1. The parasympathetic nervous system

2. The Parasympathetic Nervous System All information should be reviewed by reading –Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th edition –Basic and Clinical Pharmacology, 12th edition

3. Functions of the Parasympathetic Nervous System Protects the retina from excess light (miosis) Decreases heart rate Promotes glandular secretions Promotes the emptying of hollow organs Promotes the conservation of energy Promotes rest and repair Physiologically antagonizes the sympathetic nervous system

4. Dual Innervation at Most Sites

5. Concept of Dominance in the Autonomic Nervous System The sympathetic nervous system dominates at some sites The parasympathetic nervous system dominates at other sites

6. Parasympathetic Innervation From Brain

7. Parasympathetic Innervation From the Sacral Cord

8. Synthesis of Acetylcholine Acetylcholine Choline Acetyl CoA + Choline acetylase

9. Cholinergic Fiber

10. Acetylcholine and Its Metabolites Acetylcholine CholineAcetate hydrolysis + AChE

11. Agents Affecting Cholinergic Transmission Hemicholinium Latrotoxin Vesamicol Calcium Physostigmine Atropine d-Tubocurarine Botulinus Toxin

12. Uses of Botulinum Toxin Type A Therapeutic Uses –Blepharospasm –Strabismus –Cervical dystonia (spasmodic torticollis) –Spasm of vocal cords –Achalasia Cosmetic Uses –Eyebrow furrows –Frontalis muscle hyperactivity –Lateral canthal wrinkles –Axillary and palmar hyperhydrosis

13. Neuronal Innervation to Organs

14. General Actions of Acetylcholine Promotes transmission in postganglionic autonomic fibers Promotes release of epinephrine and norepinephrine from the adrenal medulla Promotes transmission in skeletal muscle fibers Promotes the functions of the parasympathetic nervous system at cardiac muscle, smooth muscles and glands Promotes sympathetic thermoregulatory sweating

15. Autonomic ganglia –Nicotinic sites –Muscarinic sites Adrenal medulla –Nicotinic sites: Release of epinephrine (90%) and norepinephrine (10%) into the circulation. Reproduced from Basic and Clinical Pharmacology Actions Mediated by N N Nicotinic Receptor

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

17. End plate of skeletal muscle fiber - generation of the EPP Actions Mediated by N M Nicotinic Receptor

18. Nature of Nicotinic Receptors Nicotinic receptors are pentameric and ionotropic - the receptor proteins themselves form ion channels The ion channels are ligand-gated Two subtypes –N N subtype is present on cell body of postganglionic autonomic neuron –N M subtype is present at the endplate of the neuromuscular junction

19. Agonists and Antagonists at Nicotinic Receptor Subtypes

20. Response to Doses of Nicotine Low Dose –Autonomic ganglia –Adrenal medullary cell –End plate of skeletal muscle High Dose –Autonomic ganglia –Adrenal medullary cell –End plate of skeletal muscle

21. Muscarinic Receptors Muscarinic receptors –The alkaloid muscarine mimics the actions of acetylcholine at these receptor sites –Metabotropic Associated with guanine nucleotide binding proteins (G- proteins) Span the cell membrane seven times –Several subtypes: M 1, M 2, M 3, M 4, M 5 –Associated with various biochemical and electrophysiological responses

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

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

24. Activation of Phospholipase C  by Muscarinic Receptor Subtypes M 1, M 3, M 5 muscarinic receptors Gq-GTP binding protein involved Agonist binds to the receptor The receptor associates with Gq-protein Gq-protein exchanges GDP for GTP The  subunit of Gq-protein dissociates from the  dimer and activates the effector molecule phospholipase C  Phospholipase C  hydrolyzes phosphatidylinositolbiphosphate (PIP 2 ) to inositoltriphosphate (IP 3 ) and diacylglycerol (DAG) IP 3 releases Ca 2++ from the endoplasmic reticulum and with DAG, activates protein kinase C The reaction is terminated by hydrolysis of GTP by the  q monomer; reassociation of  q with the  dimer

25. Specific Antagonists for Muscarinic Receptor Subtypes DarifenacinSmooth muscles and glands M3M3 Tripitamine Gallamine* Cardiac muscle fiber M2M2 Pirenzepine Telenzepine Autonomic ganglia, gastric tissue M1M1 SELECTIVE ANTAGONIST(S) TISSUERECEPTOR *Also blocks the nicotinic receptor

26. ACTIONS OF ACETYLCHOLINE AT ORGAN SITES

27. Parasympathetic Innervation to the Eye

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

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

30. Parasympathetic Function at Organs Sites (1) Gastrointestinal tract –Longitudinal muscles –Circular muscles –Sphincter muscles Bile duct Gall bladder Urinary tract –Ureters –Detrusor muscle of the bladder –Trigone –Sphincter muscle of the bladder Bronchial smooth muscles

31. Parasympathetic Function at Organs Sites (2) Lacrimal glands Pharyngeal glands Salivary glands Mucus glands –Respiratory tract –Esophagus Intestinal glands Gastric glands Pancreas

32. Parasympathetic Control of the Cardiovascular System SA Node Atrial muscle AV node Purkinje fibers Ventricles Blood vessels

33. Nitric Oxide Mediated Vasodilation

34. Neuronal and Hormonal Control of Blood Pressure

35. Cardiovascular Responses to Low and High Doses of ACh

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

37. Cholinergic Agents

38. Alkaloids Nicotine (N) Lobeline Arecoline Muscarine(M) Pilocarpine(M) Synthetic Agents (MN) Dimethylphenylpiperazinium- (DMPP) Oxotremorine Methacholine Bethanechol Carbachol Cevimeline

39. Nicotine Nicotine mimics the actions of acetylcholine at nicotinic sites –Cell body of the postsynaptic neurons ( N N) sympathetic and parasympathetic divisions –Chromaffin cells of the adrenal medulla –End plate of skeletal muscle fiber ( N M) Affinity for N N sites versus N M sites Used as an insecticide

40. Muscarine Muscarine mimics the actions of acetylcholine at smooth muscles, cardiac muscles, and glands Poisoning by muscarine produces intense effects qualitative to those produced by cholinergic stimulation of smooth muscles, cardiac muscle, and glands Muscarine is found in various mushrooms –Amanita muscaria: content of muscarine is very low –Inocybe sp: content of muscarine is high –Clitocybe sp: content of muscarine is high

41. Pilocarpine Has muscarinic actions Used for xerostomia Used for glaucoma

42. Structure of Acetylcholine and its Derivatives AcetylcholineMethacholine BethanecholCarbachol

43. Therapeutic Uses of Cholinergic Agonists Dentistry –Pilocarpine –Cevimeline Ophthalmology –Pilocarpine –Carbachol Gastrointestinal tract –Bethanechol Urinary bladder –Bethanechol

44. Contraindications to the Use of Choline Esters Hyperthyroidism Asthma Coronary insufficiency Peptic ulcer Organic obstruction in bladder or gastrointestinal tract

45. Toxicity of Choline Esters Flushing SWEATING (diaphoresis) Abdominal cramps Spasm of the urinary bladder Spasm of accomodation Miosis Headache Salivation Bronchospasm Lacrimation Hypotension Bradycardia

46. Agents That Inhibit Acetylcholinesterase

47. Acetylcholinesterase (True Cholinesterase)

48. Acetylcholinesterase (1) Sites of location –Cholinergic neurons –Cholinergic synapses –Neuromuscular junction –Red blood cells Substrates –Acetylcholine is the best substrate –Methacholine is a substrate –Hydrolyzes ACh at greater velocity than choline esters with acyl groups larger than acetate or proprionate

49. Acetylcholinesterase (2) Esters that are not substrates –Bethanechol –Carbachol –Succinylcholine Its inhibition produces synergistic interaction with methacholine and additive actions with bethanechol and carbachol Drugs that block its hydrolysis of esters are called cholinesterase inhibitors

50. Drug Interactions of Choline Esters and Inhibitors of Acetylcholinesterase - Synergism versus Additivity Methacholine Carbachol Bethanechol

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

52. Butyrylcholinesterase (1) Sites of location –Plasma, liver, glial cells, other tissues Substrates –Butyrylcholine is the best –Acetylcholine –Succinylcholine –Procaine

53. Butyrylcholinesterase (2) Esters that are not substrates –Methacholine, bethanechol, and carbachol Is inhibited by carbamyl and organophosphate inhibitors of acetylcholinesterase

54. Active Site of Acetylcholinesterase

55. Interaction of AChE and Acetylcholine

56. Acetylation of AChE and Release of Choline

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

58. Carbamyl Inhibitors of AChE

59. Their action promoting accumulation of ACh at muscarinic or nicotinic receptors is the basis of their pharmacological, therapeutic, and toxic actions Are derivatives of carbamic acid Bind covalently to the esteratic site of AChE, resulting in carbamylation of the enzyme Carbamyl Inhibitors of AChE (1) Carbamic acidCarbamic acid ester

60. Quaternary compounds bind to the ionic binding site of AChE Their induce accumulation of AChE at nicotinic and muscarinic sites, producing pharmacological responses qualitative to cholinergic stimulation Inhibition of AChE is reversible, in the order of hours Are metabolized in the plasma by plasma esterases Carbamyl Inhibitors of AChE (2)

61. High doses produce skeletal muscle weakness due to depolarizing blockade at the end plate of the neuromuscular junction High doses produce a profound fall in cardiac output and blood pressure Their inhibition of AChE is not reversed by pralidoxime Carbamyl Inhibitors of AChE (3)

62. Quaternary ammonium compounds do not cross the blood-brain barrier For oral administration, high doses must be given Carbamyl Inhibitors of AChE (4)

63. Neostigmine Carbamylates Acetylcholinesterase

64. Slow Hydrolysis of Carbamylated-AChE and Enzyme Liberation

65. Organophosphate Inhibitors of Acetylcholinesterase (indirect action, irreversible)

66. Chemical characteristics Promote accumulation of ACh at –N M nicotinic receptor –N N nicotinic receptor –Muscarinic receptor Organophosphate Inhibitors of Acetylcholinesterase (1)

67. Their action promoting accumulation of ACh at the muscarinic receptor of the ciliary muscle is the basis of their therapeutic effectiveness in open angle glaucoma Only two of these agents are used for therapeutics –Echothiophate for glaucoma –Diisopropylflurophosphate (DFP) for glaucoma (?) Organophosphate Inhibitors of AChE (2)

68. Inhibition of AChE by these agents is irreversible –New enzyme synthesis is required for recovery of enzyme function They also inhibit pseudocholinesterase Metabolized by A-esterases (paroxonases) present in plasma and microsomes. They are metabolized by CYP450. Organophosphate Inhibitors of AChE (3)

69. Enzyme inhibition by these agents can be reversed by cholinesterase reactivators such as pralidoxime if administered before “aging” of AChE has occurred. Inhibition by agents that undergo rapid “aging” is not reversed. Except for echothiophate, these agents are extremely lipid soluble, and some are very volatile. Organophosphate Inhibitors of AChE (4)

70. Diisopropylflurophosphate (DFP) is a Substrate for AChE

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

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

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

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

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

76. AGING OF ACETYLCHOLINESTERASE

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

78. “Aging” of Phosphorylated- AChE

79. Cholinesterase Reactivation

80. Reactivation of Phosphorylated Acetylcholinesterase Oximes are used to reactivate phosphorylated AChE The group (=NOH) has a high affinity for the phosphorus atom Pralidoxime has a nucleophilic site that interacts with the phosphorylated site on phosphorylated-AChE

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

82. Oxime Phosphonate and Regenerated AChE

83. Limitations of Pralidoxime Pralidoxime does not interact with carbamylated-AChE Pralidoxime in high doses can inhibit AChE Its quaternary ammonium group does not allow it to cross the blood brain barrier “Aging” of phosphorylated-AChE reduces the effectiveness of pralidoxime and other oxime reactivators

84. Other Cholinesterase Reactivators Diacetylmonoxime –Crosses the blood brain barrier and in experimental animals, regenerates some of the CNS cholinesterase HI-6 is used in Europe –Has two oxime centers in its structure –More potent than pralidoxime

85. Edrophonium

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

87. Pharmacology of Acetylcholinesterase Inhibition

88. Inhibition of Acetylcholinesterase Produces Stimulation of All Cholinergic Sites

89. Carbamyl Inhibitors of AChE (indirect, reversible action) Physostigmine Neostigmine (N + ) Pyridostigmine (N + ) Ambenonium (N + ) Demecarium (N + ) Carbaryl

90. Pharmacology of Carbamyl Inhibitors of Acetylcholinesterase Eye Exocrine glands Cardiac muscle Smooth muscles Skeletal muscle Toxicity

91. Therapeutic Uses of Inhibitors of Acetylcholinesterase Glaucoma (wide angle) Atony of the bladder Atony of the gastrointestinal tract Intoxication by antimuscarinic agents (use physostigmine) Intoxication by tricyclic antidepressants (TCA’s) or phenothiazines (use physostigmine) Recovery of neuromuscular function after competitive blockade of N N receptor of skeletal muscle fibers Myasthenia gravis

92. Therapeutic Uses of Edrophonium Diagnosis of myasthenia gravis In conjunction with chosen therapeutic agent to determine proper dose of agent

93. Determining Proper Dose of AChE Inhibitor

94. Inhibitors of AChE Are Used for Therapy of Alzheimer’s Disease Tacrine Donepezil Rivastigmine Galantamine

95. Organophosphate Inhibitors of AChE

96. Some Organophosphate Inhibitors of Acetylcholinesterase Tetraethylpyrophosphate Echothiophate (N + ) Diisopropylflurophosphate (DFP) Sarin Soman Tabun Malathion Parathion Diazinon Chlorpyrifos Many others

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

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

99. Conversion of Parathion to Paraoxon

100. Conversion of Malathion to Malaoxon

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

102. Carboxyl Esterases Preferentially hydrolyzes aliphatic esters Malathion is a substrate Are inhibited by organophosphates May also be called aliesterases

103. Uses of Malathion Insecticide Therapeutics –Used as a lotion for Pediculus humanus capitis associated with pediculosis –0.5% solution in 78% isopropranolol is pediculicidal and ovicidal –Ovide is the brand name –Primoderm was the former brand name

104. Malathion Metabolism Rapidly metabolized by birds and mammals Plasma carboxylases are involved Insects do not possess the enzyme Organophosphates inhibit malathion metabolism Malathion is toxic to fish

105. Aryl Esterases Are found in the plasma and liver Hydrolyzes organophosphates at the – P-F bond – P-CN bond – Phosphoester bond – Anhydride bond

106. EPA And Organophosphates Diazinon –No longer allowed to be manufactured for indoor use in as of March 1, 2001 or for garden use as of June 3, 2001 –Found in Real Kill ®, Ortho ®, Spectracide ® –Limited agricultural use is allowed Chlorpyrifos (Dursban) has been phased out Parathion has been phased out for agricultural use in the United States

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

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

109. Organophosphates as Nerve Gas Agents in Chemical Warfare (1) Extremely volatile agents such as sarin, tabun, soman, and agent VX may be used as nerve agents in chemical warfare. Accumulation of ACh at cholinergic receptors produces effects reflecting stimulation of cardiac muscle, smooth muscles and glands. Such effects would be identical to those caused by muscarine poisoning. Bradycardia and hypotension occur. However, in some cases, tachycardia may be observed, due to intense sympathetic discharge in response severe hypoxemia.

110. Organophosphates as Nerve Gas Agents in Chemical Warfare (2) Irreversible inhibition of acetylcholinesterase by these agents produces accumulation of ACh at the end plate of skeletal muscle fibers. This in turn leads to depolarizing blockade of the N M nicotinic receptor. Skeletal muscle paralysis occurs. Movement is impossible. The diaphragm is also paralyzed. The individual eventually dies due to respiratory paralysis. Pralidoxime, atropine, and removal of the person from the source of exposure are all to be employed in cases of posioning.

111. Use of Pyridostigmine During the Gulf War

112. Pharmacology of Muscarinic Receptor Blockade

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

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

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. X X

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

117. Atropine

118. Characteristics of Atropine Source –Atropa belladonna –Datura stramonium Known as Jamestown weed or jimsonweed Chemical nature –An alkaloid Alternate name is d,l-hyoscyamine Nature of blockade –Competitive

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

120. Actions of Atropine at Tissue Sites Eye –Sphincter muscle of the iris: mydriasis –Ciliary muscle: cycloplegia Atropine limits focusing to distant objects Accomodation is blocked by atropine

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

122. Actions of Atropine At Smooth Muscles And Glands Eye Lacrimal glands Mucus glands of the pharynx and nasal cavity Bronchial smooth muscle Gastric glands Intestinal glands Pancreas Mucus glands of the respiratory tract Lacrimal glands Eccrine sweat glands

123. Cardiovascular Actions of Atropine Heart rate –Low dose –High dose Systemic blood vessels Peripheral resistance Cutaneous blood vessels

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

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 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 x 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). 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. x x x i.v. infusion

129. Effect Of Atropine in Relation to Dosage...

130. Dose of Atropine DOSEEFFECT 0.5 mgSlight decline in heart rate Some dryness of mouth Inhibition of sweating

131. Dose of Atropine DOSEEFFECT 1.0 mgDefinited dryness of mouth Thirst Inreased heart rate, sometimes preceded by slowing Mild dilatation of pupil

132. Dose of Atropine DOSEEFFECT 2.0 mgRapid heart rate Palpitation Marked dryness of mouth Dilated pupils Some blurring of near vision

133. Dose of Atropine DOSEEFFECT 5.0 mgAll the previous symptoms are marked Difficulty in speaking and swallowing Restlessness and fatigue Headache Dry hot skin Difficulty in micturition Reduced intestinal peristalsis

134. Dose of Atropine DOSEEFFECT 10 mgPrevious symtoms are more marked and morePulse, rapid and weak Iris practically obliterated Vision very blurred Skin flushed, hot, dry, and scarlet Ataxia Restlessness and excitement Hallucinations and delirium Coma

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

136. Scopolamine (1) Source - Hyoscyamus niger (henbane) Chemical nature of the molecule Nature of blockade Changes in the dose response curve of muscarinic agonists in the presence of scopolamine Lower doses of scopolamine (0.1 - 0.2 mg) produce greater cardiac slowing than an equivalent dose of atropine. Higher doses produce tachycardia Low doses of scopolamine produce CNS effects that are not seen with equivalent doses of atropine

137. Scopolamine (2) Therapeutic doses of scopolamine normally produce CNS depression, manifested as drowsiness, amnesia, fatigue, dreamless sleep, reduction in REM, euphoria In the presence of pain, the same therapeutic dose occasionally cause excitement, restlessness, hallucinations, or delirium. Such excitement is always seen with large doses, as is also seen with large doses of atropine Therapeutic use - prophylaxis of motion sickness; an adhesive preparation, the Transderm scop is used

138. Therapeutic Uses of Antimuscarinic Agents

139. Therapeutic Uses of Muscarinic Antagonists (1) Cardiovascular System - atropine is generally used for the following cases –Improper use of choline esters –Sinus or nodal bradycardia in cases of excessive vagal tone associated with myocardial infarct –Hyperactive carotid sinus (syncope and severe bradycardia) –Second degree heart block

140. Therapeutic Uses of Muscarinic Antagonists (2) Gastrointestinal Tract –Peptic ulcers In Europe, Japan, and Canada, M 1 muscarinic receptor antagonists such as pirenzepine and telenzepine are used In the U.S. H 2 histamine antagonists such as cimetidine are used –Spasticity of the g.i. tract M 3 muscarinic antagonists are being investigated –Excessive salivation associated with heavy metal poisoning and parkinsonism –Production of partial blockade of salivation in patients unable to swallow

141. Therapeutic Uses of Muscarinic Antagonists (3) Urinary Bladder –Reverse spasm of the ureteral smooth muscle (renal colic) –Increase bladder capacity in cases of enuresis –Reduce urinary frequency in cases of hypertonic bladder

142. Therapeutic Uses of Muscarinic Antagonists (4) Central Nervous System –Parkinson’s disease –Motion sickness –Produce tranquilization and amnesia prior to surgery and in certain cases such as labor (not a prominent use anymore) –Anesthesia, to inhibit salivation (not a prominent use anymore) –Prevent vagal reflexes induced by surgical manipulation of organs

143. Therapeutic Uses of Muscarinic Antagonists (5) Posioning by inhibitors of acetylcholinesterase Mushroom poisoning due to muscarine In conjunction with inhibitors of acetylcholinesterase when they are used to promote recovery from neuromuscular blockade after surgery Injudicious use of choline esters Prevent vagal reflexes induced by surgical manipulation of visceral organs Atropine is used for the above

144. Toxicity of Atropine

145. Contraindications to the Use Of Antimuscarinic Agents Narrow Angle Glaucoma

146. Flow of Aqueous and Its Escape From the Eye

147. Contraindications to the Use of Antimuscarinic Agents Narrow angle glaucoma Hypertrophy of the prostate gland Atony of the bladder Atony of the G.I. Tract

148. Tertiary Muscarinic Antagonists and Their Uses Ophthalmic applications –Cyclopentolate –Tropicamide –Homatropine Parkinson’s disease –Benztropine –Trihexphenidyl

149. Tertiary Muscarinic Antagonists and Their Uses Used for antispasmodic purposes –Flavoxate - urinary bladder –Oxybutynin - urinary bladder –Tolterodine - urinary bladder –Dicyclomine –Oxyphencyclimine In general, they are useful for spasms of the g.t. tract, bile duct, ureters,

150. Tolterodine Therapeutic use - reduce urinary urgency Metabolism –Cytochrome P450 –Active metabolite is DD-01 Drug interactions –Ketoconazole –Erythromycin

151. Quaternary Ammonium Antagonists (1) General characteristics Pharmacology and therapeutic uses Distinct side effects with high and sometimes therapeutic doses

152. Quaternary Ammonium Antagonists (2) Methantheline (N + ) Propantheline (N + ) Methscopolamine (N + ) Homatropine methylbromide (N + ) Oxyphenonium (N + )

153. Quaternary Ammonium Antagonists (3) Anisotropine (N + ) Glycopyrrolate (N + ) Isopropamide (N + ) Mepenzolate (N + ) Ipratropium (N + )

154. Ipratropium Uses Distinctiveness from atropine

155. M 1 Muscarinic Receptor Antagonists Pirenzepine – Blocks the M 1 and the M 4 receptor – Its usefulness for peptic ulcer Telenzepine –Blocks the M 1 receptor –Its usefulness for peptic ulcer

156. M 2 Muscarinic Receptor Antagonists Tripitamine – Blocks the M 2 receptor – Blocks the action of acetylcholine at cardiac muscle fibers Gallamine –Blocks M 2 muscarinic and the N N nicotinic sites

157. M 3 Muscarinic Receptor Antagonist Darifenacin – Blocks the M 3 receptor – Blocks the actions of acetylcholine at smooth muscles and glands

158. Drugs of Other Classes With Antimuscarinic Activity (1) Tricyclic antidepressants –Imipramine –Amitriptyline –Protriptyline –Others.: DEMONSTRATION.: DEMONSTRATION

159. Drugs of Other Classes With Antimuscarinic Activity (2) Phenothiazine Antipsychotic Agents –Chlorpromazine –Thioridazine –Perphenazine –Others.: DEMONSTRATION.: DEMONSTRATION

160. Drugs of Other Classes With Antimuscarinic Activity (3) Dibenzodiazepine antipsychotic agents –Clozapine –Olanzepine Dibenzoxazepine antipsychotic agents –Loxapine.: DEMONSTRATION.: DEMONSTRATION

161. Drugs of Other Classes With Antimuscarinic Activity (4) H 1 Histamine receptor blocking agents –Diphenhydramine –Dimenhydrinate –Promethazine –Carbinoxamine –Dimenhydrinate –Pyrlamine –Tripelennamine –Brompheniramine –Chlorpheniramine –Cyproheptadine.: DEMONSTRATION.: DEMONSTRATION