Drugs Acting on Nicotinic Receptors PDF

Welcome To Basic principles of pharmacology YFRM202 MBChB II 1  Welcome To This Topic DRUGS AFFECTING THE CHOLINERGIC NERVOUS SYSTEM D YFRM202 2  Welcome To This Topic Drugs actin...

Welcome To Basic principles of pharmacology YFRM202 MBChB II 1  Welcome To This Topic DRUGS AFFECTING THE CHOLINERGIC NERVOUS SYSTEM D YFRM202 2  Welcome To This Topic Drugs acting on nicotinic receptors Neuromuscular blockers & acetylcholinesterase inhibitors YFRM202 3  Learning Outcomes At the end of this lecture, you should be able to:  Describe nicotinic receptor types, locations and electrical events in the synapse and post synaptic membranes  Describe the action of drugs (with examples) in the autonomic ganglion  Describe the mechanism of action, classes, and examples of neuromuscular blocking drugs (NMBs)  Describe the clinical uses (indications) and adverse effects of NMBs  Describe the mechanism of action, classes and examples of acetylcholine esterase inhibitors  Discuss the physiological effects and clinical uses of acetylcholinesterase inhibitors  Describe the clinical effects, manifestations and management of organophosphate poisoning 4  Nicotinic Receptors Nn Nm Inhibit Inhibit Ganglion Blockers Neuromuscular Blockers Katzung, B.G. Chapter8. Cholinergic Agonists & Antagonists. 5 Katzung, B.G.. Netter’s Illustrated Pharmacology. 2nd ed. Philadelphia: Saunders, p. 76– Figure 7.2 Sites of action of cholinergic antagonists ( antimuscarinic drugs). Autonomic and somatic pathways are shown, and three types of cholinergic antagonists portrayed. Ganglionic blockers block the first half of both the sympathetic and parasympathetic pathways, and the sympathetic innervation of the adrenal medulla. Antimuscarinic agents block the second half of the parasympathetic pathway only. The site of action of the neuromuscular blockers is only on the nicotinic receptors of the somatic nervous system, which blocks muscle contraction (paralysis). 6  Muscle type Ganglion type CNS Type Main synaptic location Skeletal neuromuscular Autonomic ganglia: mainly Many brain regions: pre- junction: mainly postsynaptic and postsynaptic postsynaptic Membrane response Excitatory Excitatory Pre- and postsynaptic Increased cation Increased cation excitation + + permeability (mainly Na , permeability (mainly Na , Increased cation + + + K ) K ) permeability (mainly Na , + K ) Agonists Acetylcholine Acetylcholine Nicotine Carbachol Carbachol Epibatidine Succinylcholine Nicotine Acetylcholine b Epibatidine Varenicline Antagonists Tubocurarine Mecamylamine Mecamylamine Pancuronium Trimetaphan Methylaconitine Atracurium Hexamethonium Vecuronium Nicotinic receptor subtypes a This table shows only the main subtypes expressed in mammalian tissues. Several other subtypes are expressed in selected brain regions, and also in the peripheral nervous system and in non-neuronal tissues. For further details, see Ch. 40 and review by Kalamida et al. (2007). b Varenicline is used as an aid to smoking cessation. It acts as a partial agonist on (α4) 2 (β2) 3 receptors and a full agonist on (α7) 5 receptors (see Ch. 50 ) Rang & Dale’s Pharmacology.2024. Chapter 14. Cholinergic transmission. pages 182-204 – Table 14.1 7  ACh, acting on the Stimulation of postsynaptic membrane of a nicotinic (neuromuscular or ganglionic) synapse, influx of cations, particularly to Na + and K +, Ca 2+ to a lesser extent causing depolarisation of the postsynaptic membrane. Endplate potential ( epp ) in a skeletal muscle fibre. Localised epp spreads to adjacent, electrically excitable parts of the muscle fibre; if its amplitude reaches the threshold for excitation, an action potential is initiated, which propagates to the rest of the fibre and evokes a contraction. Fast excitatory postsynaptic potential ( fast epsp ) at the ganglionic synapse. Causes a local current to flow. depolarises the axon hillock region of the cell, where, if the epsp is large enough, an action potential is initiated. Rang & Dale’s Pharmacology.2024. Chapter 14. Cholinergic transmission. Pages 182-204 8  Depolarising block Occurs when the excitatory nAChRs are persistently activated, Resulting in a decrease in the electrical excitability of the postsynaptic cell. Application of nicotine to a sympathetic ganglion activates nAChRs, causing a depolarisation of the cell, which at first initiates action potential discharge. After a few seconds, this discharge ceases and transmission is blocked. The main reason for the loss of electrical excitability during a period of maintained depolarisation is that the voltage-sensitive sodium channels become inactivated (i.e. refractory) and no longer able to open in response to a brief depolarising stimulus. After nicotine has acted for several minutes, the cell partially repolarises and its electrical excitability returns but, despite this, transmission remains blocked. Rang & Dale’s Pharmacology.2024. Chapter 14. Cholinergic transmission.pages182-204 9  Depolarising block Main factor responsible for the secondary block (known clinically as phase II block ) appears to be receptor desensitisation. This causes the depolarising action of the blocking drug to subside, but transmission remains blocked because the receptors are desensitised to ACh. This type of secondary, non-depolarising block occurs also at the neuromuscular junction if repeated doses of the depolarising drug suxamethonium 10 Drug Main site Type of action Notes Agonists Nicotine Autonomic ganglia Stimulation then block CNS Stimulation Epibatidine Autonomic ganglia CNS Stimulation Isolated from frog skin Highly potent No clinical use Varenicline CNS Stimulation Used for nicotine addiction Autonomic ganglia Suxamethonium Neuromuscular junction Depolarisation block Used clinically as muscle relaxant Antagonists Hexamethonium Autonomic ganglia Transmission block No clinical use Pancuronium Neuromuscular junction Transmission block Widely used as muscle relaxants in Atracurium anaesthesia Vecuronium Rang & Dale’s Pharmacology.2024. Chapter 14. Cholinergic transmission.pages182-204 11  Drugs acting on autonomic ganglia Rang & Dale’s Pharmacology.2024. Chapter 14. Cholinergic transmission.pages182-204 12  Both sympathetic and parasympathetic ganglia are stimulated, so effects are complex: Tachycardia and increase of blood pressure; variable effects on gastrointestinal motility and secretions; increased bronchial, salivary and sweat secretions. Additional effects result from stimulation of other neuronal structures, including sensory and noradrenergic nerve terminals. Ganglion stimulation may be followed by depolarisation block. Nicotine also has important central nervous system effects. Therapeutic uses are limited to assisting smoking cessation (nicotine, varenicline) Rang & Dale’s Pharmacology.2024. Chapter 14. Cholinergic transmission.pages182-204 13  Ganglion-blocking drugs are used experimentally to study autonomic function, but their clinical use is obsolete. Ganglion block can occur by several mechanisms: By interference with ACh release, as at the neuromuscular junction. By prolonged depolarisation. Nicotine can block ganglia, after initial stimulation, in this way, as can ACh itself if cholinesterase is inhibited, thereby prolonging its action on the postsynaptic membrane. Interfering with the postsynaptic action of ACh, by blocking neuronal nAChRs or the associated ion channels. Rang & Dale’s Pharmacology.2024. Chapter 14. Cholinergic transmission.pages182-204 14  Source: Goodman & Gilman's: The Pharmacological Basis of Therapeutics – Figure 10.2 Source: Goodman & Gilman's: The Pharmacological Basis of Therapeutics – Figure 10.2 15  Block all autonomic outflow (e.g. hexamethonium) Since both the sympathetic and parasympathetic divisions are inhibited, drug effects are difficult to predict Main effects: hypotension and loss of cardiovascular reflexes, inhibition of secretions, gastrointestinal paralysis, impaired micturition This lack of selectivity causes a broad range of undesirable effects No longer clinically used Historically, they were the first therapeutic drugs for treating hypertension Rang & Dale’s Pharmacology.2024. Chapter 14. Cholinergic transmission.pages182-204. 16 Neuromuscular Blocking Drugs (NMBs) 17  Neuromuscular blocking drugs interfere with transmission at the neuromuscular end plate and lack CNS activity. Their primary effect is to cause skeletal muscle paralysis. Act at Nm receptors. Used primarily as adjuncts during general anesthesia to optimise surgical conditions and to facilitate endotracheal intubation in order to ensure adequate ventilation. Basic & Clinical Pharmacology – Chapter 27. Katzung, B.G. (Year). Chapter 27. Cholinergic Agonists & Antagonists. In: Basic & Clinical Pharmacology. 14th ed. New York: McGraw- Hill, Brenner & Stevens’ Pharmacology. 2024. Chapter 7. Cholinergic Receptor Antagonists. Pages 75-81 Rang & Dale’s Pharmacology.2024. Chapter 14.Cholinergic transmission. Pages 186-187. 18  Nm receptor Katzung, B.G. (Year). Chapter 7.Cholinergic Agonists & Antagonists. In: Basic & Clinical Pharmacology. 14th ed. New York: McGraw-HillBasic & Clinical Pharmacology –Figure 7.4 Nicotinic transmission at the skeletal neuromuscular junction. ACh released from the motor nerve terminal interacts with subunits of the pentameric nicotinic receptor to open it, allowing Na+ influx to produce an excitatory postsynaptic potential (EPSP). The EPSP depolarizes the muscle membrane, generating an action potential, and triggering contraction. Acetylcholinesterase (AChE) in the extracellular matrix hydrolyzes ACh. 19  Clinical Uses Adjuncts during general anaesthesia to optimise surgical conditions Reduce the amount of anaesthetic required Facilitate intracavitary surgery Facilitate endotracheal intubation in order to ensure adequate ventilation Control ventilation in critically ill patients who have ventilatory failure Adjunct to electroconvulsive therapy to prevent injuries that might be caused by involuntary muscle contractions To relieve spasticity resulting from tetanus Treatment of convulsions Katzung B.J. Year). Chapter 27. In: Basic & Clinical Pharmacology. 14th ed. New York: McGraw-HillBasic & Clinical Pharmacology. Brenner & Stevens’ Pharmacology. Chapter 7. Cholinergic Receptor Antagonists. Pages 75-81. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 20  Act as competitive Act as agonists at Nm antagonists at Nm receptors to cause receptors at the NMJ depolarising blockade NON-DEPOLARISING 2 GROUPS OF DEPOLARISING NEUROMUSCULAR DRUGS THAT CAUSE NEUROMUSCULAR BLOCKERS NEUROMUSCULAR BLOCKERS Rocuronium BLOCKADE Pancuronium Alcuronium i.e. Vecuronium Alloferin is no longer Cisatracurium used) Atracurium Katzung B.J (Year) Chapter 27. In: Basic & Clinical Pharmacology. 14th ed. New York: McGraw-HillBasic & Clinical Pharmacology. Brenner & Stevens’ Pharmacology. Chapter 7. Cholinergic Receptor Antagonists. Pages 75-81. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 21 Non-Depolarising Neuromuscular Blockers 22  One of the original drugs, tubocurarine, was extracted from plants used by native South Americans as arrow poisons for hunting wild game. Rocuronium Curare is another name for the arrow poisons and their chemical derivatives. Pancuronium The curariform drugs are not well absorbed Vecuronium from the gut, and do not cross the BBB or placenta. Cisatracurium Administered IV Atracurium Image source:https://slideplayer.com/slide/11622895/ Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. Strychnos toxifera called bush rope and devil doer, is a species of flowering plant in the genus Strychnos, native to Costa Rica, Panama, Colombia, Ecuador, Venezuela, the Guianas, Brazil, Peru and Bolivia. It is the principal source of curare. 23  Competitive antagonists at Nm receptors. Prevent ACh binding and skeletal muscle contraction. Since binding is competitive, increasing ACh concentrations at the NMJ will displace the NMB, resulting in greater ACh binding and recovery of muscle contraction. This is why AChE inhibitors are used to reverse neuromuscular blockade following surgery (e.g. Neostigmine). At high doses of NMB, the drug also physically blocks the pore of the ligand- gated ion channel, causing more intense motor blockade. More difficult to reverse the muscle paralysis with AChE-I’s. Image source: https://slideplayer.com/slide/11622895/ Katzung B.J (Year) Chapter 27. In: Basic & Clinical Pharmacology. 14th ed. New York: McGraw-HillBasic & Clinical Pharmacology. Brenner & Stevens’ Pharmacology. Chapter 7. Cholinergic Receptor Antagonists. Pages 75-81. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 24  Non-depolarising NMBs bind to the same site as ACh on the Nm receptor and act as antagonist → Prevents ACh binding → Inhibits channel opening → Prevent skeletal muscle contraction Katzung B.J.(Year) Chapter 27. In: Basic & Clinical Pharmacology. 14th ed. New York: McGraw-HillBasic & Clinical Pharmacology. The action of the normal agonist, acetylcholine (red) in opening the channel. A nondepolarizing blocker, eg, rocuronium (yellow), is shown as preventing the opening of the channel when it binds to the receptor 25  RECOVERY TAKES PLACE PARALYSIS OCCURS Smaller muscles: face, foot, hand ORDER IN WHICH ORDER IN WHICH Larger muscles: abdominal, trunk, paraspinous Respiratory muscles: diaphragm, intercostals NO LOSS OF CONSCIOUSNESS OCCURS Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 26 Depolarising Neuromuscular Blockers 27  Succinylcholine binds to Nm receptors in skeletal muscle and causes persistent depolarisation of the motor end plate (acts as an agonist). When the drug is first administered, it produces transient muscle contractions called fasciculations. The fasciculations are quickly followed by a sustained muscle paralysis. 2 phases to its action: 1. Phase 1 – depolarising 2. Phase 2 – desensitising Katzung B.J (Year) Chapter 27. In: Basic & Clinical Pharmacology. 14th ed. New York: McGraw-HillBasic & Clinical Pharmacology. Brenner & Stevens’ Pharmacology. Chapter 7. Cholinergic Receptor Antagonists. Pages 75-81. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 28  Prevent electrical recovery of the motor end plate ↓ Depolarising Fasciculations blockade ↓ Muscle paralysis Basic & Clinical Pharmacology – Chapter 7 – Figure 7.4 Nicotinic transmission at the skeletal neuromuscular junction. ACh released from the motor nerve terminal interacts with subunits of the pentameric nicotinic receptor to open it, allowing Na+ influx to produce an excitatory postsynaptic potential (EPSP). The EPSP depolarizes the muscle membrane, generating an action potential, and triggering contraction. Acetylcholinesterase (AChE) in the extracellular matrix hydrolyzes ACh. 29  Succinylcholine reacts with the Nm receptor to open the channel and cause depolarisation of the motor end plate. Leads to transient contractions of muscle motor units (fasciculations). Succinylcholine is not metabolised effectively at the synapse by cholinesterase, so the drug remains bound to the receptor. The depolarised membranes remain depolarised and unresponsive to subsequent impulses. Known as being in a state of depolarising blockade. Excitation-contraction coupling requires end plate repolarisation and repetitive firing to maintain muscle tension, so a flaccid paralysis results due to the depolarising blockade. Katzung B.J (Year) Chapter 27. In: Basic & Clinical Pharmacology. 14th ed. New York: McGraw-HillBasic & Clinical Pharmacology. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 30  With prolonged exposure to succinylcholine, the initial end plate depolarisation decreases and the membrane becomes repolarized. Despite this repolarisation, the membrane cannot easily be depolarised again because it is desensitized. The channels behave as if they are in a prolonged closed state. Later in phase 2, the characteristics of the blockade are nearly identical to those of a non-depolarising block, with possible reversal by acetylcholinesterase inhibitors. Katzung B.J (Year) Chapter 27. In: Basic & Clinical Pharmacology. 14th ed. New York: McGraw-HillBasic & Clinical Pharmacology. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 31  Succinylcholine is hydrolysed by cholinesterase in the plasma and liver. Hydrolysis is slower than for ACh, but metabolism occurs more quickly than with the non-depolarising NMBs. Neuromuscular block typically lasts less than 10 minutes. ORDER IN Chest and abdomen (transient) WHICH PARALYSIS Arm, neck and leg muscles OCCURS Respiratory muscles Katzung B.J (Year) Chapter 27. In: Basic & Clinical Pharmacology. 14th ed. New York: McGraw-HillBasic & Clinical Pharmacology. Brenner & Stevens’ Pharmacology. Chapter 7. Cholinergic Receptor Antagonists. Pages 75-81. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 32  Post-operative muscle pain Due to initial muscle contraction and fasciculations prior to paralysis. Bradycardia Due to direct myocardial effects, increased muscarinic stimulation, and ganglionic stimulation. Potassium release During administration of succinylcholine, potassium is released from muscles, likely due to fasciculations. ↑ Intraocular pressure Due to tonic contraction of myofibrils or transient dilation of ocular choroidal blood vessels. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 33  A rare inherited condition caused by a mutation of the ryanodine receptor - a Ca2+ release channel of the sarcoplasmic reticulum Malignant hyperthermia results in intense muscle spasm and a dramatic rise in body temperature when certain drugs are given Succinylcholine is the most common culprit but can also be precipitated by a variety of other drugs. The condition carries a high mortality (about 65%) It is treated by administration of dantrolene, a drug that inhibits muscle contraction by preventing Ca2+ release from the sarcoplasmic reticulum via the ryanodine receptor (RγR1) channel Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 34  Succinylcholine is hydrolysed by cholinesterase in the plasma, so paralysis often only lasts for 2-6 min. Paralysis may be prolonged in certain individuals: Genetic variants of plasma cholinesterase with reduced activity Severe deficiency can increase the duration of action to >2 hours (occurs in ±1 in 3500 individuals). If the enzyme is completely absent paralysis lasts for many hours. Neonates may have low plasma cholinesterase activity. Acetylcholinesterase inhibitors (AChE-I’s) can inhibit plasma cholinesterase and prolong the action of succinylcholine. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 35  DRUG DEPOLARIZI HISTAMIN GANGLIONI EFFECTS DURATION OF ROUTES OF NG AGENT E C REVERSED BY ACTION ELIMINATION a RELEASE BLOCKADE CHOLINESTER (MINUTES) b ASE INHIBITORS Succinylcholin Yes Minimal None No Short (5–10) Plasma (butyryl) c e cholinesterase d Atracurium No Varies Low Yes Intermediate Plasma esterase (30–60) Cisatracurium No None Low Yes Intermediate Spontaneous (30–60) chemical degradation Pancuronium No None Medium Yes Long (60– Renal excretion 120) Rocuronium No None Low Yes Intermediate Biliary and renal (30–60) excretion Vecuronium No None Low Yes Intermediate Biliary and renal (30–60) excretion and hepatic metabolism TABLE 7.1 Properties of Neuromuscular Blocking Agents a May cause bronchospasm, hypotension, and excessive salivary and bronchial secretions. b May cause hypotension and tachycardia. c May cause bradycardia by stimulating parasympathetic (vagal) ganglia, or may cause tachycardia and hypertension by stimulating sympathetic ganglia. d At higher doses (e.g., for tracheal intubation), histamine release becomes clinically significant. Brenner & Stevens’ Pharmacology. 2023. Page 79. 36  Acetylcholinesterase inhibitors Drugs that result in activation of cholinergic receptors by not binding directly to muscarinic or nicotinic receptors 37  The indirect-acting acetylcholine receptor agonists include the cholinesterase inhibitors (also known as the ‘Anticholinesterases’). Inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The cholinesterase inhibitors prevent the breakdown of acetylcholine at all cholinergic synapses. Increase ACh levels in the synapse which can interact with cholinergic receptors (both N and M) → ↑ cholinergic/parasympathetic effects. Based on the strength of the binding interaction between the drug and the cholinesterase enzyme, drugs can be classified as: Reversible cholinesterase inhibitors (shorter-acting drugs). Irreversible cholinesterase inhibitors (longer-acting drugs). Katzung B.J (Year) Chapter 27. In: Basic & Clinical Pharmacology. 14th ed. New York: McGraw-HillBasic & Clinical Pharmacology. Brenner & Stevens’ Pharmacology. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Pages 59-73. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 38  Acetylcholinesterase inhibitors (AChE-I’s) increase levels of Ach. Organ system effects are the same as when ACh binds to cholinergic receptors. Effects are due to increased binding to nicotinic and muscarinic receptor binding. Leads to parasympathomimetic effects i.e. similar to the organ system effects seen with the direct-acting cholinomimetic effects ( In previous section) i.e., the ocular, cardiovascular, respiratory, GI and urinary effects. Brenner & Stevens’ Pharmacology. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Pages 59-73. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 39  Simple Alcohols E.g. Edrophonium Only binds to the anionic site of AChE without forming a covalent bond, (Reversible thus binding is easily reversed to reform free AChE Short-acting) Brief duration of action ~10min Carbamate Esters E.g. Neostigmine, physostigmine, pyridostigmine Carbamyl drugs that bind to anionic site to form a carbamoylated enzyme (Reversible which takes longer to hydrolyse to form free AChE again Medium-acting) Drug effects last from 30 min – 6 hours E.g. Ecothiophate, parathion, malathion, isoflurophate Organophosphates Form a strong covalent bond with the catalytic site of cholinesterase and (Irreversible) are very slowly hydrolyzed by the enzyme (hundreds of hours) Recovery depends on synthesis of new AChE enzymes Katzung B.J (Year) Chapter 27. In: Basic & Clinical Pharmacology. 14th ed. New York: McGraw-HillBasic & Clinical Pharmacology Brenner & Stevens’ Pharmacology. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Pages 59-73. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 40  DURATION ROUTE OF DRUG CLINICAL USE OF ACTION ADMINISTRATION Diagnosis of myasthenia gravis (too short-acting to be used for treatment) Edrophonium 5-15 min Intravenous To differentiate between a myasthenic crisis and cholinergic crisis Brenner & Stevens’ Pharmacology. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Pages 59-73. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. Patients with myasthenia gravis may experience muscle weakness from either under treatment or overtreatment with a cholinesterase inhibitor drug. In the untreated condition and in patients not receiving adequate doses of the drug, muscle weakness is caused by an acetylcholine deficiency and is called a myasthenic crisis. In this situation, a test dose of edrophonium will increase acetylcholine levels and muscle strength. In patients who are overtreated with a cholinesterase inhibitor, muscle weakness is caused by an excessive amount of acetylcholine at the neuromuscular junction, causing depolarization neuromuscular blockade similar to that produced by succinylcholine. This condition is called a cholinergic crisis, and a test dose of edrophonium will cause the muscle weakness to increase. This finding indicates that the patient's dose of cholinesterase inhibitor should be decreased. 41  Physostigmine is more lipophilic than the positively-charged neostigmine and pyridostigmine, so it can cross the BBB DURATION ROUTE OF DRUG CLINICAL USE OF ACTION ADMINISTRATION Treatment of myasthenia gravis 2-4 hours Oral, SC, IM Post-operative urinary retention and Neostigmine ileus Reversal of competitive neuromuscular 2-5 min IV blockade following surgery Management of anticholinergic Physostigmine 1-5 hours IM or IV poisoning (especially CNS effects) 4-6 hours Oral Treatment of myasthenia gravis Pyridostigmine 2-5 min (IV) Reversal of competitive neuromuscular IM or IV 15 min (IM) blockade following surgery Brenner & Stevens’ Pharmacology. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Pages 59-73. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 42 Myasthenia Gravis AChE-I’s ↑ACh concentrations at the NMJ which increases the effectiveness and duration of ACh binding to the few remaining Nm receptors Improves skeletal muscle contraction, reducing muscle weakness associated with the disease. Edrophonium is used to diagnose myasthenia gravis. Too short-acting to be used for treatment. Neostigmine and pyridostigmine are used to treat myasthenia gravis. Brenner & Stevens’ Pharmacology. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Pages 59-73. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 43  Competition to bind Reversal of Neuromuscular Blockade Pyridostigmine and neostigmine are used to reverse neuromuscular blockade following surgery. To cause neuromuscular blockade during surgery so that skeletal muscle paralysis occurs, the non-depolarising neuromuscular blocking agents (NMBA) used act as competitive antagonists at Nm receptors at the NMJ. By inhibiting AChE, Neostigmine increases ACh concentrations at the NMJ Competition for binding to Nm receptors at the NMJ occurs. Displacement of the NMBA occurs, and ↑ ACh binding takes place. Reverses the muscle paralysis. Katzung B.J (Year) Chapter 27. In: Basic & Clinical Pharmacology. 14th ed. New York: McGraw-HillBasic & Clinical Pharmacology Brenner & Stevens’ Pharmacology. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Pages 59-73. 44  ROUTE OF DURATION DRUG ADMINISTRATIO CLINICAL USE OF ACTION N Ecothiophate >100 hours Topical ocular Glaucoma Insecticide (causes toxicity in Parathion - N/A humans) Malathion - Topical Treatment of lice (pediculosis) Brenner & Stevens’ Pharmacology. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Pages 59-73. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 45  Ocular Effects (Ecothiophate) Increased Ach stimulate M3 receptors in the eye and cause Contraction of the iris sphincter muscle Causes pupil constriction (miosis) Contraction of the ciliary muscle Accommodation of the lens to focus on close objects Opens pores in the trabecular meshwork Enhances outflow of aqueous humor into the canal of Schlemm Used in the treatment of glaucoma, but less frequently than the direct- acting cholinomimetics Brenner & Stevens’ Pharmacology. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Pages 59-73. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. Effects of pilocarpine and atropine on the eye. A, The relationship between the iris sphincter and ciliary muscle is shown in the normal eye. B, When pilocarpine, a muscarinic receptor agonist, is administered, contraction of the iris sphincter produces pupillary constriction (miosis). Contraction of the ciliary muscle causes the muscle to be displaced centrally. This relaxes the suspensory ligaments connected to the lens, and the internal elasticity of the lens allows it to increase in thickness. As the lens thickens, its refractive power increases so that it focuses on close objects. Atropine competitively inhibits acetylcholine (ACh) at the muscarinic cholinergic receptors so any effects due to the increase in ACH produced by AChEi is counteracted by Atropine. Atropine causes blocking of the parasympathetic system. 46  The organophosphates are seldom used therapeutically in humans. They are widely used as pesticides/insecticides. Some have been developed as chemical warfare agents (e.g. nerve agents such as sarin and soman). The organophosphates are highly lipid soluble and are effectively absorbed from all sites in the body, including the skin, mucous membranes, and gut. Organophosphate toxicity can occur after dermal or ocular exposure or after the oral ingestion of these compounds. Their lipophilicity means they distribute to all parts of the body, including the CNS Leads to frequent accidental or intentional cases of poisoning. Brenner & Stevens’ Pharmacology. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Pages 59-73. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 47  Increased ACh throughout the body available to activate all cholinergic Signs and Symptoms of Toxicity receptors Muscarinic Effects Nicotinic Effects CNS Effects Salivation Depolarising neuromuscular Anxiety Lacrimation blockade with resulting muscle Restlessness Miosis weakness Headaches Accommodative spasm Weakness of respiratory Seizures muscles Bronchoconstriction Respiratory depression Fasciculations Bradycardia Coma Hypotension Emesis Intestinal cramps Diarrhoea Urinary incontinence SAMF. 2022. Cholinesterase inhibitors (organophosphates and carbamates). Page 645- 646 48 Management Remove Ensure an adequate Administer activated contaminated clothing airway – intubate if charcoal if within 1-2 and wash patient with necessary hours of exposure soap and water Cholinesterase Atropine reactivator Brenner & Stevens’ Pharmacology. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Pages 59-73. SAMF. 2022. Cholinesterase inhibitors (organophosphates and carbamates) Page 645- 646 49  Management – Atropine Antimuscarinic drug Binds to muscarinic receptors and acts as an antagonist. Reduces the signs and symptoms due to activation of muscarinic receptors. Must be initiated as soon as possible – high doses may be necessary. An intermittent or continuous IV infusion can be set up for maintenance therapy. The criterion of adequate therapy is control of bronchial and oral secretions. As the patient improves, the dose of atropine must be reduced slowly, over 24 hours or longer – do not discontinue abruptly. Brenner & Stevens’ Pharmacology. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Pages 59-73 SAMF. 2022. Cholinestarase inhibitors (organophospates and carbamates) Page 645-646 50  Pralidoxime and obidoxime Reactivates AChE by bringing an oxime group into close proximity with the phosphorylated esteratic site. This group is a strong nucleophile and lures the phosphate group away from the serine hydroxyl group of the enzyme Must be administered within 24 hours of exposure. Brenner & Stevens’ Pharmacology. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Pages 59-73. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Pages 186-187. 51  Checklist Can you...  Describe nicotinic receptor types, locations and electrical events in the synapse and post synaptic membranes?  Describe the action of drugs (with examples) in the autonomic ganglion?  Describe the mechanism of action, classes, and examples of neuromuscular blocking drugs (NMBs)?  Describe the clinical uses (indications) and adverse effects of NMBs?  Describe the mechanism of action, classes and examples of acetylcholine esterase inhibitors?  Discuss the physiological effects and clinical uses of acetylcholinesterase inhibitors?  Describe the clinical effects, manifestations and management of organophosphate poisoning? 52  References Brenner & Stevens’ Pharmacology. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Pages 59-73 & Chapter 7. Cholinergic Receptor Antagonists. Pages 75- 81. Brunton, L.L., Hilal-Dandan, R. and Knollmann, B.C. Chapter 10. Pharmacotherapy of the Autonomic Nervous System. In: Goodman & Gilman's: The Pharmacological Basis of Therapeutics. 13th ed. New York: McGraw-Hill. Katzung, B.G. Chapter 7 & Chapter 8.Cholinergic Agonists & Antagonists & Chapter 27. In: Basic & Clinical Pharmacology. 14th ed. New York: McGraw-Hill. Katzung B.G.. Netter’s Illustrated Pharmacology. 2nd ed. Philadelphia: Saunders, p. 76– Figure 7.2. Rang & Dale’s Pharmacology.2024. Chapter 14. Cholinergic transmission. Pages 182-204. SAMF. 2022. Cholinesterase inhibitors (organophosphates and carbamates). Page 645-646. 53 54 55