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Cholinergic Agents. AlkaloidsNicotineLobelineArecolineMuscarinePilocarpine. Synthetic AgentsDimethylphenylpiperazinium-(DMPP)OxotremorineMethacholineBethanecholCarbacholCevimeline. Nicotine . Nicotine mimics the actions of acetylcholine at nicotinic sitesCell body of the postsynaptic neuronssympathetic and parasympathetic divisionsChromaffin cells of the adrenal medullaEnd plate of skeletal muscle fiberAffinity for NN sites versus NM sitesUsed as an insecticide.
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1. Cholinergic Agents
3. Nicotine Nicotine mimics the actions of acetylcholine at nicotinic sites
Cell body of the postsynaptic neurons
sympathetic and parasympathetic divisions
Chromaffin cells of the adrenal medulla
End plate of skeletal muscle fiber
Affinity for NN sites versus NM sites
Used as an insecticide
4. 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
5. Pilocarpine Has muscarinic actions
Used for xerostomia
Used for glaucoma
6. Structure of Acetylcholine and its Derivatives
7. Therapeutic Uses of Cholinergic Agonists Dentistry
Pilocarpine
Cevimeline
Ophthalmology
Pilocarpine
Carbachol
Gastrointestinal tract
Bethanechol
Urinary bladder
Bethanechol
8. Contraindications to the Use of Choline Esters Hyperthyroidism
Asthma
Coronary insufficiency
Peptic ulcer
Organic obstruction in bladder or gastrointestinal tract
9. Toxicity of Choline Esters Flushing
SWEATING (diaphoresis)
Abdominal cramps
Spasm of the urinary bladder
Spasm of accomodation
Miosis
Headache
Salivation
Bronchospasm
Lacrimation
Hypotension
Bradycardia
10. Agents That Inhibit Acetylcholinesterase
11. Acetylcholinesterase
12. 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
13. 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
14. Drug Interactions of Choline Esters and Inhibitors of Acetylcholinesterase - Synergism versus Additivity Methacholine
Carbachol
Bethanechol
15. Butyrylcholinesterase
16. Butyrylcholinesterase (1) Sites of location
Plasma, liver, glial cells, other tissues
Substrates
Butyrylcholine is the best
Acetylcholine
Succinylcholine
Procaine
17. Butyrylcholinesterase (2) Esters that are not substrates
Methacholine, bethanechol, and carbachol
Is inhibited by carbamyl and organophosphate inhibitors of acetylcholinesterase
18. Active Site of Acetylcholinesterase
19. Interaction of AChE and Acetylcholine
21. Acetylation of AChE and Release of Choline
22. Hydroxyl Group of Water Attacks the Carbonyl Group of Acetylated-AChE to Liberate AChE
23. Carbamyl Inhibitors of AChE
24. 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)
25. 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)
26. 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)
27. Quaternary ammonium compounds do not cross the blood-brain barrier
For oral administration, high doses must be given Carbamyl Inhibitors of AChE (4)
28. Neostigmine Carbamylates Acetylcholinesterase
29. Slow Hydrolysis of Carbamylated-AChE and Enzyme Liberation
30. Organophosphate Inhibitors of Acetylcholinesterase
31. Chemical characteristics
Promote accumulation of ACh at
NM nicotinic receptor
NN nicotinic receptor
Muscarinic receptor Organophosphate Inhibitors of Acetylcholinesterase (1)
32. 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)
33. 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)
34. 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)
35. Diisopropylflurophosphate (DFP) is a Substrate for AChE
36. The Extremely Slow Hydrolysis of Phosphorylated-AChE
37. Various “States” of Acetylcholinesterase
38. Acetylated-AChE Is Very Rapdily Hydrolyzed
39. Carbamylated-AChE Is Hydrolyzed Slowly
40. Phosphorlylated-AChE Is Hydrolyzed Extremely Slowly
41. AGING OF ACETYLCHOLINESTERASE
42. Loss of An Alkyl Group From Phosphorylated AChE “Ages” the Enzyme
43. “Aging” of Phosphorylated- AChE
44. Cholinesterase Reactivation
45. 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
46. Pralidoxime Reacts Chemically with Phosphorylated-AChE
47. Oxime Phosphonate and Regenerated AChE
48. 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
49. 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
50. Edrophonium
51. Edrophonium is a Short Acting Inhibitor that Binds to the Ionic Site but Not to the Esteratic Site of AChE
52. Pharmacology of Acetylcholinesterase Inhibition
53. Inhibition of Acetylcholinesterase Produces Stimulation of All Cholinergic Sites
54. Carbamyl Inhibitors of AChE Physostigmine
Neostigmine (N+)
Pyridostigmine (N+)
Ambenonium (N+)
Demecarium (N+)
Carbaryl
55. Pharmacology of Carbamyl Inhibitors of Acetylcholinesterase Eye
Exocrine glands
Cardiac muscle
Smooth muscles
Skeletal muscle
Toxicity
56. 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 NN receptor of skeletal muscle fibers
Myasthenia gravis
57. Therapeutic Uses of Edrophonium Diagnosis of myasthenia gravis
In conjunction with chosen therapeutic agent to determine proper dose of agent
58. Determining Proper Dose of AChE Inhibitor
59. Inhibitors of AChE Are Used for Therapy of Alzheimer’s Disease Tacrine
Donepezil
Rivastigmine
Galantamine
60. Organophosphate Inhibitors of AChE
61. Some Organophosphate Inhibitors of Acetylcholinesterase Tetraethylpyrophosphate
Echothiophate (N+)
Diisopropylflurophosphate (DFP)
Sarin
Soman
Tabun
Malathion
Parathion
Diazinon
Chlorpyrifos
Many others
62. Organophosphate Inhibitors - 2
63. Echothiophate
64. Conversion of Parathion to Paraoxon
65. Conversion of Malathion to Malaoxon
66. Malathion Is Hydrolyzed by Plasma Carboxylases in Birds and Mammals but Not Insects
67. Carboxyl Esterases Preferentially hydrolyzes aliphatic esters
Malathion is a substrate
Are inhibited by organophosphates
May also be called aliesterases
68. 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
69. 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
70. Aryl Esterases Are found in the plasma and liver
Hydrolyzes organophosphates at the
P-F bond
P-CN bond
Phosphoester bond
Anhydride bond
71. 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
72. NERVE AGENT VX
73. NERVE AGENT VX
74. 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.
75. 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 NM 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.
76. Use of Pyridostigmine During the Gulf War