MPP block 2 lecture 2.pdf

1.Describe how antisense therapy could be used to treat DMD 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 - Increas...

1.Describe how antisense therapy could be used to treat DMD 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 - Goal: slow or prevent the progression of DMD 2.Compare and contrast how cholinergic agonists and cholinergic antagonist work Acetylcholinesterase: 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 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 Indirect-Acting Cholinergic Agonists Anticholinesterase Agents: - Edrophonium - Physostigmine - Neostigmine 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 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, used to manage symptoms of MG - Adverse effects: ”Generalized cholinergic stimulation”, Generalized cholinergic stimulation: Contraindicated when intestinal or urinary bladder obstruction is present. Salivation, flushing, decreased blood pressure, nausea, abdominal pain, diarrhea, and bronchospasm 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, used to manage symptoms of MG - Adverse effects: “generalized cholinergic stimulation” 5.List the mechanism of action of NMBAs and relate how they alter the NMJ physiology Cholinergic Antagonists: Term for drugs that bind to cholinoceptors (muscarinic or nicotinic) and prevent the effects of acetylcholine (ACh) and other cholinergic agonists 6.Predict the changes in an action potential with NMBAs Pharmacologic Classes: 1. Antimuscarinic agents 2. Ganglionic blockers - mostly for nicotinic receptors 3. Neuromuscular-blocking agents - mostly nicotinic Neuromuscular-blocking agents: block cholinergic transmission between motor nerve endings and the nicotinic receptors on the skeletal muscle, Act either as antagonists (nondepolarizing) or as agonists (depolarizing) at the receptors of the NMJ Non-depolarizing agents (-curonium) – Competitive Blockers: Nicotinic receptor antagonists - 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 (agonists): 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 – rapid onset, but shorter-acting than compared to above Succinylcholine - High affinity for nicotinic receptors and is resistant to AChE - Persists at the NMJ and activate the nicotinic receptor channels continuously, works in 2 phases Succinylcholine 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 Succinylcholine Phase II: gradual repolarization as the sodium channel closes or is blocked = resistance to depolarization and flaccid paralysis