem did not produce analgesia [154, 155].Indeed, stimulation of the alpha-2 adrenoceptors in thelocus coeruleus potentially reduces the analgesia elicited atthe level of the spinal cord by inhibition of noradrenergicantinociceptive descending pathways [156].

There have been reports to suggest that systemic alpha-2adrenoceptor agonists have an analgesic action by decreas-ing the unpleasantness of pain, and this may be related totheir sedative actions [157]. Bernard and co-workersreported the analgesic effects of an intravenous infusionof clonidine after major spinal surgery [158]. They admin-istered either clonidine 5 mg.kgÿ1 during the first hourfollowed by 0.3 mg.kgÿ1.hÿ1 for 11 h or placebo. A visualanalogue scale assessed pain. Intramuscular morphine wasused to supplement analgesia if the pain scores were above50%. In the clonidine group, pain onset was delayed, totalmorphine requirements were decreased significantly andpain scores reduced compared with placebo.

Aho and co-workers [159] demonstrated the analgesiceffects of intravenous dexmedetomidine (0.2 and 0.4 mg.



kgÿ1) after laparoscopic tubal ligation. Dexmedetomidine0.4 mg.kgÿ1 was reported to provide analgesia requiringsignificantly less supplementation with morphine com-pared with the analgesia provided by diclofenac 250 mg.kgÿ1. There was a high incidence of sedation and brady-cardia in the dexmedetomidine 0.4 mg.kgÿ1 group, butthere was no increase in respiratory depression and thebradycardia responded to atropine.

Epidural administrationThe first report of the use of epidural clonidine was byTamsen and Gordh in 1984 [160]. However, it was Bonnetand colleagues [161] who first demonstrated in a blinded,placebo-controlled study, analgesia from epidural cloni-dine in postoperative patients. They observed a >50%decrease in the visual analogue pain score in patients whohad received clonidine 2 mg.kgÿ1 for up to 4 h followingperineal or orthopaedic surgery. There was no change inthe placebo group. Since then a number of studies haveshown that epidural clonidine is effective and safe in themanagement of acute postoperative pain, improvinganalgesia and reducing opioid requirements [162, 163].

Ciagarini and co-workers [164] reported that 75 mg ofepidural clonidine increased the duration of epidural bupi-vacaine analgesia in labour with no adverse effects tomother or neonate. Eisenach and colleagues [165] in adose-finding study in postoperative patients found that adose of 100–300 mg provided minimal analgesia, definedas time to first use and total dose of PCA morphine. A700–900 mg clonidine dose resulted in complete analgesiafor 4–7 h. Rostaing and colleagues [166] reported theeffects of the addition of epidural clonidine 150 mg toepidural fentanyl 100 mg analgesia. The onset of actionremained the same, but the duration of analgesia wasdoubled, without any effect on fentanyl pharmacokinetics.

Bernard and colleagues [167] have also reported thatpatients who self-administered epidural clonidine as a soleanalgesic used less clonidine than those using self-admini-stered intravenous clonidine after major orthopaedic sur-gery. This study clearly demonstrated the superiority of theepidural route compared with the intravenous route. Oralclonidine, however, prolongs both sensory and motorblockade following intrathecal lignocaine; clearly, there-fore, there may be more than one mechanism involved inthe analgesic action. It may be beneficial to administeralpha-2 adrenoceptor agonists, opioids and local anaes-thetic drugs together. This may make it possible to decreasethe dose of each agent without loss of efficacy and hencereduce the side-effects of each agent.

Intrathecal administrationCoombs and colleagues [168] were the first to use intra-thecal clonidine in 1985, 300 mg providing 18 h of pain

relief in a morphine-tolerant cancer patient. A numberof authors have, however, reported no advantages inusing the intrathecal route. Klimscha and co-workers [169]compared epidural clonidine and bupivacaine with intra-thecal clonidine and bupivacaine. They reported that thespinal route led to a significantly greater reduction inblood pressure with no additional analgesia. In anotherstudy, the addition of intrathecal clonidine provided nofurther postoperative analgesic benefit to intrathecal mor-phine [170]. However, the duration of block after intra-thecal bupivacaine was longer with clonidine than withadrenaline [171] and a dose of 150 mg provided adequateanalgesia for 6 h after Caesarean section [172]. Currently,clonidine remains the only alpha-2 adrenoceptor agonistavailable for epidural and intrathecal use and it appears tohave no effect on spinal-cord histology in animal studies[173]. However, Fukushima and co-workers [174] haveadministered epidural dexmedetomidine successfully toman for postoperative analgesia in clinical trials.

Chronic pain

Alpha-2 adrenoceptor agonists have been reported to beuseful adjuncts in the treatment of chronic pain syndromesin animal and human studies [175–177]. Lee & Yaksh[178] demonstrated that the intrathecal administrationclonidine or MK-801, an N-methyl-D-aspartate antagonist(NMDA), abolished, in a dose-dependent manner, a modelof neuropathic pain in rats. The administration of boththese drugs together revealed a significant synergisticeffect. It is thought that NMDA-receptor activation inthe dorsal horn facilitates the discharge of wide dynamicrange neurones, which are important for the centripetaltransmission of painful impulses. Glynn & O’Sullivan [179]reported the effective use of a combination of epidurallignocaine 40 mg and clonidine 150 mg in 20 patientsmostly suffering from neuropathic pain. The duration ofanalgesia was increased compared with single drug admin-istration. The epidural route has proved to be the mosteffective way of administrating clonidine in patients withneuropathic pain [180], although intravenous and trans-dermal routes [181] have been tried. Eisenach and colle-agues [182, 183] reported that epidural clonidine waseffective in treating cancer pain in patients tolerant toopioids. Topical clonidine has been used to control sym-pathetically maintained pain [184].

Miscellaneous uses

Clonidine has a number of other potential beneficialeffects during anaesthesia. In two studies, clonidine hasbeen reported to preserve renal function before and afteranaesthesia for coronary artery surgery [185, 186]. During



recovery from anaesthesia, shivering is a common prob-lem. Shivering increases oxygen consumption and carbondioxide production significantly above basal levels [187,188], which may lead to arterial desaturation and lacticacidosis [189, 190]. Delaunay and co-workers [191] reportedthat clonidine 2 mg.kgÿ1 administered intravenously at theend of surgery attenuated the increase in oxygen con-sumption and carbon dioxide production. The reductionin shivering may be particularly useful in patients withischaemic heart disease. Goldfarb and co-workers [192]reported that intravenous clonidine 150 mg is as effective asdroperidol 5 mg in diminishing postoperative shivering.Dexmedetomidine has also been reported to reduce post-anaesthesia shivering in cats [193]. Finally, clonidine hasbeen reported to be effective in reducing intraocularpressure during ophthalamic surgery [194] and the treat-ment of glaucoma [195]. Clonidine is thought to decreaseproduction and increase drainage of aqueous humour. Thedecrease in intraocular pressure has also been reportedwith dexmedetomidine premedication [196].

Veterinary anaesthesia

In 1967, Clark & Hall [197] reported the use of xylazine, anonselective alpha-2 adrenoceptor agonist, as an adjunctsedative and analgesic agent in horses and cattle. Since thenalpha-2 receptor agonists have been widely used to providedose-dependent sedation, analgesia and muscle relaxation,although it was not until 1981 that the link with centralalpha-2 receptors was first established [198]. Xylazine wasoften used in combination with ketamine; the sympatho-mimetic action of ketamine countered the xylazine-induced decreases in heart rate and cardiac output [199].Another alpha-2 adenoceptor agonist, detomidine hadgreater sedative and analgesic effects than xylazine [200],both agents have been superseded by the highly selectiveand potent alpha-2 adrenoceptor agonist medetomidine[201]. Common side-effects of these drugs when givenintravenously are bradycardia, initial hypertension andlater hypotension. Also vomiting and muscle jerkinghave been reported with the onset of sedation. Specificantagonists idazoxan and atipamezole can reverse thesedative effects.

Non-anaesthetic uses

Clonidine was initially introduced clinically as a nasaldecongestant and has been used as an antihypertensivefor 25 years [202]. Its side-effects are dry mouth, sedationand a withdrawal syndrome. Sudden discontinuation ofclonidine results in restlessness, headache, nausea, insomniaand an increase in sympathetic activity resulting in tachy-cardia and hypertension. Alpha-2 adrenoceptor agonists

have been used to treat congestive heart failure [203],angina pectoris [111] and myocardial infarction [204].

An increase in brain noradrenergic activation is com-mon in many withdrawal syndromes [205] and anxietystates. Clonidine has successfully been used to controlsymptoms in a number of withdrawal states such as opioid[206], benzodiazepine [207], alcohol [208] and tobacco[209–211]. Clonidine also controls manic symptoms [212]and has been used in hyperactive children [213]. However,it must be remembered that in large doses clonidine cancause anxiety due to activation of alpha-1 receptors. Amongother uses of clonidine may be numbered, Korsakoff ’spsychosis, motor spasticity associated with spinal cordinjury, and muscle rigidity due to the rapid administrationof large doses of opioids [214].

Conclusion

Alpha-2 adrenoceptor agonists have been used in a largenumber of clinical applications, some with little evidenceof efficacy. Anaesthetic and analgesic-sparing effects havebeen reported, but whether they offer additional benefitsto patients requiring routine surgery is yet to be decided. Abetter understanding of the interactions between alpha-2adrenoceptor, opioid and cholinergic receptors, as well aslocal anaesthetic mechanisms, should help determine themost appropriate and effective combination of their agon-ists. They may, however, have a role in anaesthesia forpatients at high risk of myocardial ischaemia undergoingmajor surgery. Drugs of this class control the blood pres-sure without reflex tachycardia, decrease the stress responseand attenuate postoperative shivering, therefore improvingthe myocardial oxygen and supply ratio. However, clinicalstudies showing improved outcome in defined high-riskpatient groups are still awaited, as peri-operative ischaemiais not always related to tachycardia or an increase incatecholamines, e.g. thrombosis or embolic phenomena.In cancer pain, clonidine is arguably the drug of secondchoice. The dose of clonidine needs to be carefully titratedto effect, with the epidural route offering some advantage.In most cases, a clonidine dose of 300 mg seems to besufficient independent of the route of administration. Itshould be noted that if haemodynamic parameters aloneare used to assess the depth of anaesthesia there is a risk ofawareness and if conventional doses of anaesthetics areused in conjunction with alpha-2 adrenoceptor agoniststhere is a risk of oversedation. The side-effects of alpha-2adrenoceptor agonists, bradycadia and hypotension, comeon slowly (15 min); therefore patients need careful mon-itoring. Some authors recommend the routine use of ananticholinergic medication with alpha-2 adrenoceptoragonists. The sedative effects of alpha-2 adrenceptor agonistsmake them unsuitable for daycase anaesthesia. Investigations



into the molecular biology of alpha-2 adrenoceptors haveimproved our understanding of noradrenergic mechan-isms in the central nervous system and in peripheral tissuesand their effect on vigilance, analgesia and sympatheticoutflow. The emerging characterisation of imidazolinereceptors has increased our understanding of blood-pressurecontrol and has led to the availability of a new generation ofcentrally acting antihypertensive agents. A definitive sub-typing of alpha-2 adrenoceptor gene expression at acellular level may allow the development of a secondgeneration of more specific agents with fewer side-effects.

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