The story of sedatives By Orion Pharma Animal

The story of sedatives By Orion Pharma Animal Health/J. Kokkonen

Once upon a time… 2 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

…there was a Finnish pharmaceutical company who tested a human hypertension drug candidate in horses. And all the horses became sedated. That was over 30 years ago and Domosedan® was born! 3 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

The first Orion alpha-2 agonist was Domosedan® injection for horses and cattle • Domosedan (detomidine hydrochloride) got its MA in Finland for horses and cattle in 1983 • It was further developed to have also an oromucosal gel formulation in 2009 4 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

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How did the story go on? 6 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

… It started to rain cats and dogs 7 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

Orion developed a dog and cat sedative range, starting with Domitor ® • Domitor (medetomidine hydrochloride) got its MA in Finland for dogs and cats in 1987 • The unique concept of sedation-reversal was developed with Antisedan ® (atipamezole hydrochloride) PAUSE 8 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen PLAY

There was magic in the air…. 9 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

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Was this the happy end ? 11 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

… No way! The medetomidine molecule was purified and a new generation sedative was made, now even for human use 12 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

Development of Dexdomitor® • Dexdomitor is pure and specific next generation alpha-2 agonist available to veterinarians for use in dogs and cats: – – – Sedation Analgesia Preanesthesia • Dexmedetomidine is the only alpha-2 agonist approved for human sedation use – – 13 3. 11. 2020 It is called Dexdor® in the EU It is indicated for sedation of adult intensive care unit patients Orion Corporation Orion Pharma Animal Health/J. Kokkonen

Domitor D L Dexmedetomidine Levomedetomidine D L L D D L D L L D Domitor contains two enantiomers and both are metabolized in the liver 14 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

Dexdomitor D D D L Dexmedetomidine Levomedetomidine D D D D D Levomedetomidine has been removed and that reduces the metabolic burden on liver. Dexmedetomidine is solely responsible for the sedation and analgesia effects in the molecule. 15 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

Alpha-2 receptors: mode of action • Alpha-2 receptors are located throughout the body • Norepinephrine is the endogenous ligand for the receptors • Sympathetic neurotransmission is prevented and the level of consciousness decreases (sedation) and nociception (analgesia) is produced 16 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

Other physiological effects by alpha-2 receptors • • 17 Peripheral vasoconstriction Initial hypertension followed by normo- or slight hypotension Compensatory reduction in heart rate Decreases in body temperature and respiratory rate 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

Medetomidine/Dexmedetomidine at the adrenoceptor, vs. xylazine α 2 : α 1 selectivity α 1 affinity Dexmedetomidine 1300 692 Medetomidine 1200 1318 Clonidine 220 713 Xylazine 160 30300 Levomedetomidine 23 2239 Dexmedetomidine acts as a full agonist on all alpha-2 adrenoceptor subtypes – – high selectivity for alpha-2 adrenoceptors (sedation and analgesia) very low affinity for alpha-1 adrenoceptors (arousal and excitation) High selectivity for alpha-2 adrenoceptors means in practice reliable sedation and analgesia Aantaa R, Kallio A, Virtanen R. 1993. Dexmedetomidine, a novel alpha-2 adrenergic agonist. A review of its pharmacodynamic characteristics. Drugs of the Future. 18: 49 -56. Schwinn DA, Correa-Sales C, Page SO, et al. 1991. Functional effect of activation of alpha-1 adrenoceptors by dexmedetomidine: in vivo and in vitro studies. J Pharmacol Exp Therap. 259: 1147 -1152. Jansson CC, Kukkonen JP, Näsman J et al. 1998. Protean agonism at alpha 2 Aadrenoceptors. Mol Pharmacol. 53: 963 -968. Guo TZ, Tinklenberg J, Oliker R, et al. 1991. Central alpha-1 adrenoceptor stimulation functionally antagonizes the hypnotic response to dexmedetomidine, an alpha-2 adrenoceptor agonist. Anesthesiol. 75: 252 -256. 18 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

Then one day the three wise men came and told about the internet… 19 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

… all you need to know about Dexdomitor dosing is found at www. goo. gl/U 1 Gra 20 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

Combinations are found in SPC and literature • Domitor and Dexdomitor can be used in premedication before General Anesthesia – The dose in combinations in dogs is usually at the level of 10 -20 µg/kg for Domitor and 125 -375 µg/m 2 (equals about 5 -15 µg/kg) for Dexdomitor – Can be combined with various other sedatives, e. g. ketamine and opioids good synergy in sedation and pain relief – Reduces the needed amount of induction agents, e. g propofol significantly (in studies 30 -60%) – Reduces also the need of inhalation anesthetics, e. g. isoflurane 21 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

Take home messages Orion’s original sedative range offer the veterinarian the reliable experience for sedation, restraint, analgesia and premedication for dogs, cats, horses and cattle. Dexdomitor comes with two strengths (0. 5 mg/ml and 0. 1 mg/ml) to offer the veterinarian the convenient choice for accurate dosing according to the patient size and selected dose range. The dosing and administration of Domitor and Dexdomitor is extremely flexible with various combinations with opioids and a variety of injectable anesthetics and inhalation drugs. The dose-sparing effect on other anesthetics even on low-dosages increases safety and has a great economical value. 22 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

The story will go on and new stars will shine in the sky next year… 23 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen

Thank You! Any Questions? THANK YOU 24 3. 11. 2020 Orion Corporation Orion Pharma Animal Health/J. Kokkonen