Drugs Acting on Cholinergic/Parasympathetic ANS PDF

Med 201 Lecture 3 Drugs Acting on Cholinergic [or] Parasympathetic ANS 1. CholinomimeticsFrugs thesame of gives Najla Taslim, PhD Email: [email protected] Assistant Professor of Pharmacology Dec. 2023 action Acetylcholine Abbreviations • ANS = autonomic nervous system • NE = Norepinephrine...

Med 201 Lecture 3 Drugs Acting on Cholinergic [or] Parasympathetic ANS 1. CholinomimeticsFrugs thesame of gives Najla Taslim, PhD Email: [email protected] Assistant Professor of Pharmacology Dec. 2023 action Acetylcholine Abbreviations • ANS = autonomic nervous system • NE = Norepinephrine • Ach = Acetylcholine • Nn = nicotinic receptors at ganglia • AV = arterio-ventricular • Nm = nicotinic receptors at skeletal muscle • BBB = Blood brain barrier • BP = Blood pressure • DA = Dopamine • GIT = Gastrointestinal tract • M = Muscarinic receptor • MAP = mean arterial pressure • MOA = Mechanism of action • PVR = peripheral vascular resistance • SA = sino-atrial • S.c = subcutaneous • Tx = treatment Important Note • Not included in Exam are: • FYI slides • Any information in green font • Caution • This lecture does not include all drugs acting on the ANS. • A vast list of clinically relevant ANS drugs is available in text books • By the time you graduate, many more drugs might be available for clinical use. Drug Acting on Cholinergic System 1 Indirectly acting drugs Drugs Inhibiting the team Synthesis 26811 Release a I Storage Metabolism of Ach** arises in I 2 Directly acting drugs Cholinergic Cholinergic agonists antagonists (Cholinomimetic (Anti-cholinergics) s) Drughas the same Action of Ach onVeleptor ** This class is considered cholinomimetics too. Cholinomimetics means that drugs mimic the effect of cholinergic stimulation. INDIRECTLY ACTING DRUGS Drugy Type Drugs Effects Synthesis Inhibitors Hemicholinium Anti-cholinergic effects Storage Inhibitors Vesamicol Anti-cholinergic effects Release Inhibitors Botulinum toxin Anti-cholinergic effects Metabolism Inhibitors Acetylcholinesterase inhibitors Cholinomimetic effects I We studies them in transmitter lecture. Only metabolism and release inhibitors are clinically used and will be discussed a little more here. Botulinum toxin will be covered in next lecture Metabolism of Acetylcholine [Ach] • Acetylcholinesterase (AChE), richly found in cholinergic synapses, terminates the action of the ACh within milliseconds • Acetylcholinesterase inhibitors (AChEI) prevent the metabolism of Ach. and e prolong the half life and effects of Ach activation. [cholinomimetics] • Other cholinesterases with a lower specificity for acetylcholine, include, butyrylcholinesterase [pseudocholinesterase], are found in blood plasma, liver, glia, and many other tissues [discussed in neuromuscular blocker drugs] FYI 0 0 Anti-acetylcholinesterase Inhibitors [AChEI] asana Competitive Inhibitors Short acting Drugs: Edrophonium, donepezil, galantamine………& others • Reversibly compete for ACh binding at the anionic site of AChE Carbamate inhibitors Medium acting Drugs: Physostigmine, neostigmine, insecticides & others • Contains carbamyl ester linkage, which carbamylates the AChE for relatively longer time. • Physostigmine is CNS permeable a Irreversible inhibitors Long acting ffitIinsecticidewm.w ano T I and win Drugs: Echothiophate and oraganophosphates [ a.ms insecticides] and nerve gas & others • Contain phosphate group which covalently bind esteric site of the AChE. The enzyme must either be resynthesized or chemically reactivated by pralidoxime [see next]. • These products are highly lipophilic [except for ecothiophate] and can enter CNS Metabolism of AChE by Long-acting Ach Inhibitors Ref. Cholinesterase Inhibitors: Including Insecticides and Chemical Warfare Nerve Agents. Part 2: What are cholinesterase inhibitors? Cholinergic Poisoning Mechanism of Action of Pralidoxime • Pralidoxime can free AChE enzyme • Hydrolyzes the covalent bond and regenerates the active enzyme from the organophosphorus-cholinesterase complex if the complex has not “aged”. • If enzyme-organophosphate bond is aged, it cannot be broken by pralidoxime. • Pralidoxime is ineffective in reversing the CNS effects of organophosphate poisoning [they cannot cross BBB]. Effects of AChE Inhibition • Enhancement of peripheral effects of cholinergic nerve stimulation. • Muscarinic effects – same as in table 1 in 1st lecture. • Low to moderate doses → DUMBEL + bradycardia + mild vasodilation • High doses → bradycardia + vasoconstriction Why vasoconstriction? • Nicotinic effects – • Nm stimulation → muscle contraction • Nn stimulation → NE and epinephrine release, sympathetic discharge at ganglia → vasoconstriction Poisoning to AChEI insecticides is common and is responsible for fair number of emergency visits. These drugs are lipophilic and will produced central effects too → tremor, convulsion, seizure, respiratory arrest. DIRECTLY ACTING DRUGS Cholinergic agonists (Cholinomimetics) Cholinergic antagonists (Anti-cholinergic) Will be → discussed in next lecture Agonists: directly bind and activate cholinergic receptors → stimulate system Antagonists: bind and inhibit cholinergic receptors activity → system inhibition Also terminate the effects of basal cholinergic activity Acetylcholine Receptors (Cholinoceptors) Muscarinic receptors M1, M2, M3, M4, M5 Nicotinic receptors Nn, Nm ACh is a universal non-selective endogenous ligand for both nicotinic and muscarinic receptor types and subtypes Muscarinic receptors (M1-M5) • Belong to G-receptor family • M1, M3, M5 • coupled via Gq/11 to phospholipase C • Activation cause hydrolysis of phosphatidylinositol (PI) to IP3 and DAG • IP3 triggers release of Ca from intracellular stores • DAG activates PKC to promote phosphorylation of other intracellular sites Inhibition of adenyl cyclase;  cAMP • M2, M4 • coupled via Gi/o to adenyl cyclase and K channels • Activation inhibits hydrolysis of ATP ( cAMP) and opens K channel → hyperpolarization Ref. Santiago & Abrol, 2019 Understanding G Protein Selectivity of Muscarinic Acetylcholine Receptors Using Computational Methods. Nicotinic receptors • Ion channel recpetors • Will be discussed in Neuromuscular [NM] Blocker lecture Classification of Cholinergic Agonists Muscarinic receptor agonists Natural Alkaloids Pilocarpine Muscarine Synthetics choline esters Methacholine Carbachol Bethanechol Cevimeline (next slide) Nicotinic receptor agonists Will be covered in NM blocker lecture Directly Acting Agonists Natural Alkaloid Agents • Muscarine • Found in mushroom (Amanita muscaria) • 100x more effective than acetylcholine • Responsible for toxicity with mushroom poisoning • Pilocarpine • Found in the Pilocarpus shrub [fig.] • Produces rapid and long-lasting reduction in intraocular pressure as a tx. for open angle glaucoma • Can trigger intense sweating and hypertension when administered systemically Both drugs are not hydrolyzed by AchE enzyme and hence are long acting and can cross BBB. Severe poisoning can occur. What will be the symptoms of poisoning ? Why hypertension with pilocarpine? Directly Acting Agonists Synthetic Agonists: Relative Affinity to ACh Receptors Drug Muscarinic receptors Nicotinic receptors Hydrolysis by AChE ACh +++ +++ +++ Carbachol ++ +++ - Methacholine +++ + ++ Bethanechol +++ - - Synthetic Choline esters • All are quaternary ammonium compounds • Poorly absorbed and no distribution into the CNS. • Vary in their selectivity for M or N receptors • Administered by oral or s.c routes and topically to the eyes Pharmacological Effects of Cholinergic Agonists • Similar to cholinergic activation [ref. Table 1 in 1st lecture] • Effects depend if a drug has muscarinic or nicotinic selectivity or both • If injected IV, in low doses, muscarinic agonists produce vasodilation and reflex tachycardia. • Higher dose → vasodilation and bradycardia. • Can you explain, Why ? • Nicotinic effects are observed only if agonist has selectivity for Nn or Nm receptors. • What will be the nicotinic effects? Therapeutic Uses of Cholinomimetics [Muscarinic agents] Clinical Use Examples Glaucoma Pilocarpine, echothiophate [ half life is 100 hours] Alzheimer’s disease Donepezil, galantamine Myasthenia gravis Phystigmine; neostigmine, [edrophonium is used for diagnosis of Myasthenia gravis] Paralytic ileus, atony of the GIT smooth muscle, urinary retention Bethanechol, neostigmine Sjogren’s syndrome, dry mouth Cevimeline To test bronchial reactivity Methacholine Anti-muscarinic Drug Intoxication Neostigmine or physostigmine [CNS effects] Toxicity of Cholinomimetics • The toxic potential of the cholinomimetics varies markedly depending on their receptor selectivity [M] or [N], absorption, access to the central nervous system, and metabolism • Side effects or toxic effects Peripheral effects • Muscarinic effects: DUMBE + salivation, cardiovascular [ all Table 1 effects] • Nicotinic effects: Muscle paralysis, hypertension and cardiac arrhythmias CNS effects → only for lipophilic drugs • Muscarinic : cognitive disturbances • Nicotinic: coma, seizure/convulsion, respiratory arrest etc. Patients with AChEI [insecticide] poisoning show both muscarinic and nicotinic effects Practice Qs A 30-year-old woman undergoes abdominal surgery which resulted in complete ileus (absence of bowel motility). Consequently, the patient complains of difficulty in urination. Which of the following drugs will be prescribed for her problem. a. Bethanechol b. Physostigmine c. Methacholine d. Cevimeline A young child was playing in his home garden. He saw a huge bottle of insecticide and tried to open it. The entire bottle content fell on him. His father carried him immediately to the hospital with the following symptoms. a. Dry skin b. Hallucination c. Convulsion d. Mydriasis