L6 Clinical pharmacology of anaesthetics 2023.pptx

Clinical pharmacology of anaesthetics BVMS3 Module 14 Supporting the patient Pat Pawson 2023 Intended Learning Outcomes • Year ILO • CP3024 a] Formulate an analgesic, sedative or anaesthetic plan for a veterinary patient, demonstrating an understanding of the underpinning principles, including ph...

Clinical pharmacology of anaesthetics BVMS3 Module 14 Supporting the patient Pat Pawson 2023 Intended Learning Outcomes • Year ILO • CP3024 a] Formulate an analgesic, sedative or anaesthetic plan for a veterinary patient, demonstrating an understanding of the underpinning principles, including pharmacology & the appropriate use of anaesthetic equipment. • Lecture content ILOs 1. Summarise key aspects of the pharmacology of commonly used injectable anaesthetics, including propofol, alfaxalone & ketamine 2. Summarise key aspects of the pharmacology of commonly used inhaled anaesthetics, including isoflurane, sevoflurane, desflurane & nitrous oxide 3. Explain how the pharmacology of anaesthetics can affect their clinical use 2 Injectable anaesthetic agents • Propofol • Steroid anaesthetics – Alfaxalone • Barbiturates – Thiopentone, pentobarbitone • Imidazole derivatives – Etomidate • Dissociative agents – Ketamine, tiletamine (+ zolazepam = Zoletil) Propofol • Rapid onset, short duration IV anaesthetic • STRUCTURE: hindered phenol • MECHANISM: potentiates GABA • FORMULATION: oil-in-water emulsion – Soya bean oil, egg lecithin & glycerol – Preservative free or … – Plus benzyl alcohol (Propoflo Plus) • In-use shelf-life 28 days • Not for infusion > 30 minutes • Not > 24 mg/kg per anaesthetic Propofol pharmacokinetics • • • • IV route of administration Highly protein bound Recovery initially due to redistribution Rapid metabolism in liver plus “another site” – Lung, kidneys, blood? • Slower metabolism in cats – Less able to conjugate with glucuronide – Avoid IV infusions Propofol - effects on… • CNS: Rapid loss of consciousness (~ 5 min) – Anticonvulsant action • CVS: Vasodilation & transient fall in BP • RESP: Post-induction apnoea • OTHER: – Pain on injection – Occasional muscle twitching/hypertonus – Heinz body anaemia in cats  Oxidative damage to RBCs  Repeated use (or continuous infusion) Propofol – clinical summary Licensed for IV administration in dogs & cats Uses: • Administered IV to induce anaesthesia in dogs & cats • Administered IV (intermittent bolus or continuous infusion) to maintain anaesthesia in dogs (TIVA) • Used to treat status epilepticus in dogs Caution in: • Shocked / hypovolaemic patients • Cats with hepatic dysfunction • Cats requiring repeat anaesthetics 7 Alfaxalone • Rapid onset, short duration injectable anaesthetic with a high therapeutic index • STRUCTURE – Steroid anaesthetic • MECHANISM – Potentiates GABA • FORMULATION – Solubilised in cyclodextrin – New formulation with preservative • In-use shelf-life 28 days Alfaxalone • PHARMACOKINETICS: – – – – IV (IM & SC) routes of administration Lower protein binding (cf. propofol) Recovery initially due to redistribution Rapid metabolism by liver (dogs AND cats) Alfaxalone - effects on … • Central nervous system: – Rapid loss of consciousness (IV) • Cardiovascular system: – Mild hypotension at clinical doses, primarily due to vasodilation • Respiratory system: – Post-induction apnoea (less frequent cf. propofol ) • Recovery: – Can be poor quality, especially if limited/poor premedication Alphaxalone – clinical use Licensed for use in dogs, cats & rabbits USES: • Administered IV to induce anaesthesia • Administered IV (intermittent bolus or continuous infusion) to maintain anaesthesia in dogs & cats • Occasionally used IM/SC for sedation – Not authorised – Large volume of injection Ketamine • Injectable dissociative anaesthetic & analgesic • MECHANISM: NMDA receptor antagonist • FORMULATION: acidic pH • PHARMACOKINETICS: – Can be given IV, IM or SC – Rapid hepatic metabolism – Suitable for TIVA in horses Dissociative anaesthesia Dissociative agents produce a different “quality” of anaesthesia FEATURES • Sensory loss with analgesia • Increased muscle tone • Eyes open ± slow nystagmus • Active reflexes incl. laryngeal/pharyngeal reflexes • Less profound CVS & respiratory depression Ketamine - effects on …. • Central nervous system – Loss of consciousness with analgesia – Convulsions in dogs/horses (especially if used as sole agent) – Hallucinations / emergence delirium • Musculoskeletal system – Increased muscle tone Ketamine – effects on … • Cardiovascular system – In vitro direct -ve inotropic effect – In vivo increased sympathetic tone  Increased heart rate, contractility, cardiac output & BP  In shock? • Respiratory system – Transient apnoea possible with IV administration  Ventilation usually well maintained when given by SC or IM routes – Laryngeal and pharyngeal reflexes maintained? 15 Ketamine – clinical use Never use as sole agent for anaesthesia Typical uses: 1) To induce anaesthesia in dogs, cats & horses • Combined with a benzodiazepine & injected IV 2) To induce & maintain anaesthesia (~ 30 min) in dogs & cats • Combined with an  2-agonist and butorphanol & injected IM (“triple combo”) 3) To provide analgesia in dogs & cats • Much lower doses given IM, SC or by IV infusion Ketamine – clinical use Licensed in dogs, cats, horses, cattle, sheep, goats & small mammals Caution in patients with: • A history of seizures • Elevated intracranial pressure • Pre-existing tachycardia Total Intravenous anaesthesia (TIVA) • The use of intravenous anaesthetics to both induce & maintain anaesthesia • When might you use it? – Where inhalational anaesthetic agents not available – Where the airway cannot be shared • Bronchoscopy • Some airway surgeries TIVA Examples • DOGS: – Propofol or alfaxalone are suitable – Poor reflex suppression so can combine with analgesics • CATS: – Only alfaxalone is suitable • HORSES: – “Triple drip” ( 2-agonist plus GGE plus ketamine) – Popular for “field” anaesthesia in horses Selecting the right agent… • Little to choose between propofol and alfaxalone (personal preference; cost) • Ketamine may be chosen if: – IM anaesthesia required • Aggressive patient • No IV access • No facilities for delivering inhaled agents – Haemodynamic instability is present (IV) • Co-induction techniques may minimise CVS depression in cases with haemodynamic instability 20 Maintenance of anaesthesia • TIVA or IM “triple combination” • Inhalational agents 21 Inhalational anaesthetic agents Typically used for maintenance of anaesthesia • Advantages: o Delivery / elimination depends on ventilation – Rapid adjustment of anaesthetic depth • Disadvantages: o Equipment required – Endotracheal tube, carrier gas (oxygen), vaporiser, breathing system etc. o Environmental pollution 22 Individual Inhaled Anaesthetic Agents      Halothane Isoflurane Desflurane Sevoflurane Nitrous Oxide • • • • Methoxyflurane Enflurane Cyclopropane Ether Minimum Alveolar Concentration (MAC) MAC is the steady-state minimum alveolar concentration of anaesthetic required to prevent gross purposeful movement in response to noxious stimulation, in 50% of test subjects • MAC allows comparison of the potency of different inhaled anaesthetics – How much agent do we need to deliver? MAC values Agent (halothane) isoflurane sevoflurane desflurane nitrous oxide (methoxyflurane ) Dog (%) 0.87 1.28 2.36 7.20 >100 0.23 Cat (%) 1.14 1.63 2.58 9.79 >100 0.23) 25 Partition coefficients • Oil:gas partition coefficient – Measure of lipid solubility – High oil:gas PC confers high potency • Blood:gas partition coefficient – Measure of solubility in blood – Low blood solubility confers a rapid onset, recovery & rate of change of anaesthetic depth 26 Blood:gas solubility coefficient Agent (halothane isoflurane sevoflurane desflurane nitrous oxide (methoxyfluran e BG solubility 2.30) 1.48 0.68 0.42 0.47 10.2) 27 Metabolism and Elimination of Inhalational Anaesthetics • Elimination primarily by exhalation • Metabolism of inhaled anaesthetics – Extent depends on agent – Doesn’t contribute significantly to recovery – Can produce toxic metabolites  Risk to patient and staff Physical properties: isoflurane vs sevoflurane Halogenated ethers Volatile liquids FEATURE ISOFLURAN SEVOFLUR E ANE MAC (%) 1.3 2.3 Oil:gas partition coefficient 91 47 Blood:gas partition coefficient 1.5 0.68 Metabolism (%) 0.2 3 Effects of isoflurane & sevoflurane • Cardiovascular system:  Hypotension – Peripheral vascular resistance falls – Cardiac output maintained (except deep plane) • Respiratory system:  Respiratory depression (reduced rate) – At equivalent doses ISO > SEVO 30 Physical properties: desflurane Halogenated ether Volatile liquid Boiling point ~ 23°C (special vaporiser) FEATURE ISOFLURA NE SEVOFLURA NE DESFLURA NE MAC (%) 1.3 2.3 7.2 Oil:gas PC 91 47 19 Blood:gas PC 1.5 0.68 0.42 Metabolism (%) 0.2 3 0.02 Desflurane - effects on … Similar to isoflurane in most respects ..cardiovascular system • Rapid increases in inspired conc. can increase heart rate & arterial BP (catecholamines) ..respiratory system • High inspired conc. can cause airway irritation Agents for mask induction • Rapid onset (need low blood:gas solubility) – Isoflurane 1.48 > sevoflurane 0.68 > desflurane 0.42 • Pleasant odour – Isoflurane x – Desflurane x – Sevoflurane  • Minimal airway irritation – Desflurane > isoflurane > sevoflurane 33 Clinical summary AUTHORISATION POTENCY RATE OF CHANGE OF DEPTH MASK INDUCTION METABOLISM COST GLOBAL WARMING POTENTIAL ** Isoflurane Sevoflurane Desflurane Dogs, cats, horses & more High Moderate Dogs & cats Unauthorised Moderate Rapid Low Very rapid X pungent odour Very low £  Low £££ X airway irritant Very low ££    ** BJA Ed article 34 Sustainability A 240mL bottle of desflurane will produce the equivalent of 886 kg of carbon dioxide, the equivalent of driving 3072 miles from London to Naples and back, in a petrol engine car. How bad are bananas? 2021 Mike Berners-Lee 35 Nitrous oxide Volatile anaesthetic agents are liquids at room temp & pressure. Nitrous oxide is a gas at room 36 Nitrous oxide • Weak anaesthetic – MAC > 100% • Weak analgesic effects – human > small animal > equine • Negligible cardiovascular & respiratory effects If used with isoflurane or sevoflurane, requirement for iso/sevo is reduced and associated CV & RESP depression is also reduced 37 Other effects of nitrous oxide • Second gas effect – Promotes uptake of other anaesthetics at start of anaesthesia • Diffusion hypoxia – Rapid elimination of N2O at end of anaesthesia can lower alveolar O2 levels • Expansion – Accumulates in closed gasfilled spaces e.g. GDV, pneumothorax etc. 38 Other effects of nitrous oxide • Long term exposure (occupational) – Anaemia/leukopaenia – Peripheral neuropathy • Teratogenic • Green house gas • More information 39 Further reading “Injectable anaesthetics” S. Kastner BSAVA Manual of Canine & Feline Anaesthesia & Analgesia, 3rd ed pp 191-200 “Options for inhalation anaesthesia” K.W. Clarke In Practice (2008) 30, 513-518 40