Injectable Anaesthetic Agents PDF

I N J E C TA B L E ANAESTHETIC AGENTS Hanna Machin Dip ACVAA, Dip SIAV, MVetMed, MRCVS Lecturer in Veterinary Anaesthesia at the University of Surrey 27th September 2024 LEARNING OBJECTIVES Describe the vari...

I N J E C TA B L E ANAESTHETIC AGENTS Hanna Machin Dip ACVAA, Dip SIAV, MVetMed, MRCVS Lecturer in Veterinary Anaesthesia at the University of Surrey 27th September 2024 LEARNING OBJECTIVES Describe the various ways in which injectable anaesthetic agents are used in Veterinary Anaesthesia and explain the relevant pharmacokinetics Explain the factors affecting the speed of induction of anaesthesia Discuss the various techniques for delivering drugs by the intravenous route in domestic species Describe the pharmacology of the intravenous anaesthetic agents used in contemporary veterinary anaesthesia Outline methods of providing muscle relaxation during general anaesthesia THE IDEAL ANAESTHETIC AGENT DOESN’T EXIST… I N J E C TA B L E A G E N T S  Propofol  Alfaxalone  Ketamine  Etomidate Used for: INDUCTION MAINTENANCE of Anaesthesia +/- Opioid, alpha-2 adrenoceptor agonist, ketamine, lidocaine Venous access required! “ off the needle” injection IM administration in exotics/ zoo animals/ small patients TOTA L I N T R A - V E N O U S A N A E S T H E S I A ( T I VA ) Use of injectable agents to both induce & maintain anaesthesia Intermittent boluses or Constant rate infusion (CRI) Adjust infusion rate over time to avoid accumulation & prolonged recoveries TOTA L I N T R AV E N O U S A N A E S T H E S I A ( T I VA ) Indications: Patient movement to different rooms/areas Field anaesthesia Disbudding Severe cardiovascular pathologies Raised ICP Bronchoscopy/ Thoracotomies … PA R T I A L I N T R AV E N O U S A N A E S T H E S I A ( P I VA ) Co-administration of injectable & inhalational anaesthetics to maintain anaesthesia Ketamine, alpha-2 adrenoceptor agonists, opioids (i.e. fentanyl, remifentanil… ), lidocaine BALANCED ANAESTHESIA Decrease inhalational anaesthetic requirement → ↓ side effects To provide analgesia & muscle relaxation R AT E O F I N D U C T I O N Dose Concentration Speed of injection Cardiac Output Lipid solubility Degree of protein binding Rate of metabolism & excretion INDUCTION AGENTS PHARMACOKINETICS PROPOFOL Hypnotic alkyl phenol Lipid water macroemulsion (propofol in soybean oil, glycerol, egg lecithin, sodium hydroxide) Licensed in dogs & cats Concentration: 1% (10mg/ml) Indications: - Induction & maintenance of anaesthesia - Status epilepticus - Fish & reptile anaesthesia P R O P O F O L F O R M U L AT I O N S PRESERVATIVE FREE VS WITH PRESERVATIVES Support bacterial growth PropoFlo Plus Discard at the end of day! Preservative (benzyl alcohol)  CRI Induction & short-term maintenance Last 28 days No CRI (toxicity) PROPOFOL IV administration (occasional pain on injection) Highly protein bound to albumin & RBC Highly lipid soluble→ rapid onset of ac on (60-90’’) → redistribu on → short dura on of ac on (~10’) Equilibra on between CNS & plasma ~ 2’ → Injec on me to avoid overdose & post induc on apnoea Induction & recovery: usually smooth & excitement free (horses: exception) Extrapyramidal signs (propofol twitches: focal or muscle fasciculation, paddling, nystagmus) Doses - premedicated animal: 1-4 mg/kg Calculate dose BEFORE induction, administer to effect ACP (not in cats), alpha2 agonists, opioids: ↓ propofol requirements PROPOFOL MECHANISM of ACTION Hypnotic agent GABAA enhancer: Binds to β subunits of GABA receptor → ↓ GABA dissocia on from the receptor → prolonged opening of Cl- channels → Hyperpolariza on of post- synaptic neuron Inhibition NMDA receptors Image from: Bruni, O.; Ferini-Strambi, L.; Giacomoni, E.; Pellegrino, P. Herbal Remedies and Their Possible Effect on the GABAergic System and Sleep. Nutrients 2021, 13, 530. https://doi.org/10.3390/nu13020530 PROPOFOL MECHANISM of ACTION Image from: Paramsothy J, Gutlapalli S, Ganipineni V, et al. (June 15, 2023) Propofol in ICU Settings: Understanding and Managing Anti- Arrhythmic, Pro-Arrhythmic Effects, and Propofol Infusion Syndrome. Cureus 15(6): e40456. doi:10.7759/cureus.40456 PROPOFOL PHARMACODYNAMIC P R O P O F O L I N C AT S Slower hepatic metabolism (glucuronidation enzymes deficiency) Feline Hb prone to oxidative injury by repeated daily administration Andress et al. 1995: X 7 days Bley et al. 2007: Minimal clinically significant haematological changes with repeated low dose propofol administration P R O P O F O L I N C AT S AL FAX ALO N E Synthetic neuroactive steroid Insoluble in water (Cyclodextrin) Preservatives (last 28 days) Licensed in dogs, cats & rabbits for IV administration Concentration: 10mg/ml Image from: https://www.jurox.com/us/product/alfaxan/history Indications: Induction & maintenance of anaesthesia Sedation (not licensed) Suitable for immersion anaesthesia in amphibians, reptiles & fish AL FAX ALO N E MECHANISM of ACTION Enhance inhibitory effect of GABA on GABAA receptor @ high dose: GABAA agonist (open Cl- channels) AL FAX ALO N E IV, IM, SC administration (occasional pain on injection) Rapid induction: 30-60’ (IV) Dose premedicated animal: 1-2 mg/Kg (to effect) IM sedation/anaesthesia (7-10’) Alpha 2 agonist, opioids, ACP, midazolam: ↓ induction dose Induction usually smooth without excitement Recovery quality ~ to propofol Prolonged recoveries if long infusions Excitable recovery (Paddling, rigidity, vocalisation possible, especially if used alone) Rapid metabolism (hepatic) AL FAX ALO N E PHAR M AC ODYN AM IC K E TA M I N E Phencyclidine derivative Licensed: Dog, cat, horse, cattle, sheep, goat, pig, rabbits… Used also for exotic & wildlife anaesthesia IV, IM, SC, transmucosal absorption Aqueous solution: Acidic PH: pain on IM injection 10% solution (most commonly used) Indications: Induction ( + other agent(s) to provide myorelaxation) Analgesia Sedation ( aggressive/ painful patients) No reversal K E TA M I N E Can be administered as a bolus, CRI Sedation: 0.5-3 mg/kg IM Induction dose: ~ 2.5 up to 5 mg/Kg (higher dose for exotics) Rapid onset IV (60-90’’) Pain (CRI 10-20 mcg/kg/min intra-op, 2-5 mcg/kg/min post-op) Hepa c metabolism → ac ve metabolite: Norketamine Ketamine & Norketamine excreted unchanged (urine) in : careful if renal dx Dog, horse: Norketamine further metabolised (inactive compounds), urinary + biliary excretion K E TA M I N E MECHANISM of ACTION NMDA RECEPTOR Interacts with ≠ receptors: Non – competitive NMDA receptor antagonist: prevents Glutamate (excitatory neurotransmitter) from binding to the receptor pain, memory, learning, processing & modulation of neural activity  CHRONIC PAIN , central sensitization non-NMDA glutamate receptors muscarinic & nicotinic receptors monoaminergic receptors opioid receptors Inhibition voltage - dependent Na+ & Ca2+ channels Image from: Earnshaw, Berton & Supervisor, & Bressloff, Paul. Diffusion model of AMPA receptor trafficking in the postsynaptic membrane. K E TA M I N E P H A R M A C O DY N A M I C E TO M I D AT E Imidazole derivative Not licensed for animals in UK ≠ formulations available: - Hypnomidate (with propylene glycol) Pain on injection (propylene glycol + hyperosmolar to plasma) Damage to RBCs, tissue irritation/necrosis - Etomidate-Lipuro (lipid emulsion) No pain on injection No tissue irritation Indications: Induction (with premed +/- co-induction) 1-3 mg/Kg IV E TO M I D AT E Rapid induction & recovery (poor quality) Metabolism (hepatic & plasma estereses) Inactive metabolites excreted in urine, bile, faeces Mechanism of action: @ low dose: GABAA enhancer @ higher dose: GABAA agonist E TO M I D AT E P H A R M A C O D Y N A M I C CO-INDUCTION Administration of two or > drugs together for induction of anaesthesia Drug synergism Dose sparing effect (< side effects) Cost sparing Improve cardiovascular stability Helpful properties of the non-induction agents (i.e. muscle relaxation, analgesia, cough response to intubation…) Example of drugs that can be used for co-induction with propofol/alfaxalone: Midazolam (excitement if given BEFORE induction agent) Ketamine Lidocaine Fentanyl TO O BTA I N A D D I T I O N A L M YO R E L A X I O N CENTRAL muscle relaxation Depress internuncial transmission at spinal cord & brainstem Guaifenesin (GGE) Benzodiazepines PERIPHERAL muscle relaxion Action at neuromuscular junction (acetylcholine receptors) Neuromuscular blocking agents (NMDA) - Depolarising - Non-Depolarising REFERENCES REFERENCES Martín Bellido V, Vettorato E. Clinical review of the pharmacological and anaesthetic effects of alfaxalone in dogs. J Small Anim Pract. 2022 May;63(5):341-361. doi: 10.1111/jsap.13454. Epub 2021 Dec 10. PMID: 34893985 Taylor PM, Chengelis CP, Miller WR, Parker GA, Gleason TR, Cozzi E. Evaluation of propofol containing 2% benzyl alcohol preservative in cats. Journal of Feline Medicine and Surgery. 2012;14(8):516-526. doi:10.1177/1098612X12440354 Baetge CL, Smith LC, Azevedo CP. Clinical Heinz Body Anemia in a Cat After Repeat Propofol Administration Case Report. Front Vet Sci. 2020 Oct 26;7:591556. doi: 10.3389/fvets.2020.591556. PMID: 33195628; PMCID: PMC7649157. Andress JL, Day TK, Day D. The effects of consecutive day propofol anesthesia on feline red blood cells. Vet Surg. 1995 May-Jun;24(3):277-82. doi: 10.1111/j.1532-950x.1995.tb01331.x. PMID: 7653043. THANK YOU FOR YOUR AT T E N T I O N. ANY QUESTIONS?