Alfa2 Su Fisio

Anaesthesia, 1999, 54, pages 146165 ................................................................................................................................................................................................................................................
R E V I E W A RT I C L E
Alpha-2 and imidazoline receptor agonists

therapeutic role
Z. P. Khan,1 C. N. Ferguson2 and R. M. Jones3
Their pharmacology and
1 Lecturer, 2 Honorary Lecturer and 3 Professor, Department of Anaesthetics, Imperial College School of Medicine, St Marys Hospital, London W2 1NY, UK Summary
Clonidine has proved to be a clinically useful adjunct in clinical anaesthetic practice as well as in chronic pain therapy because it has both anaesthetic and analgesic-sparing activity. The more selective alpha-2 adrenoceptor agonists, dexmedetomidine and mivazerol, may also have a role in providing haemodynamic stability in patients who are at risk of peri-operative ischaemia. The side-effects of hypotension and bradycardia have limited the routine use of alpha-2 adrenoceptor agonists. Investigations into the molecular pharmacology of alpha-2 adrenoceptors have elucidated their role in the control of wakefulness, blood pressure and antinociception. We discuss the pharmacology of alpha-2 adrenoceptors and their therapeutic role in this review. The alpha-2 adrenoceptor agonists are agonists at imidazoline receptors which are involved in central blood pressure control. Selective imidazoline agonists are now available for clinical use as antihypertensive agents and their pharmacology is discussed.
Keywords Receptors; alpha-2, imidazoline. ...................................................................................... Correspondence to: Dr Z. P. Khan. Present address: Department of Anaesthesia and Intensive Care, City Hospital NHS Trust, Dudley Road, Birmingham B18 7QH, UK Accepted: 24 June 1998
The widespread use of alpha-2 adrenoceptor agonists in veterinary practice has provided extensive experience over 20 years. In addition, alpha-2 adrenoceptor agonists have been used to a limited degree in clinical practice and their molecular pharmacology has been elucidated. This has also cast some light on the mechanisms of action of a variety of other drugs not directly associated with alpha-2 adrenoceptors. Alpha-2 adrenoceptor agonists are not routinely used by the majority of anaesthetists despite having many desirable effects, including anxiolysis, analgesia, sedation, anaesthetic-sparing and peri-operative haemodynamic-stabilising effects. Their potential thus remains to be fully realised. This may be because there are no highly specic alpha-2 adrenoceptor agonists currently available for anaesthesia (clonidine has some alpha-1 activity) and there is a possibility of undesirable haemodynamic effects
146
at certain doses. Indeed there is still debate as to whether these drugs offer real clinical benets. Clonidine, mivazerol and to a lesser extent dexmedetomidine are not pure alpha-2 adrenoceptor agonists but are also able to combine with nonadrenergic imidazoline receptors [1]. These receptors are binding sites specically recognising the imidazoline or oxazoline chemical structure and have been classied into I1 found in the brain, and I2 found in the brain, kidney and pancreas. Imidazolinereceptor stimulation mediates a central hypotensive and anti-arrhythmogenic action. It may be possible that some of the effects of alpha-2 adrenoceptor agonists are mediated by imidazoline receptors. Moxonidine and rilmenidine are the rst orally active imidazoline receptor agonists to be introduced into clinical practice. In this review we discuss the clinical pharmacology of alpha-2 adrenoceptor
1999 Blackwell Science Ltd
Anaesthesia, 1999, 54, pages 146165 Z. P. Khan et al. Alpha-2 and imidazoline receptor agonists ................................................................................................................................................................................................................................................
agonists and reect on their potential use in anaesthesia as well as critical-care practice.
Molecular pharmacology
Receptor classication History In 1948 Ahlquist challenged the view that adrenergic receptors were either excitatory or inhibitory by differentiating adrenergic receptors into alpha and beta [2]. In 1969, Paton and co-workers found that a subclass of alpha adrenoceptors located presynaptically regulated the release of neurotransmitter [3]. This led to the subdivision of alpha adrenoceptors into postsynaptic alpha-1 and presynaptic alpha-2 [4, 5]. However, this proved to be misleading with the characterisation of alpha-2 adrenoceptors postsynaptically and extrasynaptically [6]. A functional classication of alpha-2 adrenoceptors as inhibitory and alpha-1 as excitatory also proved to be inaccurate, as not all alpha-2 adrenoceptors are inhibitory [7]. Stimulation of alpha-1 and alpha-2 adrenoceptors in vascular smooth muscle results in vasoconstriction. Clearer characterisation of alpha-1 and alpha-2 adrenoceptors on a pharmacological basis followed the discovery of selective antagonists, prazosin being more potent at alpha-1 adrenoceptors and yohimbine being more potent at alpha-2 adrenoceptors [8]. Bylund and co-workers [215] dened three alpha-2 isoreceptors; alpha-2a, alpha-2b and alpha-2c based on their afnity for alpha adrenoceptor ligands. The regional distribution of the isoreceptors has been demonstrated autoradiographically using radiolabelled probes. The genes responsible for encoding alpha-2 adrenoceptors in the human platelet have been identied on chromosome 10 [9] and the human kidney on chromosome 4 [10]. Further alpha-2 adrenoceptors have been cloned from genes located on chromosome 2 [11]. Therefore the alpha-2 adrenoceptors can be further classied as alpha-2 C10, alpha-2 C4 and alpha-2 C2 and these correspond with alpha-2a, alpha-2c and alpha-2b, respectively. The three alpha-2 adrenoceptor subtypes bind alpha-2 agonists and antagonists with similar afnities. Structure of alpha-2 adrenoceptors The alpha-2 adrenoceptor is a transmembrane receptor. This is an excitable protein which traverses the cell membrane and reacts selectively with extracellular ligands (endogenous hormones or exogenous molecules such as drugs) to initiate a cascade of events leading to a physiological effect. The long chain of amino acids making up the alpha-2 adrenoceptor protein contains hydrophobic and hydrophilic areas. It winds in and out of the cell membrane, crossing the cell membrane seven times at the hydrophobic areas. The seven hydrophobic segments are
made up of 2025 amino acids forming alpha helices that are embedded in the membrane. The three alpha-2 receptor subtypes are 7275% identical to each other with respect to amino acid sequence in the membrane-spanning domains. This sequence homology can be compared with a similarity between different adrenoceptors of 4245% and alpha-2 and muscarinic receptors of 35%. This indicates that the transmembrane area of the receptors is important for selectivity of ligand binding. To bind a ligand, a receptor must have charged counterbalancing ions located within it, but the transmembrane region itself is nonpolar. This apparent inconsistency can be explained by the way the side-chain groups in critical amino acids are charged and coalesce to form a binding pocket permitting access from the extracellular space for binding charged ligands. The third and fourth transmembrane domains are most important [12] with more minor involvement from the sixth and seventh domains. It can be inferred that these domains are closely related in the three-dimensional structure of the molecule. The structure of the ligand determines whether it has agonistic or antagonistic effects on the receptor. Mutation of amino acids in these regions affects the binding of agonists and antagonists and their physiological effects. The cytoplasmic aspect of the receptor protein forms a contact point for the G-protein providing a means of signal transduction and therefore rapid stimulation of the effector system. G-proteins Alpha-2 adrenoceptors are examples of G-proteincoupled receptors. G-proteins are ubiquitous transmembrane signalling mediators [13]. They are proteins that bind the guanine nucleotides, GDP (guanosine diphosphate) and GTP (guanosine triphosphate). The adrenergic receptors and opioid receptors are also coupled to G-proteins. Other receptors, which are also G-protein coupled include the following: adenosine (AI), acetylcholine (M2), GABAB, dopamine (D2) and histamine (H2). The G-proteins are composed of three polypeptide subunits designated as alpha, beta and gamma in order of decreasing molecular mass. The G-proteins can be classied according to their action on adenyl cyclase and the sensitivity of their alpha subunit to ribosylation by Bordetella pertussis toxin. The alpha-2 adrenoceptors are coupled to pertussis-toxin-sensitive G-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 which is not pertussis-toxin sensitive and stimulates the activation of adenylyl cyclase. In the inactive state, the G-protein is not closely associated with the alpha-2 receptor and is bound to GDP. When an agonist binds to the receptor, the structure of the receptor changes and it associates with the
147
Z. P. Khan et al. Alpha-2 and imidazoline receptor agonists Anaesthesia, 1999, 54, pages 146165 ................................................................................................................................................................................................................................................
alpha subunit of the G-protein. This results in a reduced afnity of the G-protein for GDP and in the presence of magnesium, it is replaced by GTP. The alpha subunit then uncouples from the beta and gamma subunits and couples with the effector, resulting in a decrease in the afnity of the receptor for the agonist and the agonist leaves its receptor site. The duration of binding of the agonist to the receptor determines the amount of amplication of the intracellular response. The GTPase on the alpha subunit is then activated and hydrolyses GTP to GDP, releasing an inorganic phosphate; the receptor then returns to the inactive state [15]. A number of effector mechanisms (see below) have been described: each alpha-2 receptor may stimulate more than one effector mechanism and although each may not represent a pathway to a biological response, the physiological and clinical relevance remains to be elucidated. Adenylyl cyclase An important consequence of alpha-2 adrenoceptor stimulation is the inhibition of adenylyl cyclase and this results in decreased formation of 3H 5H -cyclic adenosine monophosphate (cAMP). This is an important regulator of many cellular functions by controlling the phosphorylation state of regulatory proteins by cAMP-dependent protein kinase [16]. Although the inhibition of adenylyl cyclase is an almost universal effect of alpha-2 adrenoceptor activation, the decrease in intracellular cAMP cannot explain many of the physiological results. Alternative effector mechanisms These include activation of Gi-protein-gated potassium ion channels [17], causing hyperpolarisation of the neuronal
cell and so reducing the rate of ring of excitable cells in the central nervous system [18]. The increase in potassium-ion conductance is calcium dependent in many systems and the inhibition of adenylyl cyclase may also play a permissive role. Alpha-2-adrenoceptor stimulation resulting in inhibition of neurotransmitter release is mediated through a decrease in calcium-ion conductance. The decrease in calcium-ion conductance involves direct regulation of calcium entry by voltage-gated calcium ion channels [19] and these may be coupled to a Go-protein [20]. Activation of alpha-2 adrenoceptors can also accelerate sodiumhydrogen-ion exchange causing alkalinisation of the interior of platelets and stimulating an increase in phospholipase A2 activity resulting in increased formation of thromboxane A2 [21]. Alpha-2 receptors can modulate the actions of phospholipase C that mediate the hydrolysis of phosphatidyl inositol biphosphate into diacyglycerol and inositol triphosphate (Fig. 1). Distribution of alpha-2 adrenoceptors Presynaptic alpha-2 adrenoceptors are present in sympathetic nerve endings and noradrenergic neurones in the central nervous system where they inhibit the release of noradrenaline [22]. Postsynaptic alpha-2 adrenoceptors exist in a number of tissues where they have a distinct physiological function; these include the liver, pancreas, platelets, kidney, adipose tissue and the eye. The medullary dorsal motor complex in the brain has a high density of alpha-2 adrenoceptors and activation of these may be responsible for the hypertensive and bradycardic effects of alpha-2 adrenoceptor agonists. The locus coeruleus is a small neuronal nucleus located
Figure 1 Diagrammatic representation of the structure of the alpha-2 adrenoceptor, G-proteins and possible effector mechanisms. The
alpha-2 adrenoceptor agonist binds to the alpha-2 adrenoceptor (a2 R). This results in coupling with G-proteins due to a conformational 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 coupled in an inhibitory fashion to calcium ion (Ca2) translocation and to the membrane-bound enzyme phospholipase C (Pc). The alpha-2 adrenoceptor is coupled through yet another undetermined G-protein to hydrogen (H) and sodium (Na) ion exchange and phospholipase A2 (PA2).
148
bilaterally in the upper brainstem and is the largest noradrenergic cell group in the brain. The locus coeruleus is an important modulator of wakefulness and may be the major site for the hypnotic action of alpha-2 adrenoceptor agonists mediated by alpha-2a adrenoceptors located there [23]. The locus coeruleus has a number of efferent connections. Cortical activity is inuenced by the connection with the subthalamic relay nucleus and the thalamus via noradrenergic bres. Nociceptive transmission at a spinal level is decreased via descending bres in the dorsolateral funiculus tracts. There are also efferent bres to the reticular formation with connections to the vasomotor centres [24]. There are afferent connections from the rostral ventrolateral medullary nuclei. A high density of alpha-2 adrenoceptors has also been demonstrated in the vagus nerve, intermediolateral cell column and the substantia gelatinosa. The dorsal horn of the spinal cord contains alpha-2a subtype adrenoceptors, while the primary sensory neurones contain both alpha-2a and alpha-2c subtypes of adrenoceptors.
Imidazoline receptor agonists
Blood pressure control The ventromedial (depressor) and the rostral-ventrolateral (pressor) areas of the medulla are responsible for the central regulation of cardiovascular tone and blood pressure. They receive afferent bres from the carotid and aortic baroreceptors, which form the tractus solitarius via the nucleus tractus solitarius. Variations in blood pressure are detected by the carotid and aortic baroreceptors and their ring is altered. This results in an increase or decrease in both sympathetic outow and vagal impulses to maintain blood pressure. Sympathetic overactivity and decreased parasympathetic tone is present in human hypertension [25]. History First generation centrally acting antihypertensives such as clonidine and a-methyl dopa were originally thought to decrease sympathetic tone by stimulating alpha-2 adrenoceptors in the medulla. When substances with an imidazoline or catecholamine structure were injected directly into the medulla of anaesthetised animals only imidazolines had hypotensive effects and there was no correlation between their afnity for alpha-2 adrenoceptors and their hypotensive effects [26]. In the early 1980s, Bousquet et al. [27, 28] proposed the existence of receptors specically recognising the imidazoline or similar chemical structure and which were not adrenergic receptors. This was because the central hypotensive effects of clonidine-like drugs could not be explained by their alpha-2 receptor actions alone. It was suggested that these receptors might be found in the nucleus reticularis lateralis of the ventrolateral medulla, the
site of the hypotensive action of these drugs. In 1987, Ernsberger and co-workers [29] were the rst to verify the existence of specic imidazoline-binding sites in the ventrolateral medulla which were insensitive to catecholamines. Two subtypes of imidazoline receptor (I) have been isolated, I1 and I2. I1 receptors have a more restricted distribution in the ventrolateral medulla [30]. They are thought to be G-protein linked although the signalling pathway remains to be fully elucidated. However, it is likely that activation of phospholipase A2 leading to the release of arachidonic acid and the subsequent generation of prostaglandins plays a major role [31]. I1 receptors are involved in blood-pressure regulation. I2 receptors have been found in the liver, platelets, adipocytes, kidneys, adrenal medulla and brain, including the frontal cortex [3236]. They have been implicated in neuroprotection in the animal model of ischaemic infarction [37]. I2 receptors are found mainly on the mitochondrial membrane and are not G-protein linked [37]. Unlike the I1 receptors, I2 receptors are not found on neuronal plasma membranes [38]. The imidazoline receptor protein has a molecular mass of 70 kDa but the exact amino acid sequence is not yet known. Several endogenous ligands for I receptors, collectively termed clonidine-displacing substances (CDSs), have been detected in tissues and serum. The only CDS whose structure is known is agmatine. It is bioactive and widely distributed and binds to alpha-2 adrenceptors and all classes of imidazoline receptors [39]. The exact role of agmatine remains to be elucidated but its presence in specic neuronal pathways, as well as in serum, suggests that it might be a novel neurotransmitter or hormone [40]. It has been suggested that imidazoline receptors play a role in the genesis of adrenaline-induced dysrhythmia under halothane anaesthesia. Rilmenidine dose dependently inhibits adrenaline-induced dysrhythmias under halothane anaesthesia in dogs [41]. This action was blocked by bilateral vagotomy and by pretreatment with a nonspecic alpha-2 adrenoceptor and imidazoline receptor antagonist idazoxan 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 imidazoline receptors and vagal tone are critical to the antiarrhythmic action of rilmenidine. Moxonidine, which is selective for the I1 receptor, increased the threshold for oubain-induced cardiac dysrhythmias in guinea pigs, this suggests that the I1 subtype may be responsible for the anti-arrhythmic effects [42]. Agonists (Table 1) Rilmenidine The oxazoline, rilmenidine, has a structure similar to that of imidazolines and is a centrally acting imidazoline receptor
149
Table 1 Imidazoline receptor agonists in order of preference for imidazoline receptor.

Moxonidine Rilmenidine Clonidine Dexmedetomidine Mivazerol
agonist (Fig. 2). It is one of a new generation of centrally acting antihypertensive agents. The safety and efcacy of rilmenidine as a treatment for human hypertension has been demonstrated in clinical trials [43]. It was found to be equally efcacious in elderly hypertensive patients [44] and those who also suffered from diabetes [45], renal impairment [46] or left ventricular hypertrophy [47]. In animal studies, rilmenidine has been shown to increase sodium excretion and urine ow rates [48]. It is comparable with atenolol [49] and hydrochlorothiazide [47] as a rst line antihypertensive. Both rilmenidine and idazoxan, an imidazoline receptor antagonist, have neuroprotective effects in the animal model of ischaemic infarction. The precise nature of this is not known, but an interaction with the imidazoline 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 administration, with a peak plasma concentration within 1.52 h. It undergoes some oxazoline-ring hydrolysis and oxidation, but 65% of the dose is eliminated through the kidneys unchanged. Rilmenidine is 10% protein bound and its elimination half-life is 8 h. Unlike clonidine, there appears to be no withdrawal syndrome following the cessation of treatment [50]. Moxonidine A more potent and selective agonist for the imidazoline I1 receptor is moxonidine. It is three times more selective for the I1 receptor in the ventrolateral medulla than rilmenidine and has a 4070 times greater afnity for I1 receptors than alpha-2 adrenoceptors. Clonidine is twice as potent as moxonidine at the I1 receptor but has a similar afnity for alpha-2 and I receptors. Moxonidine acts by decreasing systemic vascular resistance secondary to a reduction in central sympathetic tone, reducing plasma catecholamine and renin levels [51]. Moxonidine may also increase sodium and water excretion. It was shown to be as effective and well tolerated as atenolol [52], nifedipine [53], captopril [54] and prazosin [55] in controlling hypertension. After oral administration, moxonidine is rapidly and almost completely absorbed. Maximum plasma concentration is achieved in 1 h. It has a plasma half-life of 2 h and is 9096% excreted by the kidneys, 51% as unchanged drug. A dose of 0.4 mg daily will effectively lower the blood pressure over 24 h, although the dose should be reduced if there is renal impairment. The imidazoline receptor agonists have few of the adverse effects of clonidine such as dry mouth, sedation, depression and tiredness and can be given as a once-daily dose. The hypotensive effects of these drugs can be antagonised by idazoxan and efaroxan which are antagonists at both imidazoline receptors and alpha-2 adrenoceptors, but not by 2-MI a selective alpha-2 adrenoceptor antagonist [5658].
Alpha-2 receptor agonists (Table 2)
Figure 2 The chemical structure of imidazoline agonists
moxonidine and rilmenidine.

150
Clonidine is an imidazoline and is the only alpha-2 adrenoceptor agonist currently available for use in anaesthetic practice (Fig. 3). It is available as 100/250/300 mg tablets for oral administration, as a transdermal patch releasing 100/200/300 mg over 24 h and in an injectable solution containing 150 mg.ml1 for intravenous, intramuscular, local and regional use. It is a partial agonist with an alpha-2a-to-alpha-1 selectivity ratio of 39 [59]. The alpha-2a-to-imidazoline selectivity ratio is 16. The adult oral dose is 100600 mg administered 8 hourly; the corresponding intravenous dose is 150300 mg, a dose of 150 mg
Table 2 Selective and nonselective alpha-2 adrenoceptor agonists
in order of preference for alpha-2 adrenoceptor.

Non-selective alpha-2 adrenoceptor agonists Noradrenaline Adrenaline Selective alpha-2 adrenoceptor agonists Dexmedetomidine Mivazerol Clonidine a-Methyldopa
less than 1.0 ng.ml1 it can produce profound physiological alterations. Dexmedetomidine is an isomer and the active component of medetomidine. Although initially designed to prevent myocardial ischaemia, mivazerol is an alpha-2 agonist which may have potential for perioperative use; it has an alpha-2a-to-alpha-1 selectivity ratio of 119 and an alpha-2a-to-imidazoline selectivity ratio of 215, the specicity is between clonidine and dexmedetomidine [59].
Alpha-2 receptor antagonists (Table 3)
as been used epidurally. Methyldopas use is limited to the control of blood pressure in pregnancy; it has a slow onset of action because the active component is the metabolite methylnoradrenaline. Currently under investigation is dexmedetomidine, a more specic and shorter-acting alpha-2 adrenoceptor agonist with an alpha-2a-to-alpha-1 ratio of 1300 [59] and alpha-2a-to-imidazoline selectivity ratio of 32. Dexmedetomidine is a potent drug, at plasma concentrations
A drug which could cross the bloodbrain barrier and selectively reverse the central effects of alpha-2 adrenoceptors would be a useful adjunct to anaesthetic practice. Atipamezole, idazoxan and yohimbine are selective and centrally acting alpha-2 adrenoceptor antagonists; all have been used in veterinary practice. Currently, the more selective alpha-2 adrenoceptor antagonists are not available for clinical application. However, Karhuvaara and colleagues [60] gave atipamezole intravenously to human volunteers to reverse the effects of a preceding dose of dexmedetomidine. Atipamezole, the most selective of the alpha-2 adrenoceptor antagonists, was able to reverse the sedation and hypotension caused by dexmedetomidine.
Pharmacokinetics
Clonidine is lipid soluble and so has both rapid and complete absorption after oral administration, reaching a peak plasma level in 6090 min. Time release transdermal patches are also available; 2 days of administration are required before therapeutic plasma concentrations are achieved. Because of its high lipid solubility clonidine crosses the bloodbrain barrier and disappears rapidly from the cerebrospinal uid (CSF). The elimination half-life after epidural injection of clonidine 150 mg is 30 min. It is 20% bound to plasma proteins and the volume of distribution is 1.72.5 l.kg1. Clonidine is less than 50% metabolised in the liver to inactive metabolites, the remaining drug being excreted unchanged in the kidney; about
Table 3 Selective and nonselective alpha-2 adrenoceptor anta-
gonists in order of preference for alpha-2 adrenoceptor.

Non-selective alpha-2 adrenoceptor antagonists Phentolamine Tolazoline Selective alpha-2 adrenoceptor antagonist Atipamezole Idazoxan Yohimbine Efaroxan Rauwolscine
Figure 3 The chemical structure of alpha-2 adrenoceptor
agonists clonidine, dexmedetomidine and mivazerol.

151
20% is excreted in the faeces. The elimination half-life is of the order of 623 h and is prolonged if renal impairment exists; the clearance is 1.94.3 ml.min1.kg1. Dexmedetomidine has a volume of distribution of 200 l and a systemic clearance of 0.5 l.min1 after administration of an intravenous infusion. Dexmedetomidine exhibits a concentration-dependent nonlinear pharmacokinetic prole [61]. At high concentrations following an intravenous bolus, dexmedetomidine decreases the initial volume of distribution and intercompartmental clearance due to its peripheral vasoconstrictive action. Dexmedetomidine behaves in a biphasic manner, as the concentration declines vasodilatation occurs due to its central effect. Therefore, dexmedetomidine should not be administered rapidly as it can result in undesirable hypertension as well as altered pharmacokinetics. The decline in the plasma concentration of dexmedetomidine following the cessation of an infusion is described by its context-sensitive half-life, which is similar to that of fentanyl. The intramuscular route probably offers the better predictability as well as reasonably rapid onset, the peak plasma concentration occurring within 15 min. Mivazerol given as a bolus dose followed by an infusion achieved a steady plasma concentration within 30 min of the initial dose. The plasma half-life is 4 h and it is 50% protein bound. About 4045% is excreted unchanged by the kidneys and about 2025% undergoes conjugation in the liver.
Pharmacodynamics
analgesic and reduction in anaesthetic requirements of alpha-2 adrenoceptor agonists are discussed later. Cardiovascular system effects There are both alpha-1 and alpha-2 postjunctional receptors in the arterial and venous vasculature where they both mediate vasoconstriction [73]. The alpha-1 and alpha-2 adrenoceptors differ in their location and their utilisation of calcium. In the arterial vasculature, the alpha-1 adrenoceptors are junctional and the alpha-2 adrenoceptors are extra-junctional, while the reverse is true of the venous vasculature. Alpha-1 adrenoceptor stimulation produces vasoconstriction by utilising intracellular calcium while the alpha-2-adrenoceptor-mediated vasoconstriction uses extracellular calcium [74]. This makes the alpha-2 adrenoceptor agonists pressor response more sensitive to calcium antagonists [75]. Intravenous alpha-2 adrenoceptor agonist administration leads to a decrease in heart rate and a transient increase in arterial blood pressure and systemic vascular resistance, but a decrease in cardiac output due to the activation of postjunctional vascular alpha-2 adrenoceptors. This is followed by a longer lasting decrease in heart rate and blood pressure due to a centrally mediated decrease in sympathetic tone and an increase in vagal activity. Neither the exact location nor the specic receptors responsible for the central hypotensive action of alpha-2 adrenoceptor agonists are yet known. It seems that postsynaptic alpha-2 adrenoceptors and imidazoline receptors in the brainstem are involved [76]. Clonidine lowers the set point around which arterial blood pressure is regulated. It also increases the gain of the baroreceptor system, resulting in lower heart rates for a given increase in blood pressure, and broadens the range of heart-rate responses to changes in blood pressure [77]. The bradycardia commonly seen after administration of alpha-2 adrenceptor agonists may be due to the central sympatholytic action of these drugs leaving vagal tone unopposed. It may also be due to presynaptic-mediated reduction of noradrenaline release or a direct vagomimetic action [78]. Although bradycardia can be a problem with the administration of alpha-2 adrenoceptor agonists, dexmedetomidine has been shown to protect against adrenaline-induced arrhythmia during halothane anaesthesia in dogs [79]. This anti-arrhythmic action may be due to stimulation of imidazoline receptors. There are no known directly mediated alpha-2 adrenoceptor effects on the myocardium. Alpha-2 adrenoceptor reduction in sympathetic tone and increase in parasympathetic tone results in a reduced heart rate, systemic metabolism, myocardial contractility and systemic vascular resistance. These all result in a decrease in the myocardial oxygen requirements. This is may be why clonidine has been successful in the treatment of angina pectoris [80].
Central nervous system effects When adrenaline has been administered intracerebroventricularly, so that the bloodbrain barrier is avoided in a number of mammals including man, sedation ranging from sleep to surgical anaesthesia has been described [6265]. This effect may be mediated by postsynaptic alpha-2a subtype adrenoceptors located in the locus coeruleus, causing a decrease in noradrenergic activity [66]. The use of clonidine as an antihypertensive has been limited by its sedative effects, but offers advantages in anaesthetic practice. When clonidine was given in a sufcient dose to produce sleep, the EEG showed an increase in stage I and 2 sleep and decrease in rapid eye movement sleep [67]. Alpha-2 adrenoceptor agonists and benzodiazepines produce comparable anxiolysis [68]. Clonidine at high doses can be anxiogenic owing to alpha-1 [69], but paradoxically it has been used to treat panic disorders. Dexmedetomidine decreases cerebral blood ow in dogs during anaesthesia with both halothane and isourane, without evidence of global ischaemia occurring [70, 71]. It has little effect on intracranial pressure and in the animal models of brain ischaemia has been shown to be neuroprotective [72]. The
152
The effect of alpha-2 adrenoceptor agonists on coronary vasculature in humans is not yet known, as there is considerable interspecies variation in distribution and alpha-2 adrenoceptor subtypes. It is known that the alpha-2 adrenoceptors on the endothelium release nitric oxide when activated [81]. In swine this has been shown to be the alpha-2a subtype [82]. It has been postulated that the stimulation of alpha-2 adrenoceptors may lead to a postsynaptic coronary vasoconstriction, which may be countered by a nitric-oxide-mediated coronary vasodilatation [83]. Respiratory system effects Alpha-2 adrenoceptors have a minimal effect on ventilation. In humans, clonidine in doses up to 300 mg, seems to cause a small reduction in resting minute ventilation and an increase in expired carbon dioxide [84]. Dexmedetomidine has a biphasic effect on respiratory drive, with low doses decreasing and higher doses increasing resting ventilation in dogs [85]. Dexmedetomidine in doses up to 2 mg.kg1 caused mild ventilatory depression, but this was not signicantly different from that seen with placebo [86]. The locus coeruleus, described earlier, is an important site for the action of alpha-2 adrenoceptor agonists. The locus coeruleus is involved in arousal reactions; suppression of its activity by alpha-2 adrenoceptor agonists can result in a state similar to sleep with mild respiratory depression. There is no signicant effect on hypercapnic or hypoxic ventilatory drive with alpha-2 adrenoceptor stimulation. The combination of alpha-2 adrenoceptor agonists with opioids does not lead to further ventilatory depression [87, 88]. Renal system effects Activation of alpha-1 receptors in the kidney results in a redistribution of blood from the cortical to medullary areas due to an increase in renal vascular resistance. Stimulation of alpha-2 adrenoceptors has a number of effects that promote diuresis and natriuresis. They decrease the secretion of vasopressin and antagonise its action on renal tubules [89]. Alpha-2 adrenoceptors are also thought to inhibit the release of renin [90] and increase the release of atrial natriuretic factor [91] in the rat. Neuroendocrine system effects The alpha-2 adrenoceptor agonists have a number of neuroendocrine effects, mainly related to their inhibition of sympathetic outow and the decrease in plasma levels of circulating catecholamines [92]. Stimulation of alpha-2 adrenoceptors located on the b cells of the islets of Langerhans can temporarily cause direct inhibition of insulin
release [93]; clinical hyperglycaemia has not proved to be a problem. Alpha-2 adrenoceptor antagonists have been shown to increase insulin release. Alpha-2 receptor agonists also increase the release of growth hormone [94] and inhibit adipose tissue lipolysis. Clonidine can inhibit the secretion of adrenocorticotropic hormone (ACTH) and cortisol during surgery [95]. Gastrointestinal system effects Alpha-2 adrenoceptors regulate vagally mediated increases in gastric and intestinal motility and secretions. It has been postulated that gastric cholinergic prejunctional alpha-2 adrenoceptors inhibit gastric secretions during stress [96]. Activation of alpha-2 adrenoceptors inhibits water secretion and increases net absorption in the large bowel; this is the mechanism by which clonidine has been used to successfully treat diarrhoea [97]. Stimulation of alpha-2 adrenoceptors is known to reduce salivary secretions and may lead to a dry mouth [98]. Platelet effects Selective alpha-2 adrenoceptor agonists, as well as adrenaline, are known to stimulate platelet aggregation by stimulating alpha-2c receptors on platelets [99]. High concentrations of alpha-2 adrenoceptor agonists are required to cause platelet aggregation, as low concentrations of these drugs decrease plasma adrenaline concentration; the net effect may be a reduction in platelet aggregation. Alpha-2 receptor stimulation also results in the release of nitric 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 some similar pharmacological effects. It is known that they have a similar distribution in the brain and that they function through the activation of the same transduction and effector mechanisms, i.e. G-proteins and coupling to potassium channels. Therefore, if alpha-2 adrenoceptor agonists and opioids are administered together they may exhibit a synergistic action. It may also be possible to reduce the opioid dose and therefore decrease the respiratory and addictive side-effects. Alpha-2 adrenoceptor agonists also have a synergistic action with benzodiazepines. The administration of antagonists of either class of drug does not reverse the effects of the other, i.e. atipamezole and umazenil [101]. The duration of the hypnotic action of dexmedetomidine was increased by the administration of verapamil, a calcium channel blocker, the reverse effect was seen with the administration of a calcium antagonist [102].
153
Therapeutic role in anaesthesia
Haemodynamic stability and peri-operative ischaemia It is one of the goals of anaesthesia, especially in those patients at risk of cardiac ischaemia during surgery, to maintain myocardial oxygen balance. This can be achieved by attenuating sympathetically mediated hyperdynamic responses to stimulation, while maintaining peri-operative circulatory function. The ability of alpha-2 adrenoceptor agonists to modulate sympathetic tone leads to a desirable haemodynamic prole, which may help to maintain the myocardial oxygen supply/demand ratio [103]. Kulka and colleagues [104] reported that a minimum dose of 4 mg. kg1 intravenous clonidine is required to signicantly attenuate the stress response to laryngosopy in patients undergoing cardiac revascularisation surgery. In addition, a signicant reduction in peri-operative ischaemia was detected by monitoring critical ST depression in cardiac revascularisation patients who received clonidine 5 mg. kg1 [105]. De Kock and colleagues [106] reported fewer adverse haemodynamic events in the 350 patients who received intravenous clonidine 4 mg.kg1 at induction followed by 2 mg.kg1.h1 infusion undergoing major abdominal surgery compared with the 52 controls. Only two episodes of severe hypotension and bradycardia were recorded in the clonidine group. The same authors compared the haemodynamic stabilising effects of epidural clonidine 4 mg.kg1 at induction followed by an infusion of 1 mg.kg1.h1 with epidural sufentanil 0.5 mg.kg1 followed by 0.2 mg.kg1.h1 in patients undergoing major abdominal surgery with propofol and nitrous oxide anaesthesia. Clonidine was more effective than sufentanil at establishing stability at a reduced anaesthetic dose [107]. There is a ceiling to the haemodynamic stabilising effects of opioids [108]; this may be overcome by combining opioids with alpha-2 adrenoceptor agonists. Emergence from anaesthesia is a period associated with increased sympathetic activity, tachycardia and hypertension. Bernard and colleagues [109] reported that clonidine premedication decreased the unwanted haemodynamic effects seen during recovery from anaesthesia, therefore the use of long-acting alpha-2 adrenoceptor agonists is particularly useful. Clonidine has been reported in a number of studies to improve exercise tolerance in patients with angina pectoris [110, 111] and reduce exercise-induced myocardial ischaemia [112]. The hypertensive response to ketamine is also attenuated by clonidine [113]. Talke and colleagues [114] reported that a target plasma concentration of dexmedetomidine of 0.45 ng.ml1 administered to patients with coronary artery disease undergoing vascular surgery resulted in less peri-operative ischaemia compared with placebo.
154
In patients with stable angina undergoing an exercisetolerance test, mivazerol reduced ischaemia and angina [115]. In a phase 2 multicentre clinical trial Mangano and co-workers [116] investigated the benecial effects of mivazerol on haemodynamic stability and myocardial ischaemia in patients with coronary artery disease. Mivazerol was given as a continuous infusion to 197 patients intra-operatively and for 72 h postoperatively; 99 patients received a dose of 0.75 mg.kg1.h1 and 98 received 1.5 mg.kg1.h1. There were 103 placebo controls and all patients underwent noncardiac surgery. Mivazerol was reported to decrease the incidence, and treatment for, tachycardia, hypertension and myocardial ischaemia. The higher dose of mivazerol was more effective than the lower dose. There was no signicant incidence of hypotension or adverse events, although there was an increase incidence of bradycardia. Aanta & Kanto [117] highlighted the danger that a reduction in anaesthetic dose due to suppression of haemodynamic response to surgical stimulus, may lead to awareness. Sedation and anxiolysis It has long been known that clonidine causes sedation. During the rst clinical trial of clonidine, a volunteer slept for 24 h following 12 mg intranasal clonidine, [118]. Sedation, along with anxiolysis and an antisialogue effect, make alpha-2 adrenoceptor agonists useful premedication drugs. Clonidine has been used as a premedication in a number of studies. Administered in doses of 100300 mg, clonidine produced dose-related sedation [119]. A clonidine dose of 4 mg.kg1 given as premedication to children resulted in sedation and anxiolysis [120]. The use of clonidine as a premediction also has favourable haemodynamic consequences, attenuating the haemodynamic response to intubation and surgery [121]. Clonidine also reduces peri-operative plasma catecholamine concentration [121]. Dexmedetomidine has similar effects to clonidine when administered for premedication. Its disadvantage is that at present it can only be given as an intramuscular or intravenous injection. Dexmedetomidine administered at an intramuscular dose of 2.5 mg.kg1 as a premedication produced sedation and anxiolysis comparable with a midazolam dose of 80 mg.kg1 [122]. Both clonidine [123] and dexmedetomidine [124] have been shown to have anxiolytic effects independent of sedation. Anaesthetic requirements Miller and colleagues [125] rst demonstrated in 1968 that methyldopa and reserpine decreased the MAC of anaesthetic agents, both drugs reducing central noradrenaline concentration. However, Brodsky & Bravo [126] described an acute postoperative hypertensive crisis following the
acute discontinuation of clonidine therapy pre-operatively. In 1978, Kaukinen and colleagues [127] reported that continuing clonidine therapy peri-operatively in hypertensive patients on long-term clonidine medication resulted in a less variable haemodynamic prole and no hypertensive crisis. They also demonstrated that the administration of clonidine subcutaneously for 3 days reduced the MAC of halothane by 15% in rabbits [128]. Bloor & Flacke [129] also reported an anaesthetic-sparing effect in dogs, the administration of clonidine decreasing the MAC of halothane by a maximum of 50%. In addition the dose of thiopentone required for induction of anaesthesia is reduced by clonidine premedication [130]. Because MAC is reduced by a maximum of 40% when noradrenaline transmission is abolished totally [131] the reduction of MAC of 90% by selective alpha-2 adrenoceptor agonists such as dexmedetomidine [132] suggested additional mechanisms may be responsible for the anaesthetic action of alpha-2 adrenoceptor agonists. Flacke and colleagues [121] studied the effects of clonidine in patients undergoing coronary artery bypass surgery, comparing placebo against clondine premedication of 200 or 300 mg orally with a second dose given via a nasogastric tube during cardiopulmonary bypass. The clonidine-treated patients were more sedated and required 40% less sufentanil than placebo patients. They had a lower heart rate and blood pressure than placebo patients throughout the whole operative period. Post cardiopulmonary bypass, the clondine group had a higher cardiac output and lower systemic vascular resistance than the placebo group. Ghignone and colleagues [133] showed a 45% reduction in fentanyl requirement in patients given a premedication of 5 mg. kg1 of clonidine using EEG measurement of anaesthetic depth. The same dose also reduced the haemodynamic response to tracheal intubation [134]. In contrast, there are reports of no alfentanil sparing or haemodynamic stability following clonidine premedication [135]. The opioidsparing effect may not be a pure pharmacodynamic effect as clonidine has been reported to increase plasma alfentanil concentration by 60% [136] and dexmedetomidine is known to inhibit alfentanil microsomal liver metabolism [137]. Aho and colleagues [138] reported that the administration of an infusion of dexmedetomidine in patients undergoing abdominal hysterectomy was able to reduce isourane requirements by 90%. Dexmedetomidine has also been reported to be opioid- and barbiturate sparing [139]. Analgesia In 1974, Paalzow [140] was the rst to show the analgesic effect of clonidine. He reported that clonidine increased the nociceptive threshold in mice and rats. Alpha-2 adrenoceptor agonists have analgesic properties when given
parenterally, epidurally or intrathecally. Descending noradrenergic antinociceptive systems originating in the brainstem contribute to pain control by suppressing the spinal centripetal transmission of nociceptive impulses [141, 142]. These pathways are activated by stimulation of the locus coeruleus [143] and dorsal raphe nucleus [144] and analgesia may be mediated by noradrenaline release [145]. Alpha-2 adrenoceptors, predominately the alpha-2a subtype, have been identied in the substantia gelatinosa of the dorsal horn of the spinal cord. Stimulation of these alpha-2 adrenoceptors by intrathecal noradrenaline or specic agonists inhibits the ring of nociceptive neurones stimulated by peripheral Ad and C bres [146]. Also, intrathecal noradrenaline inhibits the release of substance P by primary afferents of the dorsal horn [147], and suppresses the activity of wide dynamic range neurones evoked by noxious stimulation [148]. Recent evidence suggests that the antinociception produced by alpha-2 adrenoceptor agonists may be due in part to acetylcholine release in the spinal cord [149, 150]. Because it has been suggested that the spinal cord is the major site of analgesic action of alpha-2 adrenoceptor agonists [151], the epidural and intrathecal routes have been considered preferable to the intravenous route. Clonidine is relatively lipid soluble and after epidural administration is absorbed rapidly into the blood. Although there is the possibility of cephalad spread this has not been clearly demonstrated [152]. A central mechanism for the analgesic action of alpha-2 adrenoceptor agonists has been debated although there is evidence to suggest that there is no supraspinal mechanism. The analgesia produced by spinal clonidine persists after spinal transection [153]. Also, the direct administration of alpha-2 adrenoceptor agonists into the brainstem did not produce analgesia [154, 155]. Indeed, stimulation of the alpha-2 adrenoceptors in the locus coeruleus potentially reduces the analgesia elicited at the level of the spinal cord by inhibition of noradrenergic antinociceptive descending pathways [156]. There have been reports to suggest that systemic alpha-2 adrenoceptor agonists have an analgesic action by decreasing the unpleasantness of pain, and this may be related to their sedative actions [157]. Bernard and co-workers reported the analgesic effects of an intravenous infusion of clonidine after major spinal surgery [158]. They administered either clonidine 5 mg.kg1 during the rst hour followed by 0.3 mg.kg1.h1 for 11 h or placebo. A visual analogue scale assessed pain. Intramuscular morphine was used to supplement analgesia if the pain scores were above 50%. In the clonidine group, pain onset was delayed, total morphine requirements were decreased signicantly and pain scores reduced compared with placebo. Aho and co-workers [159] demonstrated the analgesic effects of intravenous dexmedetomidine (0.2 and 0.4 mg.
155
kg1) after laparoscopic tubal ligation. Dexmedetomidine 0.4 mg.kg1 was reported to provide analgesia requiring signicantly less supplementation with morphine compared with the analgesia provided by diclofenac 250 mg. kg1. There was a high incidence of sedation and bradycardia in the dexmedetomidine 0.4 mg.kg1 group, but there was no increase in respiratory depression and the bradycardia responded to atropine. Epidural administration The rst report of the use of epidural clonidine was by Tamsen and Gordh in 1984 [160]. However, it was Bonnet and colleagues [161] who rst demonstrated in a blinded, placebo-controlled study, analgesia from epidural clonidine in postoperative patients. They observed a b50% decrease in the visual analogue pain score in patients who had received clonidine 2 mg.kg1 for up to 4 h following perineal or orthopaedic surgery. There was no change in the placebo group. Since then a number of studies have shown that epidural clonidine is effective and safe in the management of acute postoperative pain, improving analgesia and reducing opioid requirements [162, 163]. Ciagarini and co-workers [164] reported that 75 mg of epidural clonidine increased the duration of epidural bupivacaine analgesia in labour with no adverse effects to mother or neonate. Eisenach and colleagues [165] in a dose-nding study in postoperative patients found that a dose of 100300 mg provided minimal analgesia, dened as time to rst use and total dose of PCA morphine. A 700900 mg clonidine dose resulted in complete analgesia for 47 h. Rostaing and colleagues [166] reported the effects of the addition of epidural clonidine 150 mg to epidural fentanyl 100 mg analgesia. The onset of action remained the same, but the duration of analgesia was doubled, without any effect on fentanyl pharmacokinetics. Bernard and colleagues [167] have also reported that patients who self-administered epidural clonidine as a sole analgesic used less clonidine than those using self-administered intravenous clonidine after major orthopaedic surgery. This study clearly demonstrated the superiority of the epidural route compared with the intravenous route. Oral clonidine, however, prolongs both sensory and motor blockade following intrathecal lignocaine; clearly, therefore, there may be more than one mechanism involved in the analgesic action. It may be benecial to administer alpha-2 adrenoceptor agonists, opioids and local anaesthetic drugs together. This may make it possible to decrease the dose of each agent without loss of efcacy and hence reduce the side-effects of each agent. Intrathecal administration Coombs and colleagues [168] were the rst to use intrathecal clonidine in 1985, 300 mg providing 18 h of pain
156
relief in a morphine-tolerant cancer patient. A number of authors have, however, reported no advantages in using the intrathecal route. Klimscha and co-workers [169] compared epidural clonidine and bupivacaine with intrathecal clonidine and bupivacaine. They reported that the spinal route led to a signicantly greater reduction in blood pressure with no additional analgesia. In another study, the addition of intrathecal clonidine provided no further postoperative analgesic benet to intrathecal morphine [170]. However, the duration of block after intrathecal bupivacaine was longer with clonidine than with adrenaline [171] and a dose of 150 mg provided adequate analgesia for 6 h after Caesarean section [172]. Currently, clonidine remains the only alpha-2 adrenoceptor agonist available for epidural and intrathecal use and it appears to have no effect on spinal-cord histology in animal studies [173]. However, Fukushima and co-workers [174] have administered epidural dexmedetomidine successfully to man for postoperative analgesia in clinical trials.
Chronic pain
Alpha-2 adrenoceptor agonists have been reported to be useful adjuncts in the treatment of chronic pain syndromes in animal and human studies [175177]. Lee & Yaksh [178] demonstrated that the intrathecal administration clonidine or MK-801, an N-methyl-D-aspartate antagonist (NMDA), abolished, in a dose-dependent manner, a model of neuropathic pain in rats. The administration of both these drugs together revealed a signicant synergistic effect. It is thought that NMDA-receptor activation in the dorsal horn facilitates the discharge of wide dynamic range neurones, which are important for the centripetal transmission of painful impulses. Glynn & OSullivan [179] reported the effective use of a combination of epidural lignocaine 40 mg and clonidine 150 mg in 20 patients mostly suffering from neuropathic pain. The duration of analgesia was increased compared with single drug administration. The epidural route has proved to be the most effective way of administrating clonidine in patients with neuropathic pain [180], although intravenous and transdermal routes [181] have been tried. Eisenach and colleagues [182, 183] reported that epidural clonidine was effective in treating cancer pain in patients tolerant to opioids. Topical clonidine has been used to control sympathetically maintained pain [184].
Miscellaneous uses
Clonidine has a number of other potential benecial effects during anaesthesia. In two studies, clonidine has been reported to preserve renal function before and after anaesthesia for coronary artery surgery [185, 186]. During
recovery from anaesthesia, shivering is a common problem. Shivering increases oxygen consumption and carbon dioxide production signicantly above basal levels [187, 188], which may lead to arterial desaturation and lactic acidosis [189, 190]. Delaunay and co-workers [191] reported that clonidine 2 mg.kg1 administered intravenously at the end of surgery attenuated the increase in oxygen consumption and carbon dioxide production. The reduction in shivering may be particularly useful in patients with ischaemic heart disease. Goldfarb and co-workers [192] reported that intravenous clonidine 150 mg is as effective as droperidol 5 mg in diminishing postoperative shivering. Dexmedetomidine has also been reported to reduce postanaesthesia shivering in cats [193]. Finally, clonidine has been reported to be effective in reducing intraocular pressure during ophthalamic surgery [194] and the treatment of glaucoma [195]. Clonidine is thought to decrease production and increase drainage of aqueous humour. The decrease in intraocular pressure has also been reported with dexmedetomidine premedication [196].
Veterinary anaesthesia
have been used to treat congestive heart failure [203], angina pectoris [111] and myocardial infarction [204]. An increase in brain noradrenergic activation is common in many withdrawal syndromes [205] and anxiety states. Clonidine has successfully been used to control symptoms in a number of withdrawal states such as opioid [206], benzodiazepine [207], alcohol [208] and tobacco [209211]. Clonidine also controls manic symptoms [212] and has been used in hyperactive children [213]. However, it must be remembered that in large doses clonidine can cause anxiety due to activation of alpha-1 receptors. Among other uses of clonidine may be numbered, Korsakoff s psychosis, motor spasticity associated with spinal cord injury, and muscle rigidity due to the rapid administration of large doses of opioids [214].
Conclusion
In 1967, Clark & Hall [197] reported the use of xylazine, a nonselective alpha-2 adrenoceptor agonist, as an adjunct sedative and analgesic agent in horses and cattle. Since then alpha-2 receptor agonists have been widely used to provide dose-dependent sedation, analgesia and muscle relaxation, although it was not until 1981 that the link with central alpha-2 receptors was rst established [198]. Xylazine was often used in combination with ketamine; the sympathomimetic action of ketamine countered the xylazineinduced decreases in heart rate and cardiac output [199]. Another alpha-2 adenoceptor agonist, detomidine had greater sedative and analgesic effects than xylazine [200], both agents have been superseded by the highly selective and potent alpha-2 adrenoceptor agonist medetomidine [201]. Common side-effects of these drugs when given intravenously are bradycardia, initial hypertension and later hypotension. Also vomiting and muscle jerking have been reported with the onset of sedation. Specic antagonists idazoxan and atipamezole can reverse the sedative effects.
Non-anaesthetic uses
Clonidine was initially introduced clinically as a nasal decongestant and has been used as an antihypertensive for 25 years [202]. Its side-effects are dry mouth, sedation and a withdrawal syndrome. Sudden discontinuation of clonidine results in restlessness, headache, nausea, insomnia and an increase in sympathetic activity resulting in tachycardia and hypertension. Alpha-2 adrenoceptor agonists
Alpha-2 adrenoceptor agonists have been used in a large number of clinical applications, some with little evidence of efcacy. Anaesthetic and analgesic-sparing effects have been reported, but whether they offer additional benets to patients requiring routine surgery is yet to be decided. A better understanding of the interactions between alpha-2 adrenoceptor, opioid and cholinergic receptors, as well as local anaesthetic mechanisms, should help determine the most appropriate and effective combination of their agonists. They may, however, have a role in anaesthesia for patients at high risk of myocardial ischaemia undergoing major surgery. Drugs of this class control the blood pressure without reex tachycardia, decrease the stress response and attenuate postoperative shivering, therefore improving the myocardial oxygen and supply ratio. However, clinical studies showing improved outcome in dened high-risk patient groups are still awaited, as peri-operative ischaemia is not always related to tachycardia or an increase in catecholamines, e.g. thrombosis or embolic phenomena. In cancer pain, clonidine is arguably the drug of second choice. The dose of clonidine needs to be carefully titrated to effect, with the epidural route offering some advantage. In most cases, a clonidine dose of 300 mg seems to be sufcient independent of the route of administration. It should be noted that if haemodynamic parameters alone are used to assess the depth of anaesthesia there is a risk of awareness and if conventional doses of anaesthetics are used in conjunction with alpha-2 adrenoceptor agonists there is a risk of oversedation. The side-effects of alpha-2 adrenoceptor agonists, bradycadia and hypotension, come on slowly (15 min); therefore patients need careful monitoring. Some authors recommend the routine use of an anticholinergic medication with alpha-2 adrenoceptor agonists. The sedative effects of alpha-2 adrenceptor agonists make them unsuitable for daycase anaesthesia. Investigations
157
into the molecular biology of alpha-2 adrenoceptors have improved our understanding of noradrenergic mechanisms in the central nervous system and in peripheral tissues and their effect on vigilance, analgesia and sympathetic outow. The emerging characterisation of imidazoline receptors has increased our understanding of blood-pressure control and has led to the availability of a new generation of centrally acting antihypertensive agents. A denitive subtyping of alpha-2 adrenoceptor gene expression at a cellular level may allow the development of a second generation of more specic agents with fewer side-effects.
References 1 Hieble JP, Ruffolo RR. Possible structural and functional relationships between imidazoline receptors and alpha 2-adrenoceptors. Annals of the New York Academy of Sciences 1995; 763: 821. 2 Ahlquist RP. A study of the adrenotropic receptors. American Journal of Physiology 1948; 153: 5869. 3 Paton WD, Vizi ES. The inhibitory action of noradrenaline and adrenaline on acetylcholine output by guinea-pig ileum longitudinal muscle strip. British Journal of Pharmacology 1969; 35: 1028. 4 Delbarre B, Schmitt H. A further attempt to characterize sedative receptors activated by clonidine in chickens and mice. European Journal of Pharmacology 1973; 22: 3559. 5 Langer SZ. Presynaptic regulation of catecholamine release. Biochemical Pharmacology 1974; 23: 1793800. 6 Wikberg JES. Synthesis of 3H-acetylcholine in the rabbit lacrimal gland its release by electrical eld stimulation. Acta Physiologica Scandinavica 1979; 468 (Suppl.): 189. 7 Anden NE, Corrodi H, Fuxe K, Hokfelt B, Hokfelt T, Rydin C. Evidence for a central noradrenaline receptor stimulation by clonidine. Life Sciences 1970; 9: 51323. 8 Cheung Y-D, Barnett DB, Nahorski SR. 3H-rauwolscine and 3H-yohimbine binding to rat cerebral and human platelet membranes: evidence for possible heterogeneity of a2-adrenoceptors. European Journal of Pharmacology 1982; 84: 7985. 9 Kobilka BK, Matsui H, Kobilka TS et al. Cloning, sequencing and expression of the gene coding for the human platelet a2-adrenergic receptor. Science 1987; 238: 6506. 10 Regan JW, Kobilka TS, Yang-Feng TL, Caron MG, Lefkowitz RJ, Kobilka BK. Cloning and expression of a human kidney cDNA for an alpha 2-adrenergic receptor subtype. Proceedings of the National Academy of the Sciences of the United States of America 1988; 85: 63015. 11 Lomasney JW, Lorenz W, Allen LF et al. Expansion of the alpha 2-adrenergic receptor family. Proceedings of the National Academy of the Sciences of the United States of America 1990; 87: 50948. 12 Matsui H, Lefkowitz RJ, Caron MG, Regan JW. Localization of the fourth membrane scanning domain as
13 14
15 16
17
18
19
20
21
22 23
24
25
26
27
28
29
a ligand binding site in the human platelet alpha 2 adrenergic receptor. Biochemistry 1989; 28: 412530. Gilman AG. G proteins: transducers of receptor-generated signals. Annual Review of Biochemistry 1987; 56: 61549. Freissmuth M, Casey PJ, Gilman AG. G proteins control diverse pathways of transmembrane signalling. Faseb Journal 1989; 3: 212531. Neer EJ, Clapham DE. Roles of G protein subunits in transmembrane signalling. Nature 1988; 333: 12934. Birnbaumer L, Abramowitz J, Brown AM. Receptor effectors coupling by G proteins. Biochimica et Biophysica Acta 1990; 1031: 163224. Codina J, Yatani A, Grenet D, Brown AM, Birnbaumer L. The subunit of the GTP binding protein Gk opens atrial potassium channels. Science 1987; 236: 4425. Aghajanian GK, VanderMaelen CP. a2-adrenoceptormediated hyperpolarization of locus coeruleus neurons: Intracellular studies in vivo. Science 1982; 215: 13946. Lipscombe D, Kongsamut S, Tsien R a-adrenergic W. inhibition of sympathetic neurotransmitter release mediated by modulation of N-type calcium-channel gating. Nature 1989; 340: 63942. Hescheler J, Rosenthal W, Trautwein W, Schultz G. The GTP-binding protein, Go, regulates neuronal calcium channels. Nature 1987; 325: 4457. Isom LL, Cragoe EJ Jr, Limbird LE. a2 adrenergic receptors accelerate Na/H exchange in neuroblastoma x glioma cells. Journal of Biological Chemistry 1987; 262: 672087. Langer SZ. Presynaptic regulation of the release of catecholamines. Pharmacology Review 1981; 32: 33762. Scheinin M, Schwinn D. The locus coeruleus: site of hypnotic actions of a2-adrenoceptor agonists? Anesthesiology 1992; 76: 8735. Aston-Jones G, Ennis M, Pieribone VA, Nicoll WT, Shipley MT. The brain nucleus locus coeruleus: restricted afferent control of a broad efferent network. Science 1986; 234: 7347. Esler M, Zweier A, Randall O, Julius S, de Quattro V. Agreement among three different indices of sympathetic nervous system activity in essential hypertension. Mayo Clinic Proceedings 1977; 52: 37982. Ernsberger PR, Giuliano R, Willette RN, Granata AR, Reis DJ. Hypotensive action of clonidine analogs correlates with binding afnity at imidazole and not a2-adrenergic receptors in the rostral ventrolateral medulla. Hypertension 1988; 6 (Suppl. 4): S5547. Bousquet P, Feldman J, Bloch R, Schwartz J. The nucleus reticularis lateralis, a region highly sensitive to clonidine. European Journal of Pharmacology 1981; 69: 38992. Bousquet P, Feldman J, Schwartz J. Central cardiovascular effects of a-adrenergic drugs: difference between catecholamines and imidazolines. Journal of Pharmacology and Experimental Therapeutics 1984; 230: 2306. Ernsberger PR, Meeley MP, Mann JJ, Reis DJ. Clonidine binds to imidazole binding sites as well as
158
30
31
32
33
34
35
36
37
38
39
40
41
42
43
a2-adrenoceptors in the ventrolateral medulla. European Journal of Pharmacology 1987; 134: 113. Kamisaki Y, Ishikawa T, Takao Y, Omodani H, Kuno N, Itoh T. Binding of [3H]p-aminoclonidine to two sites, a2-adrenoceptors and imidazoline binding sites: distribution of imidazoline binding sites in rat brain. Brain Research 1990; 514: 1521. Ernsberger P, Graves ME, Graff LM et al. I1-imidazoline receptors. Denition, characterization, distribution, and transmembrane signalling. Annals of the New York Academy of Sciences 1995; 763: 2242. Zonnenschein R, Diamant S, Atlas D. Imidazoline receptor in rat hepatocytes: a subtype of a2-adrenergic receptor or a new receptor? European Journal of Pharmacology 1990; 183: 8534. Petrusewica J, Kaliszan R. Human blood platelet alpha adrenoceptor in view of the effects of various imidazol(in)e drugs on aggregation. General Pharmacology 1991; 22: 81923. Diamant S, Eldar-Geva T, Atlas D. Imidazoline binding sites in human placenta: evidence for heterogeneity and a search for physiological function. British Journal of Pharmacology 1992; 106: 101927. Lachaud-Pettiti V, Pdevin RA, Chetrien Y, Parini A. Imidazoline-guanidinium and a2-adrenergic binding sites in basolateral membranes from human kidneys. European Journal of Pharmacology 1991; 206: 2331. Regunathan S, Meeley MP, Reis DJ. Expression on nonadrenergic imidazoline sites in chromafn cell and mitochondrial membranes of bovine adrenal medulla. Biochemical Pharmacology 1993; 45: 166775. Regunathan S, Evinger MJ, Meeley MP, Reis DJ. Effect of clonidine and other imidazole-receptor binding agents on second messenger systems and calcium inux in bovine adrenal chromafn cells. Biochemical Pharmacology 1991; 42: 201118. Regunathan S, Feinstein DL, Reis DJ. Expression of noradrenergic sites in rat cerebral cortical astrocytes. Journal of Neuroscience Research 1993; 34: 6818. Li G, Regunathan S, Barrow CJ, Eshraghi J, Cooper R, Reis DJ. Agmatine: an endogenous clonidine displacing substance in the brain. Science 1994; 263: 9669. Regunathan S, Reis DJ. Imidazoline receptors and their endogenous ligands. Annual Review of Phamacology and Toxicology 1996; 36: 51144. Mammoto T, Kamibayashi T, Hayashi Y, Yamatodani A, Takada K, Yoshiya I. Antiarrhythmic action of rilmenidine on adrenaline-induced arrhythmia via central imidazoline receptors in halothane-anaesthetized dogs. British Journal of Pharmacology 1996; 117: 17448. Mest HJ, Thomsen P, Raap A. Antiarrhythmic effect of the selective I1-imidazoline receptor modulator moxonidine on ouabain-induced cardiac arrhythmia in guinea pigs. Annals of the New York Academy of Sciences 1995; 763: 62033. Ostermann G, Brisgand B, Schmitt J, Fillastre JP. Efcacy and acceptability of rilmenidine for mild to moderate
44
45
46
47
48
49
50
51
52
53
54
55
56
systemic hypertension. American Journal of Cardiology 1988; 61: 76D80D. Galley P, Manciet G, Hessel JL, Michel JP. Antihypertensive efcacy and acceptability of rilmenidine in elderly hypertensive patients. American Journal of Cardiology 1988; 61: 86D90D. Mpoy M, Vandeleene B, Ketelslegers JM, Lambert A. Treatment of systemic hypertension in insulin-treated diabetes mellitus with rilmenidine. American Journal of Cardiology 1988; 61: 91D94D. Lins R, Daelemans R, Dratwa M et al. Acceptability of rilmenidine and long-term surveillance of plasma concentration in hypertensive patients with renal insufciency. American Journal of Medicine 1989; 87 (Suppl. 3C): 41S45S. Trimarco B, Rosiello G, Sarno D et al. Effects of one-year treatment with rilmenidine on systemic hypertensioninduced left ventricular hypertrophy in hypertensive patients. American Journal of Cardiology 1994; 74: 36A42A. Li P, Penner SB, Smyth DD. Attenuated renal response to moxonidine and rilmenidine on kidney one-clip hypertensive rats. British Journal of Pharmacology 1994; 112: 2006. Dallocchio M, Gosse P, Grollier G, Morand P, Drici M, Corcoran C. La rilmenidine, un nouvel antihypertenseur dans le traitement de premiere intention de lhypertension arterielle essenteille: etude multicentrique en double aveugle contre atenolol. Presse Medicale 1991; 20: 126571. The UK Working Party on Rilmenidine. Rilmenidine in mild to moderate essential hypertension: a double blind, randomized, parallel group, multicenter comparison with methyldopa in 157 patients. Clinical Therapeutics Research 1990; 47: 194211. MacPhee GJA, Howie CA, Elliott HL, Reid JL. A comparison of the haemodynamic and behavioural effects of moxonidine and clonidine in normotensive subjects. British Journal of Clinical of Pharmacology 1992; 33: 2617. Prichard BNC, Simmons R, Rooks MJ, Haworth DA, Laws D, Wonnacott S. A double-blind comparison of moxonidine and atenolol in the management of patients with mild to moderate hypertension. Journal of Cardiovascular Pharmacology 1992; 20 (Suppl. 4): S45S49. Wolf R. The treatment of hypertensive patients with a calcium antagonist or moxonidine: a comparison. Journal of Cardiovascular Pharmacology 1992; 20 (Suppl. 4): S42S44. Ollivier JP, Christen MO, Schafer SG. Moxonidine: a second generation of centrally acting drugs. An appraisal of clinical experience. Journal of Cardiovascular Pharmacology 1992; 20 (Suppl. 4): S31S37. Planitz V. Intra-individual comparison of moxonidine and prazosin in hypertensive patients. European Journal of Clinical Pharmacology 1986; 229: 64550. De Vos H, Bricca G, De Keyser J, De Backer JP, Bousquet P, Vauquelin G. Imidazoline receptors,
159
57
58
59
60
61
62
63
64
65
66
67
68
69
70
non-adrenergic idazoxan binding sites and a2-adrenoceptors in the human central nervous system. Neurosciences 1994; 59: 58998. Langin D, Lafontan M, Stillings MR, Paris H. [3H]RX 821, 002: a new tool for the identication of a2A-adrenoceptors. European Journal of Pharmacology 1989; 167: 95104. Erdbrugger W, Raulf M, Otto T, Michel MC. Does [3H] 2-methoxy-idazoxan (RX 821, 002) detect more alpha-2adrenoceptor agonist high-afnity sites than [3H] rauwolscine? A comparison of nine tissue and cell lines. Journal of Pharmacology and Experimental Therapeutics 1995; 273: 128794. De Noyer M, Laveleye F, Vauquelin G, Gobert J, Wulfert E. Mivazerol, a novel compound with high binding specicity for alpha a2 adrenergic receptors: binding studies on different human and rat membrane preparations. Neurochemistry International 1994; 24: 2219. Karhuvaara S, Kallio A, Salonen M, Tuominen J, Scheinin M. Rapid reversal of a2-adrenoceptor agonist effects by atipamezole in human volunteers. British Journal of Clinical Pharmacology 1991; 31: 1605. Dyck JB, Shafer SL. Dexmedetomidine pharmacokinetics and pharmacodynamics. Anaesthetic Pharmacology Review 1993; 1: 23845. Leimdorfer A. The action of sympathomimetic amines on the central nervous system and the blood sugar: relation of chemical structure to mechanism of action. Journal of Pharmacology and Experimental Therapeutics 1950; 98: 6271. Feldberg W, Sherwood SL. Injections of drugs into the lateral ventricle of the cat. Journal of Physiology 1954; 123: 14867. Grunden LR. Action of intracerebroventricular epinephrine on gross behavior, locomotor activity and hexobarbital sleeping times in rats. International Journal of Neuropharmacology 1969; 8: 57386. Fugner A, Hoefke W. Asleep-like in chicks caused by biogenic amines and other compounds, quantitative evaluation. Arzneimittel-Forschung 1971; 21: 12437. Lidbrink P. The effect of lesion of ascending noradrenaline pathways on sleep and waking in the rat. Brain Research 1974; 74: 1940. Hossman V, Maling TJB, Hamilton CA, Reid JL, Dollery CT. Sedative and cardiovascular effects of clonidine and nitrazepam. Clinical Pharmacology and Therapeutics 1980; 28: 16776. Ferrari F, Tartoni PL, Margiaco V. B-HT 920 antagonizes rat neophobia in the X-maze test. Archives of International Pharmacodynamics and Therapeutics 1989; 298: 714. Soderpalm B, Engel JA. Biphasic effects of clonidine on conict behavior. Involvement of different a-adrenoceptors. Pharmacology, Biochemistry and Behavior 1988; 30: 4717. Karlsson BR, Forsman M, Roald OK, Heier MS, Steen PA. Effect of dexmedetomidine, a selective and potent
71
72
73
74
75
76
77
78
79
80
81
82
83
a2-agonist, on cerebral blood ow and oxygen consumption during halothane anesthesia in dogs. Anesthesia and Analgesia 1990; 71: 1259. Drummond JC. Dexmedetomidine, an a2-adrenergic agonist decreases cerebral blood ow in the isourane anesthetized dog. Anesthesia and Analgesia 1990; 70: 62430. Maier C, Steinberg GK, Hua Sun G, Tian Zhi G, Maze M. Neuroprotection by the a2-adrenoceptor agonist dexmedetomidine in a focal model of cerebral ischaemia. Anesthesiology 1993; 79: 30612. Ruffolo RR Jr Distribution and function of peripheral a-adrenoceptors on the cardiovascular system. Pharmacology, Biochemistry and Behavior 1985; 22: 82733. Nichols AJ. Alpha-adrenoceptor signal transduction mechanisms, alpha-adrenoceptors. In: Ruffolo RR Jr, ed. Molecular Biology, Biochemistry and Pharmacology. New York: Karger, 1991: 4474. Bloor BC, Frankland M, Alper G, Raybould D, Weitz J, Shurtliff M. Hemodynamic and sedative effects of dexmedetomidine in dog. Journal of Pharmacology and Experimental Therapeutics 1992; 263: 6907. Tibirica E, Feldman J, Mermet C, Gonon F, Bousquet P. An imidazoline specic mechanism for the hypotensive effect of clonidine. A study with yohimbine and idazoxan. Journal of Pharmacology and Experimental Therapeutics 1991; 256: 60613. Badoer E, Head GA, Korner PI. Effects of intracisternal and intravenous alpha-methyldopa and clonidine on haemodynamics and baroreceptor-heart rate reex properties in conscious rabbits. Journal of Cardiovascular Pharmacology 1983; 5: 7607. De Jonge A, Timmermans PBMWM, Van Zwieten PA. Participation of cardiac presynaptic a2 adrenoceptors in the bradycardic effects of clonidine and analogues. Naunyn-Schmiedebergs Archives of Pharmacology 1981; 317: 812. Hayashi Y, Sumikawa K, Maze M et al. Dexmedetomidine prevents epinephrine-induced arrhythmias through stimulation of central a2-adrenoceptors in halothane-anesthetized dogs. Anesthesiology 1991; 75: 11317. Zochowski RJ, Lada W. Intravenous clonidine in acute myocardial infarction in men. International Journal of Cardiology 1984; 6: 189201. Angus JA, Cocks TM, Satoh K. Alpha 2-adrenoceptors and endothelium-dependent relaxation in canine large arteries. British Journal of Pharmacology 1986; 88: 76777. Bockman CS, Jeffries WB, Pettinger WA, Abel PW. a2-adrenergic receptor subtypes on pig endothelial cell. FASEB Journal 1992; 6: A1556 (Abstract). Coughlan MG, Lee JG, Bosnjak ZJ, Schmeling WT, Kampine JP, Warltier DC. Direct coronary and cerebral vascular responses to dexmedetomidine. Signicance of endogenous nitric oxide synthesis. Anesthesiology 1992; 77: 9981006.
160
84 Ooi R, Pattison J, Feldman SA. The effects of intravenous clonidine on ventilation. Anaesthesia 1991; 46: 6323. 85 Nguyen D, Abdul-Rasool I, Ward D et al. Ventilatory effects of dexmedetomidine, atipamezole, and isourane in dogs. Anesthesiology 1992; 76: 5739. 86 Belleville JP, Ward DS, Bloor BC, Maze M. Effects of intravenous dexmedetomidine in humans. Anesthesiology 1992; 77: 112533. 87 Bailey PL, Sperry RJ, Johnson GK et al. Respiratory effects of clonidine alone and combined with morphine, in humans. Anesthesiology 1991; 74: 438. 88 Jarvis DA, Duncan SR, Segal IS, Maze M. Ventilatory effects of clonidine alone and in the presence of alfentanil, in human volunteers. Anesthesiology 1992; 76: 899905. 89 Smyth DD, Umemura S, Pettinger WA. Alpha 2-adrenoceptor antagonism of vasopressin-induced changes in sodium excretion. American Journal of Physiology 1985; 248: F76772. 90 Pettinger WA. Renal alpha 2-adrenergic receptors and hypertension. Hypertension 1987; 9: 36. 91 Chen M, Lee J, Huang BS, Grekin RJ, Malvin RL. Clonidine and morphine increase atrial natriuretic peptide secretion in anaesthetized rats. Proceedings of the Society for Experimental Biology and Medicine 1989; 191: 299303. 92 Hokfelt B, Hedeland H, Hansson B-G. The effect of clonidine and penbutolol, respectively on catecholamines in blood and urine, plasma renin activity and urinary aldosterone in hypertensive patients. Archives of International Pharmacodynamics 1975; 213: 30721. 93 Angel I, Langer SZ. Adrenergic induced hyperglycaemia in anaesthetized rats: involvement of peripheral a2-adrenoceptors. European Journal of Pharmacology 1988; 154: 1916. 94 Grossman A, Weerasuriya K, Al-Damluji S, Turner P, Besser GM. a2-adrenoceptor agonists stimulate growth hormone secretion but have no acute effects on plasma cortisol under basal conditions. Hormone Research 1987; 25: 6571. 95 Masal A, Satta G, Alagna S et al. Effect of clonidine on stress-induced cortisol release during surgery. Pharmacological Research Communications 1985; 17: 2938. 96 Di Joseph JF, Taylor JA, Mir GN. Alpha-2 receptors in the gastrointestinal system: a new therapeutic approach. Life Sciences 1984; 35: 103142. 97 McArthur KE, Anderson DS, Durbin TE, Orloff MJ, Dharmsathaphorn K. Clonidine and lidamidine to inhibit watery diarrhea in a patient with lung cancer. Annals of Internal Medicine 1982; 96: 3235. 98 Watkins J, FitzGerald G, Zamboulis C, Brown MJ, Dollery CT. Absence of opiate and histamine H2 receptor-mediated effects of clonidine. Clinical Pharmacology and Therapeutics 1980; 28: 60510. 99 Grant JA, Scrutton MC. Interaction of selective alpha-adrenoceptor agonists and antagonists with human and rabbit blood platelets. British Journal of Pharmacology 1980; 71: 12134. 100 Radomski MW, Palmer RM, Moncada S. The
101
102
103
104
105
106
107
108
109
110
111
112
113
114
anti-aggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. British Journal of Pharmacology 1987; 92: 63946. Salonen M, Reid K, Maze M. Synergistic interaction between a2-adrenergic agonists and benzodiazepines in rats. Anesthesiology 1992; 76: 100411. Horvath G, Szikszay M, Benedek G. Calcium channels are involved in the hypnoticanesthetic action of dexmedetomidine in rats. Anesthesia and Analgesia 1992; 74: 8848. Roizen MF. Should we all have a sympathectomy at birth or at least preoperatively. Anesthesiology 1988; 68: 4824. Kulka PJ, Tryba M, Zenz M. Doseresponse effects of intravenous clonidine on stress response during induction of anesthesia in coronary artery bypass graft patients. Anesthesia and Analgesia 1995; 80: 2638. Dorman BH, Zucker J, Verrier ED, Gartman DM, Slachman FN. Clonidine improves perioperative myocardial ischemia, reduces anesthetic requirements, and alters hemodynamic parameters in patients undergoing coronary artery bypass surgery. Journal of Cardiothoracic and Vascular Anesthesia 1993; 7: 38695. De Kock M, Versailles H, Colinet B, Karthaeuser R, Scholtes JL. Epidemiology of the adverse events occuring during Clonidine anesthesia: a prospective open trial of intravenous clonidine. Journal of Clinical Anesthesia 1995; 7: 40310. De Kock M, Famenne F, Deckers G, Scholtes JL. Epidural clonidine or sufentanil for intraoperative and postoperative analgesia. Anesthesia and Analgesia 1995; 81: 115462. Akistopolou H, Whitwam JG, Al-Khudhairi D et al. Acute tolerance to fentanyl during anesthesia in dogs. Anesthesiology 1985; 63: 2559. Bernard JM, Bourreli B, Hommeril. JL, Pinaud M. Effects of oral clonidine premedication and postoperative i.v. infusion on haemodynamic and adrenergic responses during recovery from anaesthesia. Acta Anaesthesiologica Scandinavica 1991; 35: 549. Ceremuzynski L, Zaleska T, Lada W, Zalewski A. Clonidine effect in chronic angina pectoris. Double-blind, crossover trial on, 60 patients. European Journal of Cardiology 1979; 10: 41527. Thomas MG, Quiroz AC, Rice JC, Sander GE, Giles TD. Antianginal effects of clonidine. Journal of Cardiovascular Pharmacology 1986; 8: S6975. Cocco G, Strozzi C, Haeusler G, Chu D, Amrein R, Padovan GC. Therapeutic value of clonidine in patients with coronary heart disease. European Journal of Cardiology 1979; 10: 2218. Tanaka M, Nishikawa T. Oral clonidine premedication attenuates the hypertensive response to ketamine. British Journal of Anaesthesia 1994; 73: 75862. Talke P, Li J, Jain U et al. Effects of perioperative dexmedetomedine infusion in patients undergoing vascular surgery. Anesthesiology 1995; 82: 62033.
161
115 Wright RA, Decroly P, Kharkevitch T, Oliver MF. Exercise tolerance in angina is improved by mivazerol an alpha2-adrenoceptor agonist. Cardiovascular Drugs and Therapy 1993; 7: 92934. 116 McSPI-Europe Research Group. Perioperative sympatholysis. Benecial effects of the a2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia. Anesthesiology 1997; 86: 34663. 117 Aantaa R, Kanto J. Is clonidine an anaesthetic in man? Anaesthesia 1992; 47: 533. 118 Walland A. Clonidine. In: Goldberg ME, ed. Pharmacological and Biochemical Properties of Drug Substances. Washington DC: American Pharmaceutical Association, 1977: 67107. 119 Carabine UA, Wright PMC, Moore J. Preanaesthetic medication with clonidine: a dose response study. British Journal of Anaesthesia 1991; 67: 7983. 120 Mikawa K, Maekawa N, Nishina K, Takao H, Yaku H, Obara H. Efcacy of oral clonidine premedication in children. Anesthesiology 1993; 79: 92631. 121 Flacke JW, Bloor BC, Flacke WE et al. Reduced narcotic requirement by clonidine with improved hemodynamic and adrenergic stability in patients undergoing coronary bypass surgery. Anesthesiology 1987; 67: 90917. 122 Scheinin H, Jaakola M-L, Sjovall S et al. Intramuscular dexmedetomidine as premedication for general anesthesia. Anesthesiology 1993; 78: 106575. 123 Handley SL, Mithani S. Effects of alpha-adrenoceptor agonists and antagonists in a maze-exploration model of fear-motivated behaviour. Naunyn-Schmiedebergs Archives of Pharmacology 1984; 327: 15. 124 Salonen M, Onaivi ES, Maze M. Dexmedetomidine synergism with midazolam in the elevated plus-maze test in rats. Psychopharmacology (Berlin) 1992; 108: 22934. 125 Miller RD, Way WL, Eger EI. The effects of alpha-methyldopa, reserpine, guanethidine and iproniazid on minimum alveolar anesthetic requirement (MAC). Anesthesiology 1968; 29: 11538. 126 Brodsky JB, Bravo JJ. Acute postoperative clonidine withdrawal syndrome. Anesthesiology 1976; 44: 51920. 127 Kaukinen S, Kaukinen L, Eerola R. Postoperative use of clonidine with neuroleptanaesthesia. Acta Anaesthesiologica Scandinavica 1979; 23: 11320. 128 Kaukinen S, Pyykko K. The potentiation of halothane anesthesia by clonidine. Acta Anaesthesiologica Scandanivica 1979; 23: 10711. 129 Bloor BC, Flacke WE. Reduction in halothane anesthetic requirement by clonidine, an alpha adrenergic agonist. Anesthesia and Analgesia 1982; 61: 7415. 130 Orko R, Pouttu J, Ghignone M, Rosenberg PH. Effect of clonidine on haemodynamic responses to endotracheal intubation and on gastric acidity. Acta Anaesthesiologica Scandinavica 1987; 31: 3259. 131 Roizen MF, White PF, Eger EI, Brownstein M. Effects of ablation of serotonin or norepinephrine brain stem areas on halothane and cyclopropane MACs in rats. Anesthesiology 1978; 78: 2525.
132 Segal IS, Vickery RG, Walton JK, Doze VA, Maze M. Dexmedetomidine diminishes halothane anesthetic requirements in rats through a postsynaptic alpha2adrenergic receptor. Anesthesiology 1988; 69: 81823. 133 Ghignone M, Quintin L, Duke PC, Kehler CH, Calvillo O. Effects of clonidine on narcotic requirements and hemodynamic response during induction of fentanyl anesthesia and endotracheal intubation. Anesthesiology 1986; 64: 3642. 134 Ghignone M, Calvillo O, Quintin L. Anesthesia and hypertension: The effect of clonidine on preoperative hemodynamics and isourane requirements. Anesthesiology 1987; 67: 310. 135 Abi-Jaoude F, Brusset A, Ceddaha A et al. Clonidine premedication for coronary artery bypass grafting under high dose alfentanil anesthesia: intraoperative and postoperative hemodynamic study. Journal of Cardiothoracic and Vascular Anesthesia 1993; 7: 3540. 136 Segal IS, Jarvis DA, Duncan SR, White PF, Maze M. Clinical efcacy of oral transdermal clonidine combinations during the perioperative period. Anesthesiology 1991; 74: 2205. 137 Kharasch ED, Hill HF, Eddy AC. Inuence of dexmedetomidine and clonidine on human liver alfentanil metabolism. Anesthesiology 1991; 75: 5204. 138 Aho M, Erkola O, Kallio A, Scheinin H, Korttila K. Dexmedetomidine infusion for maintenance of anesthesia in patients undergoing abdominal hysterectomy. Anesthesia and Analgesia 1992; 75: 9406. 139 Scheinin B, Lindgren I, Randell T, Scheinin H, Scheinin M. Dexmedetomidine attenuates sympathoadrenal responses to tracheal intubation and reduces the need for thiopentone and perioperative fentanyl. British Journal of Anaesthesia 1992; 68: 12631. 140 Paalzow L. Analgesia produced by clonidine in mice and rats. Journal of Pharmacy and Pharmacology 1974; 26: 3613. 141 Fields HL, Basbaum AI. Brainstem control of spinal neurones. Annual Review of Physiology 1978; 40: 21748. 142 Mayer DJ, Liebskind JC. Pain reduction by focal electrical stimulation of the brain: an anatomical and behavioral analysis. Brain Research 1974; 68: 7393. 143 Marwaha J, Kehne JH, Commissaris RL, Lakoski J, Shaw W, Davis M. Spinal clonidine inhibits neural ring in locus coeruleus. Brain Research 1983; 276: 37982. 144 Alojado ES, Ohta Y, Kemmotsu O. The effect of clonidine on the activity of neurons in the rat dorsal raphe nucleus in vitro. Anesthesia and Analgesia 1994; 79: 25760. 145 Jones SL, Gebhart GF. Characterization of coeruleus inhibition of the nociceptive tail-ick reex in the rat: mediation by spinal 2-adrenoreceptor. Brain Research 1986; 364: 31530. 146 Howe JR, Wan J-Y, Yaksh TL. Selective antagonism of the antinociceptive effect of intrathecally applied alpha adrenergic agonists by intrathecal prazosin and intrathecal yohimbine. Journal of Pharmacology and Experimental Therapeutics 1983; 224: 5528.
162
147 Kuraishi Y, Hirota N, Sato Y, Kaneko S, Satoh M, Takagi H. Noradrenergic inhibition of the release of substance P from primary afferents in rabbits spinal dorsal horn. Brain Research 1985; 359: 17782. 148 Murata K, Nakagawe I, Kumeta Y, Kitahata LM, Collins JG. Intrathecal clonidine suppresses noxiously evoked activity of spinal wide dynamic range neurons in cats. Anesthesia and Analgesia 1989; 69: 18591. 149 Bouaziz H, Hewitt C, Eisenach JC. Subarachnoid neostigmine potentiation of alpha, 2-adrenergic agonist analgesia. Regional Anesthesia 1995; 20: 1217. 150 Klimscha W, Tong C, Eisenach JC. Intrathecal a2-adrenergic agonists stimulate acetylcholine and norepinephrine release from the spinal cord dorsal horn in sheep. An in vivo microdialysis study. Anesthesiology 1997; 87: 11016. 151 Eisenach J, Detweiler D, Hood D. Hemodynamic and analgesic actions of epidurally administered clonidine. Anesthesiology 1993; 78: 27787. 152 Post C, Gordh T, Milnor BG, Archer T, Freedman J. Antinociceptive effects and spinal cord tissue concentrations after intrathecal guanfacine or clonidine into rats. Anesthesia and Analgesia 1987; 66: 31724. 153 Eisenach JC, Tong C. Site of hemodynamic effects of intrathecal a2-adrenergic agonists. Anesthesiology 1991; 74: 76671. 154 Coote JH. The organisation of cardiovascular neurons in the spinal cord. Review of Physiology, Biochemistry and Pharmacology 1988; 110: 148277. 155 Castro MI, Eisenach JC. Pharmacokinetics and dynamics of intravenous, intrathecal, and epidural clonidine in sheep. Anesthesiology 1989; 71: 41825. 156 Gordh T Jr Epidural clonidine for treatment of postoperative pain after thoracotomy. A double-blind placebo-controlled study. Acta Anaesthesiologica Scandinavica 1988; 32: 7029. 157 Priddle HD, Andros GJ. Primary spinal anesthetic effects of epinephrine. Anesthesia and Analgesia 1950; 29: 15661. 158 Bernard JM, Hommeril JL, Passuti N, Pinaud M. Postoperative analgesia by intravenous clonidine. Anesthesiology 1991; 75: 57782. 159 Aho M, Erkola O, Scheinin H, Lehtinen AM, Korttila K. Effect of intravenously administered dexmedetomidine on pain after laparoscopic tubal ligation. Anesthesia and Analgesia 1991; 73: 11218. 160 Tamsen A, Gordh T. Epidural clonidine produces analgesia. Lancet 1984; 2: 2312. 161 Bonnet F, Boico O, Rostaing S et al. Postoperative analgesia with extradural clonidine. British Journal of Anaesthesia 1989; 63: 4659. 162 Rockermann MG, Seeling W, Brinkmann A et al. Analgesic and hemodynamic effects of epidural clonidine, clonidine/morphine, and morphine after pancreatic surgery. Anesthesia and Analgesia 1995; 80: 86974. 163 Anzai Y, Nishikawa T. Thoracic epidural clonidine and morphine for postoperative pain relief. Canadian Journal of Anaesthesia 1995; 42: 2927.
164 Cigarini I, Kaba A, Bonnet F et al. Epidural clonidine combined with bupivacaine for analgesia in labor. Regional Anesthesia 1995; 20: 11320. 165 Eisenach JC, Lysak SZ, Vkiscomin CM. Epidural clonidine following surgery; phase I. Anesthesiology 1989; 71: 6406. 166 Rostaing S, Bonnet F, Levron J, Vodinh J, Pluskwa F, Saada M. Effect of epidural clonidine on analgesia and pharmacokinetics of epidural fentanyl in postoperative patients. Anesthesiology 1991; 75: 4205. 167 Bernard JM, Kick O, Bonnet F. Comparison of intravenous and epidural clonidine for postoperative patient-controlled analgesia. Anesthesia and Analgesia 1995; 81: 70612. 168 Coombs DW, Saunders RL, Lachance D. Intrathecal morphine tolerance. Use of intrathecal clonidine, DADLE, and intraventricular morphine. Anesthesiology 1985; 62: 35863. 169 Klimscha W, Chiari A, Krafft P et al. Hemodynamic and analgesic effects of clonidine added repetitively to continuous epidural and spinal blocks. Anesthesia and Analgesia 1995; 80: 3227. 170 Grace D, Bunting H, Milligan KR, Fee JPH. Postoperative analgesia after co-administration of clonidine and morphine by the intrathecal route in patients undergoing hip replacement. Anesthesia and Analgesia 1995; 80: 8691. 171 Racle JP, Benkhadra A, Poy JY, Gleizal B. Prolongation of isobaric bupivacaine spinal anesthesia with epinephrine and clonidine for hip surgery in the elderly. Anesthesia and Analgesia 1987; 66: 4426. 172 Filos KS, Goudas LC, Patroni O, Polyzou V. Intrathecal clonidine as a sole analgesic for pain relief after Cesarean section. Anesthesiology 1992; 77: 26774. 173 Gordh T, Post C, Olsson Y. Evaluation of the toxicity of subarachnoid clonidine, guanfacine and a substance P antagonist on rat spinal cord and nerve roots. Anesthesia and Analgesia 1986; 65: 130311. 174 Fukushima K, Nishimi Y, Mori K, Takeda J. Central effect of epidurally administered dexmedetomidine on sympathetic activity and postoperative pain in man (abstract). Anesthesia and Analgesia 1996; 82: S121. 175 Puke MJC, Wiesenfeld-Hallin Z. The differential effects of morphine and the a2-adrenoceptor agonists clonidine and dexmedetomidine on the prevention and treatment of experimental neuropathic pain. Anesthesia and Analgesia 1993; 77: 1049. 176 Yaksh TL, Pogrel JW, Lee YW, Chaplan SR. Reversal of nerve ligation-induced allodynia by spinal alpha-2 adrenoceptor agonists. Journal of Pharmacology and Experimental Therapeutics 1995; 272: 20714. 177 Leiphart JW, Cynthia V, Dills BS et al. A comparison of intrathecally administered narcotic and non-narcotic analgesics for experimental chronic neuropathic pain. Journal of Neurosurgery 1995; 82: 5959. 178 Lee YW, Yaksh TL. Analysis of drug interaction between intrathecal clonidine and MK-801 in peripheral
163
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
neuropathic pain rat model. Anesthesiology 1995; 82: 7418. Glynn C, OSullivan K. A double-blind randomised comparison of the effects of epidural clonidine, lignocaine and the combination of clonidine and lignocaine in patients with chronic pain. Pain 1995; 64: 33743. Carroll D, Jadad A, King V, Wiffen P, Glynn C, McQuay H. Single dose, randomized, double-blind, doubledummy cross-over comparison of extradural and; i.v. clonidine in chronic pain. British Journal of Anaesthesia 1993; 71: 6659. Byas-Smith MG, Max MB, Muir J, Kingman A. Transdermal clonidine compared to placebo in painful diabetic neuropathy using a two stage enriched enrolment design. Pain 1995; 60: 26774. Eisenach JC, Rauck RL, Buzzanell C, Lysak SZ. Epidural clonidine analgesia for intractable cancer pain: phase, 1. Anesthesiology 1989; 71: 64752. Eisenach JC, DuPen S, Dubois N, Miguel R, Allin D. Epidural clonidine analgesia for intractable cancer pain. Pain 1995; 61: 3919. Davies KD, Treede RD, Raja SN, Meyer RA, Campbell JN. Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain. Pain 1991; 47: 30917. Liepert DM, Townsend GE. Improved hemodynamic and renal function with clonidine in coronary artery bypass grafting. Anesthesia and Analgesia 1990; 70: S1S450. Kulka PJ, Tryba M, Menzel C, Leurs F, Frankenberg C. Preoperative clonidine improves postoperative renal function in CABG patients. British Journal of Anaesthesia 1993; 70 (Suppl. 1): A143. Bay J, Nunn JG, Prys-Roberts C. Factors inuencing arterial PO2 during recovery from anaesthesia. British Journal of Anaesthesia 1968; 40: 398406. Macintyre PE, Pavlin EG, Dwersteg JF. Effect of meperidine on oxygen consumption, carbon dioxide production, and respiratory gas exchange in postanaesthesia shivering. Anesthesia and Analgesia 1987; 66: 7515. Flacke JW, Flacke WE. Inadvertent hypothermia: frequent, insidious, and often serious. Seminars in Anesthesia 1983; 2: 18396. Gufn A, Girard D, Kaplan JA. Shivering following cardiac surgery: hemodynamic changes and reversal. Journal of Cardiothoracic Anesthesia 1987; 1: 248. Delaunay L, Bonnet F, Duvaldestin P. Clonidine decreases postoperative oxygen consumption in patients recovering from general anaesthesia. British Journal of Anaesthesia 1991; 67: 397401. Goldfarb G, Ang ET, Debaene B, Khon S, Jolis P. Effect of clonidine on postoperative shivering in man: a double blind study. Anesthesiology 1989; 71: A650. Schmelling WT, Kampine JP, Warltier DC. Dexmedetomidine attenuates the shivering upon emergence from halothane anesthesia in chronically instrumented cats. Anesthesia and Analgesia 1992; 74: S264.
194 Ghignone M, Noe C, Calvillo O, Quintin L. Anesthesia for ophthalmic surgery in elderly; the effects of clonidine on intraocular pressure, perioperative hemodynamics and anesthetic requirement. Anesthesiology 1988; 68: 70716. 195 Krieglstein GK, Langham ME, Leydhecker W. The peripheral and central neural, actions of clonidine in normal and glaucomatous eyes. Investigative Ophthalmology and Visual Science 1978; 17: 14958. 196 Virkilla M, Ali-Melkkila T, Kanto J, Turunen J, Scheinin H. Dexmedetomidine as intramuscular premedication in outpatient cataract surgery. Anaesthesia 1993; 48: 4827. 197 Clarke KW, Hall LW. Xylazine a new sedative for horses and cattle. Veterinary Record 1969; 85: 51217. 198 Hsu WH. Xylazine induced depression and its antagonism by alpha-adrenergic blocking agents. Journal of Pharmacology and Experimental Therapeutics 1981; 218: 18892. 199 Haskins SC, Peiffer RL Jr, Stowe RM. A clinical comparison of CT 1341, ketamine, and xylazine in cats. American Journal of Veterinary Research 1975; 36: 153743. 200 Clarke KW, Taylor PM. Detomidine: A new sedative for horses. Equine Veterinary Journal 1986; 18: 36670. 201 Scheinin M, MacDonald E. An introduction to the pharmacology of a2 adrenoceptors in the central nervous system. Acta Veterinaria Scandinavica 1989; 85: 1119. 202 Barnett AJ, Cantor S. Observations on the hypotensive action of Catapres (St 155) in man. Medical Journal of Australia 1968; 1: 8791. 203 Hermiller JB, Margorien RD, Leithe ME, Unverferth DV, Leier CV. Clonidine in congestive heart failure: a vasodilator drug with negative inotropic effects. American Journal of Cardiology 1983; 51: 7915. 204 Foresti A, Massari FM, Lotto A. Hemodynamic effects of clonidine in patients with acute myocardial infarction complicated by hypertension. Journal of Cardiovascular Pharmacology 1986; 8 (Suppl. 3): S302. 205 Redmond DE Jr, Huang YH. The primate locus coeruleus and effects of clonidine on opiate withdrawal. Journal of Clinical Psychiatry 1982; 43: 259. 206 Gold MS, Pottash AL, Sweeney DR, Kleber HD. Efcacy of clonidine in opiate withdrawal: a study of thirty patients. Drug and Alcohol Dependence 1980; 6: 2018. 207 Ashton H. Benzodiazepine withdrawal. Outcome in 50 patients. British Journal of Addiction 1987; 82: 66571. 208 Cushman P Jr, Sowers JR. Alcohol withdrawal syndrome: clinical and hormonal responses to a2-adrenergic treatment. Alcoholism 1989; 13: 3614. 209 Davison R, Kaplan K, Fintel D, Parker M, Anderson L, Haring O. The effect of clonidine and the cessation of cigarette smoking. Clinical Pharmacology and Therapeutics 1988; 44: 2657. 210 Glassman AH, Jackson WK, Walsh BT et al. Cigarette craving, smoking withdrawal, and clonidine. Science 1984; 226: 8646.
164
211 Pearce KI. Clonidine and smoking. Lancet 1986; I: 810. 212 Zubenko GS, Cohen BM, Lipinski JF, Jonas JM. Clonidine in the treatment of mania and mixed bipolar disorder. American Journal of Psychiatry 1984; 141: 161718. 213 Hunt RB, Minderaa RB, Cohen DJ. Clonidine benets children with attention decit disorder and hyperactivity. Report of double-blind placebo-crossover therapeutic
trial. Journal of the American Academy of Child and Adolescent Psychiatry 1985; 24: 61729. 214 Jerussi TP, Capacchione JF, Benvenga MJ. Reversal of opioid-induced muscle rigidity in rats. Evidence for a-2-adrenergic involvement. Pharmacology, Biochemistry and Behavior 1987; 28: 2839. 215 Bylund DB. Heterogeneity of a2 adrenergic receptors. Pharmacology, Biochemistry and Behavior 1985; 22: 83543.
165

Alfa2 Su Fisio

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Alfa2 Su Fisio

Uploaded by

Copyright:

Available Formats

Anaesthesia, 1999, 54, pages 146165 ................................................................................................................................................................................................................................................

Alpha-2 and imidazoline receptor agonists

Their pharmacology and

Table 1 Imidazoline receptor agonists in order of preference for imidazoline receptor.

Figure 2 The chemical structure of imidazoline agonists

moxonidine and rilmenidine.

Table 2 Selective and nonselective alpha-2 adrenoceptor agonists

in order of preference for alpha-2 adrenoceptor.

gonists in order of preference for alpha-2 adrenoceptor.

Figure 3 The chemical structure of alpha-2 adrenoceptor

agonists clonidine, dexmedetomidine and mivazerol.

1999 Blackwell Science Ltd

Therapeutic role in anaesthesia

1999 Blackwell Science Ltd

1999 Blackwell Science Ltd

1999 Blackwell Science Ltd

1999 Blackwell Science Ltd

1999 Blackwell Science Ltd

1999 Blackwell Science Ltd

1999 Blackwell Science Ltd

1999 Blackwell Science Ltd

You might also like