Alpha 2 review horses

Br. vet../. (1996). 152, 641

R E V I E W

AI ,PHA2 A D R E N O C E P T O R A G O N I S T S I N T H E H O R S E - -

A R E V I E W

G. C. W. ENGIAND and K. W. CLARKE

l)epar/mep~l (!f l:arm Animal and Equine Medicine and Su~ge~3,, Rm, al Vete~na~ 3' Colh, ffe, I rniversiO' q/l.ondon, North Mymms, Ha(field, Her(/brdshire AI.9 773, UK

SUMMARY

In recent >,ears the usefulness of the alpha._, adrenoceptor agonist drugs has been recognized in equine practice. Several agents have become available and are now licensed for use in a number of countries. The principle actions of all alpha._, adrenoceptor agonists are similar, in that they produce a reduction in heart rate and alteration of heart rhythm, an initial hypertension followed by a prolonged hypotension, a decrease in the cardiac output and respirato D, depression. For clinical purposes, these agents produce sedation and analgesia, they are useful for premedication and markedly potentiate the effects of other sedative/analgesic agents. Differ- ences in receptor specificity between the alpha,_, adrenoceptor agonists results in the distinguishing characteristics of the individual agents, particularly with respect to their duration of action, sedative effect and analgesic properties; their cardiopulmona D, effects are however similar, when equipotent sedative closes are administered. When used in combination with other agents, the alpha,_, adrenoceptor agonists all appear to act in a similar manner, with the greatest difference being related to their duration of action.

I,h~,xwom)s: Alpha,_,-adrenoceptor; horse; sedation; premedication.

INTRODUCTION

The alpha~ adrenoceptor agonist drugs have found wide acceptance in equine veterina W practice since they offer some of the advantages required by an ideal sedative agent. The), do however have several disadvantages including cardiovascular and respirato D' depression, and ataxia. The aim of the following paper is to dis, cuss the pharmacoloD, of alpha._, adrenoceptor agonists, and {o review those specifically licensed for clinical use in the horse.

0007-1935/96/060641-17/$12.00/0 © 1996 Bailli6re Tindall

642 BRITISH \:ETERINARY JOURNAl,, 152, 6

ALPHA,., ADRENERGIC RECEPTORS

Adrenoceptors were initially classified into alpha mad beta by Ahlquist in 1948. This classification was based upon a series of natural and swlthetic agonists in a range of isolated tissues. Thus, noradrenaline and alpha-methyl-noradrenaline caused activation of smooth muscle, contraction of the vas deferens and uterine stimulation, whilst adrenaline, isoprenaline and alpha-methyl-adrenaline had the opposite effects. Ahlquist (1948) suggested that the opposing responses evoked by this range of agonists occurred by actions on two different populations of receptors. Those receptors stimulated by noradrenaline and alpha-methyl-noradrenaline were described as alpha adrenergic receptors, and those responding to adrenaline, isoprenaline and alpha-methyl-adrenaline were denoted as beta adrenergic receptors. Subsequently beta adrenoceptors were subdivided into beta~ and beta,_, subtypes on the basis of beta agonist activi~, on b,-onchodilation, vasodepression and cardiac stimulation (Lands el al., 1977). A need to classiC' alpha adrenocep- t o r s further was noted on anatomical grounds, when alpha adrenoceptors were demonstrated on nerve varicocities (Langer el al., 1977; Starke el al., 1977). How- ever, an anatomical division alone was insufficient and a nulnher of agonists and antagonists were subsequently developed to distinguish between the prejunctional alpha,_, adrenoceptors and postjunctional alphal adrenoceptors (reviewed by Timmermans & van Zwieten, 1982).

The di~dsion between alpha~ and alpha,_, adrenoceptors is now made on the basis of their sensitivity to specific agonist and antagonist agents. Adrenaline and noradrenaline are nonspecific in their actions, and affect both alpha~ and alpha,_, adrenoceptors. For alpha~ adrenoceptors, phenylephrine and methoxamine are considered to be relatively specific agonists, and prazosin a specific antagonist. Clonidine, xylazine, detomidine, medetomidine and romifidine are considered to be agonistic at the alpha., adrenoceptors, and atipamezole, yohimbine and idazoxan are considered to be specific antagonists at these receptors (Scheinin & Macdonald, 1989).

The selectivity of agonists and antagonists for alpha adrenoceptors is given in Table I. Altlaough these drugs are said to act specifically at the receptors, specificity is not ahvays absolute, and when doses are increased, some effects at other alpha receptors may occur.

Table I The selectivity of various agonists and antagonists for alpha adrenoceptors

Receptor h'pe Agonist A ntagonist

Alpha~ and alpha,_, Adrenaline Tolazoline Noradrenaline Phentolamine

Alphal Phenylephrine Prazosin Methoxamine Corynanthine

Alpha,_, Clonidine Yohimbine Xylazine Idazoxan

Detomidine Atipamezole Medetomidine

Romifidine

ALPHA.., AGONISTS IN THE HORSE 643

There are a variety of drugs that are clinically available which have an action at the alpha,, adrenoceptor. These comprise the agonists: xylazine, detomidine, medetomidine (licensed only for use in small animals), i-omifidine and clonidine (available for use in man), and the antagonists of which only atipamezole and yohimbine are widely used. The parasiticide drug ami t r~ also has alpha adrenergic activity and may produce sedation, but is not included in this review.

CLINICAL APPLICATION OF ALPHA,_, ADRENERGIC DRUGS

In veterinary practice there are a variety of clinical indications for the use of alpha, adrenergic agonists. Specifically they may be used for sedation, analgesia and premedication. The sedative actions appear to be due to depression of the locus coeruleus neurons in the pons of the lower brain stem (Svensson et aL, 1975; Cedarl)aum & Aghajaian, 1976), reducing arousal (Stenburg, 1989). Scheinin el aL (1987) found that in man alpha~ adrenergic agonists cause a dose-dependent sedative effect, with associated impairment of vigilance. Low doses of certain alpha~ adrenergic agonists have been shown to have anxiolytic properties similar to those of the benzodiazepines (Macdonald et al., 1989), probably mediated by similar modification of serotonergic pathways (Scheinin & Macdonald, 1989). These properties may also be important when attempting to control fractious or fiightened animals. The alpha,_, adrenergic agonists provide analgesia through spinal and central actions (Hall & Clarke, 1991). Nilsfors et al. (1989) demonstrated that higher doses of alpha~ adrenergic agonists were required to provide analgesia than were needed to produce sedation. However, it is often difficult to distinguish between sedative and analgesic effects.

Alphae adrenergic agonists are particularly useful as premedicants for general anaesthesia, where the sedative effects are an integral part of the whole anaesthetic process. By controlling the emotional effects of anaesthetic induction, premedication can reduce the release of catecholamines and therefore smooth both the induction and the maintenance of anaesthesia. Alpha,_, adrenergic agonists also have marked anaesthetic sparing effects both for the induction and maintenance of anaesthesia. A marked synergistic effect has been reported following the administration of alpha., adrenergic agonists with opioid agents (Klein, 1975; Short, 1992). This work suggested synergism rather than summation of drug effects; this has also been observed for other anaesthetic agents, including barbitu- rates and non barbitnrates such as propofol (England et al., 1994; Hammond & England, 1994). The alpha,_, adrenergic agonists are also useful when combined with ketamine since they can eliminate the muscular hypertonicity caused by the dissociative agent, whilst the decrease in heart rate and cardiac output induced by the alpha~ adrenergic agonists are moderated by the sympathomimetic action of ketamine. Alpha,, adrenergic agonists have been shown to reduce the dose requirement for volatile anaesthetic agents; Segal et al. (1989) showed an alphaz adrenoceptor mediated dose-dependent reduction of halothane minimal alveolar concentrations (MAC) and a reduction of up to 90% for halothane MAC has been demonstrated (Vickery et al., 1988). Perioperative management may also be improved when alpha,_, adrenergic agonists combinations are used for anaesthesia.

644 BRITISH VETERINARY JOURNAL, 152, 6

The potential for a rapid recovery from anaesthesia is possible by reversing the sedative using specific alpha,, adrenergic antagonists, provided that post-operative sedation and alpha,, induced analgesia are not required.

Both xylazine and detomidine have been administered via the epidural route to provide regional analgesia without locomotor dysfunction (Gomez de Segua et al., 1993). High doses may however have a local analgesic effect and cause ataxia and recumbency (Skarda, 1990).

EFFECTS OF ALPHA~ ADRENOCEPTOR AGONISTS IN THE HORSE

Several alpha., adrenergic agonists have been used for experimental and clinical studies in the horse. Mally studies have concentrated solely upon one agent and comparisons between different alpha., adrenergic agonists are scant. In the following re~4ew, physiological data are compared for approximately equi-sedative doses of the alpha2 adrenergic agonists.

Hea)7 rate a n d r h y t h m The administration of clonidine, xylazine, detomidine, medetomidine or romif

idine to horses produces a profound bradycardia even at low rates (Clarke & Hall, 1969; Kerr et al., 1972; Jochle, 1984; Win~er et al., 1985; Clarke, 1988; Poulsen Nautrup, 1988; Bryant, 1992). Heart rate rapidly declines, usually within 1 rain following intravenous administration of all the drugs. The complex meclaanisms by which alpha2 adrenergic agonist drugs exert these effects have been previously dis- cussed, and it appears that in most instances the effects are dose related. The actual reduction in heart rate may be similar fi~r all alpha._, adrenergic agonists used in the horse, although Clarke (1988) and England et al. (1992) showed that xylazine (1 mg kg -1) had the least effect and the shortest dm'ation of action upon heart rate when compared with approximately equisedative doses of detolnidine (20 lagkg -l) or romifidine (80 lagkg-~). The bradycardia is conamonly accompanied by heart block, most frequelatly atrio-ventricular, although it may be sino-atrial, and both forms may be seen in the same animal (McCashin & Gabel, 1975; Vainio, 1985; Clarke & Taylor, 1986; Clarke, 1988; Voetgli, 1988). In most animals, following all alpha,_, adrenergic agonists, the heart block is most intense in the first few minutes after injection, after which time heart rate gradually increases and the heart block disappears (Clarke, 1988). Bradycardia and heart block per- sist longer following the administration of romifidine than xylazine or detomidine (England et al., 1992), and a dose-dependent trend has been reported (Gasthuys et al., 1990).

There has been considerable debate over the significance of these arrthythlnias, especially since both second-degree atrio-ventricular block, and more rarely sino-atrial block, may occur in the normal horse (Smetzer el al., 1969; Fregin, 1982). Although pretreatment with atropine has been shown to prevent the second degree heart block caused by xylazine in the horse (Kerr et al., 1972), this is unreliable with detomidine (Alitalo et al., 1986; Short et al., 1986b). The use of atropine is controversial (Hall & Clarke, 1983), although recently its use has been suggested before the administration of romifidine (Gasthuys et aL, 1990). These

ALI~I-IAe AGONISTS IN THE HORSE 645

workers showed that the positive chronotropic effect of" atropine was attenuated by increasing dosages of romifidine and there were no adverse effects or alterations in the sedative eftiects of romifidine. Despite this work, {he use of anticholinergic agents prior to alpha,_, adrenergic agonists remains controversial (Hall & Clarke, 1991). Anticholinergic administration may lead to large increases in arterial blood pressure, by blocking the compensatory sino-atrial vagal reflex mechanism (Bergstrom, 1988); indeed this has been observed when atropine administration preceded the use of romifidine in horses (Young el al., 1994).

One further effect of alpha,_, adrenergic agonists is their potential for increasing the sensitivity of the heart to adrenaline-induced arrhythmias. This effect has been demonstrated following the use of xylazine in the dog (Muir el al., 1975) and, although results in the horse are not consistent (Muir, 1981; Steffey et aL, 1985), Saarinen (1986) suggested that arrhythmias were responsible for death in some animals anaesthetized following premedication with detomidine.

A r t e r i a l blood pre s sure The intravenous administration of clonidine, xylazine, detomidine, medetonaid-

ine or romifidine to horses all produce an initial transient hypertension (depending upon the dose administered), followed by a prolonged but mild reduction in blood presstire (hypotension) (Garner et al., 1971; Wintzer et al., 1985; Vainio, 1985; Savola, 1986; Clarke, 1988; Voegtli, 1988; Bryant, 1992). There have however been some conflicting reports of this effect (Short el al., 1984; Poulsen Nautrup, 1988), although this is likely to be due to the experimental methodology, rather than true pharmacological differences.

The hypertension occurs very rapidly, usually within 2 and 10 rain of administration (Poulsen Nautrup, 1988; Biwant, 1999), and mean arterial presstlres as high as 200 mmHg have been reported with most of the alpha._, adrenergic agonists. Voegtli (1988) showed that, at least for romifidine, the peak hypertensive period was also related to dose; relatively low doses (30 ~lg kg -~) produced a hypertensive peak within 1 rain, whilst high doses (120 p.g kg -I) did not produce the maximal hypertensive effect until 20 rain after administration. Similar dose dependent effects have been showed fbr other alpha<_, adrenergic agonists, and it is well documented that the hypertensive response may be absent following intramuscu- lar administration (Clarke & Hall, 1969; Kerr el al., 197-9; McCashin & Gabel, 1975). In several studies, the .length and the duration of the hypertensive phase was found to be related to the dose of the alpha,, adrenergic agonist administered (Vainio, 1985; Clarke, 1988; Sarazan et al., 1989). Vainio (1985) showed that with very high doses of detomidine (300~lgkg -l) produced only a hypertensive response, although the duration of the study was limited. A period of hypotension follows the hypertension phase. Hypotension occurs even at veD~ low drug doses. The duration of the hypotensive phase is unknown; it has not been established even for low doses of alpha,_, adrenergic agonists as most studies have ceased when sedation wears off. It would be interesting to establish whether the p ro longed hypertension induced by high doses of alpha,_, adrenergic agonists was followed by prolonged hypotension. There are few studies in which the changes in blood presstlre induced by different alpha,_, adrenergic agonist agents have been compared (Wagner et al., 1991; Scrollavezza & Zanichelli, 1993). In these studies, and

646 BRITISH VETERINARY .|OURNAL, 152, 6

others when mean arterial pressure changes are considered as a percentage fi'om the presentation value, the effects produced by different alpha,_, adrenergic agonists appear similar. Bryant (1992) however tbund that the hypotension following medetomidine was not as great as the effect of equipotent sedative doses of detomidine noted by Clarke (1988).

Cardiac ou tpu t The intravenous administration of xylazine to horses produces a significant

reduction in the cardiac output and a decrease of up to 40% has been demonstrated (Kerr et al., 1972; Muir et al., 1979b). Tiffs occurs rapidly following adnfinis- tration, and is followed by a slow return to normal (Clarke & Hall, 1969; Wagner el al., 1991), although Kerr et al. (1972) recorded cardiac outputs that were still markedly below baseline values 60 min after the administration of xylazine. There are few published studies of cardiac output in the horse following the use of other alpha._, adrenergic agonists (Daunt et aL, 1993). Bryant (1992) studied the effect of two different doses of medetonaidine, and found a similar decline in cardiac output to that seen by other workers studying the effects of xylazine. Medetomidine produced a significant reduction in both cardiac output and stroke vohnne; the maximal effect occurred 5 rain after medetomidine administration (Bryant, 1992). This researcher also noted that the point when cardiac output was maxi- mally reduced coincided with the peak hypertensive phase, when pulse pressure was also high. The decrease in cardiac output is probably the result of bradycardia, reduced filling pressure and a reduced stroke volume; since cardiac output decreases whilst arterial blood pressure increases, this suggests that the hypertension is mediated peripherally (Bryant, 1992). Wagner et al. (1991) showed that both the cardiac output and the cardiac index was reduced after the administration of both detomidine and xylazine. There are no studies which report cardiac output in horses following the administration of romifidine.

Respirator3, effects There is no doubt that all the alpha., adrenergic agonists cause some respiratory.

depression (]ones & Young, 1991), although there are no reports comparing the respiratory effects of different agents. Analysis of data from individual trials however demonstrates that the effects are similar following the administration of all alpha,_, adrenergic agonists.

Variable effects of clonidine have been observed on respiratory rate (Wintzer et al., 1985), and Garner et al. (1971) reported that xylazine initially caused rapid and superficial breathing, that gradually changed to slow deep breathing. Kerr et al. (1972) suggested that xylazine produced no significant effect upon respiratory rate, tidal flow or pulmonary ventilation, whilst McCashin and Gabel (1975) found a statistically significant reduction in respiratory rate. Several workers have demonstrated an initial decrease in respiratory rate following the administration of detomidine (Vainio, 1985; Reitmeyer et aL, 1986). Some studies found a rapid periodic respiratory pattern (Vainio, 1985; Short el al., 1984, 1986a), although this was not seen by Clarke (1988), using lower dosages. Rapid shallowing breathing has also been reported in clinical cases following sedation with detomidine; this phenom- enon appears m be self limiting (Clarke & Gerring, 1991).

ALPHA.., AGONISTS IN THE HORSE 647

Poulsen Nautrup (1988) observed a decline in the respiratory rate of horses administered low doses of romifidine. However variable effects were noted when higher romifidine doses were administered (Poulsen Nautrup, 1988; Voegtli, 1988). These dose related effects appear to be similar to those noted following administration of different doses of detomidine.

A degree of upper respiratory tract obstruction is occasionally identified in horses when there is considerable lowering of the head during sedation. These horses have inspiratory upper respiratory tract noise ('snoring') which may be due to laryngeal relaxation (Reitmeyer el al., 1986), although it probably arises from the nasal meatus (Clarke, 1988). This effect has been noted following most alpha2 adrenergic agonists but especially xylazine (Hall & Clarke, 1983; Clarke, 1988; Bryant, 1992).

Arter ia l blood gases Arterial blood gas concentrations may be altered following the administration

of alpha._, adrenergic agonists. The magnitude of these effects differs somewhat between studies, although this may be related to both the dose of the alpha,_, adrenergic agonist administered as well as the methodolog T of the study.

Muir el al. (1979b) showed that, whilst xylazine caused a small reduction in arterial oxygen concentration and rise in arterial carbon dioxide concentration, the changes were not statistically significant. Similar results were found by Garner el al. (1971) and Kerr et aL (1972). Vainio (1985) and Short et al. (1986a) found only slight reductions in arterial oxygen concentration following the administration of detomidine. However, Clarke (1988) found that there was a significant reduction in arterial oxygen concentration and rise in arterial carbon dioxide concentration 5 min after the administration detomidine. The changes in both arterial oxygen and carbon dioxide, in absolute terms, were relatively small.

Poulsen Nautrup (1988) and Clarke el aL (1991) demonstrated that the effects of romifidine were similar to those reported following the administration of other alpha._, adrenergic agonists. There was a slight but significant decrease in arterial oxygen concentration and an increase in arterial carbon dioxide concentration. Both Poulsen Nautrup (1988) and Voegtli (1988) showed that arterial oxygen concentrations had returned to baseline values 30-40 min after romifidine administration.

There are few studies which have compared the magnitude of {hese effects when different alpha,_, adrenergic agonists are used. Clarke (1988) compared the effects of xylazine and two different doses of detomidine. This researcher found that there was no significant difference in the effects produced by each of the three regimens on both arterial oxygen and carbon dioxide concentrations. Low doses of detomidine produced similar changes to xylazine, but the effects were not significant, when compared with control values.

Sedat ive effects The sedative effects of the alpha., adrenergic agonists in horses were first dem-

onstrated by Clarke and Hall (1969), using xylazine. The behavioural events are similar for horses administered any of the alpha., adrenergic agonists, and include an initial appearance of apprehension followed by lowering of the head, drooping

648 BRITISH \~ETERINARY JOURNAL 152, 6

of the eyelids and lower lip. Horses rapidly b eco m e ataxic and in males there is somet imes relaxation o f the penis. T h e r e is generally a r educed awareness of the envi ronment , a l thongh a response may occur to st imulation snch as noise or touch. For all drugs the onset of sedation is slower following intralnuscular administration.

For xylazine, the maximal effect is no ted within 5 rain, and lasts for 15-60 rain after intravenous administrat ion, d e p e n d i n g upon the dose administrat ion. Tron icke and Vocke (1970) found that sedation was good or excel lent in more than 90% of clinical cases, a l though in the r ema inde r of horses fu r ther chemical or physical restraint was required.

Several workers have investigated the effects of de tomidine . Th e behavionral changes were simila,- to those seen tbllowing xylazine. The sedative effects were no ted within 2 rain after intravenous administrat ion (Clarke, 1988), and lasted for 30-200 rain depend ing upon dose (Vainio, 1985; Clarke, 1988). Th e early studies of the sedative effects of de tomid ine are slightly confused by the ve D, high dosages used by some studies. Vainio (1985) used three high doses of de tomid ine , and showed a sedative effect that was not significantly different between the three doses adminis tered. Harem a n d J o c h l e (1984) and Jochle and Harem (1986) per- fo rmed dose - response studies on the effects o f de tomid ine as a sedative agent. They found that the effect was dose related up to a maximal point, after which increasing the dose fin ' ther only increased the dura t ion of the effect. Xylazine produced an apparent ly equal degree of sedation 1or a short per iod of time. Attempts have been made to score the degree of sedation, and Clarke (1988) p ro d u ced an arbitrary, scoring schedule for appa ren t sedation, the response to imposed stimuli, and the degree of ataxia. Clarke (1988) showed that the int ravenous administration of xylazine and de tomid ine was similar in the scored sedation responses. The degree o f ataxia p r o d u c e d by xylazine was more severe but of shor ter duration than that p roduced by de tomidine . Using slightly di f ferent dosages Dyson el

al. (1987) showed that the sedative effect of de tomid ine was grea ter than that of xylazine.

BD, ant et al. (1991a, b) c o m p a r e d the effects of two doses of m ed e to m id in e with those of xylazine in a similar study to that of Clarke (1988), and found that medetomidine p r o d u c e d sedation which was, over the two doses adminis tered, dose related and sinfilar to that p roduced by xylazine administrat ion. Higher doses produced a more reliable effect. Lowering of the head was not significantly di f ferent following all three regimens. Mede tomid ine at equi-sedative doses to xylazine produced grea ter and more p ro longed ataxia, and in some cases horses fell. For this reason m e d e t o m i d i n e is not r e c o m m e n d e d for use in horses, and is only l icensed in small animals.

The sedative effects of romif idine have also been examined (Poulsen Nautrup, 1988; Poulsen Naut rup & Keller, 1989; Kannegieter , 1993). Voegtli (1988) found dose related sedative effect for horses adminis tered romifidine. Th e highest doses also p r oduc ed a p ro longed sedative effect. Th e sedative effects of three alpha., adrenergic agonists were c o m p a r e d by England el al. (1992). These workers compared two doses o f romif idine, two doses of de tomid ine and xylazine, and found that the romif idine p roduced lowering of the head that was related to dose, a l though this did not occur to the same degree as following de tomid ine or xylaz-

ALPHA., AGONISTS IN THE HORSE 649

ine. Similarly the degree of ataxia was less severe following romifidine, although this was similar to the lower doses of detornidine. There appears to be a phase of residual sedation fbllowing romifidine administrat ion(Poulsen Nautrup, 1988; England et aL, 1992). More recently, Hamm et aL (1995) found that whilst both detomidine and romifidine produced reliable sedation, detomidine produced a deeper sedation of longer duration, with greater lowering of the head. Further- more they suggested that there was more evidence for a dose-related effect with detomidine than romifidine.

It has been well recognized that whilst horses administered most alpha2 adrenergic agonists may appear to be well sedated, they may respond following stimulation (Clarke & Hall, 1969; Clarke & Taylor, 1986; Voegtli, 1988; Bryant, 1992; England el aL, 1992), especially to touch (Tronicke & Vocke, 1970; Alitalo, 1986). This response may be important clinically and has been seen following the administration of all alpha._, adrenergic agonists that are used in veterinary practice.

A n a l g e s i c effect It is notoriously difficult to assess the degree of analgesia in animals. Exper-

imentally a variety of pain models have been used in attempt to evaluate this factor (Kerr et al., 1972; Pippi & Lumb, 1979; Vainio, 1985); despite these models considerable variation in results has been observed. For the clinical assessment of pain relief, subjective scores are often applied to minor clinical procedures.

Conflicting claims have been made as to the duration of analgesia, and the degree of analgesia induced by xylazine (Hoffman, 1974; MacKenzie & Snow, 1977; Pippi & Lumb, 1979; Kalpravidh et al., 1984). The variation in these reports may be related to the fact that different types of pain will respond to different analgesic drugs (Nolan et al., 1986). Xylazine is excellent for preventing pain of equine colic (Lowe, 1978; Pippi & Lumb, 1979; Kalpravidh et al., 1984), although it is possible that at least some of this effect may be related to the reduction of gut motility.

Detomidine produces a prolonged and intense analgesia which is related to dose (~ochle & Harem, 1986; Kamerling et al., 1988b). The nature of the analgesic effect appears to be wide; with detomidine producing a reduced response to experimental stimulation and producing a clinical response in the horse with colic (Lowe & Hilfiger, 1984, 1986;Jochle, 1990). There are no studies of the effects of medetomidine as an analgesic agent in the horse, although this effect has been well demonstrated in other species (Stenberg, 1989; Ylisela & Vainio, 1989). There have been limited studies of the analgesic effect of romifidine in the horse. Poulsen Nautrup (1988) assessed the response to clinical stimulation and found that this was diminished following romifidine in a dose related manner. However, Voegtli (1988) undertook an experimental study where the analgesic action was assessed and found that there appeared to be some analgesic effect, although this was not dose-related or consistent in its response; and he concluded that the analgesic effect was not great. Scrollavezza and Zanichelli (1993) in a clinical comparative study, showed that analgesia was difficult to measure, but found that both romifidine and detomidine were similar in their effects, although in an experimental comparative study H a m m e t al. (1995) found that romifidine was devoid of any analgesic activity. There has been some use of alpha2 adrenergic agonists in

650 BRITISH \rETERINARY .JOURNAL, 152, 6

spinal anaesthesia (Nelson et al., 1979; Waterman et aL, 1988), and although these techniques may be useful in the horse (Grubb et al., 1991; Skarda & Muir, 1994) they are not widely used.

Other effects A variety of other effects have been noted in the horse following the adminis-

tration of most alpha,_, adrenergic agonists, but these do not appear to differ significantly between agents. A dose dependent hyperglycaemia has been noted following xylazine (Thurmon et al., 1982), detomidine (Gasthuys et al., 1987; Clarke, 1988), and romifidine (Voegtli, 1988; Gasthuys et al., 1993), and elevated concentrations of glucose in urine have been noted in some but not all studies (Short et al., 1986a; Gasthuys et al., 1993). Most of the alpha,_, adrenergic agonists produce diuresis of a similar degree and duration (England et al., 1992). This effect was originally considered to be an osmotic diuresis resulting fi'om elevated blood glucose concentrations, and whilst this may be true, it is also likely mediated by an inhibition of anti-diuretic hormone (Reid et al., 1979).

It is not uncommon for body temperature to vary following the administration of alpha2 adrenergic agonists; in most cases temperature decreases (Poulsen Nautrup, 1988), although high doses of detomidine have been shown to produce a late onset hyperthermia (Kamerling et al., 1988a). Increased uterine pressure has been demonstrated to a similar degree in mares following the administration ofxylazine, detomidine and romifidine (Schatzmann et al., 1994).

Other minor effects such as sweating, muscle tremor, increased salivation, snoring or snorting, reduction in gut motility and penile protrusion have been noted with similar frequency following xylazine, detomidine and romifidine (Vainio, 1985; Clarke, 1988; England et al., 1992). Urticarial skin reactions have been noted in our clinic following the administration of both detomidine and romifidine; these are self limiting and require no treatment. Vet-), occasionally, the administration of alpha,, adrenergic agonists to 'working' stallions produces protrusion of the penis and the emission of semen. This effect is not repeatable within an indi~4dual and does not appear to be dose related (England, unpub- lished observations).

CLINICAL USE OF ALPHA,, ADRENERGIC AGONISTS IN THE HORSE

Sole agen t s A number of studies have evaluated the effectiveness of xylazine, detomidine

and romifidine for a variety of clinical procedures. These have demonstrated that all agents are useful in the clinical situation (McCashin & Gabel, 1975; Hoffman, 1974; Clarke & Taylor, 1986; Clarke, 1988; Clarke & Gerring, 1991; Harem &

Jochle, 1991; Kannegieter, 1993; Keller & Genzow, 1994), although there may be differences in the degree of sedation, analgesia and duration of action. These differences in action may influence which specific agent a veterinary surgeon may choose to administer to a particular case. For example, the short duration of action of xylazine may be useful in certain circumstances, the longer duration of detomidine in others, and the reduced lowering of the head and reduced ataxia

ALPHA2 AGONISTS IN THE HORSE 651

induced by romifidine may be useful in others. For very fractious animaIs and for certain clinical procedures, the use of an alpha,_, adrenergic agonist alone may not be sufficient.

C o m b i n a t i o n s w i th other agen ts Horses sedated with all alpha,, adrenergic agonists may suddenly respond to

stimulation, especially touch (Clarke & Hall, 1969; Clarke & Taylor, 1986; Voegtli, 1988; Bryant, 1992; England et al., 1992). This response may be dangerous both to the veterinary surgeon and the animal. The combination of opioid drugs with the alpha,_, adrenergic agonists appears to reduce this response (Muir et al., 1979a; Robertson & Muir, 1983; Nolan & Hall, 1984; Taylor, 1985; Paton & Clarke, 1986; Taylor el al., 1990). Of the opioid drugs that have been used, butorphanol tartrate has proved to be effective (Robertson & Muir, 1983; Clarke & Paton, 1988; Taylor el al., 1988; Clarke et al., 1991; Browning & Collins, 1994), and is convenient to use, as it is not subject to such stringent controls as some of the other agents. The commonly used dose of butorphanol has minimal effects upon the cardiovascular system (Robertson & Muir, 1983), and when combined with detomidine or romifidine, does not alter the cardiovascular parameters beyond the changes induced by the alpha,_, adrenergic agonist alone, although there may be a slight further respiratory depression (Clarke & Paton, 1988; Clarke et al., 1991). Some horses may walk for~vards compulsively and exhibit slight muscle twitching following these combinations (Browning & Collins, 1994): these traits are attributed to the opioid com- ponent. There are no comparisons between the sedative and cardiopulmonary effects of combinations of different alpha,_, adrenergic agonists with different opioids. Clinically, it would appear, however, there are few differences other than duration of action and the degree of ataxia between these combinations.

P r e m e d i c a t i o n The ability of alpha._, adrenergic agonists to calm and quieten patients may be

useful for premedication prior to the induction of general anaesthesia. In general, alpha,_, adrenergic agonists allow a smooth induction of anaesthesia, and have marked anaesthetic sparing effects both for induction and maintenance of anaesthesia. Xylazine has been used widely and successfully as a premedicant to several agents in the horse (Keller & Muller, 1969; McCashin & Gable, 1975). Clarke and Gerring (1991) in a study of over 1000 horses showed that detomidine was safe for premedication of the horse, and both detomidine and romifidine appear to be equally suitable (Saarinen, 1986; Short et al., 1986a; Paulsen Nautrup, 1988; Bennett et al., 1993; Diamond et al., 1993). There appears to be few differences between the character of anaesthesia when different alpha,_, adrenergic agonists are used as premedicants. Generally, alpha2 adrenergic agonists produce relaxation and allow a smooth induction and recovery from anaesthesia. It would appear that romifidine offers advantages over both xylazine and detomidine in that its longer duration of action often ensures an excitement free recovery (Diamond et al., 1993). Recently, Kerr et al. (1994b) suggested that romifidine/ ketamine anaesthesia was at least as safe and probably safer than xylazine/ ketamine anaesthesia, from the cardiopulmonary point of view. In a similar study, comparing romifidine and xylazine as premedicants to diazepam/ketamine anaes-

652 BRITISH VETERINARY .JOURNAl.. 152, 6

thesia, Kerr et aL (1994a) found that romif id ine p remed ica t i on l e n g t h e n e d the anaes thet ic per iod a l though there were no dif ferences in the recove D, fl-om anaesthesia. T h e r e are however no studies which have investigated the dura t ion of the hypotensive phase, and the deg ree to which muscle and organ perfl tsion are r educed following alpha,_, adrenerg ic agonists p r emed ica t i on to ha lo thane anaesthesia. This effect should be cons idered fbr anaesthet ics of long dura t ion .

C O N C L U S I O N

Alpha,_, adrenerg ic agonists are c o m m o n l y used in equ ine clinical pract ice for purposes of sedat ion, the provision of analgesia (e i ther a lone or c o m h i n e d with opioid agents) and p remedica t ion . The agents most conamonh ' available include xylazine, d e t o m i d i n e and romif idine. T h e pharmaco log ica l activity of these agents is similar, althougla some di f ferences in their activity, may he the result o f differences in selectivity tbr various receptors . The carc l iopuhnonarv effects o f these agents are similar, when equ ipo ten t sedative doses are adminis te red , and the main di f ference between agents is in the dura t ion of action. T h e r e are some di f ferences in the sedative and analgesic effects o f these c o m p o u n d s that may direct a veterinary surgeon towards choos ing one c o m p o u n d over o thers for a par t icular clinical p rocedure . In general , h igher doses of all three agents p roduces g rea te r and m o r e reliable sedat ion ttp to a m a x i m u m effect. Increas ing the dose beyond that which gives this effect simply increases the dura t ion of action. When used in comhi- nat ion with o the r anaes thet ic agents, xvlazine, d e t o m i d i n e and romif id ine a p p e a r to act in a similar m a n n e r , althougla the d i f ferences of dura t ion of action may he significant when they are used as part o f an anaes the t ic regime.

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(A cceptedJbr publication 3 November 1999")

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