Lecture #10: Skeletal Muscle Pharmacology

Lecture #10: Skeletal Muscle Pharmacology Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx)  L11: Learning Objecti...

Lecture #10: Skeletal Muscle Pharmacology Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx)  L11: Learning Objectives 1. Describe how antisense therapy could be used to treat DMD 2. Compare and contrast how cholinergic agonists and cholinergic antagonist work 3. Relate the clinical manifestation of MG to the underlying muscle physiology 4. Compare and contrast the mechanisms of action of drugs to diagnosis and manage MG 5. List the mechanism of action of NMBAs and relate how they alter the NMJ physiology 6. Predict the changes in an action potential with NMBAs  Clinical Connection: Muscular Dystrophy Duchenne muscular dystrophy Results from a recessive X-linked mutation in the dystrophin gene Loss of dystrophin function prevents the cytoskeleton and its embedded contractile machinery from attaching to the sarcolemma and the muscle fiber becomes necrotic, causing muscle wasting Patients eventually succumb to respiratory muscle failure LO1  Therapy for Duchenne Muscular Dystrophy Eteplirsen – form of “anti-sense therapy” Use antisense oligonucleotides to target mRNA MOA: bind to pre-mRNA of dystrophin and rearrange the splicing of the RNA so that more dystrophin is produced Increasing the quantity of an abnormal, but functional, dystrophin Lim KRQ, Maruyama R, Yokota T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther. 2017;11:533-545 Goal: slow or prevent the progression of https://doi.org/10.2147/DDDT.S97635 LO1 DMD  Therapy for Duchenne muscular dystrophy Lim KRQ, Maruyama R, Yokota T. Eteplirsen in the treatment of Duchenne muscular dystrophy. Drug Des Devel Ther. 2017;11:533-545 LO1 https://doi.org/10.2147/DDDT.S97635  Indirect-Acting Cholinergic Agonists – Anticholinesterase Agents Acetylcholinesterase is an enzyme that cleaves ACh to acetate and choline and terminates its actions Inhibitors of AChE indirectly provide a cholinergic action by preventing the degradation of ACh = accumulation of ACh in the synaptic space LO2  Indirect-Acting Cholinergic Agonists – Anticholinesterase Agents The reversible AChE inhibitors can be broadly classified as short-acting or intermediate-acting agents Edrophonium Physostigmine Neostigmine LO2  Clinical Connection: Myasthenia Gravis ht tps :// cached.imagescaler.hb pl.co.uk/res ize/ scaleWid th/ 800/cached.offlinehb pl.hbpl.co.uk/ news/ PGH /G P3-20170926095712312.png Autoimmune condition myasthenia gravis (MG) is the most common disorder affecting neuromuscular transmission Antibodies against nicotinic acetylcholine receptors interfere with normal signaling at NMJ Muscle weakness varies greatly Treatment includes anticholinesterase inhibitors LO2,3,4 https://www.tha il an dme di cal.n ews/up lo ads/e di to r/fil es/C OVID-19-News(17).jpg FYI - New cases suggest an association of COVID-19 and MG: https://www.acpjournals.org/doi/10.7326/L20-0845  Therapy for Myasthenia Gravis Acetylcholinesterase Inhibitors MOA: inhibits acetylcholinesterase from degrading acetylcholine Increases the level and duration of acetylcholine signaling Many different types - often classified by duration of action LO2,3,4  Cholinergic Agonists: Acetylcholinesterase Inhibitors Edrophonium - short-acting AChE inhibitor - rapidly absorbed, short duration of action of 10 to 20 minutes due to rapid renal elimination MOA: Binds reversibly to the active center of AChE, preventing hydrolysis of Ach Clinical Use: Diagnosis of MG - IV injection of edrophonium leads to a rapid increase in muscle strength LO2,3,4  Cholinergic Agonists: Acetylcholinesterase Inhibitors Physostigmine - intermediate-acting AChE inhibitor - durations of action ~30 minutes – 2 hours MOA: a substrate for AChE, it forms a relatively stable intermediate with the enzyme, which then becomes reversibly inactivated Results in an increase of cholinergic activity throughout the body Clinical Use: increases intestinal and bladder motility, which serves as its therapeutic action in atony of either organ Physostigmine is used to manage symptoms of MG LO2,3,4  Cholinergic Agonists: Acetylcholinesterase Inhibitors Physostigmine - intermediate-acting AChE inhibitor - durations of action ~30 minutes – 2 hours Adverse effects: ”Generalized cholinergic stimulation” Salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm Contraindicated when intestinal or urinary bladder obstruction is present LO2,3,4  Cholinergic Agonists: “Generalized Cholinergic Stimulation” LO2,3,4  Cholinergic Agonists: Acetylcholinesterase Inhibitors Neostigmine - reversibly inhibits AChE in a manner similar, intermediate duration of action, ~ 30 minutes to 2 hours MOA: a substrate for AChE, it forms a relatively stable intermediate with the enzyme, which then becomes reversibly inactivated More polar, absorbed poorly from the GI tract, and does not enter the CNS Effect on skeletal muscle is greater than that of physostigmine, can stimulate contractility before it paralyzes Clinical Use: stimulate the bladder and GI tract Neostigmine is used to manage symptoms of MG LO2,3,4  Cholinergic Agonists: Acetylcholinesterase Inhibitors “Generalized Cholinergic Stimulation” Neostigmine - reversibly inhibits AChE in a manner similar, intermediate duration of action, ~ 30 minutes to 2 hours Adverse effects: “generalized cholinergic stimulation” salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm Contraindicated when intestinal or urinary bladder obstruction is present LO2,3,4  Cholinergic Antagonists Term for drugs that bind to cholinoceptors (muscarinic or nicotinic) and prevent the effects of acetylcholine (ACh) and other cholinergic agonists Pharmacologic Classes: Antimuscarinic agents Ganglionic blockers - mostly for nicotinic receptors Neuromuscular-blocking agents - mostly nicotinic LO2  Cholinergic Antagonists: Neuromuscular Blocking Agents (NMBA’s) Drugs block cholinergic transmission between motor nerve endings and the nicotinic receptors on the skeletal muscle Some chemical similarities to Ach Act either as antagonists (nondepolarizing) or as agonists (depolarizing) at the receptors of the NMJ NMJ blockers are clinically useful during surgery LO2,5,6  Neuromuscular Blocking Agents (NMBA’s): Example from Intensive Care Unit Initial Chest X-ray reveals diffuse infiltrates Despite appropriate management the patient status continues to deteriorate Decision made to paralyze the patient to allow for better respiratory management LO2,5,6  Neuromuscular Blocking Agents (NMBA’s) All these agents work by modulating the nicotinic receptor (only found in skeletal muscles) Non-depolarizing agents (-curonium) – Competitive Blockers Pancuronium – one of the longest acting, careful with renal failure Vecuronium – few side effects, not affected by renal function Rocuronium – one of the shortest acting, careful with liver failure Depolarizing agents - Succinylcholine – rapid onset, but shorter-acting than compared to above LO2,5,6  Neuromuscular Blocking Agents (NMBA’s) Non-depolarizing agents (-curonium) Nicotinic receptor antagonists Main difference between these is their onset and duration of action Pancuronium – long acting Vecuronium – short acting Rocuronium – shortest acting LO2,5,6  Skeletal Muscle Action Potential LO2,5,6  Neuromuscular Blocking Agents (NMBA’s) Depolarizing agents Work by depolarizing the plasma membrane of the muscle fiber, similar to the action of ACh More resistant to degradation by AChE and can more persistently depolarize the muscle fibers Succinylcholine - Nicotinic Receptor Agonists High affinity for nicotinic receptors and is resistant to AChE Persists at the NMJ and activate the nicotinic receptor channels continuously LO2,5,6  Neuromuscular Blocking Agents (NMBA’s) Depolarizing agents Succinylcholine - Nicotinic Receptor Agonists Phase I: first causes the opening of the sodium channel associated with the nicotinic receptors, which results in depolarization of the receptor = transient twitching of the muscle Continued binding renders the receptor incapable of transmitting impulses Phase II: gradual repolarization as the sodium channel closes or is blocked = resistance to depolarization and flaccid paralysis LO2,5,6