Acepromazine

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Acepromazine
Acepromazine.svg
Systematic (IUPAC) name
1-{10-[3-(dimethylamino)propyl]-10H-phenothiazin-2-yl}ethanone
Clinical data
AHFS/Drugs.com International Drug Names
Legal status not approved for use in cattle
Routes IV, IM, oral
Pharmacokinetic data
Bioavailability 6.6L/kg, high volume of distribution
Half-life 3 hours in horses 15.9 hours in canines
Excretion found in equine urine up to 96 hours after dosage
Identifiers
CAS number 61-00-7 YesY
ATC code N05AA04
PubChem CID 6077
DrugBank DB01614
ChemSpider 5852 YesY
UNII 54EJ303F0R YesY
KEGG D07065 YesY
ChEBI CHEBI:44932 YesY
ChEMBL CHEMBL39560 YesY
Chemical data
Formula C19H22N2OS 
Mol. mass 326.456 g/mol
 YesY (what is this?)  (verify)

Acepromazine or acetylpromazine (more commonly known as ACP, Ace, or by the trade names Atravet or Acezine 2, number depending on mg/ml dose) is a phenothiazine derivative antipsychotic drug. It was first used in humans in the 1950s,[1] but is now little used in humans (the closely related analogue, chlorpromazine, is still used as an antipsychotic in humans). Acepromazine is frequently used in animals as a sedative and antiemetic. Its principal value is in quietening and calming anxious animals. The standard pharmaceutical preparation, acepromazine maleate, is used in veterinary medicine in dogs, and cats. It is used widely in horses as a pre-anaesthetic sedative and has been shown to reduce anaesthesia related death. However, it should be used with caution (but is not absolutely contraindicated) in stallions due to the risk of paraphimosis and persistent priapism. Its potential for cardiac effects, namely hypotension due to peripheral vasodilation, can be profound and as such is not recommended for use in geriatric or debilitated animals, especially dogs. In these cases it is most often substituted with midazolam or diazepam and left out of the preanesthetic medication altogether.

Administration[edit]

Canine[edit]

When used as a premedication it is commonly administered via the subcutaneous or intramuscular route.

Potential adverse effects in dogs[edit]

Literature from the 1950s raised concerns about phenothiazine-induced seizures in human patients. A family of Boxer in the UK were implicated for an increased seizure risk when given acepromazine and it was previously recommended to avoid this medication in this breed. For this reason, caution has typically been advised when contemplating acepromazine use in epileptic canine patients although no veterinary studies have been published until quite recently. The two published veterinary studies have failed to show a positive association between use of acepromazine and seizure activity and show a possible role for acepromazine in seizure control: in a retrospective study at University of Tennessee, acepromazine was administered for tranquilization to 36 dogs with a prior history of seizures and to decrease seizure activity in 11 dogs. No seizures were seen within 16 hours of acepromazine administration in the 36 dogs that received the drug for tranquilization during hospitalization. After acepromazine administration, seizures abated for 1.5 to 8 hours (n=6) or did not recur (n=2) in eight of 10 dogs that were actively seizing. Excitement-induced seizure frequency was reduced for 2 months in one dog.[2] A second retrospective study also concluded that administration of acepromazine to dogs with prior or acute seizure history did not potentiate seizures and there was some trend toward seizure reduction.[3] It should be noted that the original seizure cautions reported in the 1950s were in human patients on relatively high anti-psychotic doses of chlorpromazine while the doses of acepromazine used in the only two published veterinary studies cited above are much lower.

Recently a multi-drug resistance gene (MDR1) has been isolated by researchers at Washington State University College of Veterinary Medicine. Mutations in the gene are more common in certain herding breeds and whippets (although Border Collies are underrepresented) as well as many mixed breeds. The mutation causes increased sensitivity to ivermectin and related avermectins, acepromazine, certain opioids and opioid derivatives, as well as vincristine and certain other chemotherapeutics. It is recommended that acepromazine dose be reduced by 25% in heterozyogtes and by 30-50% in dogs homozygous for the mutation. Owners may test their dogs via a kit available from WSU and are strongly encouraged to share those results with their veterinarian.[4]

The Boxer is reported to have a breed-related sensitivity to acepromazine. In 1996 a warning was placed in the cardiology section of the Veterinary Information Network (VIN), a US-based network for practicing veterinarians, entitled "Acepromazine and Boxers." It described several adverse reactions to acepromazine in three Boxers at the University of California at Davis veterinary teaching hospital. The reactions included collapse, respiratory arrest, and profound bradycardia (slow heart rate, less than 60 beats per minute). While there is disagreement among some veterinarians on this point, a number of veterinary publications recommend the drug be avoided in the breed.[5] Individual dogs of any breed can have a profound reaction characterized by hypotension (low blood pressure), especially if there is an underlying heart problem.

Acepromazine should be used with caution in sighthounds.[5]

Equine[edit]

Acepromazine can be administered by the intramuscular route, taking effect within 30–45 minutes, or may be given intravenously, taking effect within 15 minutes. Sedation usually lasts for 1–4 hours, although some horses may feel the effects for up to 24 hours. The standard dose is highly variable, depending upon the desired effect following administration. An oral gel formulation is also available (Sedalin gel). The dosage by this route is also highly variable, but it is generally accepted that the recommended dose will give moderate sedation in most horses.

In the UK, acepromazine is not authorised for use in horses intended for human consumption.[6] In equine surgery, premedication with acepromazine has been shown to reduce the perianaesthetic mortality rate,[7] although the reasons for this are unclear.

Additionally, acepromazine is used as a vasodilator in the treatment of laminitis, where an oral dose equivalent to "mild sedation" is commonly used, although the dose used is highly dependent on the treating veterinarian. While it is shown to elicit vasodilation in the distal limb, evidence showing its efficacy at increasing perfusion in the laminae is lacking. It is also sometimes used to treat a horse experiencing Equine Exertional Rhabdomyolysis.

Precautions when using in horses[edit]

Acepromazine is a prohibited class A drug under FEI rules, and its use is prohibited or restricted by many other equestrian organizations. It can be detected in the blood for 72–120 hours, although repeated doses may make it remain present for several months.

Side effects are not common, but the use of acepromazine in stallions should be used with caution (but is not absolutely contraindicated) due to the risk of paraphimosis and priapism.[8]

Acepromazine should not be used in horses dewormed with piperazine. It lowers blood pressure, and should therefore be used with caution in horses that are experiencing anemia, dehydration, shock, or colic.

Feline[edit]

Acepromazine is sometimes recommended or prescribed in tiny oral doses to the pet cats of allergy sufferers. [9]

Drug reaction in herding dogs[edit]

For over 20 years herding dogs have died from negative reactions to acepromazine that were rooted in genetic mutations.[citation needed] This reveals a lack of understanding about acepromazine, and other drugs with potentially toxic side effects. Scientists isolated the problem: the Multi Drug Resistant 1 (MDR1) gene. In addition, more than 30 potentially toxic drugs have been identified, and a lab test has been developed to identify dogs with the abnormal MDR1 gene. Three different factors are now recognized that contribute to drug toxicity especially common in herding dogs: a genetic mutation, drugs that inactivate normal cell pumps, and substances that inactivate cell enzymes so they cannot break down drugs.

In addition to having proteins on the membrane that remove drugs from the cell, most cells have enzymes that break down drugs and inactivate them. Cytochrome P 450 is a family of enzymes that inactivates about 60% of drugs used in pets. One of the CYP 450 family—CYP3A—can be blocked or inactivated by ketoconazole and by grapefruit juice. With CYP3A inactivated, drugs reach toxic concentrations within cells.

Dogs can have both the defective MDR1 gene and have inactivated CYP3A enzymes. These dogs are very likely to develop toxicity with certain drugs.

Breeds with MDR1 gene

Herding dogs: Australian Shepherd, Border Collie, Collie, English Shepherd, German Shepherd, Old English Sheepdog, and Sighthounds.

Drugs that become toxic if not pumped out by P-glycoproteins[edit]

Many different drugs are normally pumped from cells by P-glycoproteins: anticancer drugs, antiparasitics, antibiotics, cardiac drugs, immunosuppressants, opioids, steroid hormones, and miscellaneous drugs. Acepromazine can become toxic in dogs with the MDR1 mutation. The commonly used veterinary antihelmintic ivermectin is another example of a drug which is peripherally acting due to p-glycoprotein.

The anxiolytic drugs like acepromazine can lead to hearing loss and other serious side effects.

References[edit]

  1. ^ Collard JF, Maggs R (June 1958). "Clinical Trial of Acepromazine Maleate in Chronic Schizophrenia". British Medical Journal 1 (5085): 1452–4. doi:10.1136/bmj.1.5085.1452. PMC 2029326. PMID 13536530. 
  2. ^ Tobias KM, Marioni-Henry K, Wagner R (2006). "A retrospective study on the use of acepromazine maleate in dogs with seizures". Journal of the American Animal Hospital Association 42 (4): 283–9. PMID 16822767. 
  3. ^ McConnell J, Kirby R, Rudloff E (2007). "A retrospective study on the use of acepromazine maleate in dogs with seizures". Journal of Veterinary Emergency and Critical Care 17 (3): 262–7. doi:10.1111/j.1476-4431.2007.00231.x. 
  4. ^ http://www.vetmed.wsu.edu/depts-VCPL/test.aspx
  5. ^ a b Jennifer Walker, ABC Health & Research Committee. "Acepromazine and Boxers - References". Retrieved 2009-01-16. 
  6. ^ NOAH, Compendium of Data Sheets for Animal Medicines (2005)
  7. ^ GM Johnston, JK Eastment, JLN Wood, PM Taylor (2002). "The confidential enquiry into perioperative equine fatalities (CEPEF): mortality results of Phases 1 and 2". Veterinary Anaesthesia and Analgesia 29 (4): 159–70. doi:10.1046/j.1467-2995.2002.00106.x. 
  8. ^ Plumb, Donald C. (2011). Plumb's Veterinary Drug Handbook, 7th ed.. Ames, Iowa: Wiley-Blackwell. pp. 4–5. ISBN 978-0-4709-5965-7. 
  9. ^ Klucka, Charles V.; Ownby, Dennis R.; Green, Jack; Zoratti, Edward (June 1, 1995). "Cat shedding of Fel d I is not reduced by washings, Allerpet-C spray, or acepromazine". The Journal of allergy and clinical immunology 95 (6): 1164–1171. doi:10.1016/S0091-6749(95)70072-2. PMID 7797784. Retrieved September 1, 2010. "Conclusions: Our data do not show significant reductions in Fel d I shedding as a result of any of these treatments. Therefore we cannot recommend them to patients allergic to cats."