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A RATIONAL APPROACH TO THE USE OF DRUGS FOR SEDATION AND RESTRAINT OF THE LARGER MAMMALS
A RATIONAL APPROACH TO THE USE OF DRUGS FOR SEDATION AND RESTRAINT OFTHE LARGER M A M M A L S David M. Jones B.Sc., B.Vet.Med., M.R.C.V.S. Zoological Society of London Whipsnade Park
Introduction: The taxonomists of the last century principally utilised the variations in the anatomical structure of animals to determine their zoological relationships with each other. If we had to solve the same problems today, there are many physiological phenomena discovered more recently which would help us to confirm such a classification. To anybody who regularly uses sedative and narcotic drugs on a variety of mammals, it quickly becomes evident, even without much prior zoological knowledge, which species are related. Conversely a Veterinary Surgeon who knows a little of the Orders and Families of mammals should have no difficulty in choosing between Phencyclidine or Etorphine for the immobilisation for example of a Tapir (Tapirus spp.). The Tapirs (Tapiridae) have common ancestors with the Horses (Equidae) which react much more favourably to Etorphine than Phencyclidine. It would be reasonable to assume that this was also the case with the Tapirs and clinical trials confirm this (Jones, D.M. 1972, Hime, J.M. 1972). This paper is not intended to be a comprehensive list of dose rates of the various drugs suitable for mammals. Such information is already available in print elsewhere (Jones, D.M. 1972, Banditz, R. 1972, Seal, U.S., Erickson, A.W., Mayo, J.G. 1970, Janssen Pharmaceutica 1969, Reckitt and Colman Limited 1969). The primary intention is to illustrate that a basic understanding of the clinical pharmacology of the available drugs and a little knowledge of the classification of mammals improves the ability to select the most suitable drugs for a particular species and occasion.
The horse and its relatives: Acepromazine maleate at a low dose rate of 0.05 mg/kg usually produces a state of tranquility in a tractable domestic horse (Equus caballus). Increasing the dose rate to 0.3 mg/kg may produce sedation with slight ataxia (Pugh, D.M. 1964). A handreared, quiet Zebra (Equus burchelli) would react in the same way, but in a wild individual of either species, there may be no appreciable effect. Increasing the dose rate of Acepromazine further will not improve the situation as regards sedation and adverse side-effects on blood pressure and body temperature may be induced. Temperament is therefore an important factor in the choice of sedatives and in deciding on the optimum dose rates. This variation in effect also applies to Xylazine which has been used as a sedative in horses although this group are not nearly as sensitive to the drug as the ruminants (Clarke, K.W. and Hall, L.W. 1969). Where a fractious animal is involved, complete immobilisation may become necessary. Opinions vary as to the efficacy and safety of using narcotics in horses. The ctlmmobiIon)) mixture of Etorphine Hydrochloride and Acepromazine has received a varied reception in clinical practice. (Jones, D.M., Manton, V.J.A. 1970, Stockman, M.J.R.
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1970, Adams, A.J. 1970, Mitchell, R.J. 1970, Whiteley, H. 1970, Cullen, C.J. 1970; Hillidge, C.J. 1970). The greatest advantage of utilising this type of combination is that the effect is partly reversible and the animal is usually able to rise to its feet quickly. Unfortunately, the excitatory effects, of the narcotic are often more apparent than the central depressant effects, especially in the larger breeds such as hunters, arabs and thoroughbreds. These effects are manifest by struggling, sweating and severe dyspnoea. They are sometimes caused by underdosing and if so can be partly relieved by giving in addition, half the initial dose by rapid intravenous injection. The other members of the horse family tend to react more favourably to this riiixture. The Przewalski Horse (Equus przewalski) which is the most closely related to the domestic species behaves in a similar way to the pony breeds. Excitement is occasionally seen in some individuals but these side-effects are not a common feature of the species. The Zebras (Equus burchelli, E..grevyi and E. zebra) and the Asses (Equus asinus and E. hemionus) are more sensitive to Etorphine and only demonstrate serious excitation very rarely. These require half the dose rate needed for the horses. Because the depressant effects are more marked than the excitatory effects with Etorphine, these species can be caught without the addition of Acepromazine although for examination of the animal in recumbency, the addition of this sedative does improve the degree of relaxation. Occasionally, residual sedation is seen in Equidae following the administration of the ((Mn series antidotes Cyprenorphine and Diprenorphine. This tends to follow a short period during which the animal is initially fairly active, but often takes the form of a more gradual recovery from deep narcosis. At the present time, it is not known whether this is caused by the sedative, the ((antidote))or the original narcotic which may be recycling. The same effect is more consistently seen in the White Rhinoceros (Diceros simus) but it is unusual in the Black (0.bicornis) or Great Indian (Rhinoceros unicornis) species in the authors experience. The effect still occurs even when Acepromazine is not combined with Etorphine. This tends to eliminate the sedative as a possible cause. Diprenorphine when used alone, exerts some depressant activity, but it also tends to cause emesis in the White Rhinoceros. Keep (Keep, M.E. 1970) has reported that Nalorphine reverses the effects of Etorphine more completely than the ((MNseries antidotes in this species, but this has not been the case at Whipsnade. The Rhinocerosesare remarkably sensitive to Etorphine. As little as 3 mgm of the drug will completely immobilise a 2000 kilogram White Rhinoceros (Harthoorn, A.M. 1967). As was implied earlier, the Tapirs (Tapiridas) possess a similar sensitivity to Etorphine as the Equidae and their responses to this drug are also similar. Although the nineteenth century taxonomist has placed them in a separate Order, pharmacologically, the Elephants (Proboscidea)fall into the same group as the horses and rhinos. The African species (Loxodonta africana) in particular has a similar sensitivity to a mixture of Etorphine and Acepromazine as the African Rhinos (King, J.M. 1969, Pienaar, U de V 1966). However without any known reason, the Indian Elephant (Elephas maximum) like the Indian Rhinoceros (Rhinoceros unicornis) requires twice the dose rate needed to achieve a similar affect in its African relative. (Jones, D.M. 1972, Gray,C.W., Nettasinghe,A.P.W. 1967).
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Ruminants: Although a combination of Etorphine and Acepromazine (usually the ctlmmobiIon)) combination) is used extensively to immobilise both domestic and wild ruminants, excitatory side-effects leading to hyperthermia and dyspnoea are often seen. Besides the undesirability of this for safety reasons, these make handling difficult. The main advantage of using Etorphine or Fentanyl, another potent narcotic with similar properties, is that its effects are partly reversible. The degree of excitement noted with the ((Immobilon))combination varies considerably from one group of ruminants to another. Excitation is rare in the Wildebeests and Hartebeests (Alcelaphinae). On the whole the Deer (Cervidae), Sheep and Goats (Caprinae) show mild excitatory signs but still remain handleable. The Cattle (Bovinae) and most of the Antelopes (Tragelaphinae, Reduncinae, Hippotraginae and Antilopinae) tend to show a degree of excitement which may be acceptable purely for rapid capture but which often makes clinical examination extremely difficult. It would appear that the problem partly lies with the sedative or neuroleptic which is usually combined with the narcotic. The narcotic principally exerts a depressant effect on the Wildebeests and their relatives. This means that a sedative is usually unnecessary in these cases. In the second group, the Deer (Cervidae) and the Sheep (Caprinae), the addition of Acepromazine or Azaperone to the narcotic usually improves the degree of immobility. The intensity of excitement in the other groups is such that both the Promazines and the Butyrophenones, even at high dose rates, are ineffective for the purposesof clinicalexamination. If Xylazine is used in the combination instead of Acepromazine or Azaperone, the excitement is reduced considerably or even abolished. Tractable, domestic ruminants can be sedated and completely immobilised using Xylazine alone (Clarke et al. 1969). If recumbency is induced, the animal tends to remain on its brisket and regurgitation rarely occurs. Muscular relaxation is marked at the level of deep sedation. Cardiovascular and respiratory effects are of little clinical significance. These features tend to make Xylazine the drug of choice for ruminants at the present time. There are however two major disadvantages. The drug is not reversible and the dose rate required to produce a given effect is dependant on the temperament of the animal. A nervous or aggressive bullock may require up to 30 times as much Xylazine to produce a similar effect in a placid dairy cow of the same weight. Many of the so called ((speciesdifferences))reported in the literature (Bauditz, P. 1972) were almost certainly due to individual differences in the tractability of the animals concerned. Under the same conditions of management, a wide variety of ruminants with a similar temperament will require the same dose rates of Xylazine to produce a similar effect. Handreared individuals will require much less than closely related animals which have never been handled. This is not to say that species variation does not exist. Musk Ox (Ovibos moschatus), despite their a.ggressive nature, seem to require consistently lower dose rates than equally nervous antelope such as Oryx (Oryx tao) or Roan (Hippotragus equinus) (Kooi, P. 1971, Hime, J.M., Jones, D.M. 1970). Where very large dose rates of Xylazine are required it often becomes impractical to use a projectile syringe because the missile would need to be far too large to fly any distance. When Xylazine is combined with Etorphine its effects become more consistent. The dose rate of Xylazine for this combination does not alter as much with variations in temperament and in all cases it is relatively low (0.3-0.5 mg/kg). A considerably reduced volume of solution is then feasible (Jones, D.M. 1971). As both Etorphine and Xylazine are powerful respiratory depressants, the therapeutic index of
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the mixture is not high and care must be taken to assess the doses accurately. Problems with the votume would also be encountered if Ketamine became widely used for ruminants. Although it has been used in Sheep (Taylor, P., Hopkins, Lynda, Young Maureen, McFadyen, I.R. 1972) there are no records yet of its extensive use in wild ruminants. Its older relative Phencyclidine is still used occasionally in these species but the therapeutic index is much lower, the effect is more prolonged and there is a tendency for regurgitation to occur. In addition, excitation has been noted during the recovery phase with Phencyclidine, adding to the dangers of using this drug (Manton, V.J.A. 1962-1966).
Pigs and hippopotami: Amongst the larger mammals, this group is the most difficult to restrain efficiently and safely. Azaperone produces a state of tranquillity at 1.0 mg/kg in the domestic pig (Sus scrofa) which as the dose increases to 3 mg/kg usually leads to immobilisation (Marsboom, R. and Symoens, J. 1968, Symoens, J., Van den Brande, M. 1969). These effects are more consistent in the pig than those produced by the promazine derivatives and there is no appreciable action on body temperature or blood pressure. Doses of Azaperone up to 15 mg/kg have had no appreciable effect on Collared Peccaries (Tayassu tajacu) or Wild Boar (Sus scrofa) at Whipsnade, probably because they are far more aggressive and nervous than their domestic relatives. Mixtures of Fentanyl and Azaperone or Etorphine and Acepromazine have been used on wild Warthogs (Phacochoerus aethiopicus). Pienaar reports a useful effect with the former combination but the latter has produced excitement, shock and death on occasions (Pienaar, U. de V. 1968). Similar effects have been noted with Etorphine and Acepromazine (as ctlmmobilon))) in the domestic pig. Pigs are very susceptible to shock and the promazine derivates tend to exacerbate the resultant temperature and blood pressure changes. The Butyrophenone derivatives ((protect)) against these effects to some extent and this may explain the more favourable results with these drugs. In Pigs and Hippopotami intravenous injection is difficult and a rapid reversal of narcosis cannot therefore be guaranteed. This adds to the problems of using these mixtures in this group. The Hippopotami (Hippopotamu's amphibius) and (Choeropsis liberiensis) react very similarly to the pigs under the influence of these drugs. There is often considerableexcitement, with salivation and hyperthermia. If the animal has access to water there is also a serious risk of it drowning (Pienaar U. de V. 1968).The risk is still present when Phencyclidine is used. Phencyclidine though has a more consistent action in Hippopotami and Pigs than the mixtures of a narcotic and sedative, but it is not reversible. It was withdrawn from general use after the finding that residues of the drug remained in the tissues even if sedation had taken place some days prior to slaughter. It is however a relatively useful drug if the subject is not to be used for human consumption but it has disadvantages. The induction and recovery phases are often accompanied by excitement and total recovery may be prolonged to as much as 48 hours. Acepromazine is usually added, but this does not seem to control the excitement totally.
The Carnivora: The Dogs (Canidae), Bears (Ursidae), Cats (Felidae)and the Racoons and their relatives (Procyonidae) can all be sedated with Xylazine (Bauditz, R. 1972). The
side-effects are minimal, but the dose rates are often so high that the resultant volume is usually impractical to administer except to the relatively small species. As in the other groups discussed, temperament will also affect the dose required. More predictable in this respect are Phencyclidine and Ketamine; Phencyclidine has more significant side-effects but Ketamine is available at such a low concentration that the administration of large volumes is once again a problem. Ketamine has only recently been released for general use and it has therefore not been used yet as extensively as Phencyclidine. Nevertheless, it is becoming evident that Ketamine has a number of notable advantages over the older cyclohexamine (Hime, J.M. 1972). The degree of excitement is considerably reduced especially in the Felidae where intense spasmodic contractions of the limb and neck muscles are a common feature with Phencyclidine. In addition the animal loses its aggression and begins to relax long before it becomes completely immobile. Recovery is much more rapid with Ketamine than with Phencyclidine. Usually these drugs are combined with a sedative such as Promazine which tends to counteract to some extent any excitation produced. The initial salivation which occurs sometimes in Felids and Procyonids can be counteracted by premedicating with Atropine. Phencyclidine particularly has a tendency to recycle and is not readily excreted from the body. The drug is therefore contraindicated in ageing and debilitated animals, particularly those with liver or kidney disease. Prolonged recumbency in such cases produces the additional problems of disturbed fluid balance, lowered blood glucose levels and a falling body temperature. A mixture of the steroids Alphaxalone and Alphadolone marketed under the name ((Saffan)) has recently been introduced for use primarly in the domestic cat (Felis catus) (Evans, J.M., Aspinall, K.W., Hendy, P.G. 1972). Its principal advantages are that it is short acting, produces marked relaxation and does not recycle. The sedative effect is most predictable when ((Saffannis given intravenously, for although the drug is absorbed from muscle, special care must be exercised to ensure that the needle penentrates into this tissue and does not deliver the drug into connective fascia. As the action of the drug is very short, inaccurate injection would lead to poor absorption and metabolism of the drug before it could produce a useful effect. This is not a practical drug to use for the larger wild cats unless they can be physically restrained first for hand injection. Even then, relatively large volumes would have to be used and this might prove impractical. The narcotics are contraindicated in the cat family on account of their severe excitatory effects. Mixtures of neuroleptics with narcotics are useful for other families in this group, mainly because a relatively rapid recovery can be produced. Bears and Dogs are sensitive to relatively small doses of Etorphine or Fentanyl (Lasen, T. 1966, Blane, G.F., Brown, A.L.A., Dobbs, H.E. 1968, Marsboom, R., Verstraete, A. Thienpont, D., Mathews, D. 19641. The dogs tend to show some excitement during induction but this can be reduced considerably by combining the narcotic with Promazine, Azaperone or Methotrimeprazine. The therapeutic indices of these mixtures are not high in this group and even an increase of 50 % in the optimum dose rate often produces respiratory depression. In Bears, marked residual sedation regularly occurs after the ((antidoten is given though there seems to be some individual variation in this respect. Recent trials suggest that this sedation is due to the sedative and not the narcotic (Jones 1973).
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Primates: Three cyclohexamines are regularly used for the restraint of primates. The oldest of the group, Phencyclidine is being replaced gradually by Tiletamine and Ketamine mainly because of the shorter recovery time experienced with these latter drugs. All three produce a state of dissociative anaesthesia and with the lower dose ranges it is possible to handle animals safely even though they may still be relatively mobile. A state of indifference without aggression or flight is seen. With Phencyclidine in particular, mild excitement occasionally occurs during the induction phase, but this is usually counteracted by combining Promazine in the initial injection. Athetoid movements are also occasionally seen with Tiletamine and Ketamine even during light anaesthesia but these are not of much practical significance as they can be overcome by deepening anaesthesia with shortacting barbiturates. Primates are more sensitive to Phencyclidine than to the other two drugs. With all three of these agents there is some variation in the dose rate required by different species of the Order to achieve the same effect. Most primates require about 1.O mg/kg of Phencyclidine to produce light anaesthesia but the same effect can be achieved with half this dose in the great apes (Seal et al. 1970, Chen and Weston 1960). Bree (1972) reported that even within the genus Macaca there were significant differences in sensitivity to Tiletamine at dose rates of from 3 to 6 mg/kg. Primates can be immobilised with Xylazine (Hime and Jones 1970) and there do not seem to be any significant side-effects. However, marked individual variation is found in the dose rate required and this is presumably due to the differences in the temperament of individual animals. The steroid mixture of Alphaxolone and Alphadolone has been found to be effective in small primates at the same dose rates as those required for the domestic cat (Brancker 1973). This is 9 mg per kg. It is almost always necessary to give the initial injection intramuscularly in these animals. Unlike the other drugs mentioned in this section it is essential that this mixture is absorbed rapidly. To achieve any significant effect the drugs must be injected into muscle and not fascia or subcutaneous tissues. Some workers prefer to use mixtures of narcotics and sedatives for handling these species despite the fact that intense excitement is occasionally produced by Morphine like substances. Although a mixture of Etorphine and Promazine or Methotrimeprazine has been used, the most widely accepted combination is that of Fentanyl and Droperidol (Marsboom, Mortelmans, Vercruysse 1963, Field, Yelnosky, Mundy, Mitchell 1966). The dose of Droperidol remained at 1.0 mg/kg but it was found that anthropoid apes were more sensitive than other species to Fentanyl (0,02mg/kg sufficient for apes, while 0.04 mg/kg was required for other species). Slight bradycardia usually occurs and some respiratory depression may be seen when the higher dose rates are used. The degree of analgesia produced is profound. Reversal of the effect is achieved with Nalorphine although spontaneous recovery will occur after 2-4 hours. Because the narcotic is absorbed very rapidly from mucous membranes, oral administration is a practical proposition with this combination.
Summary: During the last decade, a number of drugs have become available which, when used separately, or when combined with another have facilitated the handling and movement of nervous or aggressive animals. These drugs are usually grouped accord-
ing to their principal properties into narcotics, such as Etorphine and Fentanyl, sedatives such as Azaperone and Xylazine and anaesthetics such as Phencyclidine and Alphaxalone. This is a somewhat loose terminology as the properties of a number of these agents when used at different dose rates or in different species may place them into more than one of these groups. Knowledge of the clinical pharmacology of these drugs and of the different responses found amongst the various orders of mammals is necessary if the effect required is to be accurately and safely obtained. Narcotics for instance are contraindicated in the Felidae on account of their severe excitatory side-effects but in some carnivore families the milder side-effects can be overcome by combining the narcotic with a sedative. This paper sets out to describe these different effects and to show that an understanding of them is important when selecting the appropriate drugs for a particular case.
References
1. Adams, A.J. (1970). The Use of Immobilon. Vet. Record 87,560. 2. Bauditz, R. (1972). Sedation, lmmobilisation and Anaesthesia with Rompun in Captive and Free living Wild Animals. Vet. Med. Rev. 314,204.
3. Blane, G.F., Brown,A.L.A., Dobbs, H.E. (1968). Neuroleptanalgesia in the dog caused by the interaction of Etorphine with Methotrimeprazine. J. Physiol. 196,26. 4. Brancker, M. (1973). Personal communication/unpublished.
5. Bree, M.M. (1972). Clinical evaluation of Tiletamine as an anaesthetic in non human Primate species J.A.V.M.A. 161, No.6,693. 6. Chen,G.M., Weston, J.K. (1960). The analgesic and anaesthetic effect of 14 1 -Phenylcyclohexyl)Piperadine HCI on the Monkey. Anaesthesia and Analgesia. 39, No. 2, 132.
7. Clarke, K.W., Hall, L.W. (1969). (TXylazine))- A New Sedative for Horses and Cattle. V%t. Record 85,512. 8. Cullen, C.J. (1970). The Use of Immobilon. Vet. Record 87,669. 9. Evans, J.M., Aspinall, K.W., Hendy, P.G. (1972). Clinical evaluation in cats of a new anaesthetic CT. 1341. J. Sm. An. Prac. 13,479.
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10. Field, W.E., Yelnosky, J. Mundy, J., Mitchell, J. (1966). The Use of Droperidol and Fentanyl for Analgesia and Sedation in Primates. J.A.V.M.A.149,No.7,896. 11. Gray, C.W., Nettasinghe,A.P.W. (1967). A Preliminary study on the immobilisation of the Asiatic Eleljhant (Elephas maximus) utilising Etorphine (M. 99). Report of Nat. Zool. Park, Smithsonian Institute, Washington, p. 51. 12. Harthoorn, A.M. (1967). Comparative pharmacological reactions of wild and domestic mammals to Thebaine derivatives in the ct M Nseries of compounds. Fed. Proc. 26,1251. 13. Hillidge, C.J. (1970). The Use of Immobilon. Vet. Record 87,669. 14. Hime, J.M., Jones, D.M. (1970). The Use of Xylazine in Captive Wild Animals. Proc. Int. Symp. on Diseases in Zoo Animals. Budapest, p. 143. 15. Hime, J.M. (1972). Unpublished.
16. Janssen Pharmaceutica (1969). lmmobilisation and Restraint of large wild mammals with Azaperoneand Fentanyl. Booklet published by company. 17. Jones, D.M., Manton,V.J.A. (1970). ((The Use of Immobilon)). Vet. Record 87,701. 18. Jones, D.M. (1971). The lmmobilisation of Cattle and related species. Vet. Record 89,174. 19. Jones, D.M. (1972). The Use of Drugs for the Immobilisation, Capture and Translocation of Nondomestic animals. Vet. Annual, 320.
20. Jones, D.M. (1973). Unpublished paper. 21. Keep, M.E. (1970). Personal communication. 22. King, J.M. (1969). The capture and translocation of the Black Rhinoceros. E. Afr. W. Journal7,115.
23. Koci, P. (1971). Practical results with the application of BAY Va 1470 10 % (Rompun) for the imrnobilisation of Hippotragus equinus. Veterinarstvi21,565. 24. Larsen T. (1966). The trapping and study of polar bears. Spitsbergen Polar Record, 13,(86),587.
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25. Manton, V.J.A. (1962-1966). Unpublished.
26. Marsboom, R., Mortelmans, J., Vercruysse, J. (1963). Neuroleptanalgesia in Monkeys. Vet. Record75, No. 6, 132. 27. Marsboom, R., Verstraete, A., Thienpont, D., Mathews, D. (1964). The Use of Haloanisone and Fentanyl for Neuroleptanalgesiain Dogs. Brit. Vet. J. 120,466. 28. Marsboom, R., Symoens, J. (1968). Experiences with Azaperone, a sedative for pigs. Tijdschr. diergeneesk. 93,3. 29. Mitchell, R.J. (1970). The Use of lmmobilon Vet. Record 81,600. 30. Pienaar, U. de V. (1966). The use of oripavine hydrochloride (M. 99) in the drug immobilisation and marking of wild African Elephant (Loxodonta africana Blumenbeck) in the Kruger National Park. Koedoe, 9,108. 31. Pienaar U. de V. (1968). Recent advances in the field lmmobilisation of and restraint of wild ungulates in South African National Parks. Acta Zoologica et Path. Ant. verpiensis, 46,17. 32. Pugh, D.M. (1964). Acepromazine in Veterinary Use. Vet. Record, 76,439. 33. Reckitt and Colman Limited (1969). series in game immobilisation Booklet published by company. The c t M ~ 34. Seal, U.S., Erickson, A.W., Mayo, J.G. (1970). Drug immobilisation of the Carnivora. Int. Zoo Yearbook, 10,157. 35. Stockman, M.J.R. (1970) ((The Use of Immobilon)). Vet. Record, 87,518. 36. Symoens, J., Van den Brande, M. (1969). Prevention and cure of aggressiveness in pigs using the Sedative Azaperone Vet. Record, 8564. 37. Taylor, P.; Hopkins, Lynda; Young, Maureen; McFadyen, I.R. (1972). Ketamine anaesthesia in the Pregnant Sheep. Vet. Record, 90,35. 38. Whiteley, H. (1970). The Use of Immobilon. Vet. Record, 87,637.
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Drugs mentioned in the Text Drug Name
Trade Name
M. 99 or Etorphine M. 5050 or Diprenorphine M. 285 or Cyprenorphine Etorphine + Acepromazine Etorphine + Methotrimeprazine Nalorphine Azaperone Fentanyl + Droperidol Xylazine Acepromazine maleate Alphaxolone and Alphadolone Phencyclidine Tiletamine Ketamine
Reckitt and Colman Reckitt and Colman Reckitt and Colman Large Animal lmmobilon Reckitt and Colman Small Animal lmmobilon Reckitt and Colman Lethidrone Burroughs Wellcome Suicalm Crown/Janssen Hypnorm Janssen Rompun Bayer Acetylpromazine Boots Saffan Glaxo Sernylan Phillips Roxane Parke Davis KetalarNetalar Parke Davis Revivon
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Manufacturer
Introduction: The taxonomists of the last century principally utilised the variations in the anatomical structure of animals to determine their zoological relationships with each other. If we had to solve the same problems today, there are many physiological phenomena discovered more recently which would help us to confirm such a classification. To anybody who regularly uses sedative and narcotic drugs on a variety of mammals, it quickly becomes evident, even without much prior zoological knowledge, which species are related. Conversely a Veterinary Surgeon who knows a little of the Orders and Families of mammals should have no difficulty in choosing between Phencyclidine or Etorphine for the immobilisation for example of a Tapir (Tapirus spp.). The Tapirs (Tapiridae) have common ancestors with the Horses (Equidae) which react much more favourably to Etorphine than Phencyclidine. It would be reasonable to assume that this was also the case with the Tapirs and clinical trials confirm this (Jones, D.M. 1972, Hime, J.M. 1972). This paper is not intended to be a comprehensive list of dose rates of the various drugs suitable for mammals. Such information is already available in print elsewhere (Jones, D.M. 1972, Banditz, R. 1972, Seal, U.S., Erickson, A.W., Mayo, J.G. 1970, Janssen Pharmaceutica 1969, Reckitt and Colman Limited 1969). The primary intention is to illustrate that a basic understanding of the clinical pharmacology of the available drugs and a little knowledge of the classification of mammals improves the ability to select the most suitable drugs for a particular species and occasion.
The horse and its relatives: Acepromazine maleate at a low dose rate of 0.05 mg/kg usually produces a state of tranquility in a tractable domestic horse (Equus caballus). Increasing the dose rate to 0.3 mg/kg may produce sedation with slight ataxia (Pugh, D.M. 1964). A handreared, quiet Zebra (Equus burchelli) would react in the same way, but in a wild individual of either species, there may be no appreciable effect. Increasing the dose rate of Acepromazine further will not improve the situation as regards sedation and adverse side-effects on blood pressure and body temperature may be induced. Temperament is therefore an important factor in the choice of sedatives and in deciding on the optimum dose rates. This variation in effect also applies to Xylazine which has been used as a sedative in horses although this group are not nearly as sensitive to the drug as the ruminants (Clarke, K.W. and Hall, L.W. 1969). Where a fractious animal is involved, complete immobilisation may become necessary. Opinions vary as to the efficacy and safety of using narcotics in horses. The ctlmmobiIon)) mixture of Etorphine Hydrochloride and Acepromazine has received a varied reception in clinical practice. (Jones, D.M., Manton, V.J.A. 1970, Stockman, M.J.R.
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1970, Adams, A.J. 1970, Mitchell, R.J. 1970, Whiteley, H. 1970, Cullen, C.J. 1970; Hillidge, C.J. 1970). The greatest advantage of utilising this type of combination is that the effect is partly reversible and the animal is usually able to rise to its feet quickly. Unfortunately, the excitatory effects, of the narcotic are often more apparent than the central depressant effects, especially in the larger breeds such as hunters, arabs and thoroughbreds. These effects are manifest by struggling, sweating and severe dyspnoea. They are sometimes caused by underdosing and if so can be partly relieved by giving in addition, half the initial dose by rapid intravenous injection. The other members of the horse family tend to react more favourably to this riiixture. The Przewalski Horse (Equus przewalski) which is the most closely related to the domestic species behaves in a similar way to the pony breeds. Excitement is occasionally seen in some individuals but these side-effects are not a common feature of the species. The Zebras (Equus burchelli, E..grevyi and E. zebra) and the Asses (Equus asinus and E. hemionus) are more sensitive to Etorphine and only demonstrate serious excitation very rarely. These require half the dose rate needed for the horses. Because the depressant effects are more marked than the excitatory effects with Etorphine, these species can be caught without the addition of Acepromazine although for examination of the animal in recumbency, the addition of this sedative does improve the degree of relaxation. Occasionally, residual sedation is seen in Equidae following the administration of the ((Mn series antidotes Cyprenorphine and Diprenorphine. This tends to follow a short period during which the animal is initially fairly active, but often takes the form of a more gradual recovery from deep narcosis. At the present time, it is not known whether this is caused by the sedative, the ((antidote))or the original narcotic which may be recycling. The same effect is more consistently seen in the White Rhinoceros (Diceros simus) but it is unusual in the Black (0.bicornis) or Great Indian (Rhinoceros unicornis) species in the authors experience. The effect still occurs even when Acepromazine is not combined with Etorphine. This tends to eliminate the sedative as a possible cause. Diprenorphine when used alone, exerts some depressant activity, but it also tends to cause emesis in the White Rhinoceros. Keep (Keep, M.E. 1970) has reported that Nalorphine reverses the effects of Etorphine more completely than the ((MNseries antidotes in this species, but this has not been the case at Whipsnade. The Rhinocerosesare remarkably sensitive to Etorphine. As little as 3 mgm of the drug will completely immobilise a 2000 kilogram White Rhinoceros (Harthoorn, A.M. 1967). As was implied earlier, the Tapirs (Tapiridas) possess a similar sensitivity to Etorphine as the Equidae and their responses to this drug are also similar. Although the nineteenth century taxonomist has placed them in a separate Order, pharmacologically, the Elephants (Proboscidea)fall into the same group as the horses and rhinos. The African species (Loxodonta africana) in particular has a similar sensitivity to a mixture of Etorphine and Acepromazine as the African Rhinos (King, J.M. 1969, Pienaar, U de V 1966). However without any known reason, the Indian Elephant (Elephas maximum) like the Indian Rhinoceros (Rhinoceros unicornis) requires twice the dose rate needed to achieve a similar affect in its African relative. (Jones, D.M. 1972, Gray,C.W., Nettasinghe,A.P.W. 1967).
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Ruminants: Although a combination of Etorphine and Acepromazine (usually the ctlmmobiIon)) combination) is used extensively to immobilise both domestic and wild ruminants, excitatory side-effects leading to hyperthermia and dyspnoea are often seen. Besides the undesirability of this for safety reasons, these make handling difficult. The main advantage of using Etorphine or Fentanyl, another potent narcotic with similar properties, is that its effects are partly reversible. The degree of excitement noted with the ((Immobilon))combination varies considerably from one group of ruminants to another. Excitation is rare in the Wildebeests and Hartebeests (Alcelaphinae). On the whole the Deer (Cervidae), Sheep and Goats (Caprinae) show mild excitatory signs but still remain handleable. The Cattle (Bovinae) and most of the Antelopes (Tragelaphinae, Reduncinae, Hippotraginae and Antilopinae) tend to show a degree of excitement which may be acceptable purely for rapid capture but which often makes clinical examination extremely difficult. It would appear that the problem partly lies with the sedative or neuroleptic which is usually combined with the narcotic. The narcotic principally exerts a depressant effect on the Wildebeests and their relatives. This means that a sedative is usually unnecessary in these cases. In the second group, the Deer (Cervidae) and the Sheep (Caprinae), the addition of Acepromazine or Azaperone to the narcotic usually improves the degree of immobility. The intensity of excitement in the other groups is such that both the Promazines and the Butyrophenones, even at high dose rates, are ineffective for the purposesof clinicalexamination. If Xylazine is used in the combination instead of Acepromazine or Azaperone, the excitement is reduced considerably or even abolished. Tractable, domestic ruminants can be sedated and completely immobilised using Xylazine alone (Clarke et al. 1969). If recumbency is induced, the animal tends to remain on its brisket and regurgitation rarely occurs. Muscular relaxation is marked at the level of deep sedation. Cardiovascular and respiratory effects are of little clinical significance. These features tend to make Xylazine the drug of choice for ruminants at the present time. There are however two major disadvantages. The drug is not reversible and the dose rate required to produce a given effect is dependant on the temperament of the animal. A nervous or aggressive bullock may require up to 30 times as much Xylazine to produce a similar effect in a placid dairy cow of the same weight. Many of the so called ((speciesdifferences))reported in the literature (Bauditz, P. 1972) were almost certainly due to individual differences in the tractability of the animals concerned. Under the same conditions of management, a wide variety of ruminants with a similar temperament will require the same dose rates of Xylazine to produce a similar effect. Handreared individuals will require much less than closely related animals which have never been handled. This is not to say that species variation does not exist. Musk Ox (Ovibos moschatus), despite their a.ggressive nature, seem to require consistently lower dose rates than equally nervous antelope such as Oryx (Oryx tao) or Roan (Hippotragus equinus) (Kooi, P. 1971, Hime, J.M., Jones, D.M. 1970). Where very large dose rates of Xylazine are required it often becomes impractical to use a projectile syringe because the missile would need to be far too large to fly any distance. When Xylazine is combined with Etorphine its effects become more consistent. The dose rate of Xylazine for this combination does not alter as much with variations in temperament and in all cases it is relatively low (0.3-0.5 mg/kg). A considerably reduced volume of solution is then feasible (Jones, D.M. 1971). As both Etorphine and Xylazine are powerful respiratory depressants, the therapeutic index of
35
the mixture is not high and care must be taken to assess the doses accurately. Problems with the votume would also be encountered if Ketamine became widely used for ruminants. Although it has been used in Sheep (Taylor, P., Hopkins, Lynda, Young Maureen, McFadyen, I.R. 1972) there are no records yet of its extensive use in wild ruminants. Its older relative Phencyclidine is still used occasionally in these species but the therapeutic index is much lower, the effect is more prolonged and there is a tendency for regurgitation to occur. In addition, excitation has been noted during the recovery phase with Phencyclidine, adding to the dangers of using this drug (Manton, V.J.A. 1962-1966).
Pigs and hippopotami: Amongst the larger mammals, this group is the most difficult to restrain efficiently and safely. Azaperone produces a state of tranquillity at 1.0 mg/kg in the domestic pig (Sus scrofa) which as the dose increases to 3 mg/kg usually leads to immobilisation (Marsboom, R. and Symoens, J. 1968, Symoens, J., Van den Brande, M. 1969). These effects are more consistent in the pig than those produced by the promazine derivatives and there is no appreciable action on body temperature or blood pressure. Doses of Azaperone up to 15 mg/kg have had no appreciable effect on Collared Peccaries (Tayassu tajacu) or Wild Boar (Sus scrofa) at Whipsnade, probably because they are far more aggressive and nervous than their domestic relatives. Mixtures of Fentanyl and Azaperone or Etorphine and Acepromazine have been used on wild Warthogs (Phacochoerus aethiopicus). Pienaar reports a useful effect with the former combination but the latter has produced excitement, shock and death on occasions (Pienaar, U. de V. 1968). Similar effects have been noted with Etorphine and Acepromazine (as ctlmmobilon))) in the domestic pig. Pigs are very susceptible to shock and the promazine derivates tend to exacerbate the resultant temperature and blood pressure changes. The Butyrophenone derivatives ((protect)) against these effects to some extent and this may explain the more favourable results with these drugs. In Pigs and Hippopotami intravenous injection is difficult and a rapid reversal of narcosis cannot therefore be guaranteed. This adds to the problems of using these mixtures in this group. The Hippopotami (Hippopotamu's amphibius) and (Choeropsis liberiensis) react very similarly to the pigs under the influence of these drugs. There is often considerableexcitement, with salivation and hyperthermia. If the animal has access to water there is also a serious risk of it drowning (Pienaar U. de V. 1968).The risk is still present when Phencyclidine is used. Phencyclidine though has a more consistent action in Hippopotami and Pigs than the mixtures of a narcotic and sedative, but it is not reversible. It was withdrawn from general use after the finding that residues of the drug remained in the tissues even if sedation had taken place some days prior to slaughter. It is however a relatively useful drug if the subject is not to be used for human consumption but it has disadvantages. The induction and recovery phases are often accompanied by excitement and total recovery may be prolonged to as much as 48 hours. Acepromazine is usually added, but this does not seem to control the excitement totally.
The Carnivora: The Dogs (Canidae), Bears (Ursidae), Cats (Felidae)and the Racoons and their relatives (Procyonidae) can all be sedated with Xylazine (Bauditz, R. 1972). The
side-effects are minimal, but the dose rates are often so high that the resultant volume is usually impractical to administer except to the relatively small species. As in the other groups discussed, temperament will also affect the dose required. More predictable in this respect are Phencyclidine and Ketamine; Phencyclidine has more significant side-effects but Ketamine is available at such a low concentration that the administration of large volumes is once again a problem. Ketamine has only recently been released for general use and it has therefore not been used yet as extensively as Phencyclidine. Nevertheless, it is becoming evident that Ketamine has a number of notable advantages over the older cyclohexamine (Hime, J.M. 1972). The degree of excitement is considerably reduced especially in the Felidae where intense spasmodic contractions of the limb and neck muscles are a common feature with Phencyclidine. In addition the animal loses its aggression and begins to relax long before it becomes completely immobile. Recovery is much more rapid with Ketamine than with Phencyclidine. Usually these drugs are combined with a sedative such as Promazine which tends to counteract to some extent any excitation produced. The initial salivation which occurs sometimes in Felids and Procyonids can be counteracted by premedicating with Atropine. Phencyclidine particularly has a tendency to recycle and is not readily excreted from the body. The drug is therefore contraindicated in ageing and debilitated animals, particularly those with liver or kidney disease. Prolonged recumbency in such cases produces the additional problems of disturbed fluid balance, lowered blood glucose levels and a falling body temperature. A mixture of the steroids Alphaxalone and Alphadolone marketed under the name ((Saffan)) has recently been introduced for use primarly in the domestic cat (Felis catus) (Evans, J.M., Aspinall, K.W., Hendy, P.G. 1972). Its principal advantages are that it is short acting, produces marked relaxation and does not recycle. The sedative effect is most predictable when ((Saffannis given intravenously, for although the drug is absorbed from muscle, special care must be exercised to ensure that the needle penentrates into this tissue and does not deliver the drug into connective fascia. As the action of the drug is very short, inaccurate injection would lead to poor absorption and metabolism of the drug before it could produce a useful effect. This is not a practical drug to use for the larger wild cats unless they can be physically restrained first for hand injection. Even then, relatively large volumes would have to be used and this might prove impractical. The narcotics are contraindicated in the cat family on account of their severe excitatory effects. Mixtures of neuroleptics with narcotics are useful for other families in this group, mainly because a relatively rapid recovery can be produced. Bears and Dogs are sensitive to relatively small doses of Etorphine or Fentanyl (Lasen, T. 1966, Blane, G.F., Brown, A.L.A., Dobbs, H.E. 1968, Marsboom, R., Verstraete, A. Thienpont, D., Mathews, D. 19641. The dogs tend to show some excitement during induction but this can be reduced considerably by combining the narcotic with Promazine, Azaperone or Methotrimeprazine. The therapeutic indices of these mixtures are not high in this group and even an increase of 50 % in the optimum dose rate often produces respiratory depression. In Bears, marked residual sedation regularly occurs after the ((antidoten is given though there seems to be some individual variation in this respect. Recent trials suggest that this sedation is due to the sedative and not the narcotic (Jones 1973).
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Primates: Three cyclohexamines are regularly used for the restraint of primates. The oldest of the group, Phencyclidine is being replaced gradually by Tiletamine and Ketamine mainly because of the shorter recovery time experienced with these latter drugs. All three produce a state of dissociative anaesthesia and with the lower dose ranges it is possible to handle animals safely even though they may still be relatively mobile. A state of indifference without aggression or flight is seen. With Phencyclidine in particular, mild excitement occasionally occurs during the induction phase, but this is usually counteracted by combining Promazine in the initial injection. Athetoid movements are also occasionally seen with Tiletamine and Ketamine even during light anaesthesia but these are not of much practical significance as they can be overcome by deepening anaesthesia with shortacting barbiturates. Primates are more sensitive to Phencyclidine than to the other two drugs. With all three of these agents there is some variation in the dose rate required by different species of the Order to achieve the same effect. Most primates require about 1.O mg/kg of Phencyclidine to produce light anaesthesia but the same effect can be achieved with half this dose in the great apes (Seal et al. 1970, Chen and Weston 1960). Bree (1972) reported that even within the genus Macaca there were significant differences in sensitivity to Tiletamine at dose rates of from 3 to 6 mg/kg. Primates can be immobilised with Xylazine (Hime and Jones 1970) and there do not seem to be any significant side-effects. However, marked individual variation is found in the dose rate required and this is presumably due to the differences in the temperament of individual animals. The steroid mixture of Alphaxolone and Alphadolone has been found to be effective in small primates at the same dose rates as those required for the domestic cat (Brancker 1973). This is 9 mg per kg. It is almost always necessary to give the initial injection intramuscularly in these animals. Unlike the other drugs mentioned in this section it is essential that this mixture is absorbed rapidly. To achieve any significant effect the drugs must be injected into muscle and not fascia or subcutaneous tissues. Some workers prefer to use mixtures of narcotics and sedatives for handling these species despite the fact that intense excitement is occasionally produced by Morphine like substances. Although a mixture of Etorphine and Promazine or Methotrimeprazine has been used, the most widely accepted combination is that of Fentanyl and Droperidol (Marsboom, Mortelmans, Vercruysse 1963, Field, Yelnosky, Mundy, Mitchell 1966). The dose of Droperidol remained at 1.0 mg/kg but it was found that anthropoid apes were more sensitive than other species to Fentanyl (0,02mg/kg sufficient for apes, while 0.04 mg/kg was required for other species). Slight bradycardia usually occurs and some respiratory depression may be seen when the higher dose rates are used. The degree of analgesia produced is profound. Reversal of the effect is achieved with Nalorphine although spontaneous recovery will occur after 2-4 hours. Because the narcotic is absorbed very rapidly from mucous membranes, oral administration is a practical proposition with this combination.
Summary: During the last decade, a number of drugs have become available which, when used separately, or when combined with another have facilitated the handling and movement of nervous or aggressive animals. These drugs are usually grouped accord-
ing to their principal properties into narcotics, such as Etorphine and Fentanyl, sedatives such as Azaperone and Xylazine and anaesthetics such as Phencyclidine and Alphaxalone. This is a somewhat loose terminology as the properties of a number of these agents when used at different dose rates or in different species may place them into more than one of these groups. Knowledge of the clinical pharmacology of these drugs and of the different responses found amongst the various orders of mammals is necessary if the effect required is to be accurately and safely obtained. Narcotics for instance are contraindicated in the Felidae on account of their severe excitatory side-effects but in some carnivore families the milder side-effects can be overcome by combining the narcotic with a sedative. This paper sets out to describe these different effects and to show that an understanding of them is important when selecting the appropriate drugs for a particular case.
References
1. Adams, A.J. (1970). The Use of Immobilon. Vet. Record 87,560. 2. Bauditz, R. (1972). Sedation, lmmobilisation and Anaesthesia with Rompun in Captive and Free living Wild Animals. Vet. Med. Rev. 314,204.
3. Blane, G.F., Brown,A.L.A., Dobbs, H.E. (1968). Neuroleptanalgesia in the dog caused by the interaction of Etorphine with Methotrimeprazine. J. Physiol. 196,26. 4. Brancker, M. (1973). Personal communication/unpublished.
5. Bree, M.M. (1972). Clinical evaluation of Tiletamine as an anaesthetic in non human Primate species J.A.V.M.A. 161, No.6,693. 6. Chen,G.M., Weston, J.K. (1960). The analgesic and anaesthetic effect of 14 1 -Phenylcyclohexyl)Piperadine HCI on the Monkey. Anaesthesia and Analgesia. 39, No. 2, 132.
7. Clarke, K.W., Hall, L.W. (1969). (TXylazine))- A New Sedative for Horses and Cattle. V%t. Record 85,512. 8. Cullen, C.J. (1970). The Use of Immobilon. Vet. Record 87,669. 9. Evans, J.M., Aspinall, K.W., Hendy, P.G. (1972). Clinical evaluation in cats of a new anaesthetic CT. 1341. J. Sm. An. Prac. 13,479.
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10. Field, W.E., Yelnosky, J. Mundy, J., Mitchell, J. (1966). The Use of Droperidol and Fentanyl for Analgesia and Sedation in Primates. J.A.V.M.A.149,No.7,896. 11. Gray, C.W., Nettasinghe,A.P.W. (1967). A Preliminary study on the immobilisation of the Asiatic Eleljhant (Elephas maximus) utilising Etorphine (M. 99). Report of Nat. Zool. Park, Smithsonian Institute, Washington, p. 51. 12. Harthoorn, A.M. (1967). Comparative pharmacological reactions of wild and domestic mammals to Thebaine derivatives in the ct M Nseries of compounds. Fed. Proc. 26,1251. 13. Hillidge, C.J. (1970). The Use of Immobilon. Vet. Record 87,669. 14. Hime, J.M., Jones, D.M. (1970). The Use of Xylazine in Captive Wild Animals. Proc. Int. Symp. on Diseases in Zoo Animals. Budapest, p. 143. 15. Hime, J.M. (1972). Unpublished.
16. Janssen Pharmaceutica (1969). lmmobilisation and Restraint of large wild mammals with Azaperoneand Fentanyl. Booklet published by company. 17. Jones, D.M., Manton,V.J.A. (1970). ((The Use of Immobilon)). Vet. Record 87,701. 18. Jones, D.M. (1971). The lmmobilisation of Cattle and related species. Vet. Record 89,174. 19. Jones, D.M. (1972). The Use of Drugs for the Immobilisation, Capture and Translocation of Nondomestic animals. Vet. Annual, 320.
20. Jones, D.M. (1973). Unpublished paper. 21. Keep, M.E. (1970). Personal communication. 22. King, J.M. (1969). The capture and translocation of the Black Rhinoceros. E. Afr. W. Journal7,115.
23. Koci, P. (1971). Practical results with the application of BAY Va 1470 10 % (Rompun) for the imrnobilisation of Hippotragus equinus. Veterinarstvi21,565. 24. Larsen T. (1966). The trapping and study of polar bears. Spitsbergen Polar Record, 13,(86),587.
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25. Manton, V.J.A. (1962-1966). Unpublished.
26. Marsboom, R., Mortelmans, J., Vercruysse, J. (1963). Neuroleptanalgesia in Monkeys. Vet. Record75, No. 6, 132. 27. Marsboom, R., Verstraete, A., Thienpont, D., Mathews, D. (1964). The Use of Haloanisone and Fentanyl for Neuroleptanalgesiain Dogs. Brit. Vet. J. 120,466. 28. Marsboom, R., Symoens, J. (1968). Experiences with Azaperone, a sedative for pigs. Tijdschr. diergeneesk. 93,3. 29. Mitchell, R.J. (1970). The Use of lmmobilon Vet. Record 81,600. 30. Pienaar, U. de V. (1966). The use of oripavine hydrochloride (M. 99) in the drug immobilisation and marking of wild African Elephant (Loxodonta africana Blumenbeck) in the Kruger National Park. Koedoe, 9,108. 31. Pienaar U. de V. (1968). Recent advances in the field lmmobilisation of and restraint of wild ungulates in South African National Parks. Acta Zoologica et Path. Ant. verpiensis, 46,17. 32. Pugh, D.M. (1964). Acepromazine in Veterinary Use. Vet. Record, 76,439. 33. Reckitt and Colman Limited (1969). series in game immobilisation Booklet published by company. The c t M ~ 34. Seal, U.S., Erickson, A.W., Mayo, J.G. (1970). Drug immobilisation of the Carnivora. Int. Zoo Yearbook, 10,157. 35. Stockman, M.J.R. (1970) ((The Use of Immobilon)). Vet. Record, 87,518. 36. Symoens, J., Van den Brande, M. (1969). Prevention and cure of aggressiveness in pigs using the Sedative Azaperone Vet. Record, 8564. 37. Taylor, P.; Hopkins, Lynda; Young, Maureen; McFadyen, I.R. (1972). Ketamine anaesthesia in the Pregnant Sheep. Vet. Record, 90,35. 38. Whiteley, H. (1970). The Use of Immobilon. Vet. Record, 87,637.
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Drugs mentioned in the Text Drug Name
Trade Name
M. 99 or Etorphine M. 5050 or Diprenorphine M. 285 or Cyprenorphine Etorphine + Acepromazine Etorphine + Methotrimeprazine Nalorphine Azaperone Fentanyl + Droperidol Xylazine Acepromazine maleate Alphaxolone and Alphadolone Phencyclidine Tiletamine Ketamine
Reckitt and Colman Reckitt and Colman Reckitt and Colman Large Animal lmmobilon Reckitt and Colman Small Animal lmmobilon Reckitt and Colman Lethidrone Burroughs Wellcome Suicalm Crown/Janssen Hypnorm Janssen Rompun Bayer Acetylpromazine Boots Saffan Glaxo Sernylan Phillips Roxane Parke Davis KetalarNetalar Parke Davis Revivon
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Manufacturer