Drugs Acting on Muscarinic Receptors PDF

Welcome To Basic principles of pharmacology YFRM202 1  Welcome to this topic DRUGS AFFECTING THE CHOLINERGIC NERVOUS SYSTEM YFRM202 2  Welcome to this topic Drugs acting on muscarinic...

Welcome To Basic principles of pharmacology YFRM202 1  Welcome to this topic DRUGS AFFECTING THE CHOLINERGIC NERVOUS SYSTEM YFRM202 2  Welcome to this topic Drugs acting on muscarinic receptors Agonists and antagonists YFRM202 3  Learning Outcomes At the end of this lecture, you should be able to:  Define the terms ‘Parasympathomimetic’, ‘Parasympatholytic’, ‘Cholinomimetic’ and ‘Cholinolytic’, ‘Direct-acting’, ‘indirect acting’ drugs  Define and classify cholinergic drugs based on the steps they affect during the neurotransmission process (including muscarinic and nicotinic receptor agonists/antagonists)  Explain the physiological actions and clinical uses of muscarinic receptor agonists (including choline esters, the plant alkaloids and synthetic drugs)  Explain the physiological actions and clinical uses of muscarinic receptor antagonists  Describe the signs and symptoms of atropine poisoning  Explain the physiological effects and clinical uses of first-generation antihistamines (H1 receptor blockers) 4 Image source: Bioninja. (n.d.). Autonomic Control. Bioninja. Available at: https://ib.bioninja.com.au/options/option-a-neurobiology-and/a2-the-human- brain/autonomic-control.html (Accessed: 14 September 2024). 5 Can you remember the effects of parasympathetic system activation: Heart rate? Blood pressure? GI movements and secretions? Eye? Urinary bladder? 6  The parasympathetic division of the ANS originates from the cranial nerves III, VII, IX, and X and some nerves originating from the sacral spinal cord. All neurons of the parasympathetic NS are cholinergic neurons, releasing Ach. Cholinergic receptors include nicotinic and muscarinic receptors, which ACh binds to: Nicotinic receptors: Nm, Nn Muscarinic receptors: M1-5 Rang & Dale’s Pharmacology.2024. Chapter 13. Chemical mediators and the autonomic nervous system. Pages 170-181 – Figure 13.1 Netter’s Illustrated Pharmacology - page 35 Brenner & Stevens’ Pharmacology.2023.Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists. Chapter 6. pages 59-73 7  ACh is released from the following neurons: Preganglionic neurons ACh binds to Nn receptors Somatic motor neurons ACh binds to Nm receptors Parasympathetic postganglionic neurons ACh binds to muscarinic receptors Some sympathetic postganglionic neurons E.g. sweat glands ACh binds to muscarinic receptors Rang & Dale’s Pharmacology.2024. Chapter 13. Chemical mediators and the autonomic nervous system. Pages 170-181 Goodman & Gilman's: The Pharmacological Basis of Therapeutics – Chapter 10 – Figure 10.2 8 Drugs Acting on the Cholinergic System 9  Parasympathomimetic Parasympatholytic Drugs that increase the Drugs that block the parasympathetic response parasympathetic response In effect, this inhibits the In effect, this increases the sympathetic response sympathetic response Since the sympathetic and parasympathetic divisions have opposing actions, if a drug increases the parasympathetic division, it decreases the sympathetic response, and vice versa. If a drug blocks the parasympathetic division, it ends up increasing the sympathetic response. 10 Cholinomimetic Drugs Cholinolytic Drugs Cholinoreceptor activating Cholinoreceptor inhibiting drugs (agonists) drugs (antagonists) Drugs that mimic/enhance the Drugs that inhibit the action of ACh action of ACh Since the sympathetic and parasympathetic divisions have opposing actions, if a drug increases the parasympathetic division, it decreases the sympathetic response, and vice versa. If a drug blocks the parasympathetic division, it ends up increasing the sympathetic response. 11 Basic & Clinical Pharmacology – Chapter 7 - Figure 7.1 The major groups of cholinoceptor-activating drugs, receptors, and target tissues. ACh, acetylcholine. 12  Direct acting Indirect acting Muscarinic receptor agonists Acetylcholinesterase & antagonists inhibitors Nicotinic receptor agonists / Others antagonists Since the sympathetic and parasympathetic divisions have opposing actions, if a drug increases the parasympathetic division, it decreases the sympathetic response, and vice versa. If a drug blocks the parasympathetic division, it ends up increasing the sympathetic response. 13  Direct-acting Indirect-acting Cholinergic Drugs Cholinergic Drugs Bind directly to one or more Inhibit AChE of N and M receptors ↓ ACh metabolism Nm M4 M5 ↑ ACh available to bind to Nn N and M receptors and activate them 14  Drugs acting on muscarinic receptors Drugs that result in activation of cholinergic receptors 15  GIT, bladder, bronchial Excitatory Inhibitory 16  G-Protein Subtype Location Function Involved M1 Autonomic ganglia CNS excitation Gq (‘neural’) Nerves Gastric acid secretion ↓ HR M2 Heart, Nerves, Gi Neuronal inhibition (‘cardiac’) Smooth muscle Presynaptic inhibition M3 Gastric, salivary secretion (‘smooth Glands, smooth Gastrointestinal smooth muscle contraction Gq muscle/ muscle, endothelium Ocular accommodation glandular’) Vasodilatation Presynaptic inhibition M4 CNS Gi ↑ Locomotion M5 CNS Gq Unknown Rang & Dale’s Pharmacology.2024. Chapter 13. Chemical mediators and the autonomic nervous system. Pages 170-181: Table 13.1 &Chapter 14. Cholinergic transmission. Chapters 182-204. Table 14.2 17 Location of M receptor Agonist effects Antagonist effects Cardiac (M2) ↓HR, ↓FC Modest tachycardia Generalised vasodilation (NO- mediated), ↓BP Smooth muscle (M3) in GIT Contract ↓ GI mo lity Smooth muscle (M3) (bladder, Contract Relax (urinary retention) bronchi) Secretions (M3) (sweating, Stimulate exocrine glands, ↑ ↓ secre ons lacrimation, salivation, bronchial) secretions Eye (M3) (ciliary muscle, constrictor Contraction, pupil constriction Pupil dilation, ↑ IOP pupillae) CNS (M1) Activation may cause tremor, Excitatory – Atropine hypothermia, improved cognition Sedation – Hyoscine Extrapyrimidal system – reduce involuntary movement and rigidity Adapted from: Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182-204-Table 14.2 Muscarinic receptor subtypes 18  Muscarinic agonists Drugs that result in inhibit activation of cholinergic receptors. Also known as cholinergic receptor blocking drugs. They inhibit the cholinergic system, and so will increase sympathetic effects 19  The direct-acting cholinergic agonists can be classified into 3 groups based on their chemical structures: the choline esters, the plant alkaloids, and other synthetic drugs. These drugs all bind to and activate acetylcholine receptors, but differ in: Their affinity for muscarinic and nicotinic receptors. Their susceptibility to hydrolysis by cholinesterase enzymes. Muscarine, Choline Acetylcholine, Plant Varenicline, nicotine, Synthetics Esters carbachol Alkaloids Cevimeline pilocarpine Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182- 204. 20 Compound Receptor specificity/selectivity Hydrolysis be Clinical uses cholinesterase Muscarinic Nicotinic Acetylcholine +++ +++ +++ - Carbachol +++ +++ - - Methacholine +++ + ++ - Bethanechol +++ - - Treatment of bladder and GI hypotonia (a) Muscarine +++ - - - (b) Pilocarpine ++ - - Glaucoma Cevimeline ++ (c) - - Sjogren’s syndrome (increase salivary and lacrimal secretions Muscarinic agonists a Essential to check that bladder neck is not obstructed. b Cause of one type of mushroom poisoning. c Selective for M 3 receptors Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182- 204 21  Intraocular pressure Fig. 14.5 The anterior chamber of the eye, showing the pathway for secretion and drainage of the aqueous humour. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182- 204-Fig. 14.5 22  M3 receptors M3 receptors FIGURE 10–8 The anterior chamber of the eye and the pharmacological and surgical measures used to treat glaucoma. A, The flow of aqueous humor (arrow) from the ciliary body to the trabecular meshwork. B, In angle-closure glaucoma, pressure from the posterior chamber pushes the iris against the trabecular meshwork, closing the ocular angle and preventing the drainage of aqueous humor. C, Cholinomimetics constrict the iris sphincter, thereby opening up the ocular angle and causing a decrease in intraocular pressure in closed-angle glaucoma. Cholinomimetics also elicit contraction of the longitudinal and circular ciliary muscles. Contraction of the longitudinal ciliary muscle stretches open the trabecular meshwork and facilitates the drainage of aqueous humor, particularly in open-angle glaucoma. The circular ciliary muscle forms a sphincter-like ring around the lens, into which the zonules are attached. Constriction of the circular muscle relaxes the tension on the zonules and allows the lens to relax into a more convex shape, which increases its refractive power and enables near vision. D, The surgical treatment of closed-angle glaucoma entails the placement of a hole in the peripheral iris, either surgically or with a laser. The procedure provides a pathway for drainage of aqueous humor (arrow) and thus reduces intraocular pressure. Unknown author. (n.d.). Chapter 12 - Autonomic Nervous System. Doctorlib. Available at: 23 http://doctorlib.info/pharmacology/pharmacology/12.html (Accessed: 14 September 2024) 23  Open Cholinomimetics (M3 agonist): Contract the ciliary muscles, Increase outflow of aqueous humour, Decrease intraocular pressure FIGURE 10–8 The anterior chamber of the eye and the pharmacological and surgical measures used to treat glaucoma. A, The flow of aqueous humor (arrow) from the ciliary body to the trabecular meshwork. B, In angle-closure glaucoma, pressure from the posterior chamber pushes the iris against the trabecular meshwork, closing the ocular angle and preventing the drainage of aqueous humor. C, Cholinomimetics constrict the iris sphincter, thereby opening up the ocular angle and causing a decrease in intraocular pressure in closed-angle glaucoma. Cholinomimetics also elicit contraction of the longitudinal and circular ciliary muscles. Contraction of the longitudinal ciliary muscle stretches open the trabecular meshwork and facilitates the drainage of aqueous humor, particularly in open-angle glaucoma. The circular ciliary muscle forms a sphincter-like ring around the lens, into which the zonules are attached. Constriction of the circular muscle relaxes the tension on the zonules and allows the lens to relax into a more convex shape, which increases its refractive power and enables near vision. D, The surgical treatment of closed-angle glaucoma entails the placement of a hole in the peripheral iris, either surgically or with a laser. The procedure provides a pathway for drainage of aqueous humor (arrow) and thus reduces intraocular pressure. Unknown author. (n.d.). Chapter 12 - Autonomic Nervous System. Doctorlib. Available at: 24 http://doctorlib.info/pharmacology/pharmacology/12.html (Accessed: 14 September 2024). 24 Cardiac and Vascular Effects M2 agonist effects on the heart causes the following: ↓ Heart rate Slow AV node conduction → ↑ PR interval Acetylcholine typically causes vasodilation. Mediated by M3 receptors located in vascular endothelial cells → activation of nitric oxide synthetase → formation of nitric oxide (NO) → NO diffuses into vascular smooth muscle cells → activates guanylyl cyclase → ↑ cGMP → vascular smooth muscle relaxation and vasodilation. Thus acetylcholine is sometimes used in coronary angiography. Brenner & Stevens’ Pharmacology.2023. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists – page 59-73 – Figure 6.5 Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182- 204 25 Respiratory Effects Stimulation of M3 receptors: ↑ Bronchial muscle contraction (bronchoconstriction) ↑ Secretion of mucous throughout the respiratory tract. Not used clinically for these effects, but it does mean that muscarinic agonist drugs should be avoided or used with extreme caution in patients with asthma and other forms of obstructive lung disease. Image source:Science Buzz. (n.d.). The cellular and molecular basis of bitter tastant- induced bronchodilation. Science Buzz. Available at: https://www.sciencebuzz.com/the- cellular-and-molecular-basis-of-bitter-tastant-induced-bronchodilation/ (Accessed: 14 September 2024). Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182- 204 26 GI and Urinary Tract Effects Stimulation of M3 receptors: ↑ Salivary, gastric, and other secretions in the GIT. Pilocarpine and cevimeline can be used for the treatment of dry mouth (xerostomia). ↑ GIT motility due to ↑ contraction of GI smooth muscle. Stimulate the bladder detrusor muscle and relax the internal sphincter of the bladder. Together, this promotes emptying of the bladder (micturition). Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182- 204 27  Muscarinic antagonists Drugs that result in inhibit activation of cholinergic receptors. Also known as cholinergic receptor blocking drugs. They inhibit the cholinergic system, and so will increase sympathetic effects. 28  Also called cholinolytic drugs. Cholinergic receptor blocking drugs Cholinoceptor antagonists These drugs inhibit activation of cholinergic receptors and they can thus be described as parasympatholytic. Because the sympathetic and parasympathetic nervous system have opposing effects in many tissues, the effects produced are often similar to those evoked by adrenoceptor agonists. Brenner & Stevens’ Pharmacology.2023. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists – page 59-73 29  Muscarinic receptor antagonists compete with ACh for muscarinic receptors. The two naturally occurring compounds, atropine and hyoscine (also known as scopolamine), are belladonna alkaloids found in solanaceous plants. The deadly nightshade (Atropa belladonna) contains mainly atropine. The thorn apple/jimson weed (Datura stramonium) contains mainly hyoscine. Image source:Prints Online. (n.d.). Plants - Datura Stramonium. Prints Online. Available at: https://www.prints-online.com/plants-datura-stramonium-592692.html (Accessed: 14 September 2024). Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182- 204 In SA Jimson weed seeds are known as 'malpitte". It is an alien plant from the USA where it was named after British troops boiled and ate oit and became psychotic for two days ! 30  Both atropine and hyoscine are tertiary ammonium compounds that are lipophilic enough to cross the BBB to have CNS effects. They can be highly toxic. Are sometimes the cause of accidental or intentional poisonings. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182- 204 Hyoscine butylbromide is known as Buscopan – used to relieve intestinal , ureteric and uterine cramps 31 Dose-dependent effects of atropine. Low doses of atropine inhibit salivation and sweating, and the magnitude of these effects increases as the dosage increases. Higher doses produce tachycardia, urinary retention, and central nervous system effects. Brenner and Steven’s pharmacology. 2023. Chapter 7. Cholinergic Receptor Antagonists Page 76. Pages 75-81-Fig. 7.1 32 Medicines Learning Portal. (n.d.). Anticholinergic side effects infographic. Medicines Learning Portal. Available at: https://filestore.medicineslearningportal.org/images/Anticholinergic%20side%20effects %20infographic%202.png (Accessed: 14 September 2024). 33  Synthetic antimuscarinics have also been developed but tend to be quaternary ammonium compounds that don’t have CNS effects. Used for their antimuscarinic effects in the periphery. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182- 204 Hyoscine butylbromide is known as Buscopan – used to relieve intestinal , ureteric and uterine cramps 34  Divided according to the receptor subtype that they inhibit i.e. selectivity Ipratropium, tiotropium Muscarinic Receptors Hyoscine butylbromide Oxybutinin, darifenacin (M3-selective) Cyclopentolate, tropicamide M1 M2 M3 M4 M5 Inhibit Antimuscarinics 35  (Block parasympathetic effects) Ocular Effects M3 antagonist effects on the eye cause the following: Relaxation of the iris sphincter muscle Causes pupil dilation (mydriasis). Relaxation of the ciliary muscle Paralysis of accommodation (cycloplegia), so that near vision is impaired Impairs outflow of aqueous humor into the canal of Schlemm. Can ↑ intraocular pressure. Antimuscarinics are contraindicated in glaucoma. Inhibits lacrimal gland secretion and can cause dry eyes. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182- 204 36  Ocular Effects M3 antagonist effects on the eye: Cyclopentolate and tropicamide Administered as eye drops to facilitate fundoscopy. Looking at the back of the eye. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182- 204 37  Respiratory Effects Antagonism of M3 receptors: ↓ Bronchial muscle contraction (bronchodilation). Inhibits secretions in the upper and lower respiratory tract Ipratropium and tiotropium are administered by inhalation as bronchodilators in some patients with asthma and in many with COPD. Antimuscarinics are sometimes used before the administration of inhalant anesthetics to ↓ accumulation of secretions in the trachea and ↓ possibility of laryngospasm. Image source:Science Buzz. (n.d.). The cellular and molecular basis of bitter tastant- induced bronchodilation. Science Buzz. Available at: https://www.sciencebuzz.com/the- cellular-and-molecular-basis-of-bitter-tastant-induced-bronchodilation/ (Accessed: 14 September 2024). Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182- 204 38 GIT Effects Antagonism at M3 receptors: ↓ Salivary, gastric, and other secretions in the GIT Dry mouth is a common side effect with antimuscarinic treatment ↓ GIT motility due to ↓ contraction of GI smooth muscle ↓ GI tone and propulsive movements, prolonging gastric emptying time and ↑ intestinal transit time Hyoscine butylbromide is used in the treatment of GI spasm and cramps. Atropine is used orally to treat diarrhoea but this is not recommended. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182- 204 39 Urinary Tract Effects Antagonism of M3 receptors: Relax the bladder detrusor muscle and cause contraction of the internal sphincter of the bladder. Together, this inhibits micturition. Oxybutinin and darifenacin are used to treat an overactive bladder - such as incontinence (loss of bladder control) or a frequent need to urinate. Antimuscarinics can cause urinary retention as a side effect and may precipitate urinary retention in elderly men with prostatic enlargement. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182- 204 40  Several first-generation antihistamine drugs (H1 receptor antagonists) also have anticholinergic effects at muscarinic receptors. Due to their additional antimuscarinic effects (especially at M3 receptors in the GIT), antihistamines are useful in managing: Nausea and vomiting, vertigo, and preventing motion sickness. These antihistamines can also have antimuscarinic side effects: Dry mouth, blurred vision, tachycardia, urinary retention, and at high doses, hallucinations. Rang & Dale’s Pharmacology.2024.Chapter 14. Cholinergic transmission. Chapters 182- 204 41  Drug Duration of Action Sedative Effects Antiemetic Effects Anticholinergic (h) Effects First-Generation Antihistamines Chlorpheniramine 6 Medium None Medium Dimenhydrinate 8 High Medium High Diphenhydramine 8 High Medium High Hydroxyzine 6 High High Medium Meclizine 12 Medium High Medium Promethazine 12 High High High Second-Generation Antihistamines Cetirizine 24 Low None Very low Fexofenadine 12 Very low None Very low Loratadine 24 Very low None Very low Pharmacologic Properties of Selected Histamine H 1 Receptor Antagonists Brenner & Stevens’ Pharmacology. 2023. Chapter 26. Autacoid Drugs That Mimic Endogenous Substances. Pages 301-311:TABLE 26.2 42  Checklist Can you...  Define the terms ‘Parasympathomimetic’, ‘Parasympatholytic’, ‘Cholinomimetic’ and ‘Cholinolytic’, ‘Direct-acting’, ‘indirect acting’ drugs?  Define and classify cholinergic drugs based on the steps they affect during the neurotransmission process (including muscarinic and nicotinic receptor agonists/antagonists)?  Explain the physiological actions and clinical uses of muscarinic receptor agonists (including choline esters, the plant alkaloids and synthetic drugs)?  Explain the physiological actions and clinical uses of muscarinic receptor antagonists?  Describe the signs and symptoms of atropine poisoning?  Explain the physiological effects and clinical uses of first-generation antihistamines (H1 receptor blockers)? 43  References Brenner & Stevens’ Pharmacology.2023. Chapter 6. Parasympathetic, Neuromuscular Pharmacology, and Cholinergic Agonists.Page 59-73 &. Chapter 7. Cholinergic Receptor Antagonists. Pages 75-81 & Chapter 26. Autacoid Drugs That Mimic Endogenous Substances. Pages 301-311. Brunton, L.L., Knollmann, B.C., and Hilal-Dandan, R. (Year). Pharmacology of the Autonomic Nervous System. In: Goodman & Gilman's: The Pharmacological Basis of Therapeutics. 13th ed. New York: McGraw-Hill. Netter’s Illustrated Pharmacology. Page 35. Katzung, B.G. (Year). Autonomic Pharmacology. In: Basic & Clinical Pharmacology. 14th ed. New York: McGraw- Hill, pp. 101-120. Rang & Dale’s Pharmacology.2024. Chapter 13. Chemical mediators and the autonomic nervous system. Pages 170- 181 & Chapter 14.Cholinergic transmission. Pages 182-204. 44  Feedback Please be kind enough to take a minute and rate this lesson and provide a little feedback to help us gain a better understanding of your learning experience. Let us know what you really enjoyed and what we can do better for you. Click on the link at the bottom of the lesson page on I-learn to provide feedback for this lesson. +- (2mins) 45 46 47