Cholinergic Agonists (Parasympathomimetics) Lecture Notes - Fall 2024

Cholinergic agonists Pharmacology-1 Lecture (PO-315/POC-316) Presented by Abeer Bishr Lecturer of pharmacology Fall 2024  Course LOs covered in this lecture 1-1-4-2 The pharmacological actions, side effects, drug interactions and uses o...

Cholinergic agonists Pharmacology-1 Lecture (PO-315/POC-316) Presented by Abeer Bishr Lecturer of pharmacology Fall 2024  Course LOs covered in this lecture 1-1-4-2 The pharmacological actions, side effects, drug interactions and uses of drugs acting on the autonomic nervous system and autacoids. 1-1-5-1 Utilize data from basic sciences to address therapeutic issues 3-1-4-1 Select the appropriate pharmacotherapeutic approaches based on the etiology, pathophysiology, laboratory diagnosis and clinical features of different diseases. 3-2-1-1 Recognize the pharmacological properties of different drugs.  Parasympathetic vs. Sympathetic Item Sympathetic Parasympathetic Origin Thoraco-lumbar Cranio-sacral segments segments Pre-ganglionic fibers Short Long Post-ganglionic fibers Long Short Neurotransmission in cholinergic neurons  Acetylcholine Acetylcholine ACh is synthesized in cholinergic nerve terminals by the acetylation of choline, a process catalyzed by the enzyme choline acetyltransferase (ChAT). Acetyl coenzyme A provided by mitochondria serves as the acetyl donor; choline is provided by both high-affinity uptake after ACh hydrolysis and phospholipid hydrolysis within the neuron.  Acetylcholine Following ACh synthesis, the neurotransmitter is transported actively into vesicles by the vesicular ACh transporter and stored in vesicles from which ACh is released by exocytosis to interact with cholinergic muscarinic or nicotinic receptors. The action of ACh is terminated by the enzyme acetylcholinesterase (AChE), which hydrolyzes ACh rapidly, producing acetic acid and choline. More than 50% of the choline is taken back up into the nerve terminal. Once inside the nerve terminal, choline can be reused for ACh synthesis.  Cholinergic receptors Muscarinic receptors: G-coupled protein receptors (metabotropic receptors) Bind to acetylcholine and also recognize muscarine (an alkaloid that is present in certain poisonous mushrooms). Weak affinity for nicotine. Muscarinic receptors have distinguished five subclasses of muscarinic receptors: M1, M2, M3, M4, and M5. M1, M2 and M3 are present peripherally and centrally. M4 , M5 present in the CNS.  Muscarinic receptors Receptor M1 M2 M3 Type Gq Gi Gq Main Locations CNS, Gastric parietal Cardiac muscle Smooth muscle cells, salivary gland Smooth muscle Exocrine glands Eye Receptor activation Led to IP3, DAG IP3, DAG cAMP NO (VD) Main effect Excitatory Inhibitory Excitatory Antagonists Muscarinic blockers Muscarinic blockers Muscarinic blockers  Cholinergic actions Organ Receptor Effect Heart M2 -ve inotropic ( contractility) -ve chronotropic ( HR) -ve dromotropic( conducion) Vascular smooth muscle M3 ACh activates M3 receptors found on endothelial cells lining the smooth muscles of blood vessels. This results in the production of nitric oxide. GIT Smooth muscle M3 Contraction & increase motility Sphincter Relaxation Secretion M1 Increase secretion Urinary tract Bladder wall M3 Contraction Sphincter Relaxation Glandular M3 Increase: Salivation secretions Lacrimation Sweating Eye Circular muscle M3 contraction Ciliary muscle Bronchi Smooth muscle M3 Bronchoconstriction Gland M3 Increase secretion  Nicotinic receptors Nicotinic receptors: Binds to acetylcholine Recognize by nicotine Show weak affinity for muscarine. Ligand-gated ion channel (Ionotropic receptor). Binding of two acetylcholine molecules provokes a conformational change that allows the entry of sodium ions, resulting in the depolarization. Nicotine initially stimulates and then at higher doses blocks the receptor.  NN NM Type Receptor type Ligand gated ion channel Ligand gated ion channel Location Adrenal medulla, autonomic neuromuscular junction ganglia  Cholinergic Agonists Parasympathomimetics Direct Indirect Selective Choline Natural M3 Anticholinesterase Esters Alkaloids agonist 1- ACh Muscarine 2- Carbachol Cevimeline Reversible Irreversible 3- Bethanechol Pilocarpine  Direct acting parasympathomimetics 1- Acetylcholine: Quaternary ammonium compound that cannot penetrate membranes & BBB. Non selective and rapidly inactivated by cholinesterase, so therapeutically of no importance Acetylcholine has both muscarinic and nicotinic activity.  ACh actions Heart: Negative chronotropic Reduction in the rate of firing at the SA node. Blood vessels: ACh causes vasodilation blood pressure (indirect mechanism) trough activation of M3 receptors found on endothelial cells lining the smooth muscles of blood vessels. This results in the production of nitric oxide. Nitric oxide leads to smooth muscle relaxation. N.B.: In the absence of administered cholinergic agents, the vascular receptors have no known function, because acetylcholine is never released into the blood in any significant quantities.  ACh actions GIT: Increases intestinal secretions. Increases motility. Bronchi: Increases bronchial secretions. Urinary tract: Contraction of bladder detrusor leading to urination& bile expelling Eye: Contraction of circular muscle of iris Miosis Contraction of ciliary muscle Accommodation of near vision.  Direct acting parasympathomimetics 2-Carbachol: It has Muscarinic as well as nicotinic actions. Carbachol is an ester of carbamic acid and a poor substrate for acetylcholinesterase. Actions: It mimics the effects of acetylcholine, on CVS, GIT and eye (miosis). Cause release of epinephrine from the adrenal medulla by its nicotinic action.  Carbachol Therapeutic uses: ◦ Non selective and long duration of action, so rarely used therapeutically. ◦ It is only used in the eye as a miotic agent to treat glaucoma by decrease the intraocular pressure. Adverse effects: At doses used ophthalmologically, little or no side effects occur due to lack of systemic penetration (quaternary amine).  Direct acting parasympathomimetics 3- Bethanechol: Structurally related to acetylcholine. Not hydrolyzed by acetylcholinesterase as it is an ester of carbamic acid and a poor substrate for acetylcholinesterase, although it is inactivated through hydrolysis by other esterase. Strong muscarinic activity. Mainly act on GIT & bladder.  Bethanechol actions GIT: Increases intestinal motility and tone. Urinary tract: Results in contraction the detrusor muscles of the bladder however the sphincter is relaxed, causing expulsion of urine. Therapeutic applications: Stimulates the atonic bladder. Neurogenic atony Megacolon  Bethanechol actions Adverse effects: Sweating & salivation, Flushing &decreased blood pressure Abdominal pain & diarrhea Bronchospasm. Choline ester Susceptibility to Muscarinic action Nicotinic Action cholinestrase ACh ++++ +++ +++ Carbachol Null ++ +++ Bethanechol Null ++ -  Direct acting parasympathomimetics 4- Pilocarpine: Tertiary amine Stable to hydrolysis by acetylcholinesterase. Less potent, than acetylcholine and its derivatives Uncharged and will penetrate the CNS at therapeutic doses. Shows muscarinic activity. Actions: Produces a rapid miosis and contraction of the ciliary muscle (accommodation of near vision). Potent stimulators of secretions such as sweat, tears, and saliva. Used in patients with xerostomia resulting from irradiation of the head and neck, Sjogren's syndrome.  Pilocarpine actions Used in treatment of glaucoma is the drug of choice in lowering of intraocular pressure. Effective in opening the trabecular meshwork around Schlemm's canal, causing an immediate drop in intraocular pressure as a result of the increased drainage of aqueous humor. Adverse effects: CNS side effects due to penetration of BBB. Sweating and salivation. (A) The flow of aqueous humor (arrow) from the ciliary body (B) In closed-angle glaucoma, pressure from the posterior to the trabecular meshwork. 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.  Direct acting parasympathomimetics 5- Cevimeline: Selective M3 agonist in lacrimal and salivary glands Used in treatment of both: a)Xerostomia b) Sjogren's syndrome Adverse effects: Less adverse effects than pilocarpine.  Direct acting parasympathomimetics Side effects of direct parasympathomimetics: Diarrhea Urination Miosis Bradycardia Bronchoconstriction/ Bronchorrhea Emesis Lacrimation Salivation  Indirect-Acting Cholinergic Agonists: Anticholinesterases Indirect acting cholinomimetic could be divided to: Alcohol (edrophonium) Carbamates (Neostigmine & Physostigmine) Organophosphates (Parathion & Malathion) ChE inhibitors are divided into two main types, reversible and irreversible: Reversible: Edrophonium, Physostigmine & neostigmine Irreversible: Organophosphates  Indirect-Acting Cholinergic Agonists: Anticholinesterases Inhibition of acetylcholinesterase lead to cholinergic action, as they stop the cleavage of ACh to choline and acetate, and so prolong its lifetime. AchE Ach Choline + Acetate This inhibition results in the accumulation of acetylcholine in the synaptic space and activation both muscarinic and nicotinic receptors.  Indirect-Acting Cholinergic Agonists: Anticholinesterases 1- Edrophonium (alcohol): Prototype short acting AChE inhibitor. Short duration of action (10-20 min) due to rapid renal elimination. Quaternary amine (polar) Used for diagnosis of Myasthenia gravis. Intravenous injection of edrophonium leads to a rapid increase in muscle strength. Care must be taken, because excess drug may provoke a cholinergic crisis.  Myasthenia gravis What is Myasthenia gravis? Autoimmune disease affect skeletal muscle. Antibodies bind to nicotinic receptors in NMJ Result in muscle weakness (e.g. eye, face and limb muscles). Treatment: -Neostigmine -Immunosuppressant drugs. -Surgical removal of thymus gland.  Indirect-Acting Cholinergic Agonists: Anticholinesterases 2- Physostigmine (carbamate): Found naturally Tertiary amine Stimulate M & N receptors. Intermediate acting agent (30 min.-2 hrs). It can penetrate BBB.  Physostigmine Therapeutic effects: Increase GIT & bladder motility. Anticholinergic overdose. Adverse effects: Bradycardia Paralysis of skeletal muscles (due to accumulation of ACh in NMJ). May cause convulsions in high dose.  Indirect-Acting Cholinergic Agonists: Anticholinesterases 3- Neostigmine (carbamate): Synthetic Quaternary amine (more polar than physostigmine cannot penetrate CNS) Intermediate acting agent (30 min-2 hrs) Its effect on skeletal muscles is more than physostigmine.  Neostigmine Therapeutic effects: Used in treatment of myasthenia gravis Stimulate GIT & Bladder Antidote of competitive neuromuscular blocking agents such as tubocurarine. Adverse effects: No CNS side effects Generalized cholinergic stimulation  Indirect-Acting Cholinergic Agonists: Anticholinesterases 4- Pyridostigmine: Used in the chronic management of myasthenia gravis. Durations of action is intermediate (3 to 6 hrs) Adverse effects: Similar to those of neostigmine.  Indirect-Acting Cholinergic Agonists: Anticholinesterases 5- Organophosphates: Bind covalently to AChE. They are toxic drugs used as insecticide as parathion and malathion. Also used as nerve agents as Sarin. Long duration of action Collectively, these compounds are termed organophosphorus or organophosphate ChE inhibitors The phosphorylated enzyme formed with these compounds is extremely stable, that it is not dephosphorylated, and new enzyme molecules must be synthesized for enzyme activity to recover  Organophosphates Echothiophate is an organophosphate that covalently binds via its phosphate group at the active site of acetylcholinesterase. Therapeutic uses The clinical use of organophosphates is primarily in the treatment of ocular conditions. Echothiophate has been used to treat chronic glaucoma that does not respond adequately to more conservative therapy.  Indirect-Acting Cholinergic Agonists: Anticholinesterases If the exposure of organophosphate is not immediately recognized and treated, it can be fatal. Immediately after binding to the enzyme, organophosphate can be removed by pralidoxime. Pralidoxime can reverse toxic effects of organophosphates (Nicotinic & muscarinic effects) If not recognized immediately, ageing occur and this phosphate complex become irreversible.  References 1- Title: Pharmacology, Lippincott’s illustrated reviews Authors: Richard A. Harvey, Michelle A Clark, Richard Finkel, Jose A. Rey, Karen Whalen Publisher: Wolters Kluwer, Wolters Kluwer Health Edition:7th Year:2018 2- Title: Brody’s Human Pharmacology Authors: Wecker L. Publisher: Elsevier Edition:6th Year:2018