Overview Indirect cholinergic agonism AchE inhibition Muscarinic antagonism emphasis on drugs and organ effects Nicotine Ach receptor emphasis on drugs and therapeutics Indirect cholinergic agonists Inhibitors of acetylcholinesterase Increase acetylcholine concentration and lifetime by inhibiting degradation Act by binding to AchE active site causing reversible non covalent or long lasting covalent modification Mechanisms of indirect agonism Quaternary alcohols ephodronium reversible binding limit acetylcholine access Non covalent enzyme inhibitor complex lifetime 2 10 minutes Carbamate esters neostigmine physostigmine reaction with AchE active site Covalent carbamoylation enzyme inhibitor complex lifetime 0 5 6h Organophosphates Parathion Sarin Soman phophorylates AchE active site Covalent phosphorylation very stable enzyme inhibitor complex days especially after aging AchE Inhibitors quaternary alcohols and carbamates Organophosphates Aging Organ effects therapeutic uses Effects are due to acetylcholine accumulation and are both sympathetic and parasympathetic USES Approx Duration ALCOHOLS Edrophonium Myasthenia gravis arrythmias 5 15 minutes Myasthenia gravis Myasthenia gravis Glaucoma Glaucoma 0 5 2h 3 6h 0 5 2h 4 6h Glaucoma 100 h 4 days CARBAMATES Neostigmine Pyridostigmine Physostigmine Demecarium Organophosphates Echotiophate Treatment of organophosphate poisoning 1 maintenance of vital signs respiration particularly important 2 Decontamination to avoid further absorption 3 Atropine parenterally to minimize muscarinic effects as required 4 Rescue of AchE activity with Hydroxylamines Pralidoxime Diacetylmonoxime Muscarinic antagonism Attropa belladona Muscarinic Antagonists ATROPINE SCOPOLAMINE Muscarinic Antagonists ATROPINE SCOPOLAMINE Attropa belladona Atropine and Scopolamine are belladona alkaloids competitive inhibitors Drugs differ in their CNS effects scopolamine permeates the blood brain barrier At therapeutic doses atropine has negligible effects upon the CNS scopolamine even at low doses has prominent CNS effects Mechanism of drug action Competitively block muscarinic receptors Salivary bronchial and sweat glands are most sensitive to atropine Smooth muscle and heart are intermediate in responsiveness In the eye causes pupil dilation and difficulty for far vision accomodation Relaxation of the GI slows peristalsis History sources Atropa belladona used in the renaissance Deadly nightshade used in the middle ages to produce prolonged poisoning Jimson plant leaves burned in India to treat Asthma 1800 purification of atropine 1831 Effect of muscarinic inhibitor in the eye Pupil dilation vs accomodation Effect of muscarinic inhibition in the heart and salivary glands Increases the heart rate after a transient bradychardia at the low dose Diminishes gland excretory function Graphic summary of atropine effects Organ effect drug review Antidotes ORGAN DRUG APPLICATION Benztropine Scopolamine Treat Parkinson s disease Prevent Reduce motion sickness Eye Atropine Pupil dilation Bronchi Ipatropium Bronchodilate in Asthma COPD GI Methscopolamine Reduce motility cramps GU Oxybutinin Treat transient cystitis Postoperative bladder spasms CNS Toxicity of muscarinic antagonists DRY AS BONE RED AS A BEET MAD AS HATTER Dry is a consequence of decreased sweating salivation and lacrimation Red is a result of reflex peripheral cutaneous vasodilation to dissipate heat hyperthermia Mad is a result of the CNS effects of muscarinic inhibition which can lead to sedation amnesia hypersensitivity or hallucination Nicotinic Acetylcholine Receptor polarized Relaxation depolarized contraction Signaling through Ach nicotinic receptor competitive and depolarizing blockers Competitive depolarizing Competitive Physically blocks Ach binding INHIBITOR Depolarizing Binds and locks the receptor open Examples of competitive depolarizing drugs Competitive Mivacurium Tubocurarine Depolarizing AchE Butyrylcholinesterase Sensitive sites Succinylcholine Clinical uses Adjuvant use in surgical anesthesia muscular relaxation Advantage much lighter levels of anesthesia required Other uses muscular relaxation for orthopedics correction of dislocation alignment of fractures short duration facilitate intubation laryngoscopy bronchoscopy esophagoscopy Control of muscular spasms strabism hemifacial spasms oromandibular and cervical dystonia spasms of the lower esophageal sphincter Cosmetic Bottox Botulinum toxin A Paralytic action on skeletal muscle Agents Features Duration AGENT CLASS PROPERTY ONSET DURATION Succinylcholine Dicholine ester Depolarization 1 min 5 8 min Tubocurarine Competitive 5 min 80 120 min 30 60 min Alkaloid Atracurium Benzylisoquinoline Competitive 3 min Mivacurium Benzylisoquinoline Competitive 3 min 12 18 min Pancuronium Ammonio Steroid Competitive 5 min 120 180 min Vecuronium Competitive 3 min 60 90 min Ammonio Steroid Hydrolysis by esterases Liver clearance renal elimination Both Precautions Toxicity Prolonged apnea cardiovascular collapse Sequence of paralysis Eye muscles Jaw Larynx limbs and trunk intercostal muscles and the dyaphragm Generally caused by diminished esterase activity renal malfunction liver insufficiency poor circulatory function Special caution in patients with electrolyte imbalance K Antidote Neostigmine Ephodronium to increase Ach and atropine to block Ach muscarinic stimulation Malignant hyperthermia results from a discharge of Ca 2 exacerbated muscular action tachycardia hyperthermia acidosis and rigidity mutations of RYR1 central core disease treated with Dantrolene preservation of respiration Summary Tetrodoxin Batrachotoxin Hemicholinium Botulinum toxin Curare alkaloids Snake venom Dantrolene AchE inhibitors X Ach pilocarpine Muscarine Bethanechol Neostigmine Edrophonium Atropine Scopolamine Tubocurarine Mivacurium X X X X X h si s c A ly ro d Hy Indirect Movie http www youtube com watch v yd46Hs7pTow Nicotine in the brain
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