Clinical Reasoning Lecture 2024-2025 PDF

CLINICAL REASONING 2024 | PRIYA SHARP LEARNING OBJECTIVES Identify the different forms of clinical reasoning and understand their application in different contexts of veterinary practice Understand and describe the process of inductive reasoning Develop a strategy for engaging with practitioners to develop their own clinical reasoning 2 W H AT I S C L I N I C A L R E A S O N I N G ? “ Clinical reasoning is the process by which veterinary surgeons integrate a multitude of clinical and contextual factors to make decisions about the diagnoses, treatment options and “ prognoses of their patients VINTEN C. E. K. (2020). CLINICAL REASONING IN VETERINARY PRACTICE. VETERINARY EVIDENCE, 5(2). H T T P S : / / D O I. O R G / 1 0. 1 8 8 4 9 / V E.V 5 I 2. 2 8 3 3 THE PROCESS Starts with a presenting case…… Ends with (hopefully) successful treatment 4 HOW DO WE GET CLINICAL REASONING SKILLS? Difficult to teach (sorry about that!) Experience!! Practise Guidance Vets vs Medics BUT… vets are good to go on graduation! 5 TYPES OF CLINICAL REASONING Type 1 Life & Learning Type 2 “Pattern Recognition” “First Principles” Non-analytical Analytical Intuitive Clinical Deductive Rapid decision Inductive Experience Abductive Illness-scripts ↑ Cognitive load Existing solutions Novel situations/ unexpected ↑ error risk? response May, S.A. (2013) Clinical reasoning and case-based decision making: The fundamental challenge to veterinary educators. Journal of Veterinary Medical Education, 40, 200–209. Maddison, J (2017) Chapter 24: Clinical Reasoning Skills in: Veterinary Medical Education: A Practical Guide (p380-395). Hodgson & Pelzer. 6 T Y P E 1 : “ PAT T E R N R E C O G N I T I O N ” Type 1 Clinical Reasoning Non-analytic Occurs quickly and cost effective (if diagnosis correct!) Past experience → “pattern recognition” Weaker in novices Works well for common disorders Patterns of clinical signs Illness scripts 7 T Y P E 2 : A N A LY T I C Type 2 Clinical Reasoning Analytic Takes time (and money!) to investigate Use to double check presumptive diagnoses (based on pattern recognition) Deductive Inductive Abductive TYPE 1 V S TYPE 2 REASONING Rectal Temp Bacterial 40.8oC Infection! Bacterial Response to infection Viral Inflammatory Pyrexia Response Rectal Temp Non Autoimmune 40.8oC Infectious Hyperthermia Neoplasia 9 INDUCTIVE REASONING Broad generalisations Tentative hypotheses More exploratory Seek appropriate information Structured approach KEY QUESTIONS What is the problem? Define and refine the problem What system is involved and how is it involved? Define and refine the system Where within the system is the problem located? Define the location What is the lesion? Define the lesion T H E M I N I M U M D ATA B A S E “I’ll do bloods” Haematology, serum biochemistry, urinalysis –useful and often essential Think before you jump in Don’t go fishing…. 12 PROBLEM LIST Create a problem list Clarify the clinical problems Aim is to avoid overlooking key clinical signs 13 DEFINE AND REFINE THE PROBLEM What IS the problem? “my dog is vomiting” “my dog is having fits” “my dog has red urine” Owner vs Veterinarian’s perceptions 14 DEFINE AND REFINE THE SYSTEM What systems are involved in causing the clinical sign/s? Primary problem (ie structural) Secondary problem (ie functional) Why does is matter? Diagnoses, diagnostic tools, treatment/management will differ Other questions? Local vs Systemic 15 D E F I N E T H E LO C AT I O N ( W I T H I N T H E S Y S T E M ) Where within that system is the problem? e.g. in a case of vomiting, is it upper or lower GIT? Endoscopy –where is it of value? 16 DEFINE THE LESION PROBLEM V -vascular I -inflammation SYSTEM T -trauma/toxic A -anomaly LOCATION M -metabolic I -infection N -neoplasia LESION… “What is it D -degenerative 17 EXAMPLE OF DIFFERENTIALS LIST Maddison, J (2017) Chapter 24: Clinical Reasoning Skills in: Veterinary Medical Education: A Practical Guide (p380-395). Hodgson & Pelzer. 18 CONCLUSION Use Type 1 and Type 2 clinical reasoning Pattern recognition is valid! Don’t forget what you know… Takes time Learn this process and practise it 19 REFERENCES Maddison, J (2017) Chapter 24: Clinical Reasoning Skills in: Veterinary Medical Education: A Practical Guide (p380-395). Hodgson & Pelzer. May, S.A. (2013) Clinical reasoning and case-based decision making: The fundamental challenge to veterinary educators. Journal of Veterinary Medical Education, 40, 200–209. Vinten C. E. K. (2020). Clinical reasoning in veterinary practice. Veterinary Evidence, 5(2). https://doi.org/10.18849/ve.v5i2.283 20 I N H A L AT I O N A L A G E N T S 27th September 2024 Hanna Machin Dip ACVAA, Dip SIAV, MVetMed, MRCVS Lecturer in Veterinary Anaesthesia LEARNING OBJECTIVES Describe the differences between the gaseous and volatile agents in terms of the practicalities of their administration Describe the various ways in which inhalational anaesthetic agents are used in veterinary anaesthesia and explain the relevant pharmacokinetics Define and explain the clinical importance of the terms: saturated vapour pressure, minimum alveolar concentration, blood gas partition co-efficient and second gas effect Describe the factors affecting the speed of uptake and elimination of inhaled anaesthetic agents Describe clinically relevant physical properties and agent specific considerations for the inhaled anaesthetic agents used in contemporary veterinary anaesthesia Explain the health and safety precautions for the use of inhaled anaesthetic agents, including the use of scavenging I N H A L AT I O N A L A N A E S T H E T I C A G E N T S Volatile anaesthetic drugs administered by inhalation Vapour or gases VAPOUR: gaseous phase of a substance which is normally liquid @ room temperature & atmospheric pressure (Isoflurane, Sevoflurane, Desflurane) GAS: substance which is in a gaseous state at room temperature & atmospheric pressure (Nitrous oxide) Indications: Induction & Maintenance of anaesthesia I N H A L AT I O N A L A G E N T S ' P R O P E R T I E S SATURATED VAPOUR PRESSURE (SVP) Pressure exerted by the vapour on its surroundings (liquid) in a closed container at equilibrium at certain temperature Max concentration of molecules in the vapour state that exist for a given liquid for a given temperature, at equilibrium Measure the ability to evaporate ↑ SVP → ↑ [inhalant] delivered to pa ent Isoflurane > Sevoflurane SOLUBILITY Image from: Vapor Pressure (gsu.edu) Measured as PARTITION COEFFICIENT Capacity of a solvent to dissolve the anaesthetic gas [inhalant]solvent : [inhalant]gas at equilibrium I N H A L AT I O N A L A G E N T S ' P R O P E R T I E S BLOOD/GAS PARTITION COEFFICIENT High: a lot of anaesthetic must be dissolved in the blood before equilibrium Intermediate: Isoflurane Low: N20, sevoflurane, desflurane Helps predict speed of induction, recovery, change in anaesthetic depth Low blood solubility → > rapid equilibra on: > rapid induc on, change of anaesthetic depth & elimination OIL/GAS PARTITION COEFFICIENT Anaesthetic potency I N H A L AT I O N A L A G E N T S ’ P R O P E R T I E S Induce a reversible, dose-related state of unresponsiveness of CNS, haemodynamic & endocrine responses to noxious stimuli POOR (apart from Nitrous Oxide) I N H A L AT I O N A L A G E N T S : M E C H A N I S M O F A C T I O N M I M I N U M A LV E O L A R C O N C E N T R AT I O N ( M A C ) Minimum alveolar concentration of anaesthetic agent at which 50 % of patients fails to respond (by purposeful movement) to a standard supramaximal noxious stimulus (i.e., skin incision) Express as a % Potency 1/MAC Isoflurane > potent than Sevoflurane ~ 1.3 X MAC prevent movement in 95% of animals ~ 1.5 X MAC surgical anaesthesia BUT side effects… ~ 1 X MAC ( or less) usually used + MAC sparing effect techniques used MAC determined as a sole agent administered Balanced anaesthesia: ↓ MAC requirements (MAC sparing effect) Species & individual diﬀerences → monitoring MAC IN DIFFERENT SPECIES EFFECT OF DIFFERENT FACTORS ON MAC? ↑MAC ↓MAC NO EFFECT Species (body size) Pregnancy Gender Age: neonates, geriatric CNS stimulants drugs: CNS depressant drugs: PH Catecholamines Sedative, injectables, analgesic Sympathomimetics agents Hypertheroidism Hypernatremia Severe Hypoxaemia & Anaemia Hypercapnia Hypo/Hyperkalaemia Hyperthermia Hypothermia Duration of Anaesthesia Severe Hypotension Haemorrhage ≠ depending on the sources VAPORISER Zzzzzzz 02 +/- medical air Vaporiser converts liquid anaesthetic agent into its vapour form Add a controlled amount of this vapour to fresh gas flow Controls the concentration of anaesthetic delivered to the patient Annual service is a must! (faulty vaporizer can cause ) E N D T I D A L C O N C E N T R AT I O N O F I N H A L A N T S P H A R M A C O K I N E T I C S ( U P TA K E ) Inhalational agents move down a pressure gradient (from high to low) until equilibrium Depth of anaesthesia depends on Partial Pressure of anaesthetic drugs in the brain (Pbrain) Alveolar partial pressure of anaesthetic agents 15-20 % of important to control Cardiac Output Pbrain 75% of Cardiac Output (CO) P H A R M A C O K I N E T I C S ( E L I M I N AT I O N & R E C O V E R Y ) Depends on rate of decrease of Pbrain : return of consciousness Exhalation Metabolism (liver primarily, Cyt P450 enzymes): Minimal for modern inhalational agents (Isoflurane 0.2%, Sevoflurane 2-5%, Nitrous oxide 0.004%) Prolonged general anaesthesia → inhalant accumula on in fat → slow recovery Inhalant may be lost from breathing circuit (leaks) & patient (open cavities) Adsorption or degradation by CO2 absorber FA C TO R S T H AT A F F E C T S U P TA K E & E L I M I N AT I O N O F I N H A L AT I O N A L A G E N T S UPTAKE ELIMINATION ↑ [inhala onal agent], vaporiza on/ dial se ng ↑ ↓ ↑ FGF (circle < non-rebreathing) ↑ ↑ ↑ Volume of breathing system (circle > non-rebreathing system) ↓ ↓ ↑ Alveolar ven la on = RR x alveolar volume (TV -dead space volume) ↑ ↑ ↓ Dead space ven la on ↑ ↑ 2nd Gas Effect ↑ ↑ ↑Blood/ ssue solubility ↓ ↓ ↑Cardiac Output → pulmonary & ssue perfusion ↓ ↑ ↑Alveolar- venous blood-tissue partial pressure gradient ↑ ↑ U P TA K E & E L I M I N AT I O N Blood Uptake Equilibrium Elimination PHARMACODYNAMIC: CARDIOVASCULAR SYSTEM Decrease myocardial contractility Peripheral vasodilation HYPOTENSION Attenuation of baroreceptor reflex ↓CARDIAC OUTPUT Variable effect on HR (species & agent dependent) Impaired cardiac conduction Dose dependant effects PHARMACODYNAMIC: CEREBRAL Reversible, dose related CNS unresponsiveness to noxious stimulation: general anaesthesia Decrease cerebral metabolic rate Increase in cerebral blood flow (CBF): vasodilation Increase ICP P H A R M A C O D Y N A M I C : R E S P I R ATO R Y Decrease alveolar ventilation Decrease response to hypercapnia & hypoxaemia Respiratory muscle relaxation Dose dependent ↑ in RR (not with Isoflurane) but ↓ TV Airway irritation (especially Isoflurane, desflurane) Bronchodilation (increase in dead space) Depression of Hypoxic Pulmonary Vasoconstriction Image from: Lungs Sketch Illustration Hand Drawn Stock Motion Graphics SBV- 308613041 - Storyblocks P H A R M A C O D Y N A M I C : H E PATO B I L I A R Y S Y S T E M Decrease hepatic function Hepatocellular injury Cit P 450 inhibition Sevoflurane: Compound A (hepatotoxic) formed with interaction of CO2 absorbants (minimal level) PHARMACODYNAMIC: RENAL Decrease GFR & renal blood flow (decrease CO, hypotension, splanchnic vasoconstriction) Mild, reversible, dose related Nephrotoxicity : Sevoflurane: - Fluoride metabolites - Compound A (from degradation by CO2 absorbents) PHARMACODYNAMIC: MISCELLANEOUS MUSCLES: Myorelaxation Malignant Hyperthermia (pigs, humans, horses, dogs) All inhalational anaesthetics can trigger Rapid ↑ cellular metabolic activity UTERUS: Decrease contractility & blood flow IMMUNE SYSTEM: Depression Inhibition of INSULIN secretion SECOND GAS EFFECT Ability of one gas (1st gas, soluble in plasma, i.e. nitrous oxide ) to accelerate the rise of alveolar concentration of a 2nd gas (volatile anaesthetic, O2) when administered together “first gas” that is soluble in plasma, moves rapidly from the lungs to plasma. →↑ alveolar concentration and hence rate of uptake into plasma of the “second gas” To speed anaesthetic induction DIFFUSION HYPOXIA (THIRD GAS EFFECT OR FINK EFFECT) During recovery: Nitrous oxide is discontinued → nitrous oxide (low blood solubility) diffuses rapidly back from blood to alveoli → Dilution of the [inspired 02] & hypoxia → Dilution of [inspired CO2] → decrease in PaCO2 → to ↓in respiratory drive To solve: Administer 100% oxygen on recovery H E A LT H & S A F E T Y Sources of issues: Vaporiser filling Leaks from around the patient’s airway (e.g. mask or ET tube), anaesthetic machine and breathing system, ventilator, scavenging devices & connection tubing Patient exhalation Short term exposure: headache, fatigue, nausea, depression, irritability Chronic exposure: potential mutagenic, carcinogenic, teratogenic effects? H E A LT H & S A F E T Y Mitigation:  Daily leak testing & regular maintenance  Use minimum safe FGF  Squeeze breathing bag into scavenging & flush breathing system with O2/air before disconnecting  Avoid facemask or chamber induction/ maintenance  Spills → PPE, absorbent materials, ven la on  Ventilation of operating & recovery rooms  Scavenging system  Key-indexed vaporizer filling systems  Monitoring for trace concentrations  Education/ training E N V I R O N M E N TA L E F F E C T S Greenhouse gases : Global Warming Potential Index of CO2 & methane >>> desflurane & N2O >> sevoflurane > isoflurane Ozone layer destruction: N2O >> halothane >> isoﬂurane UVL degrada on → free chlorine Image from: https://www.sciencefacts.net/ozone-layer- depletion.html REFERENCES THANK YOU FOR YOUR AT T E N T I O N. ANY QUESTIONS? 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? Introduction to Pharmacology Martin Hawes Welcome to pharmacology! First the bad news - pharmacology is one of the hardest subjects for students to understand and learn. Sorry. Now the good news – I’m going to help you go from this: to this: Our pharmacology, therapeutics and pharmacy lectures support your development of RCVS Day One Competences 7 and 23: Prescribe and dispense medicines correctly and responsibly in accordance with legislation and latest guidance including published sheets. Develop appropriate treatment plans and administer treatment in the interests of the patient and with regard to the resources available and appropriate public health and environmental considerations. In order to help you achieve these competences, I need you to make a pinky promise to read the pre-read before each lecture, so that we can spend our precious time together discussing the tricky bits rather than spending time on the topics which are relatively easy. My promise is I’ll keep the pre-read for each lecture to 4 pages maximum. So if you’re ready, let’s go …. What is pharmacology? Pharmacology is the science of drugs and their effect on the body. It’s the science that underpins the safe and effective use of the medicines you will prescribe for almost every patient you see. What is a drug? Rang & Dale’s Pharmacology1 defines a drug as “a chemical or substance (other than a nutrient or an essential dietary ingredient) which, when administered to a living organism, produces a biological effect”. Chill - You do not have to learn this definition Lecture Learning Objective 1: Be aware of the various ways of naming medicines Drugs are known by their International Non-proprietary Name (INN name). This name is assigned to them by the World Health Organization. Another term for the INN name is the drug’s generic name. I will always discuss drugs using their generic name. Here are some examples of generic names you are likely to be familiar with: paracetamol aspirin ibuprofen Drug companies may give their products a brand name – also known as the proprietary name. The active ingredient (drug) in the product is still known by its generic name, but the product is packaged and sold under a proprietary name. Can you think of any brand names for paracetamol or ibuprofen? 1 Ritter, J., Flower, R. J., Henderson, G., Loke, Y. K., MacEwan, D. J., Robinson, E. S. J., & Fullerton, J. (2024). Rang and Dale’s pharmacology (Tenth edition.). Elsevier. Lecture Learning Objective 2: Identify and use the active ingredient as the primary term of reference when describing a veterinary medicine Take a look at these veterinary medicines and see if you can identify the active ingredient (i.e. the generic name of the drug). You might need to zoom in or use a magnifying glass for some of them!! Proprietary name: Metacam Proprietary name: Frontline Active ingredient: meloxicam Active ingredient: fipronil Proprietary name: Cerenia Proprietary name: Alfaxan Active ingredient: maropitant Active ingredient: alfaxalone Learning drug names is difficult – the words are strange, and the task is made harder because when you are on EMS the vets might use the brand name rather than the generic name. You should always use the generic name in exams at the vet school. Task Learn the names of the active ingredients above - meloxicam is an antiinflammatory drug used for pain relief; fipronil is used to kill fleas, ticks and lice; maropitant is used to prevent nausea and vomiting; alfaxalone is used in anaesthesia. That’s it for now – Key points: International Non-proprietary Names (INN) identify the active pharmaceutical ingredient in a medicinal product. The INN is also known as the generic name. INNs are selected by the WHO. Proprietary (or brand) names are given to a medicinal product by the pharmaceutical company that makes the product. INTRODUCTION TO VETERINARY ANAESTHESIA Hanna Machin Dip ACVAA, Dip SIAV, MVetMed, MRCVS Lecturer in Veterinary Anaesthesia Online learning 3010, 2024 ANAESTHESIA & ANALGESIA TEACHING IN THE 3010 MODULE: VETERINARY MEDICINE 1 Practical 2: Lectures: Anaesthetic machine check Premedication & sedation Breathing system safety Injectable anaesthetic agents Endotracheal intubation dog and cat Inhalational agents Monitoring in Veterinary Anaesthesia Monitoring & patient instrumentation Common complications & accidents in Veterinary Anaesthesia Practical 4: Fluid therapy Intravenous cannulation Pain Management (2h) Online learning: Introduction Anaesthetic Equipment ECG interpretation Capnography waveforms interpretation Fluid therapy & CRI calculations LEARNING OBJECTIVES Be able to: Define the terms general anaesthesia, local anaesthesia, analgesia Describe the components of general anaesthesia Describe the stages of anaesthesia Explain the process of anaesthesia including patient preparation and immediate post- anaesthetic care SOME DEFINITIONS… ANAESTHESIA: from Greek “ an- aesthesia”: lack of feeling/ sensation GENERAL ANAESTHESIA: state of unconsciousness produced by drugs administration, characterized by controlled, reversible depression of the Central Nervous System (CNS) and perception SOME DEFINITIONS… ANALGESIA: absence of pain in response to stimulation which would normally be painful NOCICEPTION: (under general anaesthesia): process of encoding noxious stimuli (transduction, transmission, modulation of nociceptive stimuli) LOCAL ANAESTHESIA (ANALGESIA): loss of pain sensation in a circumscribed body area REGIONAL ANAESTHESIA (ANALGESIA): insensibility to pain in a larger (but limited) body area usually defined by the innervation pattern of affected nerves THE TRIAD OF GENERAL ANAESTHESIA BALANCED ANAESTHESIA: simultaneous use of multiple drugs & technique to produce a state of general anaesthesia THE IDEAL ANAESTHETIC AGENT Rapid onset Safe following extravascular injection Rapid recovery No toxic effects High lipid solubility No histamine release Does not accumulate with prolonged infusion No hypersensitivity reactions Analgesic at sub-anaesthetic concentrations Water-soluble formulation No (or Minimal) cardiovascular depression No (or Minimal) respiratory depression Long shelf-life at room temperature No emetic effects No pain on injection No excitation No emergence phenomena Does not interact with other agents THE ANAESTHESIA TIMELINE S TA B I L I S E P R E - E X I S T I N G C O N D I T I O N S Medical management (e.g. diabetes, hyperthyroidism) Fluid Therapy (i.e. treat hypovolaemia & dehydration) Analgesia Anxiolysis Oxygen supplementation Surgical procedures (e.g., thoracocentesis, tracheostomy, pericardial drainage..) C H R O N I C M E D I C AT I O N S & A N T I - A N X I E T Y M E D I C AT I O N S Consider also anti-anxiety/ sedative medication(s) if stressed/anxious/aggressive patients (i.e. TRAZODONE, GABAPENTIN…) → to be administered ~2h before transport +/- the night before Image from: Grubb T, Sager J, Gaynor JS, Montgomery E, Parker JA, Shafford H, Tearney C. 2020 AAHA Anesthesia and Monitoring Guidelines for Dogs and Cats. J Am Anim Hosp Assoc. 2020 Mar/Apr;56(2):59-82. doi: 10.5326/JAAHA-MS-7055. PMID: 32078360 FASTING GUIDELINES To help ↓gastro-oesophageal reflux (GOR) & aspiration pneumonia, ↓ stomach size No clear consensus within the literature Species differences ~ 6 hours fasting (dogs & cats) Reduce fasting times for diabetic, neonatal, geriatric patients Image from: Grubb T, Sager J, Gaynor JS, Montgomery E, Parker JA, Shafford H, Tearney C. 2020 AAHA Anesthesia and Monitoring Guidelines for Dogs and Cats. J Am Anim Hosp Assoc. 2020 Mar/Apr;56(2):59-82. doi: 10.5326/JAAHA-MS- 7055. PMID: 32078360 AMERICAN SOCIETY OF ANESTHESIOLOGISTS (ASA) P H Y S I C A L S TAT U S C L A S S I F I C AT I O N S Y S T E M ANAESTHETIC RISK ↑ ASA status = ↑risks E Q U I P M E N T P R E PA R AT I O N Check:  O2 supply  Scavanging system  Anaesthetic machine(s)  Breathing system  Endotracheal tubes (ET tubes)  Intubation tools (laryngoscope)  Monitoring equipment  Rewarming devices  Emergency drugs  …. P R E M E D I C AT I O N Intravascular (IV), Intramuscular (IM) or subcutaneous (SC) Careful monitoring throughout Give adequate time for drugs to work Calm & quiet environment If sedation level insufficient: add more drug/use ≠ drugs More on this on premedication and sedation lecture! IM administration: Neck muscles Epaxial muscles Semimembranosus/semitendinosus Quadriceps IV CANULA PLACEMENT Administration of fluids and medications (peri-anaesthetic period) Blood sample collection Emergencies Patient welfare Aseptic technique required! Image from: Image from: Intravenous catheter placement // WVS Academy https://books.lib.uoguelph.ca/vetm3430/chapter/1- 3-medication-techniques/ P R E - OX YG E N AT I O N Administration of high fraction of inspired oxygen (FIO2) before induction by: Facemask Flow-by Oxygen cage/tent  For All patients: Images from: Veterinary Anesthetic and Monitoring Equipment, edited by Kristen G. Cooley, and Rebecca A. Johnson, John Wiley & Sons, Incorporated, 2018. Especially if difficult ventilation/intubation is expected ↑body 02 stores → delay onset of Hb desatura on during apnoea →Hypoxaemia Might not be tolerated Can cause stress & anxiety B E F O R E S TA R T I N G... Crush box Emergency drugs CPR cheat sheet CPR algorithm INDUCTION OF ANAESTHESIA  Endotracheal Tubes (ET tubes) tubes of different sizes  Laryngoscope  Tie  Syringe to inflate ET Tube cuff  Helper/mouth-gag  Induction agent of choice  Local anaesthetic  Lube  Swab to hold tongue HOW TO CHOOSE THE CORRECT ET TUBE SIZE? Choose at least 3 X ET tubes: the size you think it will fit, one above, one below For brachycephalic breeds have huge selection available ≠ formulas & tables (careful with overweight patients) Image from: 3.5 - https://www.theveterinarynurse.com/content/practical/endotra cheal-intubation-of-the-dog-and-cat/ Image from: ASNA_Endotracheal_Tube_Size_Chart (aspcapro.org) E N D OT R A C H E A L I N T U B AT I O N Images from: https://www.theveterinarynurse.com/Review/article/how-to-manage-a-difficult-airway E N D OT R A C H E A L I N T U B AT I O N Measure ET tube length before insertion (thoracic inlet) Keep head elevated until airways are secured Secure ET tube Connect to breathing system with O2 Check that ET Tube is in the trachea: - Check for condensation on the ET tube - Connect to capnograph & breathing system - Give a breath if patient is not breathing Check ET Tube cuff +/- inflation Image from: https://kidocs.org/2013/11/much-hot-gas-etco2-non-anaesthetists/ Image from: https://derangedphysiology.com S EC U R I N G T H E A I R WAY S Under inflation of ET Tube cuff: Change of capnograph trace Lower ET CO2 values Risk of aspiration pneumonia Leak of anaesthetic agents: - Pollution - Safety of personnel Image from: https://www.vetfolio.com/learn/article/capnography-in-dogs S EC U R I N G T H E A I R WAY S ET tube Cuff inflation: If over inflation: risk of tracheal ischemic necrosis Recommended safe ET tube cuff pressure range: 20–30 cmH2O Methods of measuring cuff pressure: Minimum occlusive volume technique Syringe devices (Tru-Cuff , AG Cuffill syringe) Image from: https://www.researchgate.net/figure/Diagram- Image from: representing-potential-mechanism-for-tracheal-mucosal- https://aneskey.com/trac perfusion-injury-secondary_fig2_51874813 heal-tubes-tracheostomy- tubes-and-airways/ AFTER INDUCTION “ The ABCD MNEMONIC ” AIRWAY BREATHING CIRCULATION & CUFF DRUGS/DEPTH of ANAESTHESIA EQUIPMENT/EYES FORMS Image from:Measuring clinical parameters | Veterian Key MONITORING Continuous Recording Which monitoring device gives us more info? S TA G E S O F A N A E S T H E S I A Species differences Stage of voluntary movement Stage I Stage of involuntary movement or delirium Stage of surgical anaesthesia Adequate plane of anaesthesia Extreme CNS depression Recovery MAINTENANCE OF ANAESTHESIA Administration of INHALATIONAL AGENT and/or INJECTABLE AGENTS and /or additional drugs (i.e., alpha 2 agonists/opioids, ketamine, lidocaine) and O2 More info on the induction & maintenance lecture RECOVERY CHECKLIST E X T U B AT I O N Keep patient in sternal (if possible) ET tube cuff deflation Keep monitoring Dog: swallowing, head/limb movement (i.e., brachy exception) Cat: ear flick, strong medial palpebral reflex (before swallowing): laryngospasm risk +/- sedation if required RECOVERY… Critical phase: ↑ risk morbidity & mortality → con nuous monitoring important RECOVERY Starts when maintenance agents is discontinued & patient start to regain consciousness Calm & warm environment Monitoring Patient warming Fluid therapy Eye lube Express bladder Adequate padding Pain scoring & analgesia +/- Sedation RECOVERY Delay: Excessive anaesthetic depth/drug administered Drugs with long duration of action Prolonged anaesthesia Comorbidities (hepatic, renal disease) Hypothermia Hypoglycaemia (diabetic, paediatric, exotic…) Poor circulation (hypotension, haemorrhage) Hypoxaemia EMERGENCE DELIRIUM State of stress, unease, anxiety, characterized by vocalization, panting, restlessness, uncoordinated thrashing Patient may not be mentally appropriate ≠ causes: Hypoxaemia? Pain? Recent opioid administration? → if not pain related…Sedation Alpha 2 agonists, Acepromazine, Propofol (0.5-1 mg/kg IV slowly) Have ET tube, laryngoscope, tie available to re- intubate if necessary HANDOVER REFERENCES T H A N K Y O U F O R Y O U R AT T E N T I O N. ANY QUESTIONS? Pharmacodynamics Martin Hawes Learning Objective: Define the term pharmacodynamics and differentiate it from pharmacokinetics Pharmacodynamics (often abbreviated to PD) is the branch of pharmacology that considers WHAT THE DRUG DOES TO THE BODY. Pharmacodynamics explores the relationship between drug concentration at the site of action and the resulting biological effects. Pharmacokinetics (abbreviated to PK) concerns WHAT THE BODY DOES TO THE DRUG. PK involves the measurement and interpretation of changes in drug concentration in the body over time, i.e. PK follows the drug concentration-time course of drug absorption, distribution, metabolism and elimination (ADME). Learning Objective: Describe drug interactions with various types of receptor Core concept: Drug Targets are molecules, the function of which can be modulated by a drug to produce a biological effect. Drug targets can refer to a range of molecules such as receptors, ion channels, enzymes, transporters, nucleic acids and signalling proteins. Most drug targets are proteins whose function is to receive and respond to endogenous signals. Drug targets can be located on the cell membrane (e.g. G protein-coupled receptors), or intracellularly (e.g. nuclear receptors). Please revisit your notes on cell signalling from VMS1003. You will recall (hopefully) that there are 4 main types of receptors. Core concept: Drug-Target Interaction describes the different ways a drug interacts with a target to produce a biological effect. Drug binding to a receptor is analogous to a lock and a key: the ideal drug (the key) will only fit into a specific target’s binding site (the lock) in order to cause the desired biological effect. The drug will not fit into other non-target binding sites (the wrong locks) – this will help reduce the risk of side effects. A drug's ability to interact with a drug target is determined by intermolecular forces and a match between the spatial arrangement of the drug’s atoms and the target binding site. For example, morphine and other related opioid drugs are T-shaped and they fit into a T-shaped binding site. Drugs can bind to their targets reversibly or irreversibly depending on the type of bonds formed. Core concept: Structure-Activity Relationship describes the relationship between the structural characteristics of a drug and its binding site, and the resultant biological effect. Structure–activity relationships can be manipulated during drug development processes to alter therapeutic and adverse effects. For example, changing HO groups on the morphine molecule can make a more potent opioid analgesic – diamorphine. 10 mg sc diamorphine is equivalent to 15 mg sc morphine Learning Objective: Give at least one example of a pharmacodynamics action that is not dependent on cell structures Finally, some drugs do not bind to receptors, their action is not dependent on cell structures, but instead they act by purely physical or chemical means. For example some indigestion remedies neutralise stomach acid. Activity In surgery lectures this week, you will learn about alpha-2 adrenoceptor agonists for pre-medication and sedation. Click here to visit the alpha-2 adrenergic receptor Wikipedia page. Hover over the following drugs commonly used in veterinary medicine and compare their chemical structures: xylazine, detomidine, romifidine, medetomidine – can you imagine how similar the drugs will be in 3 dimensions. Appreciate that small changes in chemical structure can make the drugs have short (xylazine), intermediate (romifidine, detomidine) or long (medetomidine) duration of action – this is another example of Structure-Activity Relationships (this model here represents xylazine). That’s it for now – Key points: Pharmacodynamics is what the drug does to the body. Pharmacokinetics is what the body does to the drug. Drug Targets are molecules (most commonly protein receptors), the function of which can be modulated by a drug to produce a biological effect. The term Drug-Target Interaction describes the different ways a drug interacts with a target to produce a biological effect. Structure-Activity Relationship describes the relationship between the structural characteristics of a drug and its binding site, and the resultant biological effect. Pharmacodynamic interactions can be either structurally dependent (drugs interact with receptor binding sites like a lock and a key), or independent of cell structures e.g. activated charcoal (adsorbent) / antacid indigestion remedies. P R E M E D I C AT I O N & S E D AT I O N Hanna Machin Dip ACVAA, Dip SIAV, MVetMed, MRCVS Lecturer in Veterinary Anaesthesia 27th September 2024 LEARNING OBJECTIVES Be able to: Outline the different reasons for premedication before induction of general anaesthesia Explain the rationale and patient safety considerations for the use of sedation versus general anaesthesia Describe the pharmacology of commonly used sedative drugs and opioids used in contemporary veterinary anaesthesia Explain the principles of neuroleptoanalgesia as applied to premedication and sedation in veterinary practice SOME DEFINITIONS PREMEDICATION: administration of medication(s) before anaesthesia ANXIOLYSIS: state of mental calm & relaxation, decrease in locomotor activity, reduced anxiety, lack of concern for the surrounding environment, response to stimuli if stimulated SEDATION: state of mental calm, sleepiness, disinterest in the environment, poorer responsiveness to stimuli compared to an anxiolytic NARCOSIS: Sedation produced by opioids NEUROLEPTOANALGESIA: Joint administration of a sedative drug and an opioid analgesic especially for relief of surgical pain S E D AT I O N V S G E N E R A L A N A E S T H E S I A ( G A ) SEDATION GA Control of the airways X V (regurgitation/aspiration) Ability to ventilate X V Monitoring > Difficult, “incomplete” V Local blocks administration > Difficult ? V Time Can be > time consuming Can be time consuming Additional notes Minor procedures in healthy patients  Often deep sedation required Often patient is noise/touch/light sensitive Sudden arousal possible Level of pain? Sedation is NOT quicker & safer! W H Y P R E M E D I C AT E ? Decrease anxiety, stress & catecholamines release Patient & staff welfare Facilitate handling Facilitate IV catheter placement Pre-emptive analgesia Balanced anaesthesia:↓ anaesthetic drugs required & related side-effects (i.e., MAC sparing effect) Promote smooth induction, maintenance & recovery phase Decrease Autonomic Nervous System (ANS) activation during surgery P R E M E D I C AT I O N O P T I O N S Acepromazine https://picryl.com/media/questions- Alpha-2 agonists demand-doubts-emotions-2ea8c6 Benzodiazepines Opioids Ketamine (discussed in the injectable agents lecture) ACEPROMAZINE Phenothiazines class SC/IM/IV/PO Licensed in dogs/cats/horses Unpredictable sedative?? Especially in Combine with other drugs Slow onset of action (up 30-40’ IM) Long duration: 4-6h (up to 8 h?) No reversal Dose: 5-10 mcg/kg IV up to 20 -30 mcg/kg IM Highly protein bound Liver metabolism, urinary & faeces excretion Cross BBB, placenta (lipophilic) ACEPROMAZINE ACEPROMAZINE SYNCOPE Careful with hypovolemic animals (decreased cerebral perfusion→ fainting) Breeds with high vagal tone/bradycardia (I.e. boxers, brachycephalic breeds…) ANTI-ARRHYTHMIC effect? ↓ incidence catecholamine-induced arrhythmias in dogs anaesthetised with barbiturates & halothane COLLIES & SHEPHERDS with MDR-1 gene mutation Prolonged & profound sedation Image from: https://www.preciousgemminis.com/mdr 1.html ACEPROMAZINE PRO CONVULSANT EFFECT? ACEPROMAZINE PRIAPISM RISK (stallions)? ALPHA-2 ADRENERGIC RECEPTOR AGONISTS Activation of central & peripheral pre & post- synaptic alpha 2 receptors Effects also on alpha1 & Imidazoline receptors  Central Nervous System Cerebral cortex Locus coeruleus & Rostroventral lateral medulla (area of SNS outflow) ↓ noradrenaline release, ↓ neurotransmission → Sedation, some cardiovascular effects Image from: Zhou and Zhao, J Anesth Clin Res 2014, 5:10 DOI: 10.4172/2155-6148.1000457 Spinal (analgesia, muscle relaxation)  Peripheral Nervous System  ≠ Organs ALPHA-2 ADRENERGIC RECEPTOR AGONISTS MEDETOMIDINE & DEXMEDETOMIDINE (dog, cat) XYLAZINE (horse, cattle) DETOMIDINE (horse, cattle) ROMIFIDINE (horse) ZENALPHA (dog) ≠ selectivity of ≠ alpha 2 agonists Drug α2:α1 selectivity ratio Xylazine 160 : 1 Detomidine 260 : 1 (Dex)Medetomidine 1620 : 1 Romifidine 340 : 1 Medetomidine: = mixture of Levomedetomine & Dexmedetomidine (active entianomer) ALPHA-2 ADRENERGIC RECEPTOR AGONISTS SC, IM, IV, Oral transmucosal, Nasal, Intra-rectal, Intra-vaginal… Short onset (1-2’ IV- 15/20’ IM) Administered as bolus/constant rate infusion (CRI) Duration of action: drug dependent (~ 30- 120’) Dose related effect Synergism with opioids & benzodiazepines (to decrease side effects) Decrease dose of induction/inhalational agents (MAC sparing effect) Analgesia duration?? Liver metabolism, urine excretion ALPHA 2 ADRENERGIC RECEPTOR AGONISTS GENERAL EFFECTS ALPHA-2 ADRENERGIC RECEPTOR AGONISTS CARDIOVASCULAR EFFECTS CARE if cardiovascular disease or sick patients A N TA G O N I S T S O F A L P H A - 2 A D R E N E R G I C RECEPTOR AGONISTS  ATIPAMEZOLE: Dex/Medetomidine Can be used also with xylazine & detomidine Sedation & analgesia are both antagonised No IV unless CPR Muscle tremors, excitement, tachycardia, hypotension, panting, vomiting  YOHIMBINE  TOLAZOLINE  VATINOXAN (MK-467) no cross BBB, reversal of cardiovascular effects only BENZODIAZEPINES DIAZEPAM & MIDAZOLAM Diazepam licensed (dog, cat, horse) Midazolam licensed (horse) Schedule IV drug IV, IM (midazolam only) Dose: 0.1-0.4mg/kg IV Hepatic metabolism (active metabolites) Duration: 1-4h Midazolam, 4-12h Diazepam? Hepatic necrosis (cats) Renal and biliary excretion Antagonist: Flumazenil BENZODIAZEPINES MECHANISM of ACTION GABA A receptors Image from: GABA Receptors (diff.org) Image from: Mota, Alberto & Nascimento, Gyzelle & Pereira, Gabriel. (2022). ACUPUNCTURE AS A COMPLEMENTARY ALTERNATIVE IN THE TREATMENT OF ANXIETY: A LITERATURE REVIEW. Journal Health and Technology - JHT. 1. e1216. 10.47820/jht.v1i2.16. BENZODIAZEPINES OPIOIDS Interaction with opioid receptors: mu(μ), kappa (κ), & delta (δ) Primary endogenous ligands: β-Endorphin (μ receptor), leucine- & methionine-enkephalin (κ receptor), dynorphin A (δ receptor) Dose response relationship: Image from: Yamaoka & Auckburally (2013) Analgesia in veterinary patients- opioids (part 1) The veterinary nurse: volume 4, issue 10 OPIOIDS: EFFICACY VS POTENCY Equal Efficacy, ≠ potency Image from: Image from: https://step1.medbullets.com/pharmacology/107007/efficacy-vs- https://ketaminenightmares.com/pex/saqs/pharmacology/pharmacodynamics/2020B11 potency _dose_response_curves_opioids.htm OPIOIDS IV, IM, SC, poor availability PO, transdermal, transmucosal (OTM) Hepatic metabolism (remifentanil: plasma esterases) Excretion: urine & bile OPIOIDS MECHANISM of ACTION PRESYNAPTIC POST-SYNAPTIC Image from: In utero and Postnatal Oxycodone Exposure: Implications for Intergenerational Effects - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Simplified-mechanism-of-action-of-opioids-using-morphine- as-an-example-of-an-opioid_fig3_355422924 OPIOIDS Receptors located all around the body Species & individual differences Image from: De Rosa, Giannatiempo , Charlier et others (2023). Pharmacological Treatments and Therapeutic Drug Monitoring in Patients with Chronic Pain. Pharmaceutics. OPIOIDS OPIOIDS Reduction pain perception ANALGESIA DORSAL HORN Reduce excitatory  Transduction neurotransmitter release  Transmission Hyperpolarization post  Modulation synaptic membrane ROSTRO-VENTRAL  Perception MEDULLA & PAG PERIPHERAL NOCICEPTORS Activation of descending inhibitory pathways Inhibition of ascending nociceptive input Opioid induced HYPERALGESIA OPIOIDS MORPHINE Mu agonist Histamine release Emetic (esp IM/SC) Epidural (preservative free) Urinary retention Pruritus Horses Controlled drug (schedule II) OPIOIDS METHADONE Full mu(μ) agonist NMDA receptor antagonist Analgesia  Not very sedative (apart from sick & very young patients) Potency: ~ to morphine Duration of action 3-4h Dose 0.1-0.5mg/Kg IV/IM/SC/transmucosal Controlled drug (schedule II) Licensed (dog, cat) OPIOIDS FENTANYL µ agonist Potency: 100 x morphine Onset: 1-2 mins Short Duration: 20 mins Bolus (1-2 mcg/kg) + Constant rate infusion (CRI) (5 -10 mcg/kg/hr) IV or transdermal patches Respiratory depression Controlled Drug (schedule II) Licensed in dogs OPIOIDS BUPRENORPHINE Mu(μ) partial agonist Weak kappa (κ), & delta (δ) antagonist High affinity binding to the receptors Onset of action: 30 min Long duration of action (6-8h) Analgesic effect (moderate) Mild respiratory & cardiovascular effects, less nausea/vomiting Dose 0.01-0.02mg/Kg IM/IV/SC/OTM Controlled drug (schedule III) Licensed in dog, cat, horse OPIOIDS PETHIDINE or MEPERIDINE mu(μ) agonist ONLY IM administra on → Histamine release (IV) 1/10th morphine’s potency Sedation & analgesia Some anticholinergic activity Dose 3.5- 10mg/kg IM Duration of action: 1-2h Pain on injection Controlled drug (Schedule II) Licensed in dog, cat & horse OPIOIDS BUTORPHANOL mu(μ) antagonist, kappa (κ) agonist Sedation  Antiemetic Antitussive Analgesic? (some birds spp, reptiles, horses) Duration: controversial Dose: 0.1 - 0.5 mg/kg IV/IM/SC (dogs & cats) 0.05 - 0.2 mg/kg IV (horses) Horses: Increase locomotor activity, ataxia, excitement Controlled drug (schedule III) It can be used to reverse mu-agonists MDR1 mutation (collies & shepherds) profound prolonged sedation A D J U N C T S TO P R E M E D I C AT I O N TRAZODONE Anxiolytic/sedative Tricyclic antidepressant Serotonin reuptake inhibitors (SSRIs) Serotonin receptors antagonist Histamine 1 & α1-adrenergic receptors antagonist (sedative-hypnotic effect) 3-7 mg/kg PO SID/BID/TID 1-2h before travelling Serotonin syndrome A D J U N C T S TO P R E M E D I C AT I O N GABAPENTIN  Neuropathic pain/ seizures Blockage of Ca2+ channels presynaptic neurons →↓ Ca2+ influx→ ↓ excitatory neurotransmitters Side effects: Sedation, ataxia, vomiting, diarrhoea, increased appetite? 100 mg/cat 1-2h before veterinary visit HOW TO CHOOSE THE PERFECT DRUG C O M B I N AT I O N F O R YO U R PAT I E N T ? Anaesthetic protocol should be TAILORED to YOUR PATIENT’s NEEDS! Dosages reported on leaflets and many formularies can be quite high! Some considerations: Species Patient: aggressive/ anxious? old/ young? Many different options (e.g.,): Which procedure? Duration? Level of pain elicited? Opioid alone as sedative/ analgesic Which effects do you wish to achieve? Opioid + sedative (i.e. medetomidine/acp) Is your patient cardio-vascularly stable? Opioid + Sedative + Ketamine Are there any other comorbidities (including pain)? IV/ IM/SC/OS administration? → eﬀect on dose, dura on Calculate dose based on lean body weight & allometric scaling REFERENCES THANK YOU FOR YOUR AT T E N T I O N. ANY QUESTIONS? PROBLEM WOUNDS A N D DRAINS ALISON LIVESEY 2024 L E A R N I N G OBJECTIVES Be able to: understand strategies for dealing with infected wounds understand and describe the consequences of improper treatment of infected wounds describe the management of foreign bodies and internally penetrating wounds describe the distinction between active and passive drains identify means of producing active or passive drainage describe scenarios that may benefit from surgical drainage describe drainage of the chest and abdomen Problem Wound and Drains October 2025 2 F A C T O R S T H A T C A N A F F E C T W O U N D HEALING Patient factors Poor nutrition/malnourishment (low protein levels) Concurrent disease (hyperadrenocorticism, hypoT4, cancer) Immunosuppressive drugs/chemotherapy Cat vs dog Wound interference Wound factors Blood supply Infection/Contamination Perfusion Tissue viability/fluid accumulation Movement/pressure/skin tension Neoplasia Problem Wound and Drains October 2025 3 P R O B L E M WOUNDS Disrupted wounds Pressure wounds Wounds in areas of Movement and Pressure Problem Wound and Drains October 2025 4 F A C T O R S T H A T L E A D T O D I S R U P T E D WOUNDS Wound tension Infection Haematoma or Seroma Suturing nonviable tissue Wound molestation Problem Wound and Drains October 2025 5 DEHISCENCE Problem Wound and Drains October 2025 6 H A L S T E D ’ S PRINCIPLES 1. Gentle tissue handling 2. Meticulous haemostasis 3. Preservation of blood supply 4. Strict aseptic technique 5. Tension free closure 6. Accurate apposition of tissues 7. Eliminate dead space William Stuart Halstead 1852 - 1922 Problem Wound and Drains October 2025 7 P R E S S U R E WOUNDS Decubital ulcers Bony prominences Greater trochanter Tuber coxae Acromion of scapulae Ischial tuberosity Lateral humeral epicondyle Lateral tibial condyle Lateral malleolus Sides of digit 5 Olecranon Calcaneal tuberosity Sternum Repeated trauma when sitting or lying (tissue compression) Prolonged recumbency (neurological/spinal patients/multi orthopaedic patients Bandage induced pressure sores Problem Wound and Drains October 2025 8 P R E V E N T I O N O F D E C U B I TA L U L C E R S Turn recumbent dogs every 1-4 hours Meticulous nursing/skin care-clean and dry-well-padded bed Treat underlying condition to prevent recumbency Relieve pressure Donut dressing Splints Problem Wound and Drains October 2025 9 P R E V E N T I O N O F B A N D A G E SORES Proper bandage placement and monitoring Prevent slipping Not overtight Careful padding over bony prominences Less is more Care with rigid fixation Casting, splints Place on the side of limb opposite the healing wound Be aware of swelling Today’s VeterinaryPractice Casting too early Use bivalve casts and check regularly Problem Wound and Drains October 2025 10 M O V E M E N T A N D PRESSURE Wounds over joints Tension, compression and shearing forces Meticulous attention to closure Casting/splinting Paw pad wounds Compression with weight bearing Spread with weight bearing pulls wound edges apart Suture pull through Bandaging/splinting Palmar/plantar – prevent weight bearing on pad for 2 weeks Tension relieving sutures far-near-near-far, large diameter monofilament suture Will eventually heal by granulation if owner will tolerate Sock/bandage to keep clean, lead walks Problem Wound and Drains October 2025 11 C H R O N I C W O U N D S – M O V E M E N T A N D PRESSURE Axillary and inguinal wounds Collar wounds Shearing movement with ambulation Meticulous closure Debride and close Resect and close Reconstructive flaps Problem Wound and Drains October 2025 12 I N F E C T E D WOUNDS Inhibits wound healing Chronic/recurrent wounds Causes dehiscence of closed wounds Surface contaminants do not often reflect infective agent Deep tissue culture Nature of wounding Puncture from a bite Underlying causes Foreign bodies Grass seeds, sx implants, bone sequestra, debris/contaminants Problem Wound and Drains October 2025 13 N A T U R E O F WOUNDING More energy applied to tissues More vascular damage Less blood supply, less O2, fewer plasma proteins Slower inflammatory response, prolonged inflammation Contaminated bacteria more likely to cause infection in damaged tissues Shearing creates dead space Penetrating FBs create dead space FBs create avascular surface for bacteria Problem Wound and Drains October 2025 14 T R A U M A , C O N T A M I N A T I O N A N D INFECTION SKIN SUBCUTANEOUS TISSUE MUSCLE Problem Wound and Drains October 2025 15 T R A U M A , C O N T A M I N A T I O N A N D INFECTION SKIN SUBCUTANEOUS TISSUE DEAD SPACE MUSCLE Warm Moist Low O 2 Proteins Immune response cannot penetrate Problem Wound and Drains October 2025 16 T R A U M A , C O N T A M I N A T I O N A N D INFECTION Immune response can only reach edges Walled off area Abscess SKIN SUBCUTANEOUS TISSUE MUSCLE Problem Wound and Drains October 2025 17 T R A U M A , C O N T A M I N A T I O N A N D INFECTION SKIN SUBCUTANEOUS TISSUE MUSCLE Problem Wound and Drains October 2025 18 T R A U M A , C O N T A M I N A T I O N A N D INFECTION Heals by granulation Chronic draining sinus Abscess bursts Poor drainage Devitalised tissue Drains FB SKIN SUBCUTANEOUS TISSUE MUSCLE Problem Wound and Drains October 2025 19 F O R E I G N B O D I E S A N D P E N E T R A T I N G WOUNDS Wood splinters, grass awns, straw, broken teeth or nail of an attacker Common entry Points Interdigital Ear canal Conjunctiva Oropharynx Draining Tract/Sinus FBs Surgical implants, sutures, cotton swab strands bone sequestra Problem Wound and Drains October 2025 20 A P P R O A C H T O A D R A I N I N G TRACT Diagnostics Radiographs – plain or with contrast Impression smear Bacteriology – C+S CT/MRI Surgically explore tract fully (open along tract +/- probing) Identify and remove cause Leave to heal by 2nd intention or excise tract en bloc Tissue sample for culture (anaerobic and aerobic) Image-PDSA Thoroughly lavage Empirical antibiotics Change based on culture results Problem Wound and Drains October 2025 21 P E N E T R A T I N G W O U N D S – C A T B I T E ABSCESS Cat bite abscess Puncture wounds with some crush injury Clinical infection majority of cases Presentation Rapidly occurring swelling Brave cat/timid cat Ruptured/burst and presented for wound Systemically unwell (pyrexic, lethargi,c painful) with no visible swelling Should be top differential in cats with PUO Lameness/not using limb/tail May occur in areas where difficult to get drainage naturally Problem Wound and Drains October 2025 22 C A T B I T E A B S C E S S - TREATMENTS Presented before abscessation No necessary to explore as FB low (hair? Tooth? Nail?) Antibiotics Pain relief (NSAIDs if hydrated) Presented with abscessation Antibiotics do not penetrate pus Lance, drain, flush, place drain? (dead space) Antibiotics Pain relief (NSAIDs if hydrated) Pasturella, Staph, Strep (aerobes + anaerobes) Broad spectrum (amoxy-clav, clindamycin, cephalosporins Problem Wound and Drains October 2025 23 O R O P H A R Y N G E A L P E N E T R AT I N G T R A U M A - S T I C K INJURIES Med to large breed dogs; collies, Labradors, spaniels Acute within 7 days of presentation oral pain, dysphagia and dyspnoea, submandibular and cervical swelling, abscesses, pain on opening of the mouth, pyrexia Injury observed or knowledge of stick catching/carrying Chronic > 7 days before presentation more common systemically well recurrent cervical or submandibular swelling or discharging sinus Problem Wound and Drains October 2025 24 O R O P H A R Y N G E A L P E N E T R AT I N G T R A U M A - S T I C K INJURIES Rostral pharyngeal wounds enters at acute angle penetrates pharynx at the tonsil or just behind last molar can lead to temporal, masseter or retrobulbar involvement Lateral pharyngeal wounds most common stick enters obliquely damages parapharyngeal & cervical tissues, intermandibular area or cranial thorax Dorsal pharyngeal injuries stick enters from directly in front of the dog damages soft palate and dorsal pharynx can lacerate the oesophagus Problem Wound and Drains October 2025 25 O R O P H A R Y N G E A L S T I C K I N J U R I E S - TREATMENT Acute Examination of oral cavity and pharynx Identify site of injury and retrieve foreign material Cervical and thoracic radiographs Soft tissue swelling, loss of detail, gas between tissue planes/ subcutaneously Pneumomediastinum if oesophageal perforation To prevent chronic fistulous tracts surgically explore via ventral midline approach, inspect dorsal oesophagus for tears Chronic recurrent cervical swellings and discharging sinuses original injury often unknown difficult to treat meticulous exploration of tracts and debridement of all diseased tissue remove all the diseased tissue and hopefully the foreign material with it Problem Wound and Drains October 2025 26 Problem Wound and Drains October 2025 27 S U R G I C A L DRAINS Tissue apposition and obliteration of dead space Remove fluid that provides media for bacterial growth Relieve pressure that can affect tissue perfusion Remove inflammatory mediators, bacteria, necrotic tissue, foreign material Drains themselves incite an inflammatory response Open drain (passive) Closed suction drain (active Problem Wound and Drains October 2025 28 Problem Wound and Drains October 2025 29 O P E N P A S S I V E DRAINS Penrose Capillary action Gravity Drainage along outside of tube High surface area to volume ratio Fenestration contraindicated Problem Wound and Drains October 2025 30 PENROSE DRAINS Advantages Inexpensive Soft/malleable Low tissue trauma Disadvantages Cannot quantify fluid production Not useful when large volume drainage required Require gravity Cannot use in the thoracic cavity Cannot use to flush wound More risk of ascending infection Problem Wound and Drains October 2025 31 P L A C I N G A P E N R O S E DRAIN Proximal end placed deep in wound/dead space Exit via stab incision adjacent to wound- dependent Distal end secured to skin with single SI suture through drain Cover with dressing Must not exit through incision Do not use for flushing Can secure proximal end with a single suture (internal or external suture) Care with neoplasia - place close to wound incision Need to clean regularly and attempt to quantify drainage production Problem Wound and Drains October 2025 32 PLACING A PENROSE DRAIN Problem Wound and Drains October 2025 33 C L O S E D S U C T I O N D R A I N S (ACTIVE) Tubing and suction device/vacuum Goes into wound Fenestrations Airtight cavity Less risk of contamination Problem Wound and Drains October 2025 34 C L O S E D S U C T I O N D R A I N S (ACTIVE) Advantages More effective fluid removal Reduced risk of ascending infection Easily portable Doesn’t require a lot of dressing Can collect and record fluid Constant suction decreases occlusion Disadvantages Loss of vacuum if wound is not airtight Occlusion by clots Premature removal by patients often requires buster collar Problem Wound and Drains October 2025 35 Closed Suctions Drains trocar Problem Wound and Drains October 2025 36 Friday, 30 September 39 P L A C I N G A C L O S E D S U C T I O N DRAIN From inside to outside Choose drain exit site easy to cover, easy to manage, comfortable for the patient Tunnel to site with forceps Incise skin over forceps hole no larger than the tubing some have a trocar Grasp tubing from inside wound and pull it outwards with forceps Fenestrated portion of tubing should be dependent Entire fenestrated portion must be in wound to allow suction/airtight Purse string suture and finger trap Attach grenade Problem Wound and Drains October 2025 37 TODAY’S VETERINARY PRACTICE, November/December 2016 A C T I V A T I N G SUCTION Best to wait 4-6 hours post op Compress the grenade with evacuation port open Close the port/cap the port/clamp tubing Release compression – creates negative pressure Cover exit site with adhesive dressing Use shirt or stockinette or bandage to protect tubing/grenade Use BC if can interfere Problem Wound and Drains October 2025 38 M A I N T A I N I N G A N A C T I V E S U C T I O N DRAIN Monitor and record fluid amount quality Empty drain at least once daily or when it is half full strength of suction decreases as grenade fills Grenades lose suction as they reach 20-30% capacity Remove when fluid production is decrease cardiac output Drug and indirect action of drugs Some drugs work via an indirect effect: 1. Direct action on cellular target produces desired response. Drug -> Target -> Desired Effect 2. Indirect action – drug interacts on target that is upstream from the biochemical process that produces the desired response. Drug -> Target -> Intermediate Effect -> Desired Effect Sunday, 08 September 2024 9 Drug and indirect action of drugs 1. Direct action on cellular target produces desired response. e.g. amlodipine blocks L-type calcium channels in vascular smooth muscle and thereby relaxes the muscle 2. Indirect action – drug interacts on target that is upstream from the biochemical process that produces the desired response. e.g. amphetamine inhibits a monoamine transporter mechanism and the metabolism of monoamines. This results in an increase in dopamine (D) and norepinephrine (NE) levels. D and NE in turn are associated with reward pathways in the brain Direct effect Indirect effect Amlodipine blocks Ca2+ Amphetamine acts channels in vascular on targets which lead to smooth muscle and an increase in D and NE. thereby relaxes the D and NE in turn muscle. stimulate reward pathways in the brain Sunday, 08 September 2024 10 Action of drugs Some drugs work via an indirect effect: Opposing physiological effect e.g. glucagon can be used to oppose the effects of insulin Increasing endogenous release e.g. amphetamines increase dopamine levels (neurotransmitter associated with reward) Prevent endogenous release e.g. ACE inhibitors prevent the formation of angiotensin II (thereby reduce aldosterone) Inhibit endogenous re-uptake e.g. some antidepressants (SSIs, TCAs) inhibit the reuptake of certain neurotransmitters Inhibit endogenous metabolism e.g. the MAO inhibitor antidepressants inhibit metabolism of noradrenaline Learning Objective 5 Define agonist, partial agonist and antagonist in respect to drug action and explain how they may interact at the receptor level Drug-Target Interaction Drug-Target Interaction describes the different ways a drug interacts with a target to produce a biological effect. Agonists are endogenous molecules or drugs that interact with a receptor to elicit a biological response. Full agonists - produce the maximum possible effect Partial agonists - produce submaximal effects Antagonists are endogenous molecules or drugs that interact with a receptor and limit or block the effect of agonists Sunday, 08 September 2024 13 Drug-Target Interaction Full agonists - produce the maximum possible effect e.g. methadone Partial agonists - produce submaximal effects e.g. buprenorphine Antagonists - limit or block the effect of agonists e.g. naloxone Sunday, 08 September 2024 14 Case studies Which medicine (methadone, buprenorphine or naloxone) is most suitable for each of these cases? Minnie is undergoing a spay Timmy is being castrated Frodo has been given too much methadone in error Sunday, 08 September 2024 15 Competitive and non-competitive antagonism Competitive antagonist competes with agonist for same receptor binding site. The overall effect depends on the relative concentration of agonist and antagonist If the concentration of agonist (in green) is in excess, the biological effect will be close to maximal. Addition of a competitive antagonist (red) will diminish the effects of the agonist. Agonist (in green) is in excess Antagonist (in red) is in excess Sunday, 08 September 2024 16 Competitive and non-competitive antagonism Non-competitive antagonist either: Binds to a different site on the receptor to the agonist, or Binds to the same site as the agonist so tightly the agonist cannot displace it (irreversible competitive antagonist). Non-competitive …. binds to the antagonist (black) either same site as the binds to a different site or agonist so tightly on the receptor to the the agonist cannot agonist (green) …. displace it Sunday, 08 September 2024 17 What will happen if ….. Bambi is being treated for high blood pressure with low dose metoprolol, a β1 competitive antagonist (slows heart rate). What will happen to Bambi’s heart rate if Simba starts to chase her and she has a massive increase in adrenaline (a β1 agonist)? Agonist (in green) is in excess Antagonist (in red) is in excess Sunday, 08 September 2024 18 What will happen if ….. Winnie the Pooh has had enough of Tigger’s bouncing today and, in order to sedate his annoying friend, he has given Tigger ketamine, a non-competitive antagonist for the NMDA receptor! Tigger hallucinates about his favourite food (extract of malt) and the level of excitatory neurotransmitter glutamate (an agonist for the NMDA receptor) in his brain increases. What will happen to Tigger’s level of sedation? Ketamine, a non- competitive antagonist (black) binds to a different site to glutamate (green) on the NMDA receptor Sunday, 08 September 2024 19 Learning Objective 6 Describe dose-response relationship Dose response curves Core concept: Dose / Concentration-Response Relationship is the relationship between the dose/concentration of a drug and the magnitude of the response produced. A plot of the log10 dose/concentration on the x-axis and response on the y-axis produces a sigmoid shape known as the log dose/concentration-response curve. Sunday, 08 September 2024 21 Agonists, partial agonists and antagonists Maximum effect Sunday, 08 September 2024 22 Learning Objective 7 Define and explain the concepts of potency, therapeutic index, therapeutic ratio, efficacy and receptor affinity Drug efficacy and drug potency Core concept: Drug Efficacy is the ability of a drug to elicit a response once bound to a drug target. Different agonists will produce varying levels of response: Full agonist (maximal response), partial agonists (sub-maximal response) efficacy Core concept: Drug Potency refers to the amount of a drug, expressed as the concentration or dose, needed to produce a defined effect. Drug A requires a lower dose to achieve 50% maximal response (EC50) than Drug B. Drug A is said to be more potent than Drug B Thanks Fido, but that’s not what I meant by potent! Sunday, 08 September 2024 24 Affinity and selectivity Core concept: Drug Affinity is the binding strength of a drug to a target. Drugs with a high affinity for their receptors are less easily displaced e.g. by a competitive antagonist. Sunday, 08 September 2024 25 Affinity and selectivity Core concept: Drug Selectivity is a drug’s ability to discriminate between drug targets. e.g. propranolol is a non-selective beta-blocker – it acts on β1 receptors in the heart and β2 receptors in the lungs, whereas metoprolol selectively acts on β1 receptors in the heart Sunday, 08 September 2024 26 Adverse Drug Reaction / Adverse Drug Event Core concept: Adverse Drug Reaction or Adverse Drug Event are terms that refer to any harmful or undesirable response to a drug. Adverse drug reactions are traditionally classified as: Type A - linked to the pharmacological effects of a drug thus are predictable/dose-dependent Type B - have no link with the pharmacological mechanism of action and are thus unpredictable/idiosyncratic e.g. methadone is used as an analgesic, but it also causes constipation as it inhibits peristalsis -> increased water absorption e.g. procaine penicillin ADR in horse https://www.facebook.com/Last-Stop-Horse- Rescue-324557567565076/videos/beaus- reaction-to-medication/1149457151741776/ Sunday, 08 September 2024 27 Therapeutic range A drug needs to reach a certain level in the plasma to achieve the necessary concentration at its site of action to be fully effective – the Therapeutic range CP - Plasma Therapeutic Concentration range Time Sunday, 08 September 2024 28 Suboptimal levels Below the therapeutic range, the drug will not achieve the necessary concentration at its site of action and its effect will be suboptimal clinically CP - Plasma Concentration Sub-optimal effect or no effect Time Sunday, 08 September 2024 29 Minimum effective concentration (MEC) Minimum effective concentration (MEC) is the minimum plasma concentration required to produce the therapeutic effect CP - Plasma Concentration Minimum Effective Sub-optimal effect Concentration

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