PM 716 Pharmacology I - Ach Agonists Slides PDF

PM 716 Pharmacology I Chapter 7 Ach Agonists Cholinomimetics RMRocco, PhD PM716 C7 Cholinoceptor Activators 1  Case Study 43 year old male farm worker, unsteady gate, difficulty speaking and swallowing, blurred vision, eyes filled with tears, difficult...

PM 716 Pharmacology I Chapter 7 Ach Agonists Cholinomimetics RMRocco, PhD PM716 C7 Cholinoceptor Activators 1  Case Study 43 year old male farm worker, unsteady gate, difficulty speaking and swallowing, blurred vision, eyes filled with tears, difficulty breathing. Tightness in the chest. Fields were sprayed with a chemical that smelled like sulfur. How to treat? PM716 C7 Cholinoceptor Activators 2  Case Report Symptoms typical of AchE inhibitor. Decontaminate the patient (and yourself), remove clothing, wash exposed areas of the skin. Ventilate with O2 Block excess Ach at muscarinic receptors with atropine iv. Block excess Ach at nicotinic receptors with 2- PAM (restore/reactivate inhibited AchE). PM716 C7 Cholinoceptor Activators 3  Drugs carbachol donepezil pilocarpine neostigmine muscarine physostigmine nicotine rivastigmine methacholine edrophonium bethanechol carbamate insecticides organophosphate insecticides nerve gas (suman, sarin) PM716 C7 Cholinoceptor Activators 4  Acetylcholine (Ach) Drugs that mimic Ach. Also called, cholinergic agonists (cholinergics) acetylcholine agonists cholinoceptor-activating drugs cholinoceptor-stimulants cholinomimetics PM716 C7 Cholinoceptor Activators 5  Cholinomimetics Direct Acting Substitute for Ach and enhance the effects of Ach Indirect Acting Increase Ach levels by inhibiting the enzyme (AchE) that removes Ach. PM716 C7 Cholinoceptor Activators 6 PART 1. Cholinonmimetics DIRECT ACTING SYNTHETICS (Choline Esters) methacholine bethanechol carbachol ALKALOIDS FROM PLANTS pilocarpine muscarine nicotine PM716 C7 Cholinoceptor Activators 7  Cholinomimetics Choline Esters Poorly absorbed (po), not into CNS Short half-life due to AchE (seconds to minutes) IM injections produce only local effects Alkaloids Well absorbed, some even into the CNS PM716 C7 Cholinoceptor Activators 8  Ach Receptors Nicotinic MuscarinicReceptors Receptors Na+ or Ca++ Ligand gated Ion G-Protein Coupled Channel Serpentine Receptor Activation leads to Activation leads to Excitation. Inhibition or Excitation PM716 C7 Cholinoceptor Activators 9 Cholinergic Receptors PM716 C7 Cholinoceptor Activators 10  Receptor Organization Sympathetic Pathway CNS Ach NE Adrenergic Receptors a1a2 b1b2 Parasympathetic Pathway CNS Ach Ach Muscarinic Receptors Nicotinic Receptors PM716 C7 Cholinoceptor Activators 11  Pharmacodynamics Choline Ester Muscar Nicotinic Ach +++ +++ methacholine ++++ none carbachol ++ +++ bethanechol ++ none PM716 C7 Cholinoceptor Activators 12  Cholinomimetics Drugs that mimic acetylcholine (Ach) in actions. Drugs (including Ach) that bind to Muscarinic Receptors - G-Protein Coupled and/or Nicotinic Receptors- Ion Channel (at the neuromuscular junction) K Table 7-1 pg 106 (Receptor subtypes and tissue locations). PM716 C7 Cholinoceptor Activators 13  Cholinomimetics, Direct Acting Drugs that Stimulate Receptors Directly (agonists) Choline Esters acetylcholine (ophthalmic) (Miochol-E® ) methacholine (Provocholine®) carbachol (ophthalmic) (Carboptic® ) bethanechol (Urecholine®) Naturally occurring agents (Alkaloids) muscarine (experimental usage) nicotine pilocarpine (ophthalmic) (Isopto Carpine®) PM716 C7 Cholinoceptor Activators 14  General Actions of Cholinomimetics Typical Adverse Reactions with cholinergics due to increased levels Ach diarrhea diaphoresis (sweating) miosis (pupil constriction) nausea urinary urgency PM716 C7 Cholinoceptor Activators 15  Direct Acting At Nicotinic Receptors (ion-channel) (1) Ion channel opens and sodium flows in. (2) Nerve cell is depolarized and fires. (3) Prolonged activation of the nicotinic receptor by direct agonists leads to termination of response and paralysis. Table 7-3 PM716 C7 Cholinoceptor Activators 16 Chapter 7 Cholinoceptor-Activating & Cholinesterase- Inhibiting Drugs PM716 C7 Cholinoceptor Activators 17 © The McGraw-Hill Companies, Inc, Chapter 7 Cholinoceptor-Activating & Cholinesterase- Inhibiting Drugs PM716 C7 Cholinoceptor Activators 18 © The McGraw-Hill Companies, Inc, Cholinergic Receptors PM716 C7 Cholinoceptor Activators 19  Direct Acting At Muscarinic Receptors (all G-Protein Coupled) (1) Drugs activate IP3 cascade which releases Ca++ from SR and ER which relaxes smooth muscle. (2) Drugs increase K+ flux in cardiac muscle and decrease K+ flux in smooth muscle and ganglion. (3) Drugs modulate cAMP levels and help reduce tissue response to hormones (through inhibition of adenylyl cyclase). K97-98 PM716 C7 Cholinoceptor Activators 20  Nicotinic Mechanisms At skeletal muscle motor end plate: Drug binds to receptor channel that is selective for sodium and potassium. Channel opens when drug binds, Na + flows into cell and causes an EPSP (cell depolarizes). Intracellular Na+ mobilizes intracellular Ca+ + which causes muscle cell to fire. PM716 C7 Cholinoceptor Activators 21 Direct Acting Drugs Acetylcholine Methacholine PM716 C7 Cholinoceptor Activators 22  Muscarinic Mechanisms Drug binds to receptor G Protein couples to membrane bound enzyme, phospholipase C Second messengers diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3). DAG modulates protein kinase C which controls secretion IP3 releases calcium from intracellular sites which causes contraction. PM716 C7 Cholinoceptor Activators 23  Direct Acting Agonists Pharmacodynamics Eye: contraction (miosis) Heart: decreases in rate, contractile strength, conduction velocity. Arteries & Veins: dilation Lung: contraction GI: increased motility, secretion stimulated. Glands: secretion Urinary Bladder: detrusor muscle, contraction; trigone and sphincter, relaxation. PM716 C7 Cholinoceptor Activators 24 Chapter 7 Cholinoceptor-Activating & Cholinesterase- Inhibiting Drugs PM716 C7 Cholinoceptor Activators 25 © The McGraw-Hill Companies, Inc,  Glaucoma PM716 C7 Cholinoceptor Activators 26  Direct Acting Agonists Bethanechol urinary retention activate smooth muscle Carbachol glaucoma activate pupillary sphincter and ciliary smooth muscle Pilocarpine glaucoma as above for carbachol Nicotine smoking replace rapid acting nicotine with slower action PM716 C7 Cholinoceptor Activators 27  Therapeutic Uses Recap Bethanechol (po tablets or sc) Directly stimulates muscarinic receptors Stimulation of detrusor muscle in bladder promotes urine flow. Carbachol (topical ophthalmic, intraocular) Stimulates both musc and nicotinic Mimics Ach in the eye (miosis) For glaucoma, pupil contracts and intraocular pressure is reduced. PM716 C7 Cholinoceptor Activators 28  Therapeutic Uses Recap Pilocarpine (topical ophthalmic, po tablets) Stimulates muscarinic receptors Miosis in the eye Potent stimulator of sweat, tears, saliva. Used as a mouth spray in patients with damaged glands due to radiation treatment for head and neck CA Used to promote forearm sweating in chloride screening for cystic fibrosis. Used for emergency treatment of glaucoma. PM716 C7 Cholinoceptor Activators 29 Pilocarpine Direct acting cholinometic (agonist) derived from natural sources, an alkaloid. Drug not metabolized by AchE. Longer acting. PM716 C7 Cholinoceptor Activators 30  Therapeutic Uses Recap Pilocarpine (po tablets, Salagen©) Used to treat xerostoma (dry mouth) and Sjogren’s Syndrome (dry mouth and dry eye) due to autoimmune disorder. Entry of drug into CNS can cause marked salivation and sweating. 31 PM716 C7 Cholinoceptor Activators  Direct Acting Ach Excess Muscarinic Toxicity: (pilocarpine in overdose) nausea, vomiting, diarrhea, salivation, bronchial constriction. Effects reversed by atropine. Some poisonous mushrooms contain muscarinic alkaloids. Nicotine Toxicity: CNS, stimulation including convulsions. PNS, neuromuscular block leading to fasciculations and paralysis. PM716 C7 Cholinoceptor Activators 32  PART 2. AchE Target of Indirect Acting Drugs AchE Ach Choline + acetic acid + HAc PM716 C7 Cholinoceptor Activators 33 Acetylcholine Neuron PM716 C7 Cholinoceptor Activators 34  AchE Nomenclature Acetylcholinesterase (AchE) True Cholinesterase, Choline esterase I. Found in brain(gray matter), nerve terminals and Red Cells. Function is to terminate actions of Ach. Butyrylcholinesterase, pseudocholinesterase, Choline esterase II. Found in brain (white matter), liver, serum. Function is unknown. PM716 C7 Cholinoceptor Activators 35  AchE Inhibitors INDIRECT ACTING (Reversible) donepezil neostigmine physostigmine rivastigmine edrophonium PM716 C7 Cholinoceptor Activators 36 AchE Inhibitors INDIRECT ACTING (Slowly to non-reversible) Carbamate Insecticides Organophosphate Insecticide (> 50 000 different ones) Nerve Gases (suman, sarin) PM716 C7 Cholinoceptor Activators 37  AchE Forms and Differences Both forms inhibited by organophosphates and physostigmine Both enzymes exits in multiple molecular forms (Isozymes) Many genetic allelic forms exist. Pseudocholinesterase (serum AchE) levels are useful liver function test, screen for organophosphate poisoning and detection of atypical forms in patient serums. PM716 C7 Cholinoceptor Activators 38  Indirect Acting Cholinomimetics Drugs bind to and inhibit AchE (1) Quaternary Alcohols edrophonium (very short duration of action) (2) Carbamate Esters (the carbamates) neostigmine physostigmine Carbamate Insecticides carbaryl (Sevin®) propoxur (Baygon®) aldicarb (Temik®) PM716 C7 Cholinoceptor Activators 39  Indirect Acting Cholinomimetics (3) Organophosphates (phosphoric esters) Insecticides parathion malathion Nerve Gases soman sarin PM716 C7 Cholinoceptor Activators 40 AchE Inhibitors Neostigmine (Prostigmin®) Parathion (insecticide, pesticide) Orthophos®, Paraphos® The most highly restricted insecticide by the EPA. PM716 C7 Cholinoceptor Activators 41 AchE Inhibitors Physostigmine used to treat Myasthenia gravis Propoxur (Baygon®) a carbamate insecticide. PM716 C7 Cholinoceptor Activators 42 AchE Inhibitors Echothiophate (Phospholine®) used to treat glaucoma Sarin nerve gas PM716 C7 Cholinoceptor Activators 43 Indirect Acting Cholinomimetics The normal binding of Ach to AchE produces choline and HAc within 150ms. (1) Quaternary Alcohol Drugs bind to AchE with weak hydrogen bonds, effect lasts 2 - 10 min. neostigmine as an example (2) Carbamate Ester Drugs covalently bind and effect lasts 30 min to 6 hours. (3) Organophosphates bind with stable link that lasts 100’s hours. PM716 C7 Cholinoceptor Activators 44  Indirect Acting Carbamate absorption is poor due to charge which makes them insoluble in lipids. CNS distribution is low. Organophosphates are lipid soluble and well absorbed. Distribute into CNS. High degree of toxicity to humans. K102. Table 6-5. PM716 C7 Cholinoceptor Activators 45  Pharmacodynamics Direct and Indirect Acting cholinomimetics cholinolytics Ach, pilocarpine Atropine, scopolamine eye miosis mydriasis Heart Decrease rate Increase rate Respiratory Bronch constriction Bronch dilation GI Increase motility Decrease motility GU Relaxation sphincters Urinary retention CNS Drowsiness, hallucinations, coma PM716 C7 Cholinoceptor Activators 46  More Gems All autonomic ganglia have nicotinic receptors All receptors at the neuromuscular junction are nicotinic receptors. All target organs of the parasympathetic system have muscarinic receptors. PM716 C7 Cholinoceptor Activators 47 Indirect Acting Cholinomimetics Actions similar to Direct Acting- increase Ach levels. Major sites of pharmacological action: cardiovascular, GI, eye and skeletal muscles. PM716 C7 Cholinoceptor Activators 48 Indirect Acting Clinical Actions Clinical effects are to amplify the actions of endogenous Ach. The concentration, half- life and actions of Ach at synapses are increased. Actions of AchE drugs occur at Nicotinic and Muscarinic Receptors. PM716 C7 Cholinoceptor Activators 49  Indirect Acting Clinical Uses In diseases which benefit from increased Ach activity. (neostigmine, physostigmine, etc) urinary retention (increase bladder tone, promote urine flow) Myasthenia gravis (autoimmune receptor disease) reversal of neuromuscular blockade (increased Ach at motor end plate receptors may overcome the drug that is blocking the receptor). glaucoma (decrease intraocular pressure) PM716 C7 Cholinoceptor Activators 50  Indirect Acting Clinical Uses EYE: glaucoma,increased intraocular pressure. (These drugs replaced with beta blockers) GI: neostigmine (indirect) atony or paralysis of the bowel without obstruction, or urinary retention post operatively, postpartum or secondary to spinal cord injury. CNS: AchE inhibitors used in Alzheimer’s disease. PM716 C7 Cholinoceptor Activators 51 Alzheimer’s Disease Donepezil (Aricept®) approved by the FDA for use in Alzheimer’s Disease. AchE inhibitor which increases CNS Ach levels. ADRs from excess Ach (nausea, diarrhea, vomiting) PM716 C7 Cholinoceptor Activators 52  Myasthenia Gravis Autoimmune disease of the neuromuscular junction. ~ 60 000 cases in the US Patient antibodies bind to and reduce the number of nicotinic receptors in the neuromuscular junction. IgG anti-receptor antibodies. AchE inhibitor drugs (Indirect Acting) improve patient response by increasing the amount of Ach per reduced number of receptors. PM716 C7 Cholinoceptor Activators 53 Mary B. Walker (1888-1974) The first to describe the use of physostigmine to treat Myasthenia gravis. Walker, M. B. Treatment of myasthenia gravis with physostigmine. Lancet I:1200-1201 (1934) PM716 C7 Cholinoceptor Activators 54  The Rationale for the Use of Physostigmine (1) Tetanus is produced by Clostridium tetani which secretes tetanospasmin toxin (TT). (2) TT causes muscular rigidity (“lockjaw”), muscle spasms and respiratory failure. (3) Mechanism is block of inhibitory neurons by TT in CNS which causes outflow (excess) of Ach. (4) Treat Tetanus (1934) with curare (“arrow poison”) because it binds to nicotinic receptors and blocks Ach. (5) Myasthenia gravis causes a curare-like paralysis, give physostigmine to inhibit AchE and increase Ach at motor end plates. PM716 C7 Cholinoceptor Activators 55  Toxicity and ADRs of AchE Inhibitors Accidental exposure to pesticides (parathion). The degree of toxicity related to the amount of time that the agent remains bound to AchE. “Aging” of the AchE-Agent complex if allowed to occur then reversal becomes more difficult. PM716 C7 Cholinoceptor Activators 56  Indirect Acting Toxic actions similar to Direct Acting. Major source of cholinesterase inhibitors are pesticides (~ 100 organophosphates and 20 carbamates available in the US). Toxicity is similar to muscarinic excess: miosis, salivation, sweating, bronchial constriction, vomiting, diarrhea. Treatment is supportive and atropine. PM716 C7 Cholinoceptor Activators 57  Toxicity of AchE Agents DUMBBELSS Diarrhea Urination Miosis (constricted pupils) Bronchoconstriction Bradycardia (< 60 beats/min) Excitation (CNS and skeletal muscles) Lacrimation (tears) Salivation Sweating PM716 C7 Cholinoceptor Activators 58  Jamaica Ginger A Patent Medicine Ethanol extract of Jamaica Ginger Root sold worldwide as a tonic 1920’s. Add a few drops to water, seltzer or other soda and used for improved digestion and colds. Ethanol content 70%. Cost about 35 cents 2 oz. PM716 C7 Cholinoceptor Activators 59 Jamaica Ginger Prohibition in 1920 in the US changed the law on ethanol content of all extracts. Ethanol content must be reduced. Molasses too expensive. One company in Boston used TOCP (Lindol®) In 1930, 20 000 people paralyzed. PM716 C7 Cholinoceptor Activators 60 Tri Ortho Cresyl Phosphate (TOCP) Clear liquid dissolves fat soluble compounds. Industrial uses include:plasticizer to keep synthetic materials from becoming brittle and as an additive in cooling lubricants. Made by Eastman Kodak and Cellulloid Corp. K107 PM716 C7 Cholinoceptor Activators 61  TOCP TOCP is an organophosphate that inhibits AchE and another esterase enzyme found in the CNS and PNS. Agent induces acute cholinergic effects including a “delayed” PNS neurotoxicity. TOCP causes irreversible muscle weakness, leg weakness, paralysis. Mechanism of action(s) not well understood and may involve AchE and/or other neuro esterases. PM716 C7 Cholinoceptor Activators 62  Ginger Jake Paralysis Over 20 000 in the Eastern and Southern US in the early 1930’s due to TOCP contaminated Jamaican Ginger extract. 10 000 people in Morocco from contaminated cooking oil in 1959. Similar cases and numbers from outbreaks from contaminated cooking oil in India, Rumania, Italy, Fijii Islands, Sri Lanka through the 1990’s. PM716 C7 Cholinoceptor Activators 63  TOCP “…he would drink Jake or whiskey until he was a shaken paralytic with red eyes.” The Grapes of Wrath John Steinbeck, 1939 CD singers: Gene Autry Tommy Johnson Mississippi Sheiks and other blues singers PM716 C7 Cholinoceptor Activators 64