Cholinergic Drugs Lecture Notes PDF

Cholinergic Drugs PHAR 134 – Lecture #9 September 26, 2024 Shankar Munusamy, BPharm, MS Pharm, PhD Professor of Pharmacology & Director of Assessment Drake University College of Pharm...

Cholinergic Drugs PHAR 134 – Lecture #9 September 26, 2024 Shankar Munusamy, BPharm, MS Pharm, PhD Professor of Pharmacology & Director of Assessment Drake University College of Pharmacy & Health Sciences Munusamy, 2024  Learning Objectives By the end of this lecture, the student should be able to: 1. Classify the cholinergic drugs based on their mode of action (direct- vs. indirect-acting) and give two examples for each class where available. 2. Explain the mechanism of action, pharmacological effects, pharmacokinetic properties, clinical uses, adverse effects, and contraindications of the following cholinergic agents. – Choline esters: Acetylcholine, Bethanechol, Carbachol – Alkaloids: Pilocarpine, Cevimeline – Carbamates: Physostigmine, Neostigmine, Pyridostigmine, Rivastigmine, Donepezil – Organophosphates: Echothiophate 3. Explain how neostigmine and pyridostigmine differs from other drugs in terms of blood-brain barrier permeability and its clinical significance. Munusamy, 2024 2  Cholinergic Drugs (Cholinomimetics) 1) Direct acting (Agonists) 2) Indirect acting (AChE inhibitors) a. Choline esters a. Reversible: Carbamates b. Alkaloids b. Irreversible: Organophosphates Direct Acting Indirect Acting Munusamy, 2024 3  1. Direct Acting Cholinergic Agonists MOA: Bind directly with Cholinergic receptors on effector organs and produces parasympathetic effect = “Parasympathomimetics” Direct Acting Act at -  Effector organs of postganglionic parasympathetic NS (M1 - M5)  Autonomic ganglia (sympathetic & parasympathetic) - NN  Certain brain synapses (CNS) – NN & M1  Neuromuscular junction (NMJ) - NM Munusamy, 2024 4  1. Direct Acting Cholinergic Agonists a. Choline esters (ABC) – Esters of acetylcholine Acetylcholine (MIOCHOL-E), Bethanechol (URECHOLINE), Carbachol (MIOSTAT) b. Alkaloids (PC) – Analogs of muscarine Pilocarpine (OCUSERT, SALAGEN), Cevimeline (EVOXAC) (Carbamyl ACh) Cevimeline (Beta-methyl Carbamyl ACh) Munusamy, 2024 5  1. Direct Acting Cholinergic Agents: a. Choline Esters: ABC ACh: Rapidly hydrolyzed by AChE acetylcholinesterase (5 – 30 secs) B and C resist hydrolysis  Intermediate acting (30 min to 2 h) vs. ACh (~ 30 secs) ABC are “Non-selective” agents – Act on both Muscarinic and Nicotinic receptors Quaternary Amines  Poor lipid solubility  Don’t cross BBB (Blood-brain barrier)  Central effects: NO Munusamy, 2024 Lippincott Illustrated Reviews: Pharmacology, 5th edition, 2012. 6  1. Direct Acting Cholinergic Agents: b. Alkaloids: Pilocarpine, Cevimeline (PC) Alkaloids resist hydrolysis  Long-acting (3 - 4 h) vs. choline esters ABC (30 min – 2 h) Muscarine analogs – Muscarinic selective  Pilocarpine (Natural): Acts on M1, M2, & M3 receptors  Cevimeline (Synthetic): M1 & M3 selective  Less cardiac side effects (due to less binding to M2) Tertiary Amines  Good lipid solubility  Crosses BBB  Central effects: YES (because crosses blood brain Cevimeline (synthetic analog) barrier): causes Excitation and emesis Munusamy, 2024 Lippincott Illustrated Reviews: Pharmacology, 5th edition, 2012. 7  2. Indirect Acting Cholinergic Agents (Acetylcholinesterase Inhibitors) MOA: Inhibit Acetylcholinesterase (AChE) enzyme  ⇊ ACh degradation Activation of both Indirect Acting muscarinic & nicotinic receptors in ANS, CNS and NMJ Net results ↓ ACh degradation  ↑ [ACh] in synaptic cleft  ↑ ACh binding with receptors  Parasympathetic effects (“parasympathomimetic”) Munusamy, 2024 8  2. Indirect Acting Cholinergic Agents a) Carbamates (Reversible Inhibitors) – Stigmine’s – Neostigmine, Physostigmine, Pyridostigmine, Rivastigmine, Donepezil* b) Organophosphates (Irreversible Inhibitors) – Echothiophate; Malathion@, Parathion@, Soman#, Sarin# @ Used as pesticides # Nerve gases used in chemical warfare *Top 300 drug Munusamy, 2024 9  AChE Inhibitors: Reversible vs. Irreversible Acetyl Choline (ACh) Acetylation (Seconds) Ser Ser Ser CARBAMATES Carbamylation (~30 minutes) Ser Ser Ser ORGANOPHOSPHATES (Hours - Days) Ser Phosphorylation Ser Ser Munusamy, 2024 See notes below 10  AChE Inhibitors: Reversible vs. Irreversible Acetylcholine (ACh) => Acetylation of AChE but the acetyl group removed quickly  Fast return of AChE activity (in seconds) CARBAMATES  Carbamylation of AChE – Carbamyl group is slowly removed from AChE  Reversible inhibition of AChE (as carbamylated AChE cannot breakdown ACh) ORGANOPHOSPHATES  Phosphorylation of AChE – Phosphate group is very slowly removed from AChE  Irreversible AChE inhibition  Cholinergic Toxicity  Seen with pesticide poisoning or nerve gases  Pralidoxime (2-PAM): Antidote that dephosphorylates & reactivates AChE in poisoning Munusamy, 2024 11  12 Munusamy, 2024  13 Munusamy, 2024  Cholinergic Agents: Pharmacologic Effects Parasympathomimetics = “DUMBBEELSS” Diarrhea Urination Miosis (Constriction of pupils) Bronchoconstriction Bradycardia Dry mouth (Xerostomia) and dry eyes Cholinergic agonists  ⇈ Salivation (Sialagogue) & lacrimation Direct-acting agonists (Alkaloids) Pilocarpine (SALAGEN®) Cevimeline (EVOXAC®) (show-grunz) Munusamy, 2024 26  Clinical Uses - Cholinergic Agonists 3. GI & Urinary disorders Surgery, Trauma, Congenital defects  Atony of bladder, stomach, and/or intestines Cholinergic agonists  Stimulate GI motility (peristalsis) and emptying of bladder  Useful in treating atony of GI & bladder 1) Direct-acting agonists Bethanechol (URECHOLINE®) – Oral, SC Quaternary amines 2) Indirect acting agents  Don’t cross BBB Neostigmine (PROSTIGMINE®) – Oral, IM, IV Pyridostigmine (MESTINON®) – Oral, IM, IV Munusamy, 2024 Mnemonic: URECHOLINE – A choline to stimulate Urination 27  Clinical Uses - Cholinergic Agonists 4. Myasthenia gravis (MG) Auto-antibodies against nicotinic receptors in NMJ (NM)  Muscle weakness, breathing difficulty, diplopia, drooping of eyelids, difficulty in swallowing and chewing  Myasthenia gravis Peripherally acting AChE inhibitors (i.e., don’t cross BBB)  ⇈ ACh levels selectively in NMJ (NM)  Useful in treating MG Indirect acting agents (Quaternary amines) Neostigmine Pyridostigmine  Longer acting than neostigmine (NM) Munusamy, 2024 28  Clinical Uses - Cholinergic Agonists 5. Alzheimer’s Disease (AD) A neurodegenerative disease associated with loss of cholinergic neurons in cortex and hippocampus  Memory loss (Dementia) Centrally acting AChE inhibitors (those with high lipid solubility to cross BBB)  ↑ ACh levels selectively in CNS  Useful in AD Indirect acting agents (Tertiary amines) Rivastigmine (EXCELON®) Donepezil* (ARICEPT®) Munusamy, 2024 *Top 300 drug 29  Adverse Effects: Cholinergic Agonists Salivation Sweating (Diaphoresis) Difficulty accommodating far vision Bradycardia Contraindications: Cholinergic Agonists Asthma Peptic ulcer Urinary tract obstructions AV block Munusamy, 2024 30  Cholinergic Drugs: Classification - Summary CHOLINERGIC DRUGS DIRECT ACTING INDIRECT ACTING (Inhibit AChE) (Resist AChE) Organophosphates (Irreversible) (Very Long acting) (Echothiophate) Choline esters Alkaloids Carbamates (Reversible) (Acetylcholine) (Muscarine) (Intermediate to Long acting) Echothiophate (Neostigmine) Alcohols Acetylcholine Pilocarpine(Reversible - Short acting) Physostigmine Bethanechol Cevimeline (Edrophonium) Neostigmine Don’t cross BBB Carbachol Muscarinic selective Pyridostigmine (Don’t cross BBB) Rivastigmine Edrophonium Donepezil (Don’t cross BBB) ABC; Neostigmine & Pyridostigmine: Do not cross BBB Munusamy, 2024 Other drugs: Cross BBB => Central side effects 31  1. Direct Acting Cholinomimetics: Summary Pharmacokinetic Classification Properties Used to treat - 1) CHOLINE ESTERS: Poor lipid solubility  Do not cross the BBB Acetylcholine (MIOCHOL-E®) To constrict pupil during cataract (Eye drops) Short-acting (~30 secs) surgery and other eye surgeries Bethanechol (URECHOLINE®) GI atony and Urinary retention due to (Oral, SC) bladder atony after surgery Intermediate-acting Carbachol (MIOSTAT®) (30 min – 2 h) Glaucoma (by ⇈ outflow/drainage of (Eye drops) aqueous humor) 2) ALKALOIDS: Good lipid solubility  Crosses the BBB Pilocarpine (OCUSERT®; SALAGEN®) Glaucoma - Only Pilocarpine (Eye drops; Oral) Long-acting (3-4 h) Xerostomia (Dry mouth) due to radiation Cevimeline (EVOXAC®) therapy & Sjogren’s disease - Both drugs (Oral) Munusamy, 2024 Mnemonic: SALAGEN – Saliva Generator 32  2. Indirect Acting Cholinomimetics: Summary Classification Pharmacokinetic Properties Used to treat - 1) CARBAMATES (Reversible) – Intermediate to Long duration of action Glaucoma Physostigmine Tertiary amine (Good lipid solubility)  (IM, IV, Eye drops) Crosses BBB CNS toxicity caused by anticholinergic toxicity Neostigmine & Quaternary amines - Poor lipid solubility  GI atony and Bladder atony Pyridostigmine Do not cross BBB after surgery (IM, IV & Oral) Pyrido- Longer-acting than neo- Myasthenia gravis Rivastigmine (Oral) Tertiary amines (Good lipid solubility)  Donepezil (Oral) Alzheimer’s disease Crosses BBB 2) ORGANOPHOSPHATES (Irreversible) – Very long duration of action (2 - 7 days) Echothiophate (Eye drops) High lipid solubility  Crosses BBB Glaucoma (2nd line) ABC; Neo- & Pyridostigmine: Do not cross BBB => No central effects Pyridostigmine is longer-acting than neostigmine Munusamy, 2024 33  34 Munusamy, 2024 1) 2) 3) 35 Munusamy, 2024  36 Munusamy, 2024  Lecture Resources 1. Chapters 6 to 10, Katzung’s Basic and Clinical Pharmacology. 16th edition. 2024 (Access Pharmacy). 2. Chapters 6 to 10, Katzung’s Pharmacology Examination & Board Review, 14th edition. 2024 (Access Pharmacy) 3. Chapters 9 & 10, Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th edition, 2017. 4. Chapters 4 & 5, Lippincott Illustrated Reviews. 5th edition. 2012. 5. Chapter 3, Lange Smart Charts: Pharmacology, 2nd edition. 2015 (Access Pharmacy) Munusamy, 2024 37