Therapeutics for the Musculoskeletal System PDF

Therapeutics for the musculoskeletal system Dr Martin Hawes Senior Lecturer in Veterinary Pharmacology and Therapeutics Saturday, 28 October 2023...

Therapeutics for the musculoskeletal system Dr Martin Hawes Senior Lecturer in Veterinary Pharmacology and Therapeutics Saturday, 28 October 2023 1  Learning Outcomes 1. State the principle functional problems caused by diseases of the musculoskeletal system 2. Identify drugs that can be used to modify neuromuscular function 3. Identify peripherally vs centrally active drugs to treat neuromuscular conditions 4. Understand possible uses of these agents to treat the most common diseases in dogs, cats, horses and production animals Saturday, 28 October 2023 2  Drugs to alter neuromuscular function Saturday, 28 October 2023 3  Benzodiazepines Benzodiazepines (e.g. diazepam, midazolam) are used as part of a pre-anaesthetic or sedation protocol as muscle relaxants (balanced anaesthesia) In addition to sedative anxiolytic affects, reduce muscle tone by central action on GABAA receptors primarily in spinal cord (i.e. enhance inhibitory signals) Muscle relaxation weak and without appreciable loss of coordination diazepam Benzodiazepines Saturday, 28 October 2023 4  Neuromuscular blocking agents (NMBAs) Used to induce paralysis – small rapid moving muscles (eyes, larynx) relax before limbs and trunk Non-depolarizing agents e.g. atracurium, vecuronium ACh antagonists which produce motor paralysis Can be reversed using anticholinesterases e.g. neostigmine, pyridostigmine Depolarizing agents - e.g. suxamethonium ACh receptor agonists – not metabolized by acetylcholinesterase –> end plate cannot repolarize Cannot be reversed. Saturday, 28 October 2023 5  Ryanodine receptor (RYR1) antagonist Ryanodine receptor (RYR1) antagonist, dantrolene - blocks release of Ca2+ ions from sarcoplasmic reticulum in striated muscle preventing muscle contraction Used to treat recurrent exertional rhabdomyolysis in horses Historically used to treat malignant hyperthermia (a runaway contraction of muscle which was a complication with older volatile anaesthetics e.g. halothane). dantrolene Saturday, 28 October 2023 6  Peripherally and centrally acting drugs to treat neuromuscular disorders Saturday, 28 October 2023 7  Pain and inflammation Tissue injury provokes a complex response involving the release of inflammatory mediators Block production of mediators e.g. glucocorticoids or non-steroidal anti-inflammatory drugs (anti-COX NSAIDs, anti EP4) or nutraceuticals Block effects of metalloproteases Inflammatory mediators trigger nociceptors Block firing e.g. anti-NGF monoclonal antibodies Pain signal is transmitted along afferent axons Block transmission e.g. local anaesthetics Block receptors e.g. TRPA1 or TRPV1 on nociceptive fibres Pain is perceived in the CNS Block perception e.g. opioids, GABA agonists, glutamate and NMDA receptor antagonists Saturday, 28 October 2023 8  Pain and inflammation Tissue injury provokes a complex response involving the release of inflammatory mediators Glucocorticoids - methylprednisolone, triamcinolone NSAIDs - aspirin, phenylbutazone, meloxicam, carprofen, firocoxib Selective EP4 receptor antagonist - grapiprant Metalloprotease inhibitors - pentosan polysulfate sodium Nutraceuticals - glucosamine, chondroitin sulfate, antioxidants, EFAs Inflammatory mediators trigger nociceptors Anti-NGF monoclonal antibodies – bedinvetmab, frunevetmab Pain signal is transmitted along afferent axons Local anaesthetics – bupivacaine, lidocaine, mepivacaine TRPA1 - paracetamol Pain is perceived in the CNS Opioids – tramadol GABA agonists - gabapentin Glutamate and NMDA receptor antagonists – ketamine, amantadine Saturday, 28 October 2023 9  Pain and inflammation Tissue injury provokes a complex response involving the release of inflammatory mediators Glucocorticoids - methylprednisolone, triamcinolone NSAIDs - aspirin, phenylbutazone, meloxicam, carprofen, firocoxib Selective EP4 receptor antagonist - grapiprant Metalloprotease inhibitors - pentosan polysulfate sodium Nutraceuticals - glucosamine, chondroitin sulfate, antioxidants, EFAs Inflammatory mediators trigger nociceptors Anti-NGF monoclonal antibodies – bedinvetmab, frunevetmab Pain signal is transmitted along afferent axons Local anaesthetics – bupivacaine, lidocaine, mepivacaine TRPA1 - paracetamol Pain is perceived in the CNS Opioids – tramadol GABA agonists - gabapentin Glutamate and NMDA receptor antagonists – ketamine, amantadine Saturday, 28 October 2023 10  Intra-articular glucocorticoids Intra-articular glucocorticoids (e.g. methylprednisolone, triamcinolone) used to treat inflammatory musculoskeletal conditions (esp. horses) Aseptic technique critical Single doses well tolerated, chronic use can lead to glucocorticoid side effects e.g. Cushingoid signs Can exacerbate laminitis methylprednisolone triamcinolone Saturday, 28 October 2023 11  Arachidonic Acid Cascade and Inflammation Cell Membrane Phospholipids Phospholipase A2 Glucocorticoids Inhibit Arachidonic Acid Lipoxygenase Cyclo-oxygenase NSAIDs Inhibit (COX) Prostaglandin H2 Leukotrienes (PGH2) Thromboxane Prostacyclin Prostaglandins A2 Saturday, 28 October 2023 12  Cyclo-oxygenase COX1 and COX2 Arachidonic Acid Cyclo-oxygenase-1 Cyclo-oxygenase-2 (COX-1) (COX-2) Homeostatic Inflammation functions Constitutive expressed Expressed in inflammatory cells in most tissues (also has homeostatic functions) Gastrointestinal cytoprotection Produces mediators of inflammation Renal blood flow autoregulation Platelet aggregation Initiation of partruition Saturday, 28 October 2023 13  COX-2 vs COX-1 selectivity Selectivity is desirable to reduce adverse effects Older NSAIDs (e.g. aspirin, phenylbutazone) are non-selective Newer NSAIDs (carprofen, meloxicam, firocoxib) are selective COX-2 selective NSAIDs mainly reduce GI side effects. The frequency of other AEs such as emesis, lethargy and death is not significantly different Saturday, 28 October 2023 14  NSAIDs Actions – anti-inflammatory, analgesic, antipyretic Adverse effects GI (nausea and vomiting, gastric & intestinal damage with risk of bleeding and ulceration) Reversible renal insufficiency – avoid in dehydrated patients and in patients on potentially nephrotoxic drugs – monitor renal function Small risk NSAIDs may precipitate cardiac failure in animals with cardiovascular disease NSAID ‘failure’ seen in 10-15% of dogs – try alternative NSAID Saturday, 28 October 2023 15  Grapiprant Non-steroidal, non-cyclooxygenase inhibiting anti- inflammatory drug Selective antagonist of the EP4 receptor The EP4 receptor is important in mediating pain and inflammation as it is the primary mediator of the prostaglandin E2-elicited sensitization of sensory neurons and prostaglandin E2-elicited inflammation. GI side effects (soft faeces/diarrhoea, vomiting) are generally transient Grapiprant inhibits PGE2 Saturday, 28 October 2023 16  Pentosan polysulfate Pentosan Polysulfate Sodium (NaPPS) is indicated for treatment of lameness and pain of degenerative joint disease/OA in dogs Semi-synthetic polymer with anti-inflammatory properties – reduces metalloproteinases thereby preserving proteoglycan content and protecting cartilage matrix from degradation Given as a course of 4 weekly sc injections Response variable Duration of effect variable – max 3 courses of 4 injections in 12 months Concurrent use with steroids and NSAIDs contraindicated (risk of bleeding due to combined effects on platelet aggregation) Saturday, 28 October 2023 17  Nutraceuticals Nutritional supplements for normal body structure and function with the intent of improving health and well-being Multiple substances commonly used in arthritis, all have variable and incomplete evidence for efficacy Chondroitin sulfate – component of cartilage Glucosamine – component of cartilage Antioxidants – counter potentially damaging oxidants EFAs – weak anti-inflammatory properties Saturday, 28 October 2023 18  Pain and inflammation Tissue injury provokes a complex response involving the release of inflammatory mediators Glucocorticoids - methylprednisolone, triamcinolone NSAIDs - aspirin, phenylbutazone, meloxicam, carprofen, firocoxib Selective EP4 receptor antagonist - grapiprant Metalloprotease inhibitors - pentosan polysulfate sodium Nutraceuticals - glucosamine, chondroitin sulfate, antioxidants, EFAs Inflammatory mediators trigger nociceptors Anti-NGF monoclonal antibodies – bedinvetmab, frunevetmab Pain signal is transmitted along afferent axons Local anaesthetics – bupivacaine, lidocaine, mepivacaine TRPA1 - paracetamol Pain is perceived in the CNS Opioids – tramadol GABA agonists - gabapentin Glutamate and NMDA receptor antagonists – ketamine, amantadine Saturday, 28 October 2023 19  Monoclonal antibodies – Human medicine Lu et al, 2020 J.Biomed.Sci Saturday, 28 October 2023 20  Monoclonal antibodies – Human medicine NGF Sanchez-Robles et al (2021) Saturday, 28 October 2023 21  Bedinvetmab / frunevetmab Nerve growth factor (NGF) increases inflammatory mediators and stimulates nociceptors Bedinvetmab is a canine monoclonal antibody (mAb) and frunevetmab is a felinised mAb targeting NGF. For long-term management of OA pain (not acute pain) Do not use in young animals (under 12 months) – critical role in development – or in pregnant or lactating animals (potentially teratogenic and foetotoxic). Limited long-term data – approved 2020/2021 bedinvetmab frunevetmab Saturday, 28 October 2023 22  Pain and inflammation Tissue injury provokes a complex response involving the release of inflammatory mediators Glucocorticoids - methylprednisolone, triamcinolone NSAIDs - aspirin, phenylbutazone, meloxicam, carprofen, firocoxib Selective EP4 receptor antagonist - grapiprant Metalloprotease inhibitors - pentosan polysulfate sodium Nutraceuticals - glucosamine, chondroitin sulfate, antioxidants, EFAs Inflammatory mediators trigger nociceptors Anti-NGF monoclonal antibodies – bedinvetmab, frunevetmab Pain signal is transmitted along afferent axons Local anaesthetics – bupivacaine, lidocaine, mepivacaine TRPA1 - paracetamol Pain is perceived in the CNS Opioids – tramadol GABA agonists - gabapentin Glutamate and NMDA receptor antagonists – ketamine, amantadine Saturday, 28 October 2023 23  Paracetamol First line pharmaceutical treatment for OA in humans NSAID with analgesic and antipyretic but weak anti- inflammatory MoA not clear - seems to have specific activity for the CNS COX enzyme, COX3 (few GI effects). It may also reduce conduction in pain sensory neurons (action through TRPA1 ion channel). Careful with the dose in dogs – no veterinary product licenced for dogs. DO NOT USE in cats. Saturday, 28 October 2023 Do not use in cats X 24  Pain and inflammation Tissue injury provokes a complex response involving the release of inflammatory mediators Glucocorticoids - methylprednisolone, triamcinolone NSAIDs - aspirin, phenylbutazone, meloxicam, carprofen, firocoxib Selective EP4 receptor antagonist - grapiprant Metalloprotease inhibitors - pentosan polysulfate sodium Nutraceuticals - glucosamine, chondroitin sulfate, antioxidants, EFAs Inflammatory mediators trigger nociceptors Anti-NGF monoclonal antibodies – bedinvetmab, frunevetmab Pain signal is transmitted along afferent axons Local anaesthetics – bupivacaine, lidocaine, mepivacaine Pain is perceived in the CNS Opioids – tramadol GABA agonists - gabapentin Glutamate and NMDA receptor antagonists – ketamine, amantadine Saturday, 28 October 2023 25  Tramadol Centrally acting analgesic with complex mechanism of action involving opioid, norepinephrine, and serotonin receptors Unlike morphine, tramadol does not have depressing effects on respiration or gastrointestinal motility Management of mild to moderate acute pain, but also as adjunctive analgesic in management of chronic arthritic pain Effects may be variable Sedation at high doses, dysphoria more likely in cats Can be combined with other classes of analgesic tramadol Saturday, 28 October 2023 26  Gabapentin Analogue of the neurotransmitter GABA. Initially used as an antiepileptic, now used in the treatment of neuropathic pain MoA of its analgesic effect is unknown Start with a low dose and increase slowly. May cause mild sedation and ataxia Withdraw therapy slowly too (potential for rebound pain shown in humans) gabapentin Saturday, 28 October 2023 27  Amantadine Amantadine is an NMDA receptor antagonist – it blocks excitatory signals in the CNS (mechanism akin to ketamine) Is used in multimodal treatment for progressive moderate- severe OA pain and for pain relief in osteosarcomas N.B. there is limited evidence for use in veterinary species and it is not licenced in veterinary species or humans for pain Common side effects in humans include anxiety; confusion; depression; hallucination; headache; mood altered; movement disorders; sleep disorders; vision disorders Can increase risk of seizures when used in combination with tramadol Saturday, 28 October 2023 28  Multimodal management of osteoarthritis Saturday, 28 October 2023 29  Key Points LO - Identify drugs that can be used to modify neuromuscular function In addition to their sedative effects, benzodiazepines (e.g. diazepam, midazolam) are used as muscle relaxants as part of pre-op protocols Neuromuscular blocking agents (NMBAs) include non- depolarizing ACh antagonists (e.g. atracurium, vecuronium), and depolarizing ACh receptor agonists (e.g. suxamethonium). Non-depolarizing agents can be reversed using anticholinesterases (e.g. neostigmine). Depolarizing agents cannot be reversed. Ryanodine receptor (RYR1) antagonists (e.g. dantrolene) - block the release of Ca2+ ions from the sarcoplasmic reticulum in striated muscle, preventing muscle contraction. Used to treat equine RER Saturday, 28 October 2023 30  Key Points LO - Identify peripherally vs centrally active drugs to treat neuromuscular conditions Glucocorticosteroids suppress the inflammatory response. Intra-articular glucocorticoids (e.g. methylprednisolone, triamcinolone) used to treat inflammatory MSK conditions. Non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. meloxicam, carprofen, firocoxib) are widely used. They inhibit the cyclo-oxygenase enzyme and thereby block the production of mediators of inflammation, pain and fever. COX-2 selective NSAIDs have fewer GI side effects compared with non-selective drugs. NSAIDs reduce renal blood flow and should not be used in dehydrated patients or patients with renal impairment. Paracetamol is an NSAID with analgesic and antipyretic but weak anti-inflammatory. DO NOT USE in cats Saturday, 28 October 2023 31  Key Points LO - Identify peripherally vs centrally active drugs to treat neuromuscular conditions Grapiprant is a non-steroidal, non-cyclooxygenase inhibiting anti-inflammatory drug. It is an antagonist for EP4, a receptor important in mediating pain and inflammation. Grapiprant is licenced for use in mild to moderate arthritis in dogs. Tramadol is a centrally acting analgesic with complex mechanism of action involving opioid receptors. Unlike morphine, tramadol does not have depressing effects on respiration or gastrointestinal motility. Used to manage mild to moderate acute pain, and adjunctive analgesia in chronic arthritis Pentosan Polysulfate Sodium (NaPPS) is a semi-synthetic polymer with anti-inflammatory properties indicated for treatment of lameness and pain of degenerative joint disease/OA in dogs. Response is variable. Saturday, 28 October 2023 32  Key Points LO - Identify peripherally vs centrally active drugs to treat neuromuscular conditions Gabapentin is an analogue of the neurotransmitter GABA. It is used in the treatment of neuropathic pain. The MoA for its analgesic effect is unknown Nutritional supplements are commonly used to treat arthritis, all have variable and incomplete evidence for efficacy. So called neutraceuticals include hondrointin sulfate, glucosamine, antioxidants and EFAs Bedinvetmab and frunevetmab are anti-NGF monoclonal antibodies (dog and cat respectively) indicated for osteoarthritis. Amantadine, an NMDA receptor antagonist, is used in multimodal therapy for moderate to severe progressive pain Saturday, 28 October 2023 33