Atipamezole
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Atipamezole (brand name Antisedan, also available in generic forms as Revertidine, is a synthetic α2 adrenergic receptor
antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, ri ...
indicated for the reversal of the sedative and analgesic effects of dexmedetomidine and medetomidine in dogs. Its reversal effect works by competing with the sedative for α2-adrenergic receptors and displacing them. It is mainly used in veterinary medicine, and while it is only licensed for
dogs The dog (''Canis familiaris'' or ''Canis lupus familiaris'') is a domesticated descendant of the wolf. Also called the domestic dog, it is derived from the extinct Pleistocene wolf, and the modern wolf is the dog's nearest living relative. ...
and for
intramuscular Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles ha ...
use, it has been used
intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
, as well as in
cats The cat (''Felis catus'') is a domestic species of small carnivorous mammal. It is the only domesticated species in the family Felidae and is commonly referred to as the domestic cat or house cat to distinguish it from the wild members o ...
and other animals. There is a low rate of side effects, largely due to atipamezole's high specificity for the α2-adrenergic receptor. Atipamezole has a very quick onset, usually waking an animal up within 5 to 10 minutes. It was originally released in 1996 and is sold in the U.S. by
Zoetis Zoetis Inc. (/zō-EH-tis/) is an American drug company, the world's largest producer of medicine and vaccinations for pets and livestock. The company was a subsidiary of Pfizer, the world's largest drug maker, but with Pfizer's spinoff of its ...
.


Medical uses

Atipamezole is a veterinary drug whose prime purpose is to reverse the effects of the sedative dexmedetomidine (as well as its
racemic In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
mixture, medetomidine).Because dexmedetomidine is the only pharmacologically active component of medetomidine, they will both be referred to as ''dexmedetomidine'' from here on out. It can also be used to reverse the related sedative
xylazine Xylazine is a pharmaceutical drug used for sedation, anesthesia, muscle relaxation, and analgesia in animals such as horses, cattle, and other non-human mammals. Veterinarians also use xylazine as an emetic, especially in cats. It is an anal ...
. While it reverses both the sedative and
analgesic An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
(pain-relieving) effects of dexmedetomidine, atipamezole may not entirely reverse the
cardiovascular The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
depression that dexmedetomidine causes. Atipamezole is licensed in the United States for
intramuscular injection Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles hav ...
(IM) in
dogs The dog (''Canis familiaris'' or ''Canis lupus familiaris'') is a domesticated descendant of the wolf. Also called the domestic dog, it is derived from the extinct Pleistocene wolf, and the modern wolf is the dog's nearest living relative. ...
; it is, however, used off-label in
cats The cat (''Felis catus'') is a domestic species of small carnivorous mammal. It is the only domesticated species in the family Felidae and is commonly referred to as the domestic cat or house cat to distinguish it from the wild members o ...
,
rabbits Rabbits, also known as bunnies or bunny rabbits, are small mammals in the family Leporidae (which also contains the hares) of the order Lagomorpha (which also contains the pikas). ''Oryctolagus cuniculus'' includes the European rabbit sp ...
, and farm animals such as
horses The horse (''Equus ferus caballus'') is a domesticated, one-toed, hoofed mammal. It belongs to the taxonomic family Equidae and is one of two extant subspecies of ''Equus ferus''. The horse has evolved over the past 45 to 55 million ...
and cows, as well as in zoo medicine for
reptiles Reptiles, as most commonly defined are the animals in the class Reptilia ( ), a paraphyletic grouping comprising all sauropsids except birds. Living reptiles comprise turtles, crocodilians, squamates ( lizards and snakes) and rhynchoceph ...
(including
tortoises Tortoises () are reptiles of the family Testudinidae of the order Testudines (Latin: ''tortoise''). Like other turtles, tortoises have a turtle shell, shell to protect from predation and other threats. The shell in tortoises is generally hard, ...
,
turtles Turtles are an order of reptiles known as Testudines, characterized by a special shell developed mainly from their ribs. Modern turtles are divided into two major groups, the Pleurodira (side necked turtles) and Cryptodira (hidden necked tu ...
, and alligators),
armadillos Armadillos (meaning "little armored ones" in Spanish) are New World placental mammals in the order Cingulata. The Chlamyphoridae and Dasypodidae are the only surviving families in the order, which is part of the superorder Xenarthra, along ...
, hippopotamuses,
giraffe The giraffe is a large African hoofed mammal belonging to the genus ''Giraffa''. It is the tallest living terrestrial animal and the largest ruminant on Earth. Traditionally, giraffes were thought to be one species, '' Giraffa camelopardal ...
s,
okapi The okapi (; ''Okapia johnstoni''), also known as the forest giraffe, Congolese giraffe, or zebra giraffe, is an artiodactyl mammal that is endemic to the northeast Democratic Republic of the Congo in central Africa. It is the only species ...
, and others. It has been given
intravenously Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
(IV), subcutaneously, intraperitoneally and, in red-eared sliders,
intranasally Nasal administration, popularly known as snorting, is a route of administration in which drugs are insufflated through the nose. It can be a form of either topical administration or systemic administration, as the drugs thus locally delivered ...
. IV administration is recommended in emergencies. Atipamezole has also been used as an antidote for various toxicities in dogs. For example, the anti-
tick Ticks (order Ixodida) are parasitic arachnids that are part of the mite superorder Parasitiformes. Adult ticks are approximately 3 to 5 mm in length depending on age, sex, species, and "fullness". Ticks are external parasites, living by ...
medication
amitraz Amitraz (development code BTS27419) is a non-systemic acaricide and insecticideCorta, E., Bakkali, A., Berrueta, L. A., Gallo, B., & Vicente, F. (1999). Kinetics and mechanism of amitraz hydrolysis in aqueous media by HPLC and GC-MS. Talanta, 48( ...
is commonly ingested by dogs who eat their anti-tick collars. Amitraz works by the same mechanism as dexmedetomidine and is thus easily reversed by atipamezole. Atipamezole also reverses the hypotension caused by
tizanidine Tizanidine, sold under the brand name Zanaflex among others, is a medication that is used to treat muscle spasticity due to spinal cord injury or multiple sclerosis as well as spastic cerebral palsy. Effectiveness appears similar to baclofen o ...
(a muscle relaxant) toxicity, and relieves toxicity from
decongestants A decongestant, or nasal decongestant, is a type of pharmaceutical drug that is used to relieve nasal congestion in the upper respiratory tract. The active ingredient in most decongestants is either pseudoephedrine or phenylephrine (the latter o ...
such as
ephedrine Ephedrine is a central nervous system (CNS) stimulant that is often used to prevent low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in ...
and
pseudoephedrine Pseudoephedrine (PSE) is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent in higher doses. It was first characteri ...
.


Available forms

Atipamezole is sold at 5 mg/mL for ease of use: 5 times as much atipamezole as medetomidine is needed for full reversal, and because medetomidine is sold as 1 mg/mL, 1 mL of atipamezole reverses 1 mL of medetomidine. When the enantiomerically pure version of medetomidine (dexmedetomidine) was released, it was sold at 0.5 mg/mL, because it was twice as strong as medetomidine. As such, 1 mL of atipamezole also reverses 1 mL of dexmedetomidine.


Specific populations

Atipamezole is not recommended for animals that are pregnant, lactating, or slated for breeding.


Contraindications

While there are no absolute contraindications to atipamezole, it is recommended against being given with
anticholinergics Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous sy ...
, as both can cause dramatic increases in heart rate. Atipamezole should also not be given too soon after an animal has been given dexmedetomidine mixed with
ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ne ...
or telazol(
tiletamine Tiletamine is a dissociative anesthetic and pharmacology, pharmacologically classified as an NMDA receptor antagonist. It is related chemically to ketamine. Tiletamine hydrochloride exists as odorless white crystals. It is used in veterinary me ...
); because it reverses only the dexmedetomidine, the ketamine or telazol will still be active, and the animal can wake up excited, delirious, and with muscle contractions. Some recommend not using it in dogs sedated with ketamine at all, since they can convulse due to the excitement effect.


Side effects

Atipamezole's low rate of side effects is due to its high specificity for ɑ2-adrenergic receptors; it has very little affinity for ɑ1-adrenergic receptors and no affinity for most
serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...
,
muscarinic Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rece ...
, and
dopamine receptors Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diffe ...
. There is occasional
vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...
,
hypersalivation Hypersalivation, or ptyalism, also known as sialorrhea or hypersialosis is the excessive production of saliva. It has also been defined as increased amount of saliva in the mouth, which may also be caused by decreased clearance of saliva.Medscape ...
, and
diarrhea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
. It can potentially cause CNS excitement, which can lead to
tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, fa ...
s,
tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...
(increased heart rate), and
vasodilation Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
. The vasodilation leads to a transient decrease in
blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...
, which (in dogs) increases to normal within 10 minutes. There have been reports of transient
hypoxemia Hypoxemia is an abnormally low level of oxygen in the blood. More specifically, it is oxygen deficiency in arterial blood. Hypoxemia has many causes, and often causes hypoxia as the blood is not supplying enough oxygen to the tissues of the body ...
. The chance of side effect can be minimized by administering atipamezole slowly. There is a possibility of the sedation reversing abruptly, leading to nervous, aggressive, or delirious dogs. Such cases are more associated with IV administration (which has a faster onset than IM administration). The rapid administration of atipamezole leads to sudden displacement of dexmedetomidine from peripheral ɑ2-adrenergic receptors; this can cause a sudden drop in blood pressure, which is followed by a reflex tachycardia and hypertension. There have been some cases where IV administration of atipamezole lead to death via
cardiovascular collapse Shock is the state of insufficient blood flow to the tissues of the body as a result of problems with the circulatory system. Initial symptoms of shock may include weakness, fast heart rate, fast breathing, sweating, anxiety, and increased thi ...
. This is thought to be combination of sudden hypotension added onto the low heart rate caused by sedatives. There is some possibility of the animal relapsing into sedation after being given atipamezole, made more likely if the original sedative was given IV. Rats and monkeys have experienced increased sexual activity after being given atipamezole.


Overdose

The LD50 of atipamezole for rats is 44 mg/kg when given subcutaneously. The
minimum lethal dose In toxicology, the lethal dose (LD) is an indication of the lethal toxicity of a given substance or type of radiation. Because resistance varies from one individual to another, the "lethal dose" represents a dose (usually recorded as dose per kilog ...
in dogs is over 5 mg/m2; dogs have tolerated getting ten times the standard dose. Signs of overdose include panting, trembling, vomiting, and diarrhea, as well as increased blood levels of
creatinine kinase Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phosphocreatine kinase, is an enzyme () expressed by various tissues and cell types. CK catalyses the conversion of creatine and uses adenosine triphosphate (ATP) to create phos ...
,
aspartate transaminase Aspartate transaminase (AST) or aspartate aminotransferase, also known as AspAT/ASAT/AAT or (serum) glutamic oxaloacetic transaminase (GOT, SGOT), is a pyridoxal phosphate (PLP)-dependent transaminase enzyme () that was first described by Arthur ...
, and
alanine transaminase Alanine transaminase (ALT) is a transaminase enzyme (). It is also called alanine aminotransferase (ALT or ALAT) and was formerly called serum glutamate-pyruvate transaminase or serum glutamic-pyruvic transaminase (SGPT) and was first character ...
. Dogs who received atipamezole without first receiving dexmedotomidine have shown no clinical signs other than mild muscle tremors.


Pharmacology


Mechanism of action

Atipamezole is a competitive antagonist at ɑ2-adrenergic receptors that competes with dexmedetomidine, an ɑ2-adrenergic receptors agonist''.'' It does not directly interact with dexmedetomidine; rather, their structural similarity allows atipamezole to easily compete for receptor binding sites. Atipamezole reverses analgesia by blocking
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
feedback inhibition on nociceptors.


Pharmacokinetics

Out of the three ɑ2-antagonists commonly used in veterinary medicine (atipamezole,
yohimbine Yohimbine (), also known as quebrachine, is an indole alkaloid derived from the bark of the African tree ''Pausinystalia johimbe''; also from the bark of the unrelated South American tree ''Aspidosperma quebracho-blanco''. Yohimbine is an α2- ...
, and tolazine), atipamezole shows the highest preference for ɑ2- over ɑ1-receptors, binding to them with a ratio of 8526:1. It shows no preference for a particular ɑ2-receptor subtype. Atipamezole has a rapid onset: it reverses the decreased heart rate caused by sedation within three minutes. The animal usually begins waking up within 5–10 minutes. In a study of over 100 dogs, more than half could stand up within 5 minutes, and 96% could stand up within 15. Atipamezole reaches maximum serum concentration within 10 minutes of IM administration. Atipamezole is distributed extensively to the tissues; at a particular time, concentrations in the brain reach two to three times the concentration in the plasma. Atipamezole undergoes heavy
first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the systemi ...
in the liver, which includes the
glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve glycosid ...
at nitrogen during. Metabolites are mostly excreted in the urine. The elimination half-life is 2.6 hours in dogs and 1.3 hours rats.


Research

Atipamezole's effects on
cognitive function Cognitive skills, also called cognitive functions, cognitive abilities or cognitive capacities, are brain-based skills which are needed in acquisition of knowledge, manipulation of information and reasoning. They have more to do with the mechanisms ...
have been studied in rats and in humans. While low doses in rats improved alertness, selective attention, learning, and recall, higher doses generally impaired cognitive function (most likely due to norepinephrine overactivity). In rats, it has also been shown to improve cognitive function decreased by
stroke A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functionin ...
s or brain lesions. Studies in humans have found it to increase focus but decrease multitasking abilities. Atipamezole has also been researched in humans as a potential anti-Parkinsonian. Because atipamezole increases sexual activity in monkeys, there have been claims of its potential to treat erectile dysfunction.


See also

*
Detomidine Detomidine is an imidazole derivative and α2-adrenergic agonist, used as a large animal sedative, primarily used in horses. It is usually available as the salt detomidine hydrochloride. It is a prescription medication available to veteri ...
*
Flumazenil Flumazenil (also known as flumazepil, code name Ro 15-1788) is a selective GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines ( ...
*
Naloxone Naloxone, sold under the brand names Narcan (4 mg) and Kloxxado (8 mg) among others, is a medication used to reverse or reduce the effects of opioids. It is commonly used to counter decreased breathing in opioid overdose. Effects begin within ...


Notes


References


Further reading

* *


External links

* * of Antisedan. {{Alpha blockers Veterinary drugs Imidazoles Indanes Antidotes Alpha-2 blockers