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CHolinergic agents
This document discusses the autonomic nervous system and cholinergic transmission. It describes the sympathetic and parasympathetic divisions of the ANS, including the locations of preganglionic and postganglionic neurons. Acetylcholine is the main neurotransmitter of cholinergic fibers. Both muscarinic and nicotinic receptors are involved in cholinergic signaling. Cholinergic drugs include direct agonists like acetylcholine and indirect agonists that inhibit acetylcholinesterase. Anticholinergic drugs act as muscarinic receptor antagonists and are used to treat various conditions.
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CHolinergic agents
- 1. www.company.com Autonomic nervous system Cholinergicagonists (CHOLINOMIMETICS) Cholinergic antagonists (CHOLINOBLOCKERS)
- 2. www.company.com Functional divisions withinthe nervous system
- 3. www.company.com Efferent neurons ofthe autonomic nervous system
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- 5. www.company.com Sympathetic ANS • The1st neuron of sympathetic division is located in the thoracolumbar region of the spinal cord (T1-L3) and the 2nd is disposed either in the paravertebral, or in the prevertebral ganglia. Postganglionic non-myelinated nerve fibres arising from neurones in the ganglia, innervate most organs of the body • The neurotransmitter released by sympathetic nerve endings is noradrenaline.
- 6. www.company.com Parasympathetic system • The1st neuron of parasympathetic system is located in the brain stem and in the sacral region of the spinal cord. The preganglionic fibres leave the central nervous system in the III, VII, IX and X pairs of cranial nerves and the third and fourth sacral spinal roots. • Ganglia are located either in the tissue of effector organ or near it. The nerve endings of the postganglionic parasympathetic fibres release neurotransmitter acetylcholine. All the preganglionic nerve fibres (sympathetic and parasympathetic;) are myelinated and release acetylcholine from the nerve terminals which depolarizes the ganglionic neurones by activating nicotinic receptors.
- 7. www.company.com Cholinergic transmission Main NTis Acetylcholine (Ach).Main NT is Acetylcholine (Ach). A large number of peripheral ANS fibers whichA large number of peripheral ANS fibers which synthesize & release Acetylcholine are calledsynthesize & release Acetylcholine are called CHOLINERGIC fibers. They include:CHOLINERGIC fibers. They include: • All pre-ganglionic efferent autonomic fibers.All pre-ganglionic efferent autonomic fibers. • Somatic motor fibers to skeletal muscles.Somatic motor fibers to skeletal muscles. • Most parasympathetic post ganglionic fibers.Most parasympathetic post ganglionic fibers. • A few sympathetic post ganglionic fibers– toA few sympathetic post ganglionic fibers– to sweat glands.sweat glands. Some parasympathetic post ganglionic fibers utilizeSome parasympathetic post ganglionic fibers utilize nitric oxide or peptides for transmission.nitric oxide or peptides for transmission.
- 8. www.company.com Cholinergic synapse • Nerveterminal of cholinergic fibre contains numerous vesicles with neurotransmitter acetylcholine (ACh) that is released from presynaptic membrane. • Release of acetylcholine depends on sufficient influx of Ca 2+, which occurs under the influence of action potential. negative feedback ATP ATP
- 9. www.company.com Fate of acetylcholinereleased by cholinergic fiber • ACh is released from the nerve into the synaptic cleft and binds to ACh receptors on the post- synaptic membrane, relaying the signal from the nerve. • Ach-esterase, located on the post-synaptic membrane, terminates the signal transmission by hydrolyzing ACh. • The liberated choline is reuptaken by the pre- synaptic membrane and used for resynthesis of ACh.
- 10. www.company.com Cholinergic receptor types •Two cholinergic receptor subtypes have been identified by selective agonists: muscarinic (M-cholinoceptors) and nicotinic (N- cholinoceptors). At least 5 subtypes of muscarinic receptors (M1 – M5) have been distinguished. • There are 3 main classes of N- cholinoceptors: the muscle, ganglionic, and CNS classes. MUSCARINIC NICOTINIC M1 M2 M3 M4 M5 Eye Heart Smooth muscles Exocrine glands CNS NM NN Ganglions Carotid sinus Skeletal muscles Adrenal glands CNS
- 11. www.company.com Muscarinic receptors • Highaffinity to muscarine • M1 – gastric parietal cells, saliva, CNS • M2 - cardiac cells, smooth muscle, CNS • M3 - bladder, exocrine glands, smooth muscle, eye, CNS • M1&M3 – Gq • M2 - Gi Amanita muscaria
- 12. www.company.com Nicotinic receptors • Highaffinity to nicotine • NM- neuro-muscular junction • NN – ganglion, adrenal gland CNS, carotid sinus
- 13. www.company.com Mechanisms of impulse transmission •Muscarinic receptors belong to G-protein coupled receptors. Transmission of impulses through M1, M3, M5 cholinoceptors is realized by phospholipase C, inositol triphosphate and diacylglycerol • Stimulation of M2 and M4 cholinoceptors results in inhibition of adenylate cyclase and decrease in intracellular cAMP. • N- cholinoceptors are ion channel coupled. Their stimulation results in opening of Na+ channels that causes depolarization.
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- 15. www.company.com M-cholinoceptors Cholinocep tors Localization Effects ofstimulation M2 Heart Smooth muscle Bradycardia, decrease in conduction, decrease in force of atrial contraction Relaxation M3 Smooth muscles Increase in tone, increase in peristalsis, decrease in sphincter tone and removal of content, bronchoconstriction M1-M3 Exocrine glands Secretion Eye a)miosis b)spasm of accommodation c)decrease in intraocular tension M1-M5 CNS Stimulation
- 16. www.company.com N-cholinoceptors Cholinoc eptors Localization Effects ofstimulation NN Autonomic ganglia (parasympatheti c and sympathetic) Increase in parasympathetic and sympathetic reactions NN Adrenal medulla Increase in adrenaline release, increase in BP NM Skeletal muscle Increase in tone, contraction Carotid sinus Reflex respiratory centre stimulation NN CNS Stimulation
- 17. www.company.com Cholinomimetics • I. DirectactingI. Direct acting • 1. Muscarinic agonists (M- cholinomimetics) • Pilocarpine • Oxothermorine • Aceclidine • 2. Nicotinic agonists • Lobeline • Dimethylphenylpiperazinum (DMPP) • 3. Muscarinic and nicotinic agonists • Acethylcholine • Carbachol • II. Indirect acting (muscarinicII. Indirect acting (muscarinic and nicotinic agonists –and nicotinic agonists – anticholinesterase agents)anticholinesterase agents) • 1. Reversible • Neostigmine (Proserinum) • Physostigmine • • Pyridostigmine • Edrophonium • Ambenonium chloride (Oxazylum) • Galanthamine • 2. Irreversible (Organophosphates) • Echotiophate • Isoflurophate • Arminum • Drugs used in poisoning with organophosphates • 1. Reactivators of acetylcholine esterase • Pralidoxime • Dipiridoxinum • Izonitrozinum • Obidoxime • 2. M-cholinoblockers • Atropine
- 18. www.company.com Pharmacological effects • Bradycardia,decrease in blood pressure • Raising the tone of smooth muscles of internal organs • Stimulation of intestinal motility • Reducing sphincter of alimentary canal and bladder • Increased secretory activity of the exocrine glands • Constriction of the pupil of the eye (miosis) • spasm of accommodation • Reducing intra ocular pressure • Relief of pulses in mionevralnomu skeletal muscle synapse, strengthening their contractility (anticholinergic drugs) • Stimulation of the central nervous system (means of penetrating the blood-brain barrier)
- 19. www.company.com Main clinical usage •1. Glaucoma (Pilocarpine, Physostigmine, Armine) • 2. Infants (Neostigmine) • 3. Postoperative atony of the intestines and bladder (Neostigmine) • 4. Paralysis, paresis, neuritis, polyneuritis (Neostigmine) • 5. Dusturbances of skeletal muscle contractile function after cranial trauma, polio and stroke (Galanthamine hydrobromide) • 6. Belladonna poisoning (Neostigmine, Physostigmine, Galanthamine) • 7. Overdose nondepolarizing muscle relaxants (Neostigmine) • 8. Xerostomia (Pilocarpine) • 9. Respiratory depression (Cititon, Lobeline)
- 20. www.company.com Side effects ofcholinomimetics • 1. Bradycardia • 2. Bronchospasm • 3. Intestinal cramps, colic, diarrhea • 4. Hypersalivation • 5. Blurred vision
- 21. www.company.com Contraindications • 1. Bradycardia,A-V block • 2. Asthma • 3. Gastric ulcer and 12 duodenal ulcer • 4. Epilepsy (Neostigmine) • 5.Pregnancy (Neostigmine)
- 22. www.company.com Direct acting cholinergicagonists ACETYLCHOLINE
- 23. www.company.com Direct acting cholinergicagonists 1. Decrease in heart rate and cardiac output 2. Decrease in blood pressure ACETYLCHOLINE
- 24. www.company.com Direct acting cholinergicagonists ACETYLCHOLINE 3. Other actions 4. Clinical use very rare: eye drops to obtain miosis
- 25. www.company.com Direct acting cholinergicagonists 1. Stimulation of atonic bladder 2. Nonobstructive urinary retention 3. Neurogenic atony 4. Megacolon Ophthalmology
- 26. www.company.com Direct acting cholinergicagonists PILOCARPINE 1. Tertiary nitrogen 2. Good adsorbtion 3. Penetrate BBB
- 27. www.company.com Direct acting cholinergicagonists Jaborandi (Pilocarpus pennatifolius) 1. Secretagoge (sweat, tears, saliva) • Jaborandi - what causes slobbering 2. Sjögren’s syndrome • Dry mouth, lack tears 3. Glaucoma PILOCARPINE
- 28. www.company.com Direct acting cholinergicagonists PILOCARPINE
- 29. www.company.com Mushroom poisoning Miosis Hyper salivation Excessive sweating, lacrimation Cold, wet skin Bradycardia Polyuria Diarrhea Convulsions
- 30. www.company.com Indirect acting cholinergicagonists Reversible Irreversible Edrophonium Neostigmine Physostigmine Rivastigmine Galantamine Echothiophate Organophosphates Arminum
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- 32. www.company.com Reversible Physostigmine Calabar Bean 1. Tertiarynitrogen 2. Good adsorbtion 3. Penetrate BBB
- 33. www.company.com Reversible Physostigmine 1. Atony ofintestine 2. Atony of bladder 3. Glaucoma 4. Overdose of ATROPINE, ANTIPSYCOTICS, ANTIDEPRESSANTS 1. Convulsions 2. Bradycardia 3. Paralysis of skeletal muscle Indications Side effects
- 34. www.company.com Reversible Neostigmine 1. Quatenary nitrogen 2.Poor adsorbtion 3. Not penetrate BBB
- 35. www.company.com Reversible Neostigmine 1. Paralyzes 2. Myasteniagravis 3. Antidote of neuro- muscular blocker TUBOCURARINE Indications Side effects 1. Salivation 2. Flushing 3. Decreased BP 4. Abdominal pain 5. Diarrhea 6. Bronchospasm
- 36. www.company.com Reversible Neostigmine 1. Bronchial asthma 2.Intestinal inflammation, obstruction 3. Bladder obstruction 4. Peritonitis
- 37. www.company.com Reversible Edrophonium 1. Quatenary nitrogen 2.Poor adsorbtion 3. Not penetrate BBB 4. Fast elimination 5. Duration 10-20 min
- 38. www.company.com Reversible Edrophonium 1. Diagnosis ofmyasthenia gravis 2. Antidote of neuro-muscular blocker
- 39. www.company.com Reversible Rivastigmine 1. Tertiary nitrogen 2.Good adsorbtion 3. Penetrate BBB
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- 44. www.company.com Toxicology 1.Reactivation of acetylcholinesterase •PRALIDOXIME Not enter BBB 2.M-cholinoblocker • ATROPINE Antimuscarinic only 3.Anticonvulsant • DIAZEPAM
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- 46. www.company.com Classification of cholinoblockers •I. M-cholinoblockers (Muscarinic antagonists) • Natural agents • Atropine • Hyoscine /Scopolamine/ • Plathyphylline • Semisynthetic and synthetic • Homatropine • Propantheline • Methacinum • Ipratropium bromide /Atrovent/ • Cyclopentolate • Pirenzepine
- 47. www.company.com Classification of N-cholinoblockers 1.Ganglion blocking drugs • Hexamethonium /Benzohexonium/ • Hygronium • Mecamylamine • Pempidine tosilate • Trimethaphan • 2. Neuromuscular blockers • a) Nondepolarizing • Atracurium • Pancuronium • Tubocurarine • Vecuronium • b) Depolarizing • Succinylcholine • Dithylinum
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- 49. www.company.com Parasympatholythics • Eye inabilityto focus for near vision, mydriasis, IOP ↑ • Saliva xerostomia • Bronchi bronchodilation, secretion ↓ • Heart Rate ↑ GIT secretion, peristalsis ↓ sphincter tone ↑ • Bladder detrusor ↓ sphincter tone ↑
- 50. www.company.com Clinical uses ofM-cholinoblockers • A-V block – Atropine • Colic, abdominal cramps – Atropine, Plathyphylline • Urinary frequency - Oxybutinin • Preanesthetic medication – Atropine, Hyoscine • Peptic ulcer – Pirenzepine (selective M1 cholinoblocker) • Bronchial asthma - Ipratropium bromide
- 51. www.company.com Clinical uses ofM-cholinoblockers • Therapeutic uses in ophthalmology: in iritis, keratitis and other inflammatory diseases and trauma of eye - Atropine • Diagnostics in ophthalmology – Atropine, Homatropine, Cyclopentolate • Prevention of motion sickness - Hyoscine • Muscarinic poisoning – Atropine • Organophosphate poisoning - Atropine
- 52. www.company.com Pharmakokinetics ATROPINE 1. Tertiary nitrogen 2.Good adsorbtion 3. Penetrate BBB Atropa belladonna
- 53. www.company.com Main effects ATROPINE • Smoothmuscle relaxation • Antisecretory Dose-dependent effects of atropine
- 54. www.company.com Therapeutic uses ATROPINE 1. Ophtalmologicaltests 2. Spasmolythic (as an antispasmodic agent to relax the GIT and bladder) 3. Antisecretory (during dental operations, tuberculosis, to block secretions in the upper and lower respiratory tracts prior to surgery) 4. Mushroom poisoning 5. Organophosphates poisoning 6. Heart block, bradycardia 7. Resuscitation (asystole)
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- 56. www.company.com Contraindications ATROPINE 1. Narrow-angle glaucoma 2.Pyloricstenosis 3. Prostatichypertrophy 4. Drivers
- 57. www.company.com Belladonna poisoning • Drymouth, difficulties in swallowing and talking • Dilated pupil, photophobia, blurred vision • Dry, flushed and hot skin • Difficulties in micturation • Constipation • Hypotension, weak and rapid pulse • Excitement, psychotic behavior,delirium, hallucination • ANTICHOLINESTERASE DRUGS ARE ANTIDOTES
- 58. www.company.com Pharmakokinetics SCOPOLAMINE Solanaceae family 1. Tertiarynitrogen 2. Good adsorbtion 3. Penetrate BBB
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- 64. www.company.com Ganglion blocking drugs •Hexamithonium • Hygronium • Mecamylamine • Trimethaphan Interfere with postsynaptic transmission of Ach Block action of Ach on nicotinic receptors Used rarely severe adverse effects: Orthostatic (postural) hypotension, tachycardia, dry-mouth, GIT atony, urine retention, digestive problems, sexual dysfunction: failure of erection and ejaculation
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- 67. www.company.com Clinical uses ofnondepolarizing myorelaxants • In surgery • General anesthesia to produce paralysis, to permit intubation of the trachea, • To optimize the surgical field by inhibiting spontaneous ventilation, and causing relaxation of skeletal muscles. • Because the appropriate dose of neuromuscular-blocking drug may paralyze muscles required for breathing (i.e., the diaphragm), mechanical ventilation should be available to maintain adequate respiration.
- 68. www.company.com Side effects ofnondepolarizing myorelaxants • Stimulation of histamine release, • Hypotension, • Flushing, • Tachycardia • Arrest of breathing. Because the appropriate dose of neuromuscular-blocking drug may paralyze muscles required for breathing (i.e., the diaphragm), mechanical ventilation should be available to maintain adequate respiration.
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- 70. www.company.com Succinylcholine • It hasa rapid onset (30 seconds) but very short duration of action (5–10 minutes) because of hydrolysis by various cholinesterases (such as butyrylcholinesterase in the blood). • Used in short lasting surgical invasions • It cause side effects: fasciculations (a sudden twitch just before paralysis occurs). post-operative pain
- 71. www.company.com TOXICITY 1. RESPIRATORY PARALYSIS- neuromuscular blockers induce a respiratory paralysis. If mechanical ventilation is not provided, the patient will asphyxiate. 2. MALIGNANT HYPERTHERMIA - Malignant hyperthermia susceptibility, an autosomal dominant disorder of skeletal muscle, is one of the main causes of death due to anesthesia. Depolarizing neuromuscular blocking drugs (succinylcholine) can trigger malignant hyperthermia. Malignant hyperthermia is a result of excessive release of Ca2+ from sarcoplasmic reticulum. • The clinical features of malignant hyperthermia are hyperthermia, metabolic acidosis, tachycardia, accelerated muscle metabolism and contructures.
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