Cholinergic agonists


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Cholinergic agonists

  1. 1. Cholinergic Agents
  2. 2. Cholinergic Agents Alkaloids Nicotine Lobeline Arecoline Muscarine Pilocarpine Synthetic Agents Dimethylphenylpiperazinium-(DMPP) Oxotremorine Methacholine Bethanechol Carbachol Cevimeline
  3. 3. Nicotine <ul><li>Nicotine mimics the actions of acetylcholine at nicotinic sites </li></ul><ul><ul><li>Cell body of the postsynaptic neurons </li></ul></ul><ul><ul><ul><li>sympathetic and parasympathetic divisions </li></ul></ul></ul><ul><ul><li>Chromaffin cells of the adrenal medulla </li></ul></ul><ul><ul><li>End plate of skeletal muscle fiber </li></ul></ul><ul><li>Affinity for N N sites versus N M sites </li></ul><ul><li>Used as an insecticide </li></ul>
  4. 4. Muscarine <ul><li>Muscarine mimics the actions of acetylcholine at smooth muscles, cardiac muscles, and glands </li></ul><ul><li>Poisoning by muscarine produces intense effects qualitative to those produced by cholinergic stimulation of smooth muscles, cardiac muscle, and glands </li></ul><ul><li>Muscarine is found in various mushrooms </li></ul><ul><ul><li>Amanita muscaria : content of muscarine is very low </li></ul></ul><ul><ul><li>Inocybe sp : content of muscarine is high </li></ul></ul><ul><ul><li>Clitocybe sp : content of muscarine is high </li></ul></ul>
  5. 5. Pilocarpine <ul><li>Has muscarinic actions </li></ul><ul><li>Used for xerostomia </li></ul><ul><li>Used for glaucoma </li></ul>
  6. 6. Structure of Acetylcholine and its Derivatives Acetylcholine Methacholine Bethanechol Carbachol
  7. 7. Therapeutic Uses of Cholinergic Agonists <ul><li>Dentistry </li></ul><ul><ul><li>Pilocarpine </li></ul></ul><ul><ul><li>Cevimeline </li></ul></ul><ul><li>Ophthalmology </li></ul><ul><ul><li>Pilocarpine </li></ul></ul><ul><ul><li>Carbachol </li></ul></ul><ul><li>Gastrointestinal tract </li></ul><ul><ul><li>Bethanechol </li></ul></ul><ul><li>Urinary bladder </li></ul><ul><ul><li>Bethanechol </li></ul></ul>
  8. 8. Contraindications to the Use of Choline Esters <ul><li>Hyperthyroidism </li></ul><ul><li>Asthma </li></ul><ul><li>Coronary insufficiency </li></ul><ul><li>Peptic ulcer </li></ul><ul><li>Organic obstruction in bladder or gastrointestinal tract </li></ul>
  9. 9. Toxicity of Choline Esters <ul><li>Flushing </li></ul><ul><li>SWEATING (diaphoresis) </li></ul><ul><li>Abdominal cramps </li></ul><ul><li>Spasm of the urinary bladder </li></ul><ul><li>Spasm of accomodation </li></ul><ul><li>Miosis </li></ul><ul><li>Headache </li></ul><ul><li>Salivation </li></ul><ul><li>Bronchospasm </li></ul><ul><li>Lacrimation </li></ul><ul><li>Hypotension </li></ul><ul><li>Bradycardia </li></ul>
  10. 10. Agents That Inhibit Acetylcholinesterase
  11. 11. Acetylcholinesterase (True Cholinesterase)
  12. 12. Acetylcholinesterase (1) <ul><li>Sites of location </li></ul><ul><ul><li>Cholinergic neurons </li></ul></ul><ul><ul><li>Cholinergic synapses </li></ul></ul><ul><ul><li>Neuromuscular junction </li></ul></ul><ul><ul><li>Red blood cells </li></ul></ul><ul><li>Substrates </li></ul><ul><ul><li>Acetylcholine is the best substrate </li></ul></ul><ul><ul><li>Methacholine is a substrate </li></ul></ul><ul><ul><li>Hydrolyzes ACh at greater velocity than choline esters with acyl groups larger than acetate or proprionate </li></ul></ul>
  13. 13. Acetylcholinesterase (2) <ul><li>Esters that are not substrates </li></ul><ul><ul><li>Bethanechol </li></ul></ul><ul><ul><li>Carbachol </li></ul></ul><ul><ul><li>Succinylcholine </li></ul></ul><ul><li>Its inhibition produces synergistic interaction with methacholine and additive actions with bethanechol and carbachol </li></ul><ul><li>Drugs that block its hydrolysis of esters are called cholinesterase inhibitors </li></ul>
  14. 14. Drug Interactions of Choline Esters and Inhibitors of Acetylcholinesterase - Synergism versus Additivity <ul><li>Methacholine </li></ul><ul><li>Carbachol </li></ul><ul><li>Bethanechol </li></ul>
  15. 15. Butyrylcholinesterase (Plasma esterase, pseudocholinesterase, serum esterase, BuChE, PseudoChE)
  16. 16. Butyrylcholinesterase (1) <ul><li>Sites of location </li></ul><ul><ul><li>Plasma, liver, glial cells, other tissues </li></ul></ul><ul><li>Substrates </li></ul><ul><ul><li>Butyrylcholine is the best </li></ul></ul><ul><ul><li>Acetylcholine </li></ul></ul><ul><ul><li>Succinylcholine </li></ul></ul><ul><ul><li>Procaine </li></ul></ul>
  17. 17. Butyrylcholinesterase (2) <ul><li>Esters that are not substrates </li></ul><ul><ul><li>Methacholine, bethanechol, and carbachol </li></ul></ul><ul><li>Is inhibited by carbamyl and organophosphate inhibitors of acetylcholinesterase </li></ul>
  18. 18. Active Site of Acetylcholinesterase
  19. 19. Interaction of AChE and Acetylcholine
  20. 21. Acetylation of AChE and Release of Choline
  21. 22. Hydroxyl Group of Water Attacks the Carbonyl Group of Acetylated-AChE to Liberate AChE
  22. 23. Carbamyl Inhibitors of AChE
  23. 24. <ul><li>Their action promoting accumulation of ACh at muscarinic or nicotinic receptors is the basis of their pharmacological, therapeutic, and toxic actions </li></ul><ul><li>Are derivatives of carbamic acid </li></ul><ul><li>Bind covalently to the esteratic site of AChE, resulting in carbamylation of the enzyme </li></ul>Carbamyl Inhibitors of AChE (1) Carbamic acid Carbamic acid ester
  24. 25. <ul><li>Quaternary compounds bind to the ionic binding site of AChE </li></ul><ul><li>Their induce accumulation of AChE at nicotinic and muscarinic sites, producing pharmacological responses qualitative to cholinergic stimulation </li></ul><ul><li>Inhibition of AChE is reversible, in the order of hours </li></ul><ul><li>Are metabolized in the plasma by plasma esterases </li></ul>Carbamyl Inhibitors of AChE (2)
  25. 26. <ul><li>High doses produce skeletal muscle weakness due to depolarizing blockade at the end plate of the neuromuscular junction </li></ul><ul><li>High doses produce a profound fall in cardiac output and blood pressure </li></ul><ul><li>Their inhibition of AChE is not reversed by pralidoxime </li></ul>Carbamyl Inhibitors of AChE (3)
  26. 27. <ul><li>Quaternary ammonium compounds do not cross the blood-brain barrier </li></ul><ul><li>For oral administration, high doses must be given </li></ul>Carbamyl Inhibitors of AChE (4)
  27. 28. Neostigmine Carbamylates Acetylcholinesterase
  28. 29. Slow Hydrolysis of Carbamylated-AChE and Enzyme Liberation
  29. 30. Organophosphate Inhibitors of Acetylcholinesterase
  30. 31. <ul><li>Chemical characteristics </li></ul><ul><li>Promote accumulation of ACh at </li></ul><ul><ul><li>N M nicotinic receptor </li></ul></ul><ul><ul><li>N N nicotinic receptor </li></ul></ul><ul><ul><li>Muscarinic receptor </li></ul></ul>Organophosphate Inhibitors of Acetylcholinesterase (1)
  31. 32. <ul><li>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 </li></ul><ul><li>Only two of these agents are used for therapeutics </li></ul><ul><ul><li>Echothiophate for glaucoma </li></ul></ul><ul><ul><li>Diisopropylflurophosphate (DFP) for glaucoma (?) </li></ul></ul>Organophosphate Inhibitors of AChE (2)
  32. 33. <ul><li>Inhibition of AChE by these agents is irreversible </li></ul><ul><ul><li>New enzyme synthesis is required for recovery of enzyme function </li></ul></ul><ul><li>They also inhibit pseudocholinesterase </li></ul><ul><li>Metabolized by A-esterases (paroxonases) present in plasma and microsomes. They are metabolized by CYP450. </li></ul>Organophosphate Inhibitors of AChE (3)
  33. 34. <ul><li>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. </li></ul><ul><li>Except for echothiophate, these agents are extremely lipid soluble, and some are very volatile. </li></ul>Organophosphate Inhibitors of AChE (4)
  34. 35. Diisopropylflurophosphate (DFP) is a Substrate for AChE
  35. 36. The Extremely Slow Hydrolysis of Phosphorylated-AChE New enzyme synthesis is required for recovery of enzyme function
  36. 37. Various “States” of Acetylcholinesterase Clockwise: free AChE, acetylated AChE, carbamylated AChE, phosphorylated AChE
  37. 38. 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
  38. 39. 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
  39. 40. 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
  41. 42. Loss of An Alkyl Group From Phosphorylated AChE “Ages” the Enzyme AChE, phosphorylated and inhibited by DFP “ Aged” AChE
  42. 43. “ Aging” of Phosphorylated- AChE
  43. 44. Cholinesterase Reactivation
  44. 45. Reactivation of Phosphorylated Acetylcholinesterase <ul><li>Oximes are used to reactivate phosphorylated AChE </li></ul><ul><li>The group (=NOH) has a high affinity for the phosphorus atom </li></ul><ul><li>Pralidoxime has a nucleophilic site that interacts with the phosphorylated site on phosphorylated-AChE </li></ul>
  45. 46. Pralidoxime Reacts Chemically with Phosphorylated-AChE The oxime group makes a nucleophilic attack upon the phosphorus atom
  46. 47. Oxime Phosphonate and Regenerated AChE
  47. 48. Limitations of Pralidoxime <ul><li>Pralidoxime does not interact with carbamylated-AChE </li></ul><ul><li>Pralidoxime in high doses can inhibit AChE </li></ul><ul><li>Its quaternary ammonium group does not allow it to cross the blood brain barrier </li></ul><ul><li>“ Aging” of phosphorylated-AChE reduces the effectiveness of pralidoxime and other oxime reactivators </li></ul>
  48. 49. Other Cholinesterase Reactivators <ul><li>Diacetylmonoxime </li></ul><ul><ul><li>Crosses the blood brain barrier and in experimental animals, regenerates some of the CNS cholinesterase </li></ul></ul><ul><li>HI-6 is used in Europe </li></ul><ul><ul><li>Has two oxime centers in its structure </li></ul></ul><ul><ul><li>More potent than pralidoxime </li></ul></ul>
  49. 50. Edrophonium
  50. 51. Edrophonium is a Short Acting Inhibitor that Binds to the Ionic Site but Not to the Esteratic Site of AChE
  51. 52. Pharmacology of Acetylcholinesterase Inhibition
  52. 53. Inhibition of Acetylcholinesterase Produces Stimulation of All Cholinergic Sites
  53. 54. Carbamyl Inhibitors of AChE <ul><li>Physostigmine </li></ul><ul><li>Neostigmine (N + ) </li></ul><ul><li>Pyridostigmine (N + ) </li></ul><ul><li>Ambenonium (N + ) </li></ul><ul><li>Demecarium (N + ) </li></ul><ul><li>Carbaryl </li></ul>
  54. 55. Pharmacology of Carbamyl Inhibitors of Acetylcholinesterase <ul><li>Eye </li></ul><ul><li>Exocrine glands </li></ul><ul><li>Cardiac muscle </li></ul><ul><li>Smooth muscles </li></ul><ul><li>Skeletal muscle </li></ul><ul><li>Toxicity </li></ul>
  55. 56. Therapeutic Uses of Inhibitors of Acetylcholinesterase <ul><li>Glaucoma (wide angle) </li></ul><ul><li>Atony of the bladder </li></ul><ul><li>Atony of the gastrointestinal tract </li></ul><ul><li>Intoxication by antimuscarinic agents (use physostigmine) </li></ul><ul><li>Intoxication by tricyclic antidepressants (TCA’s) or phenothiazines (use physostigmine) </li></ul><ul><li>Recovery of neuromuscular function after competitive blockade of N N receptor of skeletal muscle fibers </li></ul><ul><li>Myasthenia gravis </li></ul>
  56. 57. Therapeutic Uses of Edrophonium <ul><li>Diagnosis of myasthenia gravis </li></ul><ul><li>In conjunction with chosen therapeutic agent to determine proper dose of agent </li></ul>
  57. 58. Determining Proper Dose of AChE Inhibitor
  58. 59. Inhibitors of AChE Are Used for Therapy of Alzheimer’s Disease <ul><li>Tacrine </li></ul><ul><li>Donepezil </li></ul><ul><li>Rivastigmine </li></ul><ul><li>Galantamine </li></ul>
  59. 60. Organophosphate Inhibitors of AChE
  60. 61. Some Organophosphate Inhibitors of Acetylcholinesterase <ul><li>Tetraethylpyrophosphate </li></ul><ul><li>Echothiophate (N + ) </li></ul><ul><li>Diisopropylflurophosphate (DFP) </li></ul><ul><li>Sarin </li></ul><ul><li>Soman </li></ul><ul><li>Tabun </li></ul><ul><li>Malathion </li></ul><ul><li>Parathion </li></ul><ul><li>Diazinon </li></ul><ul><li>Chlorpyrifos </li></ul><ul><li>Many others </li></ul>
  61. 62. Organophosphate Inhibitors - 2 Diisopropylfluorophosphate (DFP) Soman Sarin Tabun
  62. 63. Echothiophate Therapeutic use - local application to the eye for wide angle glaucoma
  63. 64. Conversion of Parathion to Paraoxon
  64. 65. Conversion of Malathion to Malaoxon
  65. 66. Malathion Is Hydrolyzed by Plasma Carboxylases in Birds and Mammals but Not Insects
  66. 67. Carboxyl Esterases <ul><li>Preferentially hydrolyzes aliphatic esters </li></ul><ul><li>Malathion is a substrate </li></ul><ul><li>Are inhibited by organophosphates </li></ul><ul><li>May also be called aliesterases </li></ul>
  67. 68. Uses of Malathion <ul><li>Insecticide </li></ul><ul><li>Therapeutics </li></ul><ul><ul><li>Used as a lotion for Pediculus humanus capitis associated with pediculosis </li></ul></ul><ul><ul><li>0.5% solution in 78% isopropranolol is pediculicidal and ovicidal </li></ul></ul><ul><ul><li>Ovide is the brand name </li></ul></ul><ul><ul><li>Primoderm was the former brand name </li></ul></ul>
  68. 69. Malathion Metabolism <ul><li>Rapidly metabolized by birds and mammals </li></ul><ul><li>Plasma carboxylases are involved </li></ul><ul><li>Insects do not possess the enzyme </li></ul><ul><li>Organophosphates inhibit malathion metabolism </li></ul><ul><li>Malathion is toxic to fish </li></ul>
  69. 70. Aryl Esterases <ul><li>Are found in the plasma and liver </li></ul><ul><li>Hydrolyzes organophosphates at the </li></ul><ul><ul><li>P-F bond </li></ul></ul><ul><ul><li>P-CN bond </li></ul></ul><ul><ul><li>Phosphoester bond </li></ul></ul><ul><ul><li>Anhydride bond </li></ul></ul>
  70. 71. EPA And Organophosphates <ul><li>Diazinon </li></ul><ul><ul><li>No longer allowed to be manufactured for indoor use in as of March 1, 2001 or for garden use as of June 3, 2001 </li></ul></ul><ul><ul><li>Found in Real Kill ® , Ortho ® , Spectracide ® </li></ul></ul><ul><ul><li>Limited agricultural use is allowed </li></ul></ul><ul><li>Chlorpyrifos (Dursban) has been phased out </li></ul><ul><li>Parathion has been phased out for agricultural use in the United States </li></ul>
  73. 74. Organophosphates as Nerve Gas Agents in Chemical Warfare (1) <ul><li>Extremely volatile agents such as sarin, tabun, soman, and agent VX may be used as nerve agents in chemical warfare. </li></ul><ul><li>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. </li></ul><ul><li>Bradycardia and hypotension occur. However, in some cases, tachycardia may be observed, due to intense sympathetic discharge in response severe hypoxemia. </li></ul>
  74. 75. Organophosphates as Nerve Gas Agents in Chemical Warfare (2) <ul><li>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. </li></ul><ul><li>Pralidoxime, atropine, and removal of the person from the source of exposure are all to be employed in cases of posioning. </li></ul>
  75. 76. Use of Pyridostigmine During the Gulf War