Vol. 21, No. 1January 199920TH ANNIVERSARY
FOCAL POINTKEY FACTS
5
Because of their actions onspecific receptors, the clinicalactions of
α
2
-adrenoceptoragonists can be antagonizedby selective antagonists.
Xylazine Sedation Antagonized withTolazoline
University of IllinoisLloyds, Inc.
John C. Thurmon, DVM, MS
Shenandoah, Iowa
Ragenia Sarr, BS Joseph W. Denhart, DVM, MS
ABSTRACT:
Physiologic alterations induced by xylazine depend on the dose, rate, and route ofadministration and are influenced by the concomitant administration of other classes of drugs.When these factors are appropriately considered,
α
2
-adrenoceptor agonists are safe drugs forinducing narcosis, analgesia, and muscle relaxation in healthy fasted ruminants. Tolazolinehas proven to be a safe, effective antagonist for xylazine-induced sedation and other actionswhen the proper dose is administered.
T
he
α
2
-adrenoceptor agonists, which are the most widely used drugs forimmobilizing ruminants, have most of the desirable properties of opioidsbut induce few of their undesirable actions. Unlike opioids,
α
2
-adreno-ceptor agonists do not cause excitement and only induce minimal respiratory de-pression in ruminants. They are not FDA-controlled substances and thereforedo not require extensive record keeping. In addition,
α
2
-adrenoceptor agonistsare potent analgesics that induce dose-related sedation, thereby decreasing therequired dose of primary anesthetic. When the proper dose is administered,these agonists do not cause excitement or profound respiratory depression. Xy-lazine, the most notable
α
2
-adrenoceptor agonist, induces analgesia, sedation,and muscle relaxation by activating centrally located
α
2
-adrenoceptors.The response of ruminants to xylazine is similar to that of other animals toopioids (e.g., dogs to morphine). Because of their actions on specific receptors,the clinical actions of
α
2
-adrenoceptor agonists can be antagonized by selectiveantagonists (e.g., tolazoline, yohimbine, or atipamezole).
1
XYLAZINEHistory and Actions
Xylazine, the first
α
2
-adrenoceptor agonist to be widely used in veterinary medicine, was synthesized in Germany in 1962 as an antihypertensive drug forhumans. It was subsequently found to have potent sedative actions in animals. Although xylazine was not identified as an
α
2
-adrenoceptor agonist when it wasinitially introduced for veterinary use, the drug had profound sedative–anal-gesic–muscle relaxant action in cattle and other ruminants. In the United States,
V
s
The
α
2
-adrenoceptor agonistsare potent analgesics that inducedose-related sedation, therebydecreasing the required doseof primary anesthetic.
s
Failure to achieve optimumsedation with
α
2
-adrenoceptoragonists may be caused bypreexisting stress, fear,excitement, or pain.
s
Tolazoline has been safely usedto antagonize xylazine-inducedsedation and initiate arousal; itproduces strong peripheralvasodilation with sympatheticblocking and histamine-likeactions.
s
Administration of an
α
2
-adrenoceptor antagonist toreverse sedation is not withoutrisk; deaths have occurred inanimals receiving rapidintravenous overdoses oftolazoline or yohimbine.
Refereed Peer Review
CE
xylazine is approved by the FDA for horses, dogs, cats,deer, and elk only.
1
Xylazine
’
s activation of
α
2
-adrenoceptors located inthe central nervous system (CNS) induces analgesia, se-dation, muscle relaxation, anxiolysis, sympatholysis,and other responses. In addition to centrally located re-ceptors, receptors are present in peripheral tissue (e.g.,the gastrointestinal [GI] tract, uterus, kidney, andplatelets). Activation of the
α
2
-adrenoceptors in the GItract of ruminants results in ruminal hypomotility andincreased GI fecal waste material.
2
The cardiovascularactions of
α
2
-adrenoceptor agonists include increasedblood pressure (BP) and decreased heart rate (HR), thelatter being characterized by sinus bradycardia and/oratrioventricular blockade.
1,3,12
If these actions are a response to an overdose of xy-lazine, they can be antagonized by administering tolaz-oline; however, tolazoline also antagonizes the sedationand analgesia produced by xylazine.
1
Drooling (proba-bly from suppression of the swallowing reflex) and low bellowing are often observed in ruminants.
1,3
Becausexylazine can depress the cyclic reticuloruminal motorfunction and thus result in fatal ruminal tympany inunfasted cattle, adult cattle should not receive food or
Food Animal20TH ANNIVERSARY
Compendium
January 1999
α
2
-ADRENOCEPTOR ACTIVATION
s
CARDIOVASCULAR ACTIONS
s
24-HOUR FASTING
Figure 1AFigure 1BFigure 1CFigure 1DFigure 1—
A large bull weighing 1100 kg was (
A
and
B
) sedat-ed by injecting xylazine into the tail vein and then (
C
) ke-tamine into the jugular vein. (
D
) A mouth wedge was insertedand an endotracheal tube placed to protect the airway in casethe bull regurgitated. Finally, oxygen was supplied and surgery performed on (
E
) the injured foot.
Figure 1E
water for 24 hours before animmobilizing dose of xyla-zine is administered. If fast-ing is not possible, an
α
2
-adrenoceptor antagonist (e.g.,tolazoline) should always beavailable to alleviate ruminaldepression and/or gut hypo-motility and to relieve or al-leviate tympany.
4,5
Use in Ruminants
Xylazine is a mixed
α
1
-/
α
2
-adrenoceptor agonist usedin ruminants throughoutthe world. In 1991, esti-mates indicated that 10 mil-lion doses of
α
2
-adrenocep-tor agonists (of which 7 million were apparently xylazine) were administered annually to animals.
6
Xy-lazine is considered to be a reliable sedative with pro-found muscle relaxation, making it highly desirable forimmobilizing large ruminants. Xylazine can be safely administered by the intramuscular, intravenous (Figure1), and epidural routes.
1
Cattle are apparently one of the most sensitive species to the sedative and immobi-lizing actions of xylazine and therefore require a rathersmall dose. Clinical observations suggest that cattle areapproximately 5 to 10 times more sensitive than horsesto a given dose of xylazine. Sheep and goats are appar-ently slightly more sensitive than cattle or llamas.
1,3
In cattle, the degree of sensitivity varies amongbreeds. Brahmans evidently are the most sensitivebreed, followed by Herefords, Jerseys, holsteins, and Angus.
1
The peculiarity of US breeds of cattle can leadto dangerous overdosing, especially when a dose of xy-lazine intended for horses is accidentally injected
—
astrong argument for keeping a safe, effective antagonist,such as tolazoline, nearby.
As an Anesthetic Adjunct
In the early 1970s, reports on the use of xylazine as ananesthetic adjunct were published in US and Europeanveterinary literature.
7
–
15
These reports documented theeffectiveness of xylazine in eliminating muscular hyper-tonicity in dogs and cats that had been anesthetized with ketamine
7,9,10
and the rapid onset of predictable se-dation, analgesia, and muscle relaxation in horses andcattle after being injected with xylazine.
8,11
–
16
The onsetof action for xylazine is approximately 3 to 5 minutesafter intravenous injection and within 8 to 10 minutesafter intramuscular injection. In cattle and sheep, peak plasma concentrations occur within 12 to 14 minutes.The systemic half-life is ap-proximately 23 minutes insheep and 36 minutes in cat-tle.
1,a
In the United States,meat and milk withdrawaltimes for xylazine-treatedcattle have not been estab-lished. In Canada, the Unit-ed Kingdom, France, Ger-many, and Switzerland,however, withdrawal timeshave been determined.
17,18
InFrance and the United King-dom, the meat withdrawaltime ranges from 2 to 14days; whereas the milk with-drawal time ranges from 0 to72 hours in most countries. When intramuscular xylazine is given in a dangerously high dose (i.e., 1.2 to 2.0 mg/kg), a 120-day withdrawalinterval is imposed in Germany.
17
After cattle have been injected with xylazine, adose-dependent, sleeplike state occurs and often persistsfor 1 to 2 hours, although the duration of analgesia ismuch shorter (20 to 35 minutes) depending on thedose administered. In most domestic species, xylazineminimally affects respiratory function at recommendeddoses.
1
In contrast, caution is advised when administer-ing xylazine or any other
α
2
-adrenoceptor agonist toyoung ruminants in high singular or cumulative dosesor combined with potent cardiorespiratory-depressantanesthetics (e.g., heavy doses of thiopental or pentobar-bital).
1
Special precautions should be taken when ma-ture ruminants receive xylazine before improper fastingbecause of the potential for developing life-threateningruminal tympany.
As a Sedative, Analgesic, and Muscle Relaxant
Xylazine is extensively used for sedation, analgesia,and muscle relaxation in cattle,
18,19
sheep,
20
–
22
goats,
1
and llamas
1
(Figure 2). In these animals, xylazine con-tributes to the safety and efficacy of general anesthe-sia by decreasing the required dose of anesthetic. It is adesirable adjunct when the appropriate dose is admin-istered simultaneously with ketamine, telazol, guai-fenesin
–
ketamine, or a thiobarbiturate (Table I) forinducing a short period of surgical anesthesia or whenanesthesia is to be extended with an inhalant. After theonset of xylazine-induced sedation in large bulls (Figure1), intravenous xylazine (0.11 mg/kg) followed by in-travenous ketamine (2.0 mg/kg) can produce 20 to 40
Compendium
January 199920TH ANNIVERSARYFood Animal
SENSITIVITY REACTIONS
s
ONSET OF ACTION
s
SAFETY AND EFFICACY
Figure 2
—
Becausethe jugular vein is often difficult tocatheterize in llamas, intravenous xylazine and ketamine areoften given; recovery can be hastened by administering tolaz-oline.
a
Personal communication: Mozier J, Animal Health Division,Chemagro Corporation, Stillwell, Kansas.
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Xylazine Sedation Antagonized With Tolazoline
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