Acepromazine

Acepromazine is the phenothiazine derivative most widely used in horses for both its mood-altering and its sedative actions. Intravenous (IV) doses of 0.03 mg/kg or intramuscular (IM) of 0.05 mg/kg exert a calming effect within 20–30minutes of injection and, although at these dose rates obvious sedation may only be apparent in 60% of horses, they become much easier to handle. Doses may be doubled, but the level of sedation does not always increase, although the duration will. Acepromazine (in paste or tablet forms) also may be given orally at maximally recommended doses of 0.1 mg/kg. Oral availability in horses is high and can be equal to that of the IM route (Hashem & Keller, 1993). Acepromazine is very long acting, and elimination may be further delayed in old or sick animals, particularly in those with even mild liver disease.

Acepromazine at the doses recommended has little effect on ventilation, but causes hypotension through vasodilation (Kerr et al., 1972). Hypovolaemic horses may faint. Tachycardia may result from the fall in arterial blood pressure, but sometimes first degree atrioventicular block is seen. A very small proportion of horses (the authors have seen two such cases) show aberrant reactions, and may become recumbent without any apparent cardiovascular cause; these reactions were more common with other phenothiazine agents. In stallions and geldings, effective sedation with phenothiazine derivatives is associated with protrusion of the flaccid penis or, on very rare occasions, priapism. In either case, physical damage to the penis must be avoided. In a very small proportion of horses, prolonged prolapse occurs. Treatment of this complication is by manual massage, compression bandage and replacement in the prepuce followed by suture of the preputial orifice. It is the opinion of the authors, and of many veterinarians (Driessen et al., 2011) that the low incidence of this complication coupled with the possibility of immediate treatment means that where a phenothiazine agent is the drug of choice its use is not contraindicated in stallions or geldings.

Acepromazine has proved a very safe agent in the horse. The calming and low-level sedative effects it produces make it the agent of choice for interventions such as shoeing, and when used in young animals it appears to assist in training the horse to tolerate many future procedures without sedation. When acepromazine is combined with opioid agents, deep sedation is achieved and such combinations may be used in cases where α₂-agonists would be inappropriate. Acepromazine is an excellent premedicant before general anaesthesia; it calms the horse prior to the insertion of catheters, lengthens the action of the anaesthetic agents, reduces pulmonary ‘shunt’ fraction (Marntell et al., 2005a) and statistically reduces the overall risk of anaesthesia and surgery (Johnston et al., 1995). Its prolonged duration of action means that it contributes to a quiet recovery.

Xylazine

Following the introduction of xylazine, it rapidly gained in popularity because of the reliable sedation produced in horses. Doses of 0.5–1.1 mg/kg IV are followed within 2 minutes by obvious signs of effect. The horse’s head is lowered and the eyelids and lower lip droop (Clarke & Hall, 1969; Kerr et al., 1972). Although the horse may sway on its feet, cross its hind legs or knuckle on a foreleg, with xylazine alone, it will remain on its feet and show no panic. Sedation is maximal after about 5 minutes and lasts 30–60 minutes depending on the dose. Doses of 2–3 mg/kg IM give similar effects, maximal sedation being achieved 20 minutes after injection. Xylazine has analgesic properties, particularly in colic (reviewed by England & Clarke, 1996) and, in colic cases, analgesia is associated with the marked reduction in gut movement caused by drugs of this class. Horses sedated with xylazine alone remain very sensitive to touch and the apparently well-sedated horse may, if disturbed, respond with a very sudden and accurate kick.

Investigations into the effects of xylazine in horses have been reviewed (England & Clarke, 1996). There is a transient rise in arterial blood pressures. Mean arterial pressure (MAP) peaks 1–2 minutes after IV injection; the pressure then slowly falls to below resting values and remains depressed for at least one hour (Fig. 11.1). Concurrent with the hypertensive phase, there is profound bradycardia coupled with both atrioventricular and sinoatrial heart block. Heart block is at its most intense in the first few minutes and, in many cases, disappears as the heart rate increases. Changes in blood pressure are dose dependent in intensity and duration and, following IM injection, changes are similar but less marked. Cardiac output (CO) is significantly reduced, probably because of the bradycardia; IV doses of 1.1 mg/kg cause falls of 20–40% of normal resting values of CO. The changes in MAP result from a balance between peripheral vasoconstriction and the centrally mediated fall in heart rate and CO (see Chapter 4). At doses of up to 1.1 mg/kg, xylazine does not cause severe respiratory depression although there may be a small rise in PaCO₂ and a slight decrease in PaO₂. However, some upper airway obstruction may occur; horses may snore if left in the head down position for any length of time. Heavy coated horses may sweat as sedation is waning – most commonly seen if atmospheric temperatures are high. Other side effects are those typical of α₂-agonists (see Chapter 4) and include hyperglycaemia, diuresis, gut stasis and increase in uterine tone; this latter makes it theoretically preferable not to use xylazine in pregnant mares. Changes in insulin production and hyperglycaemia do not appear to be a feature of xylazine action in neonatal foals (Robertson et al., 1990).

Detomidine, a very potent α₂-agonist was first used as a sedative and analgesic agent in 1982 and, since its introduction, has gained great popularity for sedation and premedication of all types of horse (Vainio, 1985; Alitalo, 1986; Clarke & Taylor, 1986; Short, 1992). Initially, very high doses (up to 160 µg/kg) of detomidine were recommended but it soon became obvious that maximal sedative effects were obtained with IV doses of 10–20 µg/kg (0.01–0.02 mg/kg) and that higher doses increased the duration rather than depth of sedation. Slightly higher doses appear necessary to provide good analgesia (Hamm et al., 1995). The concentrated but non-irritant form of 10 mg/ml in which detomidine (as Domosedan or Dormosedan, and now generics) is provided makes it very suitable for IM injection, doses approximately twice those given IV being required to produce the same effect.

Detomidine has some effect when injected subcutaneously (SC) and is also absorbed through mucous membranes and there is now a gel form available for this purpose (Gardner et al., 2010; Kaukinen et al., 2011). When given in food, the effect is less reliable as the drug is extensively metabolized by first pass through the liver. The property of easy absorption across mucous membranes must, for reasons of personal safety, be taken into account when handling the drug.

The type of sedation produced by detomidine is identical to that produced by xylazine; in blind trials comparing IV xylazine (1 mg/kg) IV and detomidine 20 µg/kg IV (England & Clarke, 1996), all parameters assessed and measured except duration of action were identical (see Fig. 11.1). As with xylazine, horses under detomidine sedation are sensitive to touch and may kick. Lower doses of detomidine do not always result in maximal sedation, but may prove useful where a short period of action is required. Detomidine premedication reduces the dose of anaesthetic agents subsequently required.

The cardiovascular properties, bradycardia, peripheral vasoconstriction and changes in arterial blood pressure (see Fig. 11.1) are also as described for xylazine above (Short, 1992). With higher doses, the hypertensive phase is considerably more prolonged (Short et al., 1986). At clinically used doses, respiration is slowed and PaO2 is slightly decreased. Some horses snore. The authors have noted occasional horses (usually but not always those suffering from toxaemic conditions) becoming tachypnoepic for some 10–15minutes after the administration of detomidine and similar reactions have been reported after other α₂-agonists (Bettschart-Wolfensberger et al., 1999; Kendall et al., 2010). The condition appears self-limiting and does not require treatment. Other side effects include reduction in gut motility, hyperglycaemia, sweating and an increase in urination. Doses above 60 µg/kg may cause swelling of the head; this problem can be prevented by propping the head in a normal position. Occasionally urticarial reactions have been noted; these are self-limiting and regress without treatment. Moderate doses of detomidine are claimed to be safe in pregnancy (Jedruch et al., 1989) and many mares have received multiple doses throughout gestation without any maternal or fetal harm resulting.

The actions of detomidine (and of other α₂-adrenoceptor agonists) can be reversed by the specific antagonist, atipamezole. Dose rates from 60 to 200 µg/kg have been used, that required depending on the degree of residual sedation (Nilsfors & Kvart, 1986; Bettschart-Wolfensberger et al., 2001b; Hubbell & Muir, 2006). At the doses of detomidine recommended, it is rare that antagonism is required, but the authors have been grateful of its availability in cases of overdosage of α₂/opioid combinations where a horse has become severely ataxic or even recumbent, and in one case of a massive overdose of detomidine (Di Concetto et al., 2007).

Romifidine

The type of sedation produced by romifidine differs from that produced by the other α₂-agonists; the horse’s head does not hang so low, and there is considerably less ataxia (Voetgli, 1988; England & Clarke, 1996), although (Ringer et al., 2013) found no difference from xylazine when comparing the drugs given by constant rate infusion (CRI). Despite the apparent reduced sedation, romifidine at doses of from 40 to 120 µg/kg (0.04–0.12 mg/kg) IV enables a range of clinical procedures to be performed; the effect (and the ataxia) is enhanced by combination with opioids. In clinical practice, romifidine has proved very popular where ataxia is particularly unwelcome, e.g. for shoeing. The pharmacological actions of romifidine other than sedation are similar to all α₂-agonists. Romifidine reduces gut motility, the duration of this effect being dose dependent (Freeman & England, 2001). Self-limiting urticarial reactions may occur occasionally. The degree of analgesia produced by romifidine has been questioned; the results appear to depend on the nociceptive stimulus used (England & Clarke, 1996). Spadavecchia et al. (2005) found good reliable antinociception, Voetgli (1988) that antinociception was not dose related or consistent, and Hamm et al. (1995) claimed there was no analgesic activity. Rohrbach et al. (2009) compared the antinociceptive effects of romfiidine, xylazine and detomidine; all three α₂-agonists provided equal antinociception, although duration was drug dependent. In equine practice, romifidine is widely used for premedication and, as part of anaesthetic combinations, it reduces the dose of anaesthetic agents subsequently used.

Other α₂-agonists

Medetomidine’s use has been investigated in horses (Bryant et al., 1991; Bettschart-Wolfensberger et al., 1999). Doses of 5–7 µg/kg (0.005–0.007 mg/kg) IV are sufficient to cause very deep sedation with severe ataxia, and higher doses may result in recumbency. The marked hypnotic properties make the agent unsuitable for routine use as a sedative in horses. However, it appears to be short acting, having a half-life of elimination of 29 minutes (Grimsrud et al., 2012) and its excellent analgesic and muscle relaxant properties mean that it has become quite widely used as a CRI during anaesthesia (see Box 11.1). Bettschart-Wolfensberger et al. (2005) showed that dexmedetomidine at 3.5 µg/kg IV in the horse had similar effects as medetomidine.

Infusions of α₂-agonists

Where α₂-agonists are being used to provide sedation for surgery, sometimes it is necessary to increase their duration of action. Intermittent dosing, each increment being 25–50% of the original dose administered, is effective, but a constant rate infusion (CRI) provides a more level and controllable plane of sedation. Usually, the agent used is diluted in a saline drip then, following the initial loading dose, is infused to effect. Infusions have been used alone, with opioids (see opioid combinations below) and as an adjunct to general anaesthesia (see PIVA below). Some doses that have been used in these circumstances are summarized in Box 11.1. Of these, the most thorough exploration of suitable dose rates were those of Bettschart-Wolfensberger et al. (1999) for medetomidine and Ringer et al. (2012a,b) for xylazine and romifidine, as in each case a dose that would give a steady level of sedation was elucidated, then the result confirmed with pharmacokinetic studies. However, doses from experimental studies are only a guide in the clinics; sometimes they are inadequate or too high for the individual clinical case, and the infusions should always be given ‘to effect’.