MED201 NMJ Pharmacology Spring 2023 PDF

Neural Signalling to Skeletal Muscle and Drugs Acting at The Neuromuscular Junction Hassan Alsaad, Ph.D. Department of Pharmacology Health Colleges Building Complex Office: 1038 [email protected] Sunday, January 14, 2024 Learning Objectives Students should be able to: • describe the chain of ev...

Neural Signalling to Skeletal Muscle and Drugs Acting at The Neuromuscular Junction Hassan Alsaad, Ph.D. Department of Pharmacology Health Colleges Building Complex Office: 1038 [email protected] Sunday, January 14, 2024 Learning Objectives Students should be able to: • describe the chain of events which occur during the nicotinic transmission at the skeletal NMJ • explain the actions of cholinergic inhibitors at the skeletal neuromuscular junction and understand their off-target effects • explain the actions of cholinesterase inhibitors at the skeletal neuromuscular junction and understand their off-target effects • describe the therapeutic strategies for treatment of myasthenia gravis • describe mechanisms, symptoms, pharmacotherapies of anticholinesterase poisoning Sunday, January 14, 2024 Presentation title Somatic Nervous System (SMNS) ANS SNS SNS 3 Nicotinic receptor at NMJ (NM) • is a type of cholinergic receptors; expressed in skeletal muscles • functions as a ligand-gated ion channel; fast; influx of Na+ 6 312- 63- Bind Ach lon It channel has opens selectivity to Ions . Cholinergic Receptors Muscarinic Nicotinic M1 M2 M3 M4 M5 NN NM 4 Neuromuscular transmission at the skeletal NMJ 5 Drug targets at NMJ 1. Presynaptic process • inhibit Ach synthesis, storage , or release 2. Postsynaptic process • Inhibit normal activation of NM receptor 3. Enzymatic process • Inhibit ACh-esterase, so ….. 6 P HARMA COLOGY 1. Drugs acting at the presynaptic sites 7 H Drugs acting at the presynaptic sites • e.g., Botulinum toxin • most potent bacterial toxin; how to use?! • MoA • cleaves components of SNARE proteins • inhibit the release of ACh into NMJ • prevent muscular contraction • Used to treat muscle spasms, e.g., • facial wrinkles (botox; cosmetic) ACh • Forehead lines, Glabellar lines, Lateral canthal lines • overactive bladder • SNARE protein is a complex of proteins (VAMPs, SNAPs) necessary for the exocytosis of neurotransmitters 8 P HARMA COLOGY 2. Drugs acting at the postsynaptic sites 9 H Drugs acting at the postsynaptic sites • NM blockers • Block NM receptors • classified into; • Non-depolarising NMB (competitive) • e.g., rocuronium, mivacurium • Depolarising NMB (non-competitive) • e.g., succinylcholine ACh • used adjunctively to anesthesia to produce paralysis / relaxation of skeletal muscles • permit intubation of the trachea, and optimize the ventilation/surgical conditions 10 a. Depolarising NM blockers • e.g., succinylcholine (suxamethonium) • the only depolarizing NM blocker available for clinical use • MoA • bind directly to NM receptor on the motor end-plate • cause prolonged depolarization • produces skeletal muscle relaxation • Initial muscle contraction, then paralysis of skeletal muscles • PK • metabolized by butyrylcholinesterase (plasma cholinesterase) • Patients with butyrylcholinesterase deficiency?! • unpredictable and prolonged response 11 b. Non-depolarising NM blockers • e.g., rocuronium, mivacurium, … etc. • these show variety of PKs • MoA • competing with Ach for the binding sites at Nm receptors • competitive antagonist • preventing the initiation of action potential, block transmission • muscle paralysis • Nondepolarizing NMBAs are divided into aminosteroid compounds (eg, pancuronium, vecuronium, rocuronium) and benzylisoquinolinium compounds (eg, atracurium, cisatracurium, mivacurium) 12 FYI Variety of PDs & PKs 13 Reversal of NM block • generally, for non-depolarising NM blockers, e.g., rocuronium • faster than spontaneous recovery • examples; ~ • neostigmine FYI • How! • sugammadex • antidote; selective relaxant binding agent • MoA • forms a complex with the NMB agents, particularly steroidal NMBs • reducing the plasma conc of NMB agent 14 P HARMA COLOGY 3. Drugs acting at the cholinesterase enzyme 15 H 3. Drugs acting at the cholinesterase enzyme • Cholinesterase inhibitors • e.g., pyridostigmine, neostigmine, … etc. • MoA • • • • Inhibit cholinesterase enzyme Prevent degradation of Ach Maintain higher conc. of Ach at the synapse Enhance cholinergic transmission • Used as a therapy or diagnostic for myasthenia gravis ACh 16 Myasthenia gravis • an autoimmune disease affecting skeletal muscle NMJ • antibodies are produced against the N receptor • reducing function of N receptor • Signs and symptoms • ptosis, diplopia, difficulty in speaking and swallowing, and extremity weakness • The disease resembles the NM blockade caused by nondepolarizing NM blockers • Cholinesterase inhibitor, pyridostigmine?! 17 Other therapeutic strategies for myasthenia gravis • Based on the patient condition • Immunosuppressive treatment • to eliminate the Ach receptor autoantibody • e.g., prednisolone, cyclosporine • Immunoglobulins (Ig) Antibodies • Plasmapheresis, plasma exchange • Thymectomy 18 Other effects of cholinesterase inhibitors Just Consept (no details needed) • Ach and cholinesterase are found in • SNS, NM • ANS, NN, M • CNS 19 Function of ANS • conveys the output of the CNS to the peripheral organs • regulates basic physiological processes in the body and maintains homeostasis • Parasympathetic • Ach • “rest and digest” responses • Sympathetic • NE and Ach • “fight or flight” responses 20 P HARMA COLOGY Anticholinesterase (cholinesterase inhibitor) poisoning 21 H Adverse effects and toxicity of AntiChEase agents • sources of intoxications: medication overdose, insecticides, chemical warfare • acute toxic effects of AChE inhibitors are direct extensions of the pharmacological actions • Signs of acute intoxication / ADRs of ChEase inhibitors • ANS (Mnemonics: DUMBBELL) • • • • • • • • diaphoresis / sweating Urination Miosis Bradycardia Bronchial spasm and secretions Emesis / vomiting Lacrimation / salivation Loose stool / diarrhea • CNS • cognitive disturbances, convulsions, coma • Somatic NS • NM blockade Treatment of AntiChEase toxicity • Atropine • Muscarinic receptor antagonist Cholinergic Receptors Muscarinic Nicotinic M1 M2 M3 M4 M5 NN NM • Others • Therapy often also includes treatment with pralidoxime to regenerate ChE and administration of 23 benzodiazepines for seizures P HARMA COLOGY The end .. 24 H