WHAT
Ketamine in some areas of the world and veterinary practices is one of the most common drugs administered to cats for surgical operations. It is an injectable known for its anesthetic, sedative, and pain relieving properties. One unique characteristic of this drug is that it does not affect breathing and the heart like other drugs have in the past. Some cats can tolerate the drug with little issues while others have severe side effects, some of which have led to death. More recently however pet owners and breeders have reported more negative reactions.
As of 2018 ketamine’s analgesic effects have not yet been studied in a feline surgical model.” (1, 2, 3)
In a study concerning feline drug metabolism and disposition, researchers identified several trends
1) Drugs are eliminated in three main methods a) oxidation via Cytochrome enzyme b) by conjugate elimination (a type of reaction mechanism) c) unaltered in the urine or bile
2) Drugs are eliminated slowly in felines due to a deficiency in drug conjugation pathways
3) Cats need adjusted doses to avoid reactions
(4)
SIDE EFFECTS OF KETAMINE
Various studies point to neurodegeneration in young patients as a long term risk of ketamine (5).
Numerous studies and ketamine package inserts voice further concerns and side effects.
-Muscle tremors -severe changes in behavior -noticeable decrease in energy and sleeping longer -aggressive behavior -aversion to owners -increased vocalization -increased appetite -restlessness -fearfulness -sensitivity to touch (6) -increases in body temperatures (normal is 99.5-102.5, hyperthermia results in temperatures of 106–108°F) (7,8,9) -Dysphoric recoveries
From a package insert specifically for injectable ketamine used for cats:
-Apnea (stop breathing) -respiratory arrest -vomiting -salivation -vocalization -erratic recovery and prolonged recovery -spastic jerking movements -convulsions -muscular tremors -hypertonicity (increase in muscle tone tension) -opisthotonos (muscle spasms resulting in the arching of head, neck, and spine) -dyspnea (labored breathing) -cardiac arrest -death (this is less common when ketamine is used alone and very frequent when used with sedatives or anesthetics. In most cases ketamine is combined with other drugs.)
(10) Dr. Mike Richards DVM also notes that ketamine causes an increase in blood pressure which if severe enough can cause problems with individual cats. He also comments that once in the system ketamine cannot be reversed. If the animal sustains a reaction or other problem there is nothing to do other than supportive care until the drug wears off. (11)
It is noted that to reduce the chances of a reaction to not stimulate with any noise or touching during recovery.
Side effects are also more of a concern in those with hypertrophic cardiomyopathy or other heart conditions as well as liver and kidney diseases especially as a lot of metabolism sites for drugs is located in these organs.
WHY ARE THERE REACTIONS TO KETAMINE
Dr. Will Powers, a medical doctor, and Bengal cat owner explain that cats often have an increase or decrease in an enzyme in their liver associated with the Cytochrome P450 system (12). While the metabolism of drugs can occur in the intestines, kidneys, and lungs, metabolism of ketamine primarily occurs in the liver especially in animals (13).
Cytochrome P450 or CYPs are hemeproteins (14). They are the main players involved in 75% of metabolizing drugs and other toxic substances. Most CYP isoforms (or structurally different but related proteins) are found in the liver. (15, 16, 17, 18).
A problem with Cytochrome P450 is a common reason for how a person can overdose on drugs or alcohol despite consuming the same amount as someone that would have no problems. Because the body cannot break down these materials properly an overdose or severe reaction occurs which could include “rapid heartbeat, vomiting, dehydration, and death.” Reactions may not occur right away because unlike a gas, ketamine stays in the blood for a while and doesn’t wear off as quickly (12).
CYTOCHROME P450 INHIBITION
While a deficiency in CYP isoforms can prevent the proper breakdown of drugs in the feline body, as with anything certain ingredients can alter the activity of CYP isoforms either inhibiting or encouraging activity. When this happens, drug reactions are often a result as increasing or decreasing CYP activity affects the metabolism of the drug in question. St. John’s wort, tobacco smoke, starfruit, watercress, tributyltin, and goldenseal all inhibit CYP isoforms (14, 19, 20, 21, 22, 23, 24). Ketamine specifically has hinderance on how the CPY isoforms function (25). However, the most common inhibitor that Almost completely blocks Ketamine is 1-aminobenzotriazole (26). Four other CYP inhibitors and anti CYPs reduce the N-demethylation of Ketamine (26).
TOXICITY
While most studies on ketamine primarily look at the central nervous system, few look at the liver when it comes to toxicity and reactions. While ketamine is readily used in veterinary medicine is it usually combined with other drugs. Being aware of these interactions is important in understanding the risks and benefits that could affect adverse reactions and efficiency for the drugs. (29). 65% of drug to drug interactions occur at a metabolic site (30) with metabolic enzymes like CYP in the liver are considered the most important sites. 90% of drug to drug interactions occur during CYP catalyzing steps (31). Even supplement to drug interactions and adverse side effects involve CYP activity.
In one study, researchers evaluated the effect of ketamine in relation to various Cytochrome P450 enzyme activity isoforms in rats. They found that:
1) Ketamine causes liver toxicity during extended surgery
2) Ketamine increases the activity of CYP1A2, CYP3A4 and CYP2B6 enzymes which all have the ability to decrease drug capabilities. (31)
In addition to inhibitors of Cytochrome P450, and slow elimination of drugs, felines also are missing UDP-glucuronosyltransferase (UGT) enzymes a major phenol that typically aids in breaking down certain drugs preparing them for elimination by the body. Cats are also deficient in N-acetyltransferase (NAT) 2 and thiopurine methyltransferase (TMPT).
NAT2 is important for the conjugation reaction mechanisms to initiate metabolism and subsequent elimination of drugs (32, 33, 34).
TMPT is primarily for metabolizing thiopurine drugs but due to genetic alterations and complications, the metabolism of many drugs are inhibited often resulting in toxicities and sensitivities. When this enzyme is inhibited it can also lead to bone marrow toxicity, anemia, bleeding, leukopenia, and infection (34, 35, 36). So while these enzymes may not be directly inhibited by ketamine, it's wise to be aware of drug to drug pairings (ketamine is not usually administered alone) as well as effects of other drugs on the body’s ability to process drugs that may affect the body while in surgery and reactions, side effects and toxicities that may occur during or after.
Finally, one last consideration to take into account is Niemann-Pick type C (NPC) disease. While the following study was performed in mice, this disease is found in cats as well with similar effects. NPC is a “neurodegenerative lysosomal storage disease caused by mutations in either the NPC1 or NPC2 gene.”(37). Mice with this disease had increasing toxicities to drugs that were metabolized in the liver. If you recall Cytochrome P450 is a major player in the metabolism of drugs in the liver and it is suggested that there is a dysfunction in this system that relates it to NPC. It seems that over time CYP450 continue to decrease in function as the animal ages. In addition, UGT was also reduced in mice homozygous AND heterozygous for this disease (38, 39, 40, 41).
Interestingly after supplementation with bile acid supplements, it was determined that in many cases there was a bile acid imbalance and the Cytochrome P450 enzymes could be restored to their normal function. (42, 43).
KETAMINE AND OTHER DRUGS
While there are MANY alternatives to ketamine that are safer and don’t last as long in the body, it is highly recommended that is administered “together with medetomidine (Domitor, Dorbene, Dormilan, Medetor, Sedastart, Sedator, Sededorm) and butorphanol (Alvegesic, Dolorex, Torbugesic, Torbutrol, Torphasol) with the antagonist atipamezole (Alzane, Antisedan, Atipam, Revertor, Sedastop)” (44, 45)
KETAMINE SCARE
While a reaction to ketamine is a legitimate concern, a recall in 2009 of injectable Ketamine hasn’t helped the case for the drug. Teva Animal Health was shut down by the FDA on July 21, 2010, after ketamine hydrochloride vials were ineffective, overly effective and caused death in at least five cats with many more unreported. After investigation, it was found that Teva not only failed to discard faulty vials that didn’t meet FDA guidelines, but they failed to maintain their equipment, train their employees, establish quality control and more (46).
While this may have started the worry over using ketamine in cats and specifically Bengals, there is more substantiated information that further backs this notion as evident by the numerous enzymes that cats lack, common drug interactions, diseases, and deficiencies in Cytochrome P450 that make this drug a riskier choice.
While anecdotal it is important to take into account breeder and pet owner cases. After a certain point, how many coincidences does there have to be before we connect the dots and recognize a problem? Furthermore, we need to take into account research biases, funding, access to knowledge to report issues to vets and manufacturing companies, vets and companies taking situations seriously and reporting compliance that may influence studies and statistics.
ALTERNATIVES TO KETAMINE
There are many alternatives to ketamine that reduce the risk of reactions and complications. Many include gaseous anesthetics. The great thing about them is that it is easier to control the intensity of the drug which is easily manipulated during the procedure. While all anesthesia is not 100% safe, gas seems to have fewer risks.
Sevoflurane is a gaseous anesthetic that achieves a quick loss and return of consciousness. Unfortunately, it is expensive. Isoflurane works similarly, however, loss and return of consciousness takes a little longer but is less expensive. It also is removed from the body much quicker. (11, 47).
TESTING
There are tests involving Cytochrome P450 but they are expensive and few vets will know about them. Many are also labeled for For Research Use Only. Not for use in diagnostic procedures.
Niemann-Pick C2, NPC Disease is tested for with Optimal Selection but unfortunately there no effective treatment for it even if the cat does have it. (48)
RESOURCES AND REFERENCES
1. Slingsby LS, Waterman-Pearson AE, The postoperative analgesic effects of ketamine after canine ovariohysterectomy – a comparison between pre- and post-operative administration. Res Vet Sci 2000; 69(2):147–522.
2.Bradbrook, C, and L Clark. “State of the Art Analgesia-Recent Developments Pharmacological Approaches to Acute Pain Management in Dogs and Cats: Part 2.” The Veterinary Journal, W.B. Saunders, 18 Apr. 2018, www.sciencedirect.com/science/article/pii/S1090023318301199.
3. Wagner AE, Walton JA, Hellyer PW, et al. Use of low doses of ketamine administered by constant rate infusion as an adjunct for postoperative analgesia in dogs. J Am Vet Med Assoc 2002;221(1):72–5
4. Court, Michael H. “Feline drug metabolism and disposition: pharmacokinetic evidence for species differences and molecular mechanisms.” The Veterinary clinics of North America. Small animal practice vol. 43,5 (2013): 1039-54. doi:10.1016/j.cvsm.2013.05.002 5. Mion, Georges, and Thierry Villevieille. “Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings).” CNS Neuroscience & Therapeutics, John Wiley & Sons, Ltd (10.1111), 10 Apr. 2013, onlinelibrary.wiley.com/doi/full/10.1111/cns.12099. 6. (Behavioral alterations and severity of pain in cats recovering at home following elective ovariohysterectomy or castration Misse A-M. Väisänen, dvm, phd; Suvi K. Tuomikoski, m soc sci; Outi M. Vainio, dvm, phd) 7. Niedfeldt, RL, Robertson, SA. Postanesthetic hyperthermia in cats: a retrospective comparison between hydromorphone and buprenorphine. Vet Anaesth Analg 2006; 33: 381–389 8. Posner, LP, Gleed, RD, Erb, HN. Post-anesthetic hyperthermia in cats. Vet Anaesth Analg 2007; 34: 40–47 9. Posner, LP, Pavuk, AA, Rokshar, JL. Effects of opioids and anesthetic drugs on body temperature in cats. Vet Anaesth Analg 2010; 37: 35–43 10. Ketamine, Hydrochloride Injection, USP, Veterinary Injection. Ketamine, Hydrochloride Injection, USP, Veterinary Injection, Putney, Inc., 2015. 11. Dr. Mike Richards, DVM – Cobbs Creek, VA Matthews Veterinary Clinic 12. Powers, Will. “Cytochome P450, Ketamine and Bengals.” 13 May 2019. 13. Edwards SR, Mather LE. Tissue uptake of ketamine and norketamine enantiomers in the rat: Indirect evidence for extrahepatic metabolic inversion. Life Sci 2001;69:2051–2066.Ketamine has an inhibiting action on some cytochromes belonging to P450 complex, and this could partly explain the tachyphylaxis observed during the repeated use of the molecule 1 14. Kroon LA (September 2007). "Drug interactions with smoking". American Journal of Health-System Pharmacy. 64 (18): 1917–21. doi:10.2146/ajhp060414. PMID 17823102. 15. Guengerich FP (January 2008). "Cytochrome p450 and chemical toxicology". Chemical Research in Toxicology. 21 (1): 70–83. doi:10.1021/tx700079z. PMID 18052394. (Metabolism in this context is the chemical modification or degradation of drugs.
16. Wang X, Chen M, Chen X, Ma J, Wen C, Pan J, Hu L, Lin G. The effects of acute hydrogen sulfide poisoning on cytochrome P450 isoforms activity in rats. Bio Med Res Int. 2014;2014:209393
17. Wang X, Han A, Wen C, Chen M, Chen X, Yang X, Ma J, Lin G. The effects of H2S on the activities of CYP2B6, CYP2D6, CYP3A4, CYP2C19 and CYP2C9 in vivo in rat. Int J Mol Sci. 2013;14:24055–24063
18 Wang X, Chen X, Chen M, Hu G, Ma J, Pan J, Hu L, Lin G. Assessment of effects of chronic hydrogen sulfide poisoning on cytochrome P450 isoforms activity of rats by cocktail approach. Biol Pharm Bull. 2013;36:1627–1633. 19 Chaudhary A, Willett KL (January 2006). "Inhibition of human cytochrome CYP 1 enzymes by flavonoids of St. John's wort". Toxicology. 217 (2–3): 194–205. doi:10.1016/j.tox.2005.09.010. PMID 16271822.
20. Strandell J, Neil A, Carlin G (February 2004). "An approach to the in vitro evaluation of potential for cytochrome P450 enzyme inhibition from herbals and other natural remedies". Phytomedicine. 11 (2–3): 98–104. doi:10.1078/0944-7113-00379. PMID 15070158. 21 Zhang JW, Liu Y, Cheng J, Li W, Ma H, Liu HT, Sun J, Wang LM, He YQ, Wang Y, Wang ZT, Yang L (2007). "Inhibition of human liver cytochrome P450 by star fruit juice". Journal of Pharmacy & Pharmaceutical Sciences. 10 (4): 496–503. doi:10.18433/j30593. PMID 18261370. 22 Leclercq I, Desager JP, Horsmans Y (August 1998). "Inhibition of chlorzoxazone metabolism, a clinical probe for CYP2E1, by a single ingestion of watercress". Clinical Pharmacology and Therapeutics. 64 (2): 144–9. doi:10.1016/S0009-9236(98)90147-3. PMID 9728894. 23 Walmsley, Simon. "Tributyltin pollution on a global scale. An overview of relevant and recent research: impacts and issues" (PDF). WWF UK. 24 Chatterjee P, Franklin MR (November 2003). "Human cytochrome p450 inhibition and metabolic-intermediate complex formation by goldenseal extract and its methylenedioxyphenyl components". Drug Metabolism and Disposition. 31 (11): 1391–7. doi:10.1124/dmd.31.11.1391. PMID 14570772.)
25. (Chen JT, Chen RM. Mechanisms of ketamine‐involved regulation of cytochrome P450 gene expression. Expert Opin Drug Metab Toxicol 2010;6:273–281.)
26 (D Mössner, Lone & Schmitz, Andrea & Theurillat, Regula & Thormann, Wolfgang & Mevissen, Meike. (2011). Inhibition of cytochrome P450 enzymes involved in ketamine metabolism by use of liver microsomes and specific cytochrome P450 enzymes from horses, dogs, and humans. American journal of veterinary research. 72. 1505-13. 10.2460/ajvr.72.11.1505. )
29 Equine cytochrome P450 2B6--genomic identification, expression and functional characterization with ketamine. Peters LM, Demmel S, Pusch G, Buters JT, Thormann W, Zielinski J, Leeb T, Mevissen M, Schmitz A Toxicol Appl Pharmacol. 2013 Jan 1; 266(1):101-8.)
30Gene therapy: concepts and methods. Few applications so far. Prescrire Int. 2009 Dec; 18(104):276-9.)
31. Improvement of package insert CYP information for prescription drugs marketed in Japan].Hirata-Koizumi M, Saito M, Urano T, Miyake S, Hasegawa R Kokuritsu Iyakuhin Shokuhin Eisei Kenkyusho Hokoku. 2005; (123):12-8.
32 Lin, Feiou et al. “Assessment of the effect of ketamine on cytochrome P450 isoforms activity in rats by cocktail method.” International journal of clinical and experimental medicine vol. 8,3 4335-41. 15 Mar. 2015) 33. Laureri, Nicola; Sim, Edith (2018). Arylamine N-Acetyltransferases in Health and Disease: From Pharmacogenetics to Drug Discovery and Diagnostics. World Scientific. ISBN 9789813232006. 34. McDonagh, E.M.; et al. (2014). "PharmGKB summary: very important pharmacogene infor- mation for N-acetyltransferase 2". Pharmacogenet. Genomics. 24: 409–425.
35. Rajasekaran, M.; Abirami, Santhanam; Chen, Chinpan (2011). "Effects of Single Nucleotide Polymorphisms on Human N-Acetyltransferase 2 Structure and Dynamics by Molecular Dynamics Simulation". PLoS ONE. 6 (9): 1–12.. (Oncea I, Duley J (2008). "Pharmacogenetics of Thiopurines". Goodman & Gilman's “The Pharmacological Basis of Therapeutics”, published McGraw-Hill's Access Medicine (on-line) (11th ed.). Chapter 38.)
36. ( Fujita K, Sasaki Y (August 2007). "Pharmacogenomics in drug-metabolizing enzymes catalyzing anticancer drugs for personalized cancer chemotherapy". Curr. Drug Metab. 8 (6): 554–62. doi:10.2174/138920007781368890. PMID 17691917.)
37. (Evans WE. (2004). "Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy". Ther Drug Monit. 26 (2): 186–91. doi:10.1097/00007691-200404000-00018. PMID 15228163.)
38. (Vanier M. Niemann-Pick disease type C. Orphanet journal of rare diseases. 2010;5(1):1–18. 10.1186/1750-1172-5-16)
39. Perkins S, Verschoyle RD, Hill K, Parveen I, Threadgill MD, Sharma RA, et al. Chemopreventive efficacy and pharmacokinetics of curcumin in the min/+ mouse, a model of familial adenomatous polyposis. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2002;11(6):535–40. Epub 2002/06/07.
40. Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM. The curry spice curcumin reduces oxidative damage and amyloid pathology in an Alzheimer transgenic mouse. The Journal of neuroscience: the official journal of the Society for Neuroscience. 2001;21(21):8370–7. Epub 2001/10/19.
41. Appiah-Opong R, Commandeur JN, van Vugt-Lussenburg B, Vermeulen NP. Inhibition of human recombinant cytochrome P450s by curcumin and curcumin decomposition products. Toxicology. 2007;235(1–2):83–91. Epub 2007/04/17. 10.1016/j.tox.2007.03.007 .
42. Jalbert G, Castonguay A. Effects of NSAIDs on NNK-induced pulmonary and gastric tumorigenesis in A/J mice. Cancer Letters. 1992;66(1):21–8. Epub 1992/09/14.
43. Nicoli, Elena-Raluca et al. “Defective Cytochrome P450-Catalysed Drug Metabolism in Niemann-Pick Type C Disease.” PloS one vol. 11,3 e0152007. 28 Mar. 2016, doi:10.1371/journal.pone.0152007
44. Handschin C, Podvinec M, Amherd R, Looser R, Ourlin JC, Meyer UA. Cholesterol and bile acids regulate xenosensor signaling in drug-mediated induction of cytochromes P450. Journal of Biological Chemistry. 2002;277(33):29561–7. Epub 2002/06/05. 10.1074/jbc.M202739200 . Evaluation of the effects of naloxone on recovery time and quality after ketamine-medetomidine-butorphanol anesthesia in servals (Leptailurus serval). Moresco A, Larsen RS, Lassiter AJ. J Zoo Wildl Med. 2009 Jun;40(2):289-95.
45. Cardiopulmonary and anesthetic effects of medetomidine-ketamine-butorphanol and antagonism with atipamezole in servals (Felis serval). Langan JN, Schumacher J, Pollock C, Orosz SE, Jones MP, Harvey RC. J Zoo Wildl Med. 2000 Sep;31(3):329-34.
46. Lewis, James M. “Http://Veterinarynews.dvm360.Com/Fda-Closes-Teva-Animal-Health-Plant.” DVM 360, DVM360 MAGAZINE, 4 Aug. 2009, veterinarynews.dvm360.com/fda-closes-teva-animal-health-plant.
47. Knudsen, Shelley. “Anesthesia Types.” Types of Anesthesia - All Feline Hospital Located, 2300 S. 48th St. Suite 3 Lincoln, NE 68506, www.allfelinehospital.com/types-of-anesthesia.pml.
48. L. Lyons, P6046 Precision medicine and the 99 Lives Cat Genome Sequencing Initiative, Journal of Animal Science, Volume 94, Issue suppl_4, September 2016, Pages 171–172, https://doi.org/10.2527/jas2016.94supplement4171a