Cholinergic Pharmacology Lecture Notes PDF

Cholinergic Pharmacology Dr.Leila Alblowi 2024 Lecture Objectives : 1. understand the synthesis, storage, release, and metabolism of catecholamines. 2. Identify the physiological effects mediated by adrenergic receptors (alpha and beta). 3. Examine the mechanisms of action of adrenergic agon...

Cholinergic Pharmacology Dr.Leila Alblowi 2024 Lecture Objectives : 1. understand the synthesis, storage, release, and metabolism of catecholamines. 2. Identify the physiological effects mediated by adrenergic receptors (alpha and beta). 3. Examine the mechanisms of action of adrenergic agonists and antagonists. 4. Explore the therapeutic uses and side effects of drugs that modulate adrenergic neurotransmission​  Overview of Cholinergic Pharmacology Cholinergic Pathways: Neuromuscular Junction (NMJ) Autonomic Nervous System (ANS) ▪ All autonomic ganglia ▪ Parasympathetic postganglionic nerve terminals ▪ Sympathetic postganglionic nerve terminals supplying sweat glands Central Nervous System (CNS) Non-neuronal Cholinergic System(NNCS)* Neurotransmitter: Acetylcholine (ACh)  Neurotransmitter: Acetylcholine (Ach)​ Synthesis Synthesized from choline and acetyl-CoA by choline acetyltransferase (ChAT). Storage Stored in synaptic vesicles in cholinergic neurons. Release Released into the synaptic cleft via exocytosis when action potential arrives at the nerve terminal. Action potential causes depolarization of nerve terminal→ Ca++ influx →fusion of vesicle and cell membranes → exocytosis of Ach into synaptic cleft ACh binds to muscarinic or nicotinic receptors. Reuptake There is no direct reuptake of ACh; instead, it is broken down into choline and acetate. Choline is taken up into the presynaptic terminal by a choline transporter for reuse. Metabolism Broken down by acetylcholinesterase (AChE) into choline and acetate in the synaptic cleft. Synthesis and release of acetylcholine from the cholinergic neuron Drugs that effect Ach synthesis and metabolism Storage Uptake Release Metabolism Vesamicol is a Hemicholinium Botulinus toxin AChE reversible blocks the (Botox) prevent inhibitors such blocker of the uptake of the release of as neostigmine, intracellular choline into the Ach from the they will prevent transporter nerve ending nerve terminal Ach degradation responsible for by inhibiting the enzyme → ensuring storage exocytosis of enhance Ach of ACh into presynaptic effect vesicles vesicles  Cholinergic Receptors Types of Receptors: 1. Muscarinic Receptors (M1-M5) 2. Nicotinic Receptors (Nn and Nm) a member of the G-protein-coupled a member of Ligand-gated ion channels receptors  Cholinergic Receptors- locations Muscarinic Receptors Nicotinic Receptors At the pre/postganglionic parasympathetic effectors Nn: Autonomic ganglia and CNS M1: CNS, Autonomic ganglia Nm: Skeletal muscle at the Neuromuscular M2: Cardiac muscle Junction (NMJ) M3: Smooth muscles, glands M4 & M5: Central Nervous System (CNS) Cholinergic drugs  Cholinergic drugs Cholinergic agonists Cholinergic antagonists Cholinomimetics Cholinolytic Direct acting Indirect acting Antimuscarinic (stimulate cholino- (acetylcholinesterase receptors) inhibitors) Ganglionic blockers Reversible Irreversible Neuromuscular blockers  Cholinergic Agonist Two categories of drugs: Cholinergic Agonists (Parasympathomimetics) Direct Acting: Stimulate cholinergic receptors (e.g., Acetylcholine, Pilocarpine) Indirect Acting: Inhibit acetylcholinesterase, increasing ACh concentrations (e.g., Neostigmine) Cholinergic Antagonists (Parasympatholytics) Antimuscarinic (e.g., Atropine) Neuromuscular Blockers (e.g., Succinylcholine) Effects of cholinergic agonist  Direct Cholinergic Agonist Muscarinic Receptor Agonists ▪ Acetylcholine (NOT used clinically because of its broad action and its extremely rapid hydrolysis by AchE) ▪ Methacholine ▪ Bethanechol Alkaloids ▪ Pilocarpine  Direct Cholinergic Agonist Muscarinic Receptor Agonists ▪ Methacholine: Is 3X more resistance to hydrolysis by AchE compared with Ach ▪ Selective to cardiovascular muscarinic cholinergic receptor (M2) ▪ Uses : the diagnosis of Asthma ▪ Bethanechol: completely selective for muscarinic cholinergic receptors and resist AchE ▪ Uses: 1. Promote GI and urinary tract motility, particularly for postoperative or postpartum 2. Urinary retention  Direct Cholinergic Agonist Muscarinic Receptor Agonists ▪ Pilocarpine : Is the most clinically used alkaloid (a natural source.) ▪ Uses: 1. Mitotic* agent used to treat glaucoma by relieving fluid (intraocular) pressure in the eye 2. saliva-inducing agents: used to treat dryness of the mouth secondary to reduced salivary secretion *miosis Adverse effects of direct cholinergic agonists  Indirect-acting cholinergic agonists ▪ They don’t act on receptors ▪ Inhibit acetylcholinesterase, preventing the breakdown of ACh.(↑ the conc. of ACh in the synaptic cleft) ▪ They also called anticholinesterases , acetylchoinesterase inhibitors, cholinesterase inhibitors  Indirect-acting cholinergic agonists ▪ Types of Anticholinesterases: ❑Reversible: (Effect last 3-8hr) Neostigmine: Used for myasthenia gravis and post-operative urinary retention Rivastigmine: Used for Alzheimer’s disease Physostigmine: Used to reverse anticholinergic drug toxicity (antidot) ❑Irreversible: (long lasting effect) Organophosphates : ▪ Sarin(chemical weapon) ▪ Malathion(insecticide) Indirect-acting cholinergic agonists ▪ Uses: 1. Used to increase muscular strength in patient with myasthenia gravis 2. Glaucoma 3. Alzheimer’s disease 4. Dementia 5. Reverse poisoning with anticholinergic drugs  Indirect-acting cholinergic agonists Irreversibly inhibiting acetylcholinesterase ▪ Sarin : Sarin is a highly toxic organophosphate compound. a volatile liquid, forms a covalent bond with cholinesterase, making it inactive ▪ Symptoms of sarin poisoning are due to accumulation of Antidote: The antidotes for Sarin poisoning are atropine (a acetylcholine: muscarinic receptor blocker) and pralidoxime, which reactivates ▪ Muscarinic: runny nose, shedding tears, abdominal pain, acetylcholinesterase. vomiting, defecation, urination, pupil constriction ▪ Neuromuscular: twitching, convulsion, bronchoconstriction, suffocation ▪ Salivation, Lacrimation, Urination, Defecation, Gastrointestinal distress, and Emesis  Myasthenia Gravis ▪ In myasthenia gravis, autoantibodies are generated against NM receptors, block the ability of Ach to activate the receptors ▪ As a result patient with this disease present with significant muscle weakness ▪ Cholinesterase inhibitors (e.g., neostigmine) help to improve the symptoms of myasthenia gravis by increase the levels of ACh in the neuromuscular junction. ▪ So increase muscle tone for patient with myasthenia gravis  Alzheimer ▪ Alzheimer’s disease is an incurable dementia illness characterized by chronic, progressive neurodegenerative condition Rivastigmine: First line treatment of Alzheimer’s disease ▪ Onset usually occurs between ages 45 and 65 years ▪ Degeneration of cholinergic neuron and deficiency in Ach is one theory for Alzheimer development ▪ Current therapies are aimed to: ▪ ✓ Improving cholinergic transmission within the CNS Cholinergic antagonists Parasympatholytic Cholinergic antagonists Antimuscarinic drugs Ganoglionic (Nn) blockers Neuromuscular (Nm) blockers  Cholinergic Cholinergic antagonists blocker Antimuscarinic Antinicotinic Atropine Ganglionic blocker Neuromuscular Ipratropium blocker bromide Scopolamine Nondepolarizing Depolarizing agents agents Hexamethonium D-tubocurarine Succinylcholine (Curare) (SCh): Effects of cholinergic antagonist Clinical Uses of Cholinergic antagonist (general ) 1. Motion sickness 2. Eye: mydriasis (as eye drop, for eye examination) 3. Pre-anesthetic medication –↓ airway secretion and for muscle relaxation to facilitate intubation 4. Asthma (by inhalation for bronchodilation) 5. Gastrointestinal –to reduce hypermotility (irritable bowel) 6. Relieve of urinary urgency 7. Poisoning with cholinesterase inhibitors *?? 8. Muscle spasm Antimuscarinic drugs (Muscarinic antagonist ) ▪ Atropine ▪ Is extract from a plant called: Atropa belladonna ▪ In Italian Bella donna means literally beautiful lady ▪ It is medieval cosmetic used by ladies of Italy to dilate the eye, it makes the eye turned more radiant; suppression of salivation and appetite might also have helped with their weight control Antimuscarinic drugs (Muscarinic antagonist ) ▪ Atropine ▪ Atropine act by inhibiting of Ach by occupying mainly the muscarinic receptors ▪ Useful in: Preoperative medication to ↓salivary secretion Dilate eye pupil for eye examination Antispasmodic to treat peptic ulcer because it relaxes the smooth muscle of the GIT and ↓ peristalsis To ↑ heart rate when bradycardia is present Antidote for muscarinic agonist poisoning (Sarin) Antimuscarinic drugs (Muscarinic antagonist ) ▪ Adverse effects: 7. Palpitation, tachycardia Contraindication: 1. Dry mouth 8. Urinary retention 1. Galucoma 2. Constipation 9. High doses can cause 2. Myasthenia gravis ? central stimulation 3. Flushing 3. Myocardial ischemia (excitation, hallucination) 4. Dry skin (no sweat) 5. Mydriasis 6. Blurred vision Antimuscarinic drugs (Muscarinic antagonist ) ▪ Ipratropium bromide ▪ Scopolamine (Hyoscine) ▪ Is available orally and topically as ▪ Anticholinergic bronchodilator skin patch that is placed behind the ▪ Act by blocking action of Ach at ear for motion sickness bronchial smooth muscle sites ▪ Such drugs are helpful for some asthmatics, and (COPD) Neuromuscular Blockers (NMB) Class Drugs Competitive blockers D-tubocurarine (Curare) (Nondepolarizing agents): Atracurium Depolarizing blockers: Succinylcholine  Neuromuscular Blockers (NMB) ▪ I. Competitive blockers ( Nondepolarizing agents) Curare: ▪ was used by south American Indians as an arrow poison for hunting wild animals because curare paralyzed the animal ▪ They are useful as muscle relaxant for anaesthesia ▪ MOA: ▪ Curare competes with acetylcholine for binding sites on nicotinic receptors at the neuromuscular junction. ▪ By occupying these receptors without activating them, Curare prevents acetylcholine from triggering muscle contraction. ▪ It action is reversible, theses compounds slowly dissociate from the receptors and transmission is generally restored Neuromuscular Blockers (NMB) ▪ I. Depolarizing Blockers Succinylcholine (SCh): ▪ Is a quaternary ammonium compound with structure resembling two molecules of acetylcholine joined together ▪ It is useful when rapid endotracheal intubation is required ▪ It has rapid onset and short duration of action Neuromuscular Blockers (NMB) ▪ I. Depolarizing Blockers Succinylcholine (SCh): ▪ MOA: The neuromuscular effects of Succinylcholine (SCh) are similar to those of acetylcholine (ACh). Succinylcholine stimulates nicotinic receptors, causing depolarization of the skeletal muscle membrane. However, unlike ACh, Succinylcholine is broken down much more slowly by acetylcholinesterase. As a result, the drug remains active longer, leading to persistent depolarization, which ultimately causes flaccid paralysis. Uses of Neuromuscular Blockers Endotracheal Intubation: To relax muscles for easier insertion of breathing tubes. Surgery: For muscle relaxation during operations. Mechanical Ventilation: To control breathing in critically ill patients. Muscle Spasms: To reduce spasms in conditions like tetanus or seizures. Electroconvulsive Therapy (ECT): To prevent injury by reducing muscle contractions. Prevent Shivering: In therapeutic hypothermia. Diagnostic Procedures: To relax muscles during laryngoscopy or bronchoscopy. Intracranial Pressure Control: To prevent pressure spikes in head injuries.  Other Anticholinergic drugs ▪ Botulinum Toxin (Botox) Botox inhibits acetylcholine release from presynaptic nerve terminals , causing flaccid paralysis. Uses: Treat muscle spasms* Chronic Migraines Cosmetic treatment for facial lines cerebral palsy or multiple sclerosis.  Ganglionic blockers ▪ Hexamethonium ▪ Ganglionic blockers inhibit nicotinic receptors at autonomic ganglia, preventing the transmission of nerve signals. ▪ Effect on the Sympathetic Nervous System: These drugs decrease heart rate, lower blood pressure, and cause vasodilation by blocking sympathetic outflow. ▪ Effect on the Parasympathetic Nervous System: They reduce gastrointestinal motility and secretions, potentially causing constipation, dry mouth, and pupil dilation (mydriasis). ▪ Use in Medicine: Ganglionic blockers were historically used to treat severe hypertension but have been largely replaced due to their widespread side effects.