KNOW ABOUT ONE DRUG EVERY DAY XYLAZINE

KNOW ABOUT ONE DRUG EVERY DAY

XYLAZINE

Type

Alpha₂-adrenergic agonist structurally related to clonidine.

Alternative Names

• Xylazine hydrochloride.

Pharmacology & General Information

Pharmacology

• Potent alpha₂-adrenergic agonist (alpha₂-adrenoceptor stimulant).
• CNS effects:
• Causes sedation and CNS depression.
• Muscle relaxation is mediated through central nervous system pathways.
• Emesis (in cats and sometimes in dogs, but not occurring in horses, cattle sheep, goats) is thought to be centrally mediated.
• Depresses thermoregulatory mechanisms.
• Cardiovascular effects: 
• Initial increased total peripheral resistance and increased blood pressure.
• Longer period of lowered (below baseline) blood pressure.
• Bradycardia. Due to sino-atrial and atrioventricular heart block, partially in response to the initial hypertension.
• Second degree heart block or other arrhythmias may occur.
• Overall decrease in cardiac output (up to 30%).
• Respiratory effects:
• At high doses may act as a respiratory depressant with decreases in tidal volume and respiratory rate, overall decrease in minute volume.
• Insulin-related effects:
• Decreases serum insulin levels which may lead to increased blood glucose levels (hyperglycaemia).
• Renal effects:
• Polyuria.

Therapeutic Information

Uses/Indications

Activity

• Sedative/analgesic, with muscle-relaxant properties.
• Emetic in cats and sometimes in dogs.

Appropriate Use

• As a sedative/analgesic.
• As a sedative to facilitate handling.
• As a sedative, in conjunction with local anaesthesia, to allow minor procedures.
• For premedication before anaesthesia.
• Reduce anaesthetic induction agent by 50-75% to avoid fatal overdose.
• Concurrent atropine administration may be useful in dogs/cats to reduce salivation and reduce bradycardiac effects.
• In combination with ketamine for general anaesthesia.
• Epidural injection.
• As an emetic in cats. May be useful in cats/dogs which have not been starved for at least six hours prior to anaesthesia.
• As a sedative to facilitate handling of fractious animals, veterinary examination and for premedication for minor superficial operations, painful manipulative procedures and local or regional anaesthesia.

Sheep:

• Analgesia for visceral pain; effects last about 45 minutes with dose stated below.
• Not suitable for analgesia in rams with urolithiasis as alpha-2 agonists increase urine production.

Limitations

• In horses, apparently sedated individuals may still react to auditory stimuli (e.g. kicking, avoidance responses).

Notes

• Considerable species-specific variability in sensitivity: ruminants require about a tenth of the equine dose while pigs require 20-30 times the ruminant dose.

Pharmacokinetics and Drug Interactions

Absorption /Bioavailability

• Rapid absorption following intramuscular administration.

Bioavailability following intramuscular administration:

• Incomplete, variable.
• Horse: 
• 40 to 48 %.
• Approximately doubled dose required if intramuscular rather than intravenous administration is used.
• Sheep: 
• 17 to 73 %.
• Range 17 to 73 %, mean 40.8 %.
• Following intramuscular administration of 1.0 mg/kg in sheep weighing 42-65 kg, bioavailability was in the range 17 to 73% (mean +/- SD 40.75 +/- 23.81 %).
• Dog: 
• 52 to 90 %.

Distribution

• Xylazine is distributed widely in tissues.
• Large apparent volume of distribution (1.9-2.7 L/kg).

Horse:

• Onset of action following intravenous administration 1-2 minutes; maximum effect 3-10 minutes; duration of effect approximately 1.5 hours (dose-dependant).; peak action following intravenous administration within 5 minutes and lasting for 15 minutes; sedative effect lasts 40-60 minutes.

Dog/cat:

• Onset of action following intravenous administration 3-5 minutes, following intramuscular or subcutaneous administration approximately 10-15 minutes; duration of analgesic effect 15-30 minutes; duration of sedative effect 1-2 hours (dose-dependent).

Cattle:

• Onset of action following administration usually within 5 minutes; peak effect in 15 minutes. Following intramuscular injection onset of action 5 to 10 minutes, maximum effect 15 minutes.
• For a dose of 0.2 mg/kg intravenously, t_1/2α 1.21 min, V'd_(area) 1.94 L/kg.
• Following intravenous administration of 0.2 mg/kg xylazine in cattle of weight 240-440 kg, the distribution half-life t_1/2α was 1.205 minutes and the apparent volume of distribution V_{d (area)} was 1.944 L/kg.

Sheep: 

• For a dose of 1.0 mg/kg intravenously, t_1/2α 1.89 min, V'd_(area) 2.74 L/kg.
• Following intramuscular injection onset of action 5 to 10 minutes, maximum effect 15 minutes, time to maximum concentration 14.7 minutes.
• Following intravenous administration of 1.0 mg/kg xylazine in sheep of weight 42 to 65 kg, the distribution half-life t_1/2 was 1.889 minutes and the apparent volume of distribution V_{d (area)} was 2.740 L/kg.

Elimination Route

• Extensive biotransformation.
• Extensive biotransformation in ruminants with peak excretion of metabolites at two to four hours after administration.

Cattle:

• Less than 1% unchanged xylazine is eliminated via urine in the first two hours after administration.

Elimination half-life / Clearance Rate

Plasma distribution half life 1.2-6 minutes following intravenous administration in dogs, horses, cattle and sheep.

Serum half-life:

• Horse: approximately 50 minutes.
• Dog: approximately 30 minutes.

Full recovery:

• Horse: two to three hours.
• Dog/cat: two to four hours.

Cattle:

• For a dose of 0.2 mg/kg intravenously, t_{1/2 β} 36.5 min, Cl_β 42 mL/kg/min.
• Following intravenous administration of 0.2 mg/kg xylazine in cattle of weight 240-440 kg, the half-life of elimination t_1/2β was 36.48 min and clearance Cl_β was 42 mL/kg/h.
• Note: it has been found not possible to detect xylazine during deep sedation of cattle which was induced by intramuscular administration of xylazine at 0.2 mg/kg. Administration of xylazine at 0.2 mg/kg in cattle resulted in plasma concentrations below the limits of assay sensitivity (0.01 µg/mL).

Sheep: 

• For a dose of 1.0 mg/kg intravenously, t_1/2β 23.1 min, Cl_B 83 mL/kg/min.
• Following intravenous administration of 1.0 mg/kg xylazine in sheep of weight 42-65 kg the half-life of elimination t_1/2β was 23.105 min and clearance Cl_B was 83 mL/kg/h. Following intramuscular injection of the same dose, t_1/2β was 22.36 min.

Drug Interactions

• Physical compatibility (in the same syringe) reported with acepromazine, buprenorphine, butorphanol, chloral hydrate, ketamine, meperidine.
• Increases risk of ventricular arrhythmias from epinephrine.
• Potentially additive hypotension if used with acepromazine.
• Additive CNS depression is possible if used together with other CNS depressants such as barbiturates, narcotics, anaesthetics, phenothiazines; reduced dosage of such agents may be required.
• Should not be used in conjunction with other tranquilisers.
• May be reversed using the alpha₂-antagonist atipamezole.

Administration

Doses / Administration Routes / Frequencies

Cattle: More potent than in other domestic animal species.

• Pre-treatment with atropine may be used to decrease the bradycardia and hypersalivation.
• 0.05-0.15 mg/kg intravenously or 0.1-0.33 mg/kg intramuscularly.
• Intramuscular injection, if used, should be given via an 18 or 20 gauge needle at least 1.5 inches long.
• Intravenous route may stress cardiovascular function.
• 0.044-0.11 mg/kg intravenously or 0.22 mg/kg intramuscularly.
• 0.1-0.2 mg/kg intramuscularly for analgesia. Note: sedative with dose-dependant response; Brahman cattle are particularly sensitive.
• 0.05 to 0.30 mg/kg (0.25-1.5 mL of 2% solution per 100 kg) bodyweight, depending on the required degree of sedation, by intramuscular injection: fractious animals may need the higher end of this dose range. Initial effects within five minutes of intramuscular injection and maximal effect ten minutes later. The following effects are suggested:
• 0.05 mg/kg "Sedation, with a slight decrease of muscle tone. The ability to stand is maintained."
• 0.10 mg/kg "Sedation, marked decrease in muscle tone and some analgesia. The animal usually remains standing, but may lie down."
• 0.20 mg/kg "Deep sedation, further decrease of muscle tone and a degree of analgesia. The animal lies down."
• 0.30 mg/kg "Very deep sedation, a profound decrease in muscle tone and a degree of analgesia. The animal lies down."

Sheep & goats:

• To be used with extreme caution.
• 0.05-0.1 mg/kg intravenously or 0.10-0.22 mg/kg intramuscularly.
• 0.044 - 0.11 mg/kg intravenously or 0.22 mg/kg intramuscularly.
• 0.05-0.2 mg/kg; good analgesic.
• 0.05-0.1 mg/kg intravenously or intramuscularly provides good analgesia against visceral pain for about 45 minutes.
• 0.05-0.02 mg/kg intramuscularly. Note: "usually in conjunction with adjunctive sedative or anesthetic."

Experimental data in sheep:

• Alpha-2 adrenoceptor agonists are effective against visceral pain but their effects last only a short time (e.g. 0.05 to 0.1 mg/kg xylazine intramuscularly or intravenously provides pain relief for 45 minutes.
• "The α-2 adrenoceptor agonists would seem to hold the key to successful acute pain management in the sheep."
• Xylazine at 50 µg/kg intravenously had clear anti-nociceptive activity for both thermal and mechanical pressure threshold detection. Within five minutes of administration the thermal threshold from about 55°C to higher than 70 °C (maximum cut-out) and remained above 70°C for thirty minutes, then gradually returned to normal after about 60 minutes. Similarly xylazine injection resulted in an immediate increase in mechanical threshold to above the pre-set maximum value and returned to pre-xylazine values after about 45 minutes. The anti-nociceptive effect in either case was eliminated by pretreatment with the alpha-2 antagonist idazoxan, indicating that the analgesia demonstrated was mediated by alpha-2 adrenoceptors.
• Xylazine at 50 µg/kg (0.05 mg/kg) intramuscularly produced an anti-nociceptive effect in adult sheep, as measured by the electrical current required to produce leg withdrawal, for the period 15 to 60 minutes post injection (for a statistically significant effect, P<0.05). With 0.1 mg/kg the effect occurred faster and lasted from 3-60 minutes post injection with a slightly greater increase in threshold (180% above baseline rather than 170% for the lower dose), while a dose of 0.2 mg/kg produced a statistically significant increase above baseline for the period 2 to 60 minutes and the peak effect was 510.3% above baseline at 14 minutes, however three of six sheep showed significant sedation at this dose level (head drooping and reduced alertness were observed).
• Xylazine at 50 µg/kg intramuscularly had a clear anti-nociceptive effect in lambs, as indicated by a test with an electrical current, without producing any visible signs of sedation such as ptosis or reduced alertness and without affecting responses to other stimuli such as noise or touch.
• Xylazine at 0.02 mg/kg intramuscularly plus ketamine at 1 mg/kg intramuscularly in anaesthetised sheep subjected to abdominal surgery caused some increase (P = 0.002) in the time taken for ewes to lift their heads following anaesthesia, indicating some sedation, but no difference in the time to standing. The number of unsuccessful attempts to stand was decreased in the treated ewes, indicating a smoother recovery and possibly reduced pain in these individuals. Plasma cortisol levels were slightly lower (P = 0.018) over the first five days post operation than in ewes not given the drugs, although the levels were within the normal range in both treated and untreated ewes.
• Xylazine at 50 µg/kg intravenously provided analgesia, indicated by an increase in the threshold to a noxious mechanical stimulus. However in sheep with footrot which had been present for at least one week (i.e. individuals in chronic pain) analgesia declined more rapidly than in control non-lame sheep, the difference being significant by 25 minutes; this difference was also detected in sheep after treatment, in which resolution of the clinical condition had occurred.

Elephants:

CAUTION!

Sedative and anesthetic drug dosages for African elephants often vary from those for Asian elephants. Do not assume that the recommendations for one species can be applied to the other. Significant variation may also occur between individual elephants. Higher doses may be needed in wild or excited animals. Unless otherwise specified, doses refer to captive elephants. The information provided here should be used as a guideline only. Consultation with experienced

colleagues is advised. 

a) Xylazine 100-200 mg/metric ton for Asian elephants. Extreme aggressiveness, musth, painful conditions, and ambient disturbances may necessitate higher doses (Cheeran, et.al. 2002,1992).

b) 0.10-0.11 mg/kg xylazine IM for Asian elephants; can be combined with acepromazine or ketamine; the dose of individual drugs can be reduced up to 50% when combinations are used

(Nayer et.al. 2002). 

c) Xylazine at a dose of 100-300 mg in adult Asian elephants (approximately 4-10 mg/ 100 kg body weight) injected slowly intravenously resulted in good sedative, analgesic, and muscle relaxing effects in 21 Asian elephants undergoing blood collection, biopsies and ultrasound examinations. The author advises that yohimbine or atipamezole be readily available in case of overdose or inadvertent human exposure (1mg/kg can be lethal in man) (Rietschel et.al. 2001).

d) In Asian elephants: xylazine alone (0.1 mg/kg) or in combination with ketamine (1.25: 1 ratio) (Sarma et al. 2001). 

e) Xylazine at dosages of 0.18-0.33 mg/kg (total doses 600-1000 mg) was used to sedate 3 African elephants to load into a trailer a distance of about 50 m away. The procedure was accomplished but the sedation was rated as fair (Ramsey, 2000). 

f) * Adverse effect: A 27 year-old male Asian elephant with mild bilateral corneal opacities was laid in lateral recumbency, injected with 150 mg xylazine slowly via the caudal auricular vein and then allowed to stand. After 2.5 minutes he tilted his head upwards and backwards in a tentative gait. At 4-5 minutes he trumpetted loudly and started to shake his head vigorously, followed by complete delirium. After 10 minutes of violent excitement, he gradually became normal but his degree of sedation was minimal. An additional 50 mg of xylazine was given IV and the elephant became profoundly sedated. He was reversed with 60 mg yohimbine IV. The author suggests that the elephant’s visual impairment may have caused the reaction (Sarma, 1999). 

g) Intravenous xylazine (33-72 µg/kg) was titrated to achieve standing sedation with responsiveness to voice commands in a 5000 kg male Asian elephant sedated on 3 occasions for treatment of a foot abscess. Partial reversal with atipamezole made the animal more responsive

in cases of heavy sedation (Honeyman et.al. 1998).

h) Xylazine doses ranging from 100-550 mg with a mean of 0.209 mg/kg body weight were used to capture 8 wild Asian elephants (Bosi et.al. 1997).

i) Captive Asian elephants:

For sedation: 0.04-0.08 mg/kg (180-360 mg total dose);

For immobilization 0.15-0.20 mg/kg alone or 0.12 mg/kg xylazine in combination with 0.33mg / kg ketamine.

ii) Captive African elephants:

For sedation: 0.08-0.10 mg/kg (100-640 mg total dose);

For immobilization (opiates are preferred): 0.15-0.20 mg/kg xylazine;

For babies and juveniles: 0.14 mg/kg xylazine in combination with 1.14 mg/kg ketamine (Fowler,1995).

j) Adult 700 mg; juvenile-adult 200-600mg; baby-juvenile 20-160 (species not specified); adult Asian elephant for translocation 150-2850 mg (Kock et.al. 1993). (Author’s (Mikota) note: Theanimal category and drug dose column headings for xylazine are misaligned in this reference and may cause confusion. The doses listed here have been correctly matched to their respective age categories. Regarding the Asian elephant dose, also note that in the original source (Lahiri-Choudhury, 1992), 2850 mg represents a combination of xylazine and ketamine. It does not represent a high end dose of xylazine alone. In this comparative study, 2850 mg was the maximum given to an individual elephant (over the time period that included capture and translocation, not as a single dose) and the maximum dose used during 24 hours.

k) 100 mg/ton is an ideal dose for Asian elephants (Appayya, 1992).

l) In a comparison of Asian elephant capture and translocation techniques, 400 mg xylazine was the maximum single dose used in Malaysia (tusker over 9’6”) and 150 mg was the maximum dose used in West Bengal (tusker 8’2”). Maximum total on a single elephant were 2100 mg over 4 days (Malaysia) and 1525 mg (West Bengal). Maximum during 24 hours was 1500 mg

(Malaysia) and 925 mg (West Bengal). (Lahiri- Choudhury, 1992). 

m) Xylazine, administered IM was used to induce surgical anesthesia in 8 Asian elephants. A dose of 150 mg in a1500 kg baby tusker and a dose of 400 mg in a 3000 kg tusker resulted in standing immobilization. Recumbent immobilization was achieved with doses of 400 mg (3500 kg tuskers) and 450 mg (4000 kg tusker), and with combinations of 350 mg xylazine + 350 mg ketamine (3000 kg cow), 300 mg xylazine + 150 mg acepromazine (2500 kg cow) and 350 mg xylazine + 150 mg acepromazine (3000 kg cow). Induction occurred in 10-15 minutes and duration of anesthesia varied from 30-60 minutes and provided sufficient analgesia for a variety

of surgical procedures (Nayar, et.al. 1992).
Monitoring parameters

• Level of sedation/anaesthesia/analgesia.
• Respiratory function.
• Cardiovascular function.
• Hydration status if polyuria develops.

Withdrawal period / Withholding time

Notes

"Residues in edible tissues, except for the injection site, liver, and kidney, are usually below 0.1 ppm by 10 hours after administration. The levels in all tissues are below 0.1 ppm by 72 hours after administration."

UK:

• "Cattle may be slaughtered for human consumption only after 14 days from the last treatment."
• "Do not use in cows producing milk for human consumption."

USA:

• In the USA xylazine is approved for use in dogs, cats and horses, and in various deer. It is not approved for use in food-producing animals. "The FDA is concerned about the potential carcinogenicity of xylazine now that the 2,6-dimethylaniline metabolite has been shown to be carcinogenic in rats." It was noted that "The toxicological studies of xylazine submitted to FDA to date are insufficient to allow a determination of its carcinogenic response." [1998]
• "Not approved for any species to be consumed for food purposes."
• "While xylazine is not approved for use in cattle in the USA, at labeled doses in Canada it reportedly has been assigned withdrawal times of 3 days for meat and 48 hours for milk. FARAD has reportedly suggested a withdrawal of 7 days for meat and 72 hours for milk for extra-label use in the USA."

Toxic Information

Toxic effects of Pharmaceutical Products

Contraindications / Precautions

• Contraindicated in individuals with active ventricular arrhythmias.
• Contraindicated in individuals receiving adrenoceptor stimulants (such as epinephrine).
• Use with extreme caution in individuals with pre-existing cardiac dysfunction, hypotension, shock, respiratory dysfunction, severe hepatic insufficiency, severe renal insufficiency, pre-existing seizure disorders, severe debility.
• Not recommended for use in the last trimester of pregnancy (except at parturition), particularly in cattle, as it may induce premature parturition.
• Caution in debilitated or elderly individuals due to the profound cardiovascular changes.
• Caution in individuals known/suspected to have pulmonary disease.
• In ruminants: 
• Care in dosing: check concentration and dose carefully.
• Not for use in individuals with dehydration, urinary tract obstruction or debility.
• In cattle: with higher doses (0.2 - 0.3 mg/kg) the animal may remain drowsy for some time and it is recommended that the animal should be kept in the shade.
• "In case of accidental overdosage leading to respiratory failure cold water douches and artificial respiration are indicated."
• In horses:
• Caution is required as individuals may kick following auditory or other stimulation.
• Use with caution during the vasoconstrictive phase of laminitis (reduces digital blood flow for about eight hours after administration).
• Use with caution in individuals with intestinal impaction as xylazine may inhibit gastrointestinal mobility.
• In cats and dogs: contraindicated in individuals with gastrointestinal obstruction due to emetic effects.

Adverse Effects / Side Effects / Warnings

• In large animals: ataxia.
• In bradycephalic dogs and in horses with upper airway disease: dyspnoea may be seen.
• Cardiac arrhythmias, bradycardia, polyuria, hypoxaemia, transient hyperglycaemia.
• In horses: intraarterial injection may cause severe seizures and collapse.
• Horses may still kick (accurately) in response to stimulation, particularly auditory.
• In cats and dogs: emesis generally occurs within 3-5 minutes (particularly in cats): do not induce further anaesthesia until at least 3-5 minutes after administration to avoid possible aspiration.
• Cats and dogs: adverse effects may include muscle tremors, bradycardia with partial atrio-ventricular block, reduced respiratory rate, movement in response to sharp auditory stimuli.
• Dogs: aerophagia may result in bloat; gaseous stomach distention may interfere with interpretation of radiographs.
• Cats: increased urination may occur.
• Horses: adverse effects may include muscle tremors, bradycardia with partial atrio-ventricular block, reduced respiratory rate, movement in response to sharp auditory stimuli, sweating, increased intracranial pressure, decreased mucociliary clearance rates.
• Initial bradycardia and second degree heart block resolve after about 10 minutes.
• Cattle: adverse effects may include profuse salivation, ruminal atony, bloat (maintain in sternal recumbency to avoid tympany), regurgitation, hypothermia, diarrhoea, bradycardia, polyuria, premature parturition.
• Pre-treatment with atropine may be used to alleviate hypersalivation and bradycardia.

Overdose / Acute Toxicity

• May cause cardiac arrhythmias, hypotension, profound CNS depression, profound respiratory depression, seizures.
• Reversal with yohimbine, atipamezole or tolazoline has been suggested.
• Mechanical respiratory support with respiratory stimulants such as doxapram for treatment of respiratory depression.

Detailed Toxicological Information

Reproductive effects

• Safety in first month of pregnancy "not established."