1. the parasympathetic nervous system www.freelivedoctor.com

4. Dual Innervation at Most Sites www.freelivedoctor.com

6. Parasympathetic Innervation From Brain www.freelivedoctor.com

7. Parasympathetic Innervation From the Sacral Cord www.freelivedoctor.com

8. Synthesis of Acetylcholine Acetylcholine Choline Acetyl CoA + Choline acetylase www.freelivedoctor.com

9. Cholinergic Fiber www.freelivedoctor.com

10. Acetylcholine and Its Metabolites Acetylcholine Choline Acetate hydrolysis + AChE www.freelivedoctor.com

14. Neuronal Innervation to Organs www.freelivedoctor.com

16. Activities Within Cell Bodies of Autonomic Ganglia Postganglionic neuron, sympathetic or parasympathetic www.freelivedoctor.com

19. Agonists and Antagonists at Nicotinic Receptor Subtypes www.freelivedoctor.com

22. Biochemical Actions Associated With Muscarinic Receptors M 1 , M 3 , and M 5 muscarinic receptors associate with G q -protein; result: activation of phospholipase C  M 2 , and M 4 muscarinic receptors associate with G i -protein; result: inhibition of adenyl cyclase phosphatidylinositolbiphosphate (PIP) 2 inositoltriphosphate (IP) 3 diacylglycerol (DAG) www.freelivedoctor.com X

23. G-Protein Coupled Receptors Review biochemistry, physiology, and pharmacology textbooks for the interaction of G-proteins and receptors. www.freelivedoctor.com

25. Specific Antagonists for Muscarinic Receptor Subtypes *Also blocks the nicotinic receptor www.freelivedoctor.com Darifenacin Smooth muscles and glands M 3 Tripitamine Gallamine* Cardiac muscle fiber M 2 Pirenzepine Telenzepine Autonomic ganglia, gastric tissue M 1 SELECTIVE ANTAGONIST(S) TISSUE RECEPTOR

26. ACTIONS OF ACETYLCHOLINE AT ORGAN SITES www.freelivedoctor.com

27. Parasympathetic Innervation to the Eye www.freelivedoctor.com

28. Parasympathetic Control of Accomodation From The Nurse, Pharmacology, and Drug Therapy Parasympathetic stimulation allows contraction of the ciliary muscle. www.freelivedoctor.com

29. Flow of Aqueous From the Eye From Basic and Clinical Pharmacology www.freelivedoctor.com

33. Nitric Oxide Mediated Vasodilation www.freelivedoctor.com

34. Neuronal and Hormonal Control of Blood Pressure www.freelivedoctor.com

35. Cardiovascular Responses to Low and High Doses of ACh www.freelivedoctor.com

36. Sites of Dominance in the ANS Adapted from Goodman and Gilman’s The Pharmacological Basis of Therapeutics 1 The vast majority of blood vessels do not receive parasympathetic innervation www.freelivedoctor.com

37. Cholinergic Agents www.freelivedoctor.com

38. Cholinergic Agents Alkaloids Nicotine Lobeline Arecoline Muscarine Pilocarpine Synthetic Agents Dimethylphenylpiperazinium-(DMPP) Oxotremorine Methacholine Bethanechol Carbachol Cevimeline www.freelivedoctor.com

42. Structure of Acetylcholine and its Derivatives Acetylcholine Methacholine Bethanechol Carbachol www.freelivedoctor.com

46. Agents That Inhibit Acetylcholinesterase www.freelivedoctor.com

47. Acetylcholinesterase (True Cholinesterase) www.freelivedoctor.com

51. Butyrylcholinesterase (Plasma esterase, pseudocholinesterase, serum esterase, BuChE, PseudoChE) www.freelivedoctor.com

54. Active Site of Acetylcholinesterase www.freelivedoctor.com

55. Interaction of AChE and Acetylcholine www.freelivedoctor.com

56. Acetylation of AChE and Release of Choline www.freelivedoctor.com

57. Hydroxyl Group of Water Attacks the Carbonyl Group of Acetylated-AChE to Liberate AChE www.freelivedoctor.com

58. Carbamyl Inhibitors of AChE www.freelivedoctor.com

63. Neostigmine Carbamylates Acetylcholinesterase www.freelivedoctor.com

64. Slow Hydrolysis of Carbamylated-AChE and Enzyme Liberation www.freelivedoctor.com

65. Organophosphate Inhibitors of Acetylcholinesterase www.freelivedoctor.com

70. Diisopropylflurophosphate (DFP) is a Substrate for AChE www.freelivedoctor.com

71. The Extremely Slow Hydrolysis of Phosphorylated-AChE New enzyme synthesis is required for recovery of enzyme function www.freelivedoctor.com

72. Various “States” of Acetylcholinesterase Clockwise: free AChE, acetylated AChE, carbamylated AChE, phosphorylated AChE www.freelivedoctor.com

73. Acetylated-AChE Is Very Rapdily Hydrolyzed AChE + Acetylcholine  AChE-acetylated + choline AChE-acetylated + H 2 O  AChE + acetate Hydrolysis of AChE-acetylated is rapid, in the order of microseconds P www.freelivedoctor.com

74. Carbamylated-AChE Is Hydrolyzed Slowly AChE + Carbamyl inhibitor  AChE-carbamylated + noncarbamylated metabolite AChE-carbamylated + H 2 O  AChE + carbamic acid derivative Hydrolysis of the AChE-carbamylated is slow, in the order of hours. The carbamylated enzyme is reversibly inhibited, and recovery of function is in the order of hours Enzyme after phosphorylation by neostigmine www.freelivedoctor.com

75. Phosphorlylated-AChE Is Hydrolyzed Extremely Slowly AChE + organophosphate inhibitor  AChE-phosphorylated + nonphosphorylated metabolite AChE-phosphorylated + H 2 O  AChE + phosphorylated derivative Hydrolysis of the AChE-phosphorylated is extremely slow, in the order of days. The phosphorylated enzyme is considered to be irreversibly inhibited, and recovery of function is in the order of days. Pralidoxime, a reactivating agent, may be adminstered to a subject before the enzyme has “aged.” Enzyme after phosphorylation by DFP www.freelivedoctor.com

76. AGING OF ACETYLCHOLINESTERASE www.freelivedoctor.com

77. Loss of An Alkyl Group From Phosphorylated AChE “Ages” the Enzyme AChE, phosphorylated and inhibited by DFP “ Aged” AChE www.freelivedoctor.com

78. “ Aging” of Phosphorylated- AChE www.freelivedoctor.com

79. Cholinesterase Reactivation www.freelivedoctor.com

81. Pralidoxime Reacts Chemically with Phosphorylated-AChE The oxime group makes a nucleophilic attack upon the phosphorus atom www.freelivedoctor.com

82. Oxime Phosphonate and Regenerated AChE www.freelivedoctor.com

85. Edrophonium www.freelivedoctor.com

86. Edrophonium is a Short Acting Inhibitor that Binds to the Ionic Site but Not to the Esteratic Site of AChE www.freelivedoctor.com

87. Pharmacology of Acetylcholinesterase Inhibition www.freelivedoctor.com

88. Inhibition of Acetylcholinesterase Produces Stimulation of All Cholinergic Sites www.freelivedoctor.com

93. Determining Proper Dose of AChE Inhibitor www.freelivedoctor.com

95. Organophosphate Inhibitors of AChE www.freelivedoctor.com

97. Organophosphate Inhibitors - 2 Diisopropylfluorophosphate (DFP) Soman Sarin Tabun www.freelivedoctor.com

98. Echothiophate Therapeutic use - local application to the eye for wide angle glaucoma www.freelivedoctor.com

99. Conversion of Parathion to Paraoxon www.freelivedoctor.com

100. Conversion of Malathion to Malaoxon www.freelivedoctor.com

101. Malathion Is Hydrolyzed by Plasma Carboxylases in Birds and Mammals but Not Insects www.freelivedoctor.com

107. NERVE AGENT VX Chemical name: O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYL-PHOSHONOTHIOLATE Trade name: PHOSPHONOTHIOIC ACID NERVE AGENT VX www.freelivedoctor.com

108. NERVE AGENT VX Chemical name: O-ETHYL-S-(2-DIISOPROPYLAMINOMETHYL)METHYL-PHOSHONOTHIOLATE Trade name: PHOSPHONOTHIOIC ACID www.freelivedoctor.com

111. Use of Pyridostigmine During the Gulf War www.freelivedoctor.com

112. Pharmacology of Muscarinic Receptor Blockade www.freelivedoctor.com

113. Acetylcholine is an agonist at both muscarinic and nicotinic receptors The nicotinic actions of acetylcholine remain when muscarinic receptors are blocked www.freelivedoctor.com

114. Muscarinic Receptor Blockade Does Not Affect Ganglionic Transmission Muscarinic receptor blockade prevents generation of the IPSP and the sEPSP but not the fEPSP www.freelivedoctor.com X

115. Muscarinic receptor blockade does not interfere with transmission at autonomic ganglionic sites, the adrenal medulla, or skeletal muscle fibers. Sympathetic adrenergic functions are not affected. www.freelivedoctor.com X X

116. In Dual Innervated Organs, Muscarinic Receptor Blockade Allows Sympathetic Dominance X www.freelivedoctor.com

117. Atropine www.freelivedoctor.com

119. Response to ACh in the Presence of Atropine Atropine competitively inhibits muscarinic reponses to ACh www.freelivedoctor.com Log dose of acetylcholine Response control atropine

121. Changes in Accomodation and Pupillary Diameter after Administration of an Antimuscarinic Agent Reproduced from Basic and Clinical Pharmacology www.freelivedoctor.com

124. Response to Doses of Atropine Reproduced from Basic and Clinical Pharmacology www.freelivedoctor.com

125. M 1 Receptor Activation at Parasympathetic Nerve Terminals Exerts A Small Negative Feedback Effect Upon ACh Release in Response to Nerve Impulse Flow postsynaptic fiber cardiac muscle fiber www.freelivedoctor.com ACh ACh ACh (----) M1 M2

126. M 1 Receptor Blockade Eliminates the Negative Feedback Effect and Increases ACh Release in Response to Nerve Impulse Flow postsynaptic fiber cardiac muscle fiber Pirenzepine is an M 1 antagonist www.freelivedoctor.com x ACh ACh ACh ACh M1 M2

127. Intravenous infusion of acetylcholine in high doses produces actions at numerous sites. Bradycardia and hypotension are among the results. Such actions are accentuated in the presence of inhibitors of AChE (they also block plasma pseudocholinesterase). www.freelivedoctor.com i.v. infusion

128. Prior blockade of muscarinic receptors followed by intravenous infusion of a high dose of ACh converts the bradycardiac and hypotensive responses to tachycardia and hypertension, mediated through the nicotinic receptors. www.freelivedoctor.com x x x i.v. infusion

129. Effect Of Atropine in Relation to Dosage ... www.freelivedoctor.com

130. Dose of Atropine DOSE EFFECT 0.5 mg Slight decline in heart rate Some dryness of mouth Inhibition of sweating www.freelivedoctor.com

131. Dose of Atropine DOSE EFFECT 1.0 mg Definited dryness of mouth Thirst Inreased heart rate, sometimes preceded by slowing Mild dilatation of pupil www.freelivedoctor.com

132. Dose of Atropine DOSE EFFECT 2.0 mg Rapid heart rate Palpitation Marked dryness of mouth Dilated pupils Some blurring of near vision www.freelivedoctor.com

133. Dose of Atropine DOSE EFFECT 5.0 mg All the previous symptoms are marked Difficulty in speaking and swallowing Restlessness and fatigue Headache Dry hot skin Difficulty in micturition Reduced intestinal peristalsis www.freelivedoctor.com

134. Dose of Atropine DOSE EFFECT 10 mg Previous symtoms are more marked and more Pulse, rapid and weak Iris practically obliterated Vision very blurred Skin flushed, hot, dry, and scarlet Ataxia Restlessness and excitement Hallucinations and delirium Coma www.freelivedoctor.com

135. The previous five slides are reproduced from Goodman and Gilman’s The Pharmacological Basis of Therapeutics www.freelivedoctor.com

138. Therapeutic Uses of Antimuscarinic Agents www.freelivedoctor.com

144. Toxicity of Atropine www.freelivedoctor.com

146. Flow of Aqueous and Its Escape From the Eye www.freelivedoctor.com