Your SlideShare is downloading. ×
0133
Upcoming SlideShare
Loading in...5
×

Thanks for flagging this SlideShare!

Oops! An error has occurred.

×

Saving this for later?

Get the SlideShare app to save on your phone or tablet. Read anywhere, anytime - even offline.

Text the download link to your phone

Standard text messaging rates apply

0133

2,366
views

Published on

Published in: Health & Medicine, Technology

2 Comments
2 Likes
Statistics
Notes
No Downloads
Views
Total Views
2,366
On Slideshare
0
From Embeds
0
Number of Embeds
0
Actions
Shares
0
Downloads
103
Comments
2
Likes
2
Embeds 0
No embeds

Report content
Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
No notes for slide

Transcript

  • 1. Pharmacology of Cholinergic Synapse Cholinergic synapses 1. Para symp. Post gang. Neuro.Effector junctions 2. All autonomic ganglia (pregang.symp and parasymp. Nerve endings), 3. Pregang.symp.N.endings to adrenal medulla 3. 4. Skeletal neuromuscular junctions 5. Sweat glands ( sympathetic-cholinergic) 6. CNS- brain & spinal cord
  • 2. Renshaw Cell Inhibition Ach  motor neuron Renshaw cell Glycine Collateral Skeletal Muscle Spinal cord Nic-Rc
  • 3. Cholinergic Synapse Acetyl CO-A + Choline Ach-receptors Ach-esterase Choline CH3-co+HO-CH-CH2-N(CH3)3 CH3-CO CH2.CH2.N.(CH) 3 Ach Acetate + Diet Acetyl transferase Ach O
  • 4. Cholinergic Synapse Acetyl CO-A + Choline Ach-receptors Ach-esterase Choline CH3-C= O+HO-CH 2 -CH2-N +( ( CH3)3 =( CH 3 ) 3 N + -CH 2 -CH 2 -O-C-CH 3 Ach Acetate + Diet Acetyl transferase Ach Ca ++ O Hemicholinium Botulinum Latrotoxin Vesamicol
  • 5. 2 AUTONOMIC GANGLION ACH NIC.RC ACH 3. SKELETAL NEUROMUSCULAR JUNCTION Ach ACh Nic-RC
  • 6. Classification of cholinergic Recep. Muscarinic Nicotinic Ach e.g. Muscarine Smooth muscles Cardiac Muscles Exocrine/Endo Glands/CNS ANS Gang. NMJ CNS M 1 , M 2 M 3
  • 7. Nature of Muscarinic Receptors 1. Glycoproteins (Mol.Wt. 80,000) 2. Mediated by G-proteins, PLC, IP 3 & DAG leading to increased cytosolic Ca ++ 3. 5 subtypes: M 1, M 2, & M 3 M 1 = Autonomic ganglia & secretory glds. M 2 = Heart M 3 = Smooth muscles
  • 8. Organ responses to Muscarinic Receptors
  • 9. Muscarinic Recptors Activation
  • 10. Muscarinic Receptors Activation
  • 11. Nature of Nicotinic Receptors 1. Ligand gated ion channels 2. Pentameric proteins=4 diff.polypeptides(  2  ) 3. Autonomic ganglia/ adrenal medulla 4. Motor endplate membrane, 5. CNS 5. Activation- increased permeability to Na + & K +
  • 12. Activation of Nicotinic Receptors
  • 13. Parasympathomimetics Classification of Cholinergic Drugs : Directly Acting Indirectly Acting Directly Acting I. Natural& Synthetic Choline esters II. Naturally Occuring alkaloids
  • 14. Natural & Synthetic Choline esters
    • Acetyl Choline
    • Methacholine(Acetyl-  -methyl choline)
    • Carbachol ( Carbamyl choline)
    • Bethanechol( Carbamyl methyl choline)
  • 15. N + --CH 2 --CH 2 --OH (CH 3 ) 3---- Choline N + --CH 2 --CH 2 -- (CH 3 ) 3---- (CH 3 ) 3---- O--CO- CH 3 N + --CH 2 --CH 2 -- O--CO- CH 3 (CH 3 ) 3---- CH 3 (CH 3 ) 3----c N + --CH 2 --CH 2 -- CH 3 O--CO--NH 2 (CH 3 ) 3---- N + --CH 2 --CH 2 -- O--CO- NH 2 Acetyl Choline Methacholine Carbachol Bethanechol
  • 16. Naturally occuring alkaloids
    • Muscarine
    • Pilocarpine
    • Arecoline
  • 17. Acetylcholine Not therapeutically useful , Why? Short duration of action Orally inactive Nonspecific in action
  • 18. Pharmacologic effects of Ach & its Esters
  • 19. Methacholine(Acetyl  -methyl choline) Has methyl group at the second carbon of the Ach molecule Resistant to acetylcholine esterases Longer duration Potent muscarinic agonist Not therapeutically useful
  • 20. Carbachol(Carbamylcholine)
    • Has NH 2 group on the terminal end of Ach
    • Slow inactivation by Ach esterases
    • Releases Ach from cholinergic N.endings
    • Has Nicotinic effects in addition to muscarinic effects
  • 21. Bethanechol(Carbamylmethylcholine)
    • Has both CH 3 & NH 2 groups as in Methacholine and Carbachol respectively
    • Inactivation by Ach estearses is very slow
    • Has mostly muscarinic effects
  • 22. Alkaloids
    • Nicotine:
    • Tobacco leaves- Nicotina Spp.
    • Nicotinic receptors-stimulant/depressant
    • Black leaf 40
  • 23. Muscarine
    • Amanita muscaria- a poisonous mushroom
    • Muscarinic agonist
    • Atropine- a specific antagonist
  • 24. Pilocarpine
    • Pilocarpus jaborandi-S. Amer. Shrub
    • Muscarinic agonist
    • Tertiary amine-lipid soluble
    • Miotic agent-opthalmologic use
  • 25. Veterinary Clinical Uses
    • Atony of the rumen- Carbachol ( Peristal)
    • Atony of the urinary bladder-Bethanechol (Urecholine)
    • Glaucoma- Pilocarpine- piloptic, Pilossat
    • Keratoconjunctivitis Sicca- Pilocarpine
  • 26. Iris Ciliary muscle Pupil Canal of Schlem Cornea Lens Pharmacology of Eye-Glaucoma
  • 27. Thoracolumbar Sacral Hypogastric Pelvic nerve PUDIC NERVE External spincter Trigone Detrusor body AUTONOMIC & SOMATIC INNERVATION OF URINARY BLADDER Acetylcholine NE
      • ACH
    SOMATIC ACH
      • ACH
  • 28. Classification of Acetylcholine Esterases Specific-True Nonspecific- Pseudo Acetyl ChE Butyryl ChE Neurons Synaptic clefts NMJ RBCs Glial cells Plasma Liver Other organs
  • 29. Indirectly Acting Cholinomimetics 1. Reversible Choline esterase inhibitors: Physostigmine Neostigmine Edrophonium Pyridostigmine
  • 30. Irreversible Choline Esterase Inhibitors OrganoPhosphates Insecticides Nerve gases Anthelmintics Pesticides Insecticides Herbicides
  • 31. Reversible AchE inhibitors
    • Acetyl choline
    • AchE - an extremely active enzyme
    • Binds with both the anionic and esteratic site
    • Hydrolysed - choline and acetic acid (150  sec)
  • 32. Hydrolysis of Acetylcholine N H 3 C H 3 C CH 3 CH 2 CH2 C--CH 3 O O Esterophilic Anionic + Acetylchoine esterase Choline Acetic acid Regenerated Enzyme 3x10 5 Ach mol./mol.of enzyme--150 usec. + Acetyl Co-A + H 2 O
  • 33. Carbamate Esters
    • Physostigmine
    • Neostigmine
    • Pyridostigmine
    • Bind reversibly with both the anionic and esteratic site
    • The covalent bond of carbomoylated enzyme more resistant ( 30 min. - 6hrs)
  • 34. H 3 C-N-C-O- H O N N CH 3 Physostigmine CH 3 CH 3
  • 35. Physostigmine
    • An alkaloid- Physostigma venosum
    • Tertiary amine
    • Can easily enter the CNS
  • 36. H 3 C H 3 C N--C-- O O N + (CH 3 ) 3 Neostigmine
  • 37. Mode of action of Neostigmine N N(CH 3 ) 2 CH 3 CH 3 CH 3 O C=O + N:O AchE Anionic Esteratic + H 2 O=HO-C-N(CH 3 ) 2 O N,NDMCA + Regenerated Enzyme T1/2= 3-4hrs
  • 38. Neostigmine
    • Synthetic quaternary ammonium compound
    • Directly stimulates Nic.Rc. Of Skeletal Muscles
    • Dual actions- beneficial in Myaesth. Gravis.
    • Used to treat atony of the rumen
    • Could be used to treat overdose of Curare-like compounds
  • 39. H 3 C H 3 C N--C-- O O N + (CH 3 ) 3 Pyridostigmine
  • 40. Pyridostigmine
    • Synthetic quaternary ammonium compound
    • Used for the treatment of M.G.
  • 41. O N + C 2 H 5 Edrophonium CH 3 CH 3 H
  • 42. Mode of Action of Edrophonium N CH 3 CH 3 CH 3c CH 3 OH + N + CH 3 CH 3 OH N N Regenerated Enzyme T 1/2 = 15-30 min.
  • 43. Edrophonium
    • Synthetic quaternary ammonium compound
    • Very short duration of action ?
    • Used for diagnosis of M.G.
  • 44. Veterinary Clinical Uses
    • Glaucoma: Physostigmine,
    • Diagnosis of Myasthenia related Megaoesophagus in a dog : Edrophonium(Tensilon) test
    • Megaoesophagus -Therapy : Pyridostigmine and Neostigmine
    • Poisoning of Curare like substances :
    • Atropine overdose: Physostigmine
  • 45. Chemical classification of Organophosphates R 1 R 2 P O X A. X= Halide, Cyanide, or thiocyanate DFP= Diisopropyl fluorophosphate Tabun has cyanidate Sarin has fluoridate Soman has fluoridate B. X= alkylthio, arylthio, alkoxy or aryloxy Paraoxon
  • 46. Group C: X = thiol or thionophosphorous compounds Parathion Fenthion Diazinon Malathion Group D : X= Pyrophosphates, TEPP Group E : X= Quaternary ammonium compounds Echothiophate
  • 47. Organophosphates
    • Insecticides:
    • Parathion, Malathion, etc.
    • Anthelmintics: Dichlorvos (2,2- dichlrovinyl, Dimethyl Phosphate )
    • Nerve Gases: Chemical Warfare-
    • Tabun, Sarin, Soman
    • Drugs : Echothiophosphate
  • 48. Anthelmintics-Organophosphates
    • Dichlorvos
    • Trichlorfon
    • Haloxon
    • Naphthalophos
    • Crufamate
  • 49. Pharmacological Properties
    • Irreversible inhibitors AchE
    • Accumulation of Ach
    • Phosphorilated AchE exteremely stable
    • Highly lipid soluble except echothiophate
    • Effectively absorbed from all routes
    • Endogenous Ach stimulates all cholinergic Receptors, peripheral, and CNS
  • 50. Mode of Action of Organophosphates F O P OC 3 H 7 H 7 C 3 O N:---H---O Anionic Esteratic P OC 3 H 7 O H 7 C 3 O F N:---H---O N:---H---O Phosphorilated enzyme
  • 51. Aging of Phosphorilated Enzyme
    • Covalent phosphorilated enzyme is extremely stable
    • Process of aging
    • Loss of one of the alkyl groups- strengthening the phosphorous enzyme bond
    • 2-PAM =Pyridine-2-aldoxime methyl iodide
  • 52. Veterinary clinical uses of organophosphates
    • Anthelmintics
    • Pesticides
    • Insecticides
    • Glaucoma
  • 53. Precautions
    • Potential interactions with phenothiazines
    • Debliated animals
    • Hepatic disease
    • Respiratory problems
    • Pregnancy
  • 54. Organophosphates Toxicity
    • Muscarinic signs :
    • Salivation Brochoconstriction
    • Lacrimation Increased bronchial secre.
    • Urination Bradycardia
    • Dyspnea Hypotension
    • Diarrhea Miosis
    • Death Blurred vision
  • 55. Nicotinic signs
    • Stimulation of autonomic ganglia
    • Muscular fasciculations
    • Tachycardia?
    • Hypertension?
    • Depression of autonomic ganglia
    • Ganglionic blockade
  • 56. CNS Manifestations
    • Restlessness
    • Cofusion
    • Insomnia
    • Tremors
    • Ataxia
    • Respiratory depression
    • Circulatory collapse
  • 57. Treatment of OP poisoning
    • Support respiration
    • Counteract symptoms with atropine
    • Reactivate AchE with 2-PAM ( Pyridine 2-Aldoxime methi iodide) prior to aging of the phosphorilated enzyme
    • Reduce absorption from the GIT with activated charcoal
  • 58. Mode of Action of 2-PAM H 7 C 3 O-P-OC 3 H 7    Esteratuc Anionic CH 3  + C=N-OH  Pyridine 2-Aldoxime      
  • 59. Mode of Action of 2-PAM N + CH 3 C=N----O---P O OC 3 H 7 H 7 C 3 O N:H--O Regenerated Enzyme Oxime-phosphonate Kidneys ___ Electrophilic Nucleophilic
  • 60. Organophosphates-Induced Delayed Neurotoxicity(OPIDN)
    • Not all of them produce DN
    • Latent period of 6-14 days for clinical signs
    • Damage to sciatic, Peroneal, & Tibial nerves, spinal cord & Medulla
    • Lesions begin in the distal portions of long fibers, & large diameter peripheral nerves
    • Degeneration of axons with subsequent degeneration of myelin sheath
  • 61. Species susceptibility
    • Humans- the most sensitive
    • Cats, Cows, Lambs, Water Buffalo
    • Chickens, Pheasants, Mallard, Ducklings(animals used in the investigation of OP toxicity)
    • Phosphorilation of a neurotoxic Target protein- Neurotoxic esterase
    • Triarylphosphates, Fluorine containing alkyl phosphates
  • 62. Parasympatholytics
    • Antimuscarinics
    • Anticholinergics
    • Atropine like drugs
    • Competitive antagonists for Ach’effects on muscarinic receptors
    • Block Nicotinic effects of Ach at high doses
  • 63. Source and Chemistry
    • Naturally occuring atropine like substances:
    • Atropa belladonna(Deadly night shade)
    • Datura stramonium( Jimson weed)
    • Hyocyamus niger(Henbane)
  • 64. Tertiary Ammonium Alkaloids
    • Atropine- A racemic mixture of dl-hyoscymine
    • Ester of tropic acid and Tropin or Scopine
    • Scopolamine- l-hyoscine-Hyocymus niger
  • 65. Synthetic Tertiary Amines
    • Homatropine hydrobromide
    • Tropicamide
    • Benzotropine
    • Cyclopentolate
  • 66. Synthetic Quaternary Amines
    • Glycopyrrolate
    • Iprtropium
    • Tiotropium
    • Homatropine methybromide
    • Propantheline
  • 67. Mechanism of Action
    • Competitive- reversible
    • Surmountable with a large dose of Ach
    • More effective in blocking exogenous
    • Cholinergic agonists
  • 68. Degree of Sensitivity to Atropine like drugs
    • Salivary, bronchial, sweat glands& other sec.glands-the first
    • Pupil, ciliary body, and heart-the second
    • Bladder, and gut-the third
    • Gastric Parietal cells- the last
  • 69. Pharmacological Effects of Atropine Like Drugs
    • Cardiovascular System- Heart rate, cardiac output & BP ?
    • Gastrointesinal Tract: Motility & Secretion?
    • Respiratory Tract : Bronchial secretions & muscle tone?
    • Urinary Tract: muscle tone?
    • Biliary Tract: Muscle tone?
    • Eye: Mydriasis, cycloplegia, & Lac.sec.?
  • 70. Effects on CNS
    • Atropine- stimulant on medullary center in small doses- brady cardia, followed by tachycardia in higher doses.
    • Scopolamine - depressant -sedative effects
  • 71. Veterinary Clinical Uses
    • Pre-anesthetic
    • Opthalmologic disorders
    • Gastrointestinal disorders
    • Respiratory disorders
    • Cardiac disorders
    • Antidote for cholinergic poisoning
  • 72. Contraindications
    • Horses -induce colic
    • Ruminants- respiratory difficulty
    • Ruminants- ruminal statsis
    • GIT obstructive diseases, paralytic ileus etc
  • 73. Autonomic Ganglion Stimulants& Blocking Agents ACh N-Rc Ganglionic stimulants : Nicotine, Lobeline Ganglion Blockers : Nicotine Hexamethonium,Tetraethylammonium ,Chlorisandemine, Mecamylamine
  • 74. Nicotine- Sites of Actions
    • All autonomic ganglia
    • CNS
    • Skeletal NMJ- Muscles
    • Adrenergic nerve endings in CNS & adrenal medulla
    • Sensory receptors- Chemoreceptors in the carotid body
  • 75. Nicotine -Effects
    • Predominance of sympathetic vs parasymp.ganglia
    • Complex depending on the dose
    • Tachycardia vs bradycardia
    • Hypertension vs hypotension
    • Hypermotility vs hypomotility
    • Tremors, convulsion vs depression
  • 76. Dominance of ANS Ganglia
  • 77. Nicotine -Black Leaf 40
    • Toxic Effects :
    • Black Leaf 40
    • Plant insecticide having Carbon terachloride, sodium arsenate, & copper sulfate, used as an anthelmintic in cattle
    • Toxic signs include, excitement, rapid respiration, salivation, emesis, diarrhea followed by depression, incoordination, rapid pulse, shallow and slow resp. coma& death