L3 Clinical pharmacology of analgesics 2023.pptx

Clinical pharmacology of analgesics BVMS3 Module 14 Supporting the patient Pat Pawson 2023 2 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 phar...

Clinical pharmacology of analgesics BVMS3 Module 14 Supporting the patient Pat Pawson 2023 2 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. 2. 3. Summarise key aspects of the pharmacology of commonly used analgesics, including opioids, NSAIDs & local anaesthetics Outline the indications and contraindications for commonly used analgesics Explain the factors that should be considered when choosing analgesics 3 Overview • What you need to do ... – Review pharmacology of analgesics from FP    Module 7, Week 3: Local anaesthetics Module 7, week 3: NSAIDs Module 8, Week 3: Opioids (“Pain pharmacology epidural anaesthesia”) • What I am going to do ... – – Outline key aspects of pharmacology Outline considerations when choosing analgesics • Looking ahead … – LEC 3.14.12 “How to provide adequate analgesia” 4 Analgesia • Analgesia: strictly an absence of pain but clinically a reduction in the pain perceived • Classes of analgesic drug: – Opioids – Non-steroidal anti-inflammatory drugs (NSAIDs) – Local anaesthetics – Alpha2-agonists – Ketamine 5 Opioid analgesics • Summary: – – – Mechanism: activate  , &  opioid receptors to reduce neuronal excitability Effects & side effects:  Analgesia  Sedation (excitement)  Euphoria/dysphoria  Respiratory depression  Nausea ( vomiting)  Reduced gut motility Pharmacokinetics:  Poor oral bioavailability 6 Opioid analgesics • Indications include: – To relieve pain Acute > chronic  Moderate/severe > mild  – To provide sedation  – – – Alone or in combination with other drugs To reduce required dose of general anaesthetic To treat diarrhoea To control coughing 7 Opioid analgesics • Contra-indications: • Use with caution in some patients: – Existing hypoventilation: e.g. ruptured diaphragm – Elevated intracranial pressure (ICP): e.g. head trauma or brain tumours  Opioids depress ventilation and increase PaCO2 which leads to cerebral vasodilation & further increases ICP 8 Opioids • • • • • • • • Alfentanil Buprenorphine Butorphanol Codeine Diprenorphine Etorphine Fentanyl Hydromorphone • • • • • • • • Loperamide Methadone Morphine Naloxone Oxymorphone Pethidine Remifentanil Tramadol Comparing opioids • Which receptors are activated by the opioid? – – Analgesia mediated primarily via  BUT many side effects (respiratory depression, constipation etc. are also mediated by  ) • Is it a full agonist, partial agonist or antagonist? – – – Full agonists are more efficacious analgesics A partial agonist produces a sub-maximal response An antagonist produces no response Dose Response 9 Full Partia l 1 0 NSAIDs: Non-steroidal antiinflammatory drugs • Summary: – – – – Mechanism: inhibit production of prostaglandins & thromboxanes by cyclo-oxygenase enzymes (COX) Effects:  Analgesia  Anti-inflammatory Side effects:  Dyspepsia, GIT ulceration  Renal toxicity  Hepatic toxicity  Effects on platelet function Pharmacokinetics:  Marked interspecies variability 1 1 NSAIDs • Indications include: – Pain management  – Acute and chronic Management of inflammatory disorders Antipyretic agents  Management of endotoxaemia  – Management of pro-thrombotic states  E.g. feline hypertrophic cardiomyopathy – Management of specific tumours  E.g. transitional cell carcinoma of the urinary bladder 1 2 NSAIDs Contra-indications: • NSAIDs should not be given to patients with …. – – Gastrointestinal tract disease, especially GI ulceration Acute or chronic renal disease  Low effective circulating volume – – – – Due to cardiac failure, hypovolaemia or shock NB: consider effects of anaesthesia Impaired hepatic function Haemostatic disorders  E.g. von Willebrand’s disease & thrombocytopaenia 1 3 NSAIDs • Contra-indications (contd): • NSAIDs should not be given to …. – – Patients concurrently treated with steroids Breeding, pregnant or lactating animals NSAIDs are potentially teratogenic  NB: PGs have a role in ovulation, embryo implantation & parturition  – Patients with unstable asthma  Increased production of leucotrienes 1 4 1 5 NSAIDs Aspirin (acetylsalicylate acid) Paracetamol (acetaminophen in USA) Phenylbutazone (suxibuzone), Dipyrone Piroxicam, Meloxicam Ibuprofen, Carprofen, Ketoprofen, Ketorolac, Vedaprofen Aminonicotinic acids Flunixin Indolines Pyranocarboxlic acids Indomethacin Thiophenacetic acids Etodolac Diclofenac, Eltenac Anthranilic acids Clonixin, Meclofenamic acid, Tolfenamic Coxibs acid Derecoxib, Cimicoxib, Enflicoxib, Firocoxib, Mavacoxib, Robenacoxib Salicylic Acids Para-aminophenol Pyrazolones Oxicams Propionic acids 1 6 Comparing NSAIDs • Two isoforms of cyclooxygenase – COX-1 and COX-2 • NSAIDs do not affect both isoforms equally • NSAIDs can be categorised according to their selectivity for COX-2 – – – Non-selective COX inhibitors Preferential COX-2 inhibitors Specific COX-2 inhibitors • In theory, risk of gastrointestinal toxicity should decrease with increasing specificity for COX-2! – Non-selective > preferential > specific 1 7 New developments • Grapiprant (Galliprant): – – Mechanism: antagonist of prostaglandin E2 at EP4 receptors Production of “physiological” prostaglandins not inhibited  Fewer adverse effects 1 8 Local anaesthetics • Summary: – – – Mechanism: block sodium channels preventing the initiation & conduction of action potentials Effects & side effects:  Analgesia (“block” neuronal transmission)  Antidysrhythmic action  CNS toxicity: twitching, seizures, coma  CVS toxicity: bradycardia, hypotension Pharmacokinetics:  Activity affected by tissue pH  Ionisation slows onset 1 9 Local anaesthetics • Techniques utilising local anaesthetics – – – Topical application Infiltration Instillation into a cavity or wound  – – – – Wound “soaker” catheter Peripheral nerve blocks Epidural (extradural) block Intravenous regional analgesia (Bier’s block) Intravenous infusion 2 0 Local anaesthetics • Contra-indications: • Mostly relate to techniques rather than drugs …. – E.g. contra-indications to epidural injection include:  Haemostatic disorders, pelvic/spinal fractures, pyoderma • Intravenous administration – Lidocaine only Use adrenaline-free preparation  Care in cats  – NOT bupivacaine Local anaesthetics 2 1 • • • • • • • Cocaine Lidocaine Procaine Mepivacaine Bupivacaine Ropivacaine Proxymetacaine • EMLA cream: mixture of lidocaine & prilocaine Formulate an analgesic plan … 2 2 Choosing drugs 1. Analgesic efficacy – 2. Adverse effects/“safety” – 3. 6. Is the drug licensed, is it a controlled drug? Pharmacokinetics – 5. Health status of patient: pre-existing disease Legislation – 4. Nature of pain: Severity, chronicity, pathology etc. Route of administration, speed of onset, duration etc. Potency Cost 2 3 1. Analgesic efficacy • What level of analgesia is required? – – Consider procedure: major surgery vs non-invasive procedure Consider patient: is there existing pain? • Predictable differences in analgesic efficacy: – OPIOIDS: full agonists > partial agonists  – OPIOIDS: μ receptor agonists > receptor agonists  – For e.g. methadone more effective than buprenorphine For e.g. methadone more effective than butorphanol NSAIDs: no consistent differences in analgesic 2 4 2. Adverse effects • Is the patient at increased risk of adverse effects? – – Consider pre-existing disease, concurrent medication & procedure Are any analgesics contra-indicated or best avoided? • Predictable differences in safety – OPIOIDS: partial agonists “safer” than full agonists Lower risk of hypoventilation with buprenorphine than methadone  Alternative approach: use full agonist at lower dose  – NSAIDs: specific COX-2 inhibitors may be less likely to cause GIT ulceration than non-selective COX inhibitors 2 5 3. Legislation: licensing • Is there a suitable “veterinary authorised” analgesic available? – A drug that has been approved for veterinary use should be used in preference to an unlicensed drug (e.g. a human medicine) Lots of NSAIDs are approved for veterinary use  Several opioids are approved for veterinary use  But many adjunctive analgesics, e.g. gabapentin, do NOT have a veterinary license  2 6 3. Legislation: licensing • Other licensing considerations: – Choose drugs that are approved for use in the species of interest (avoid extrapolating between species!) NSAIDS: Marked species differences in t½ e.g. aspirin  NSAIDS: Marked species differences in safety e.g. ibuprofen  – Consider peri-operative safety NSAIDs: Not all are approved for use in anaesthetised patients  E.g. carprofen, meloxicam & robenacoxib  – Consider duration of treatment  NSAIDs: Not all are approved for chronic use 2 7 3. Legislation: controlled drugs • Is the drug “controlled”? – – – Most opioids are controlled Must follow strict regulations with respect to storage, record-keeping and disposal CDs can be divided into schedules Schedule 2 includes all full agonist opioids  Schedule 3 includes buprenorphine, tramadol & gabapentin  Butorphanol & codeine are not controlled  2 8 4. Pharmacokinetics: route of administration • What route of administration is preferred? – Hospitalised patients: drugs can be injected (IV, IM, SC) OPIOIDS/NSAIDs are available as solutions for injection  OPIOIDS: IV pethidine causes significant histamine release  – Patients at home: orally-active drugs are preferred OPIOIDS: Most have low oral bioavailability (tramadol)  NSAIDs: All have good bioavailability  2 9 4. Novel routes of administration • Transmucosal: – Some drugs can be absorbed through buccal mucosa into systemic circulation  OPIOIDS: Buprenorphine in cats o o o Buprenorphine unionised in basic environment Well absorbed through feline buccal mucous membranes J Vet Pharmacol Therap 2005: 28(5), 453-460 • Transdermal: – Lipid soluble, potent drugs can be absorbed through skin into the circulation OPIOIDS: Fentanyl patch (buprenorphine solution)  LOCAL ANAESTHETIC: Lidocaine patch  3 0 4. Novel routes of administration • Fentanyl patch – Advantages Opioid treatment at home  Long duration (3 days)  – Disadvantages  Time to peak effect – Dogs 24 h, cats 12 h Uptake variable  Problems with adhesion  Abuse potential  3 1 4. Pharmacokinetics: route of administration • Convenience of administration? – NSAIDs are available as …. Granules added to feed  Oral pastes & suspensions  Palatable/chewable tablets  – – What about long-acting preparations? NSAIDs: Mavacoxib tablet lasts 2-4 weeks!  Enflicoxib tablet lasts 1 week  vetnurse.co.uk 3 2 4. Pharmacokinetics: speed of onset • What if you need analgesia right now! – For intra-op “rescue” analgesia a drug with a rapid onset of action is best! OPIOIDS: IV fentanyl has a rapid onset & short duration  BUT be aware of side effects: – Bradycardia can develop so inject slowly! – May need to support ventilation!  3 3 5. Potency • Is potency of the drug important? – Potency: amount of drug required to produce an effect  – Potent drugs have low injection volume  – Some opioids, e.g. fentanyl, are highly potent Suitable for remote administration devices Accidental self-administration is more hazardous e.g. needle prick, splash in eye etc.  Always have antagonist available! 3 4 Further reading Gruen et al. 2022 AAHA Pain Management Guidelines for Dogs and Cats J Am Anim Hosp Assoc 2022: 58: 55-76.