Autonomic Pharmacology and Cholinergics - drdhriti


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  • Endocrine and ANS have similarity – high level of integration in CNS, transmitter release (different in different types of nerves) – nerve to nerve (ganglia) then nerve to effector organ etc.
  • Angina is a Pain Syndrome due to induction of adverse oxygen supply or demand situation in a portion of myocardium. Types – classical and variant/prinzmetal`s angina. Classical – attack provoked by exercise, emotion etc. Variant – At rest or during sleep
  • Congestive heart failure
  • As of 2008, the cholinesterase inhibitors approved for the management of AD symptoms are donepezil (brand name Aricept ), [144] galantamine ( Razadyne ),
  • Most Visceral afferents are mixed nerves and non-myelinted in nature. Cell bodies of these nerves lie in spinal nerves and sensory ganglia of cranial nerves. The carry the sensory stimulations from visceral organs.
  • Paravetrtebral – lateral chain – 22 pairs
  • A highly simplified diagram of the intestinal wall and some of the circuitry of the enteric nervous system (ENS). The ENS receives input from both the sympathetic and the parasympathetic systems and sends afferent impulses to sympathetic ganglia and to the central nervous system. Many transmitter or neuromodulator substances have been identified in the ENS; see Table 6–1. (LM, longitudinal muscle layer; MP, myenteric plexus; CM, circular muscle layer; SMP, submucosal plexus; ACh, acetylcholine; NE, norepinephrine; NO, nitric oxide; NP, neuropeptides; SP, substance P; 5-HT, serotonin.)
  • Latrodectism – black widow spider
  • Autonomic Pharmacology and Cholinergics - drdhriti

    1. 1. 2011 Wish you
    2. 2. Autonomic Nervous System - “ Autonomic Pharmacology” Department of Pharmacology NEIGRIHMS, Shillong
    3. 3. Goal To Learn about the drugs affecting the autonomic nervous system Be prepared to link mechanism of drug action with knowledge mainly of cardiovascular anatomy, physiology and neurobiology to predict effects of drugs –
    4. 4. The autonomic nervous system maintains the internal environment of the body – clled HOMEOSTASIS Role of ANS in homeostasis links to target organs - (Cardivascular System , smooth muscle of GI and glands)
    5. 5. + Drug A decreases activity of organ Y Autonomic Pharmacology is Practical Nerves to organ Y release neurotransmitter X, and X increases the activity of organ Y Mimic or Block transmitters Drug A blocks receptors for neurotransmitter X
    6. 6. + Atropine blocks muscarinic receptors and decreases intestinal motility Atropine blocks muscarinic cholinergic receptors that respond to ACh Parasympathetic nerves release ACh and increase intestinal motility Understanding actions of drugs that influence the autonomic nervous system allows prediction of their effects!
    7. 7. Autonomic Drugs are very much Clinically Relevant
    8. 8. Autonomic drugs are used for the treatment of Angina
    9. 9. Autonomic drugs are used for the treatment of Heart Failure
    10. 10. Autonomic drugs are used for the treatment of High Blood Pressure <ul><li>Autonomic drugs also used for </li></ul><ul><li>treatment of </li></ul><ul><li>- Anaphylactic shock </li></ul><ul><li>- Septic shock </li></ul><ul><li>- Benign prostatic hypertrophy </li></ul><ul><li>- Alzheimer’s disease </li></ul><ul><li>- Asthma </li></ul>
    11. 11. Objectives <ul><li>Review the anatomy of the autonomic nervous system </li></ul><ul><li>Know the neurotransmitters at autonomic synapses </li></ul><ul><li>Understand the mechanism of neurotransmission in the autonomic nervous system </li></ul><ul><li>Be able to describe the distribution of adrenergic and cholinergic receptors </li></ul><ul><li>Describe general mechanisms by which drugs interact with the autonomic nervous system </li></ul>
    12. 12. Autonomic Pharmacology I. Anatomy of Peripheral Nervous System
    13. 13. Organization of The Nervous System Central Nervous System “ Brain and spinal cord” Peripheral Nervous System Autonomic Nervous System Somatic Nervous System Afferent Division Efferent Division Sympathetic “ thoracolumbar” Parasympathetic “ craniosacral”
    14. 14. Differences Between Somatic and ANS
    15. 15. Controls skeletal muscle Controls smooth & cardiac muscle & glands Peripheral Nervous System Somatic Nervous System Autonomic Nervous System One Neuron Efferent Limb Two Neuron Efferent Limb Postganglionic Preganglionic
    16. 16. Skeletal Muscle Peripheral Nervous System Somatic Nervous System Autonomic Nervous System Parasympathetic Nervous System Sympathetic Nervous System Selective Activation Diffuse Activation Glands, Smooth Muscle & Cardiac Muscle
    17. 17. AUTONOMIC NERVOUS SYSTEM <ul><li>SYMPATHETIC </li></ul><ul><ul><li>Fight or Flight </li></ul></ul><ul><li>PARASYMPATHETIC </li></ul><ul><ul><li>Rest and Digest </li></ul></ul>
    18. 18. Parasympathetic Nervous System (Craniosacral Outflow) Genitalia Bladder Large Intestines Kidney Bile Ducts Gallbladder Small Intestines Stomach Bronchi/Bronchial Glands SA & AV Node Sphincter Muscle of Iris Ciliary Muscle Lacrimal Gland Submaxillary & Sublingual Glands Parotid Gland
    19. 19. Radial Muscle of Iris Ciliary Muscle SA & AV Nodes His-Purkinje System Myocardium Bronchi/Bronchial Glands Stomach Kidneys Intestines Bladder//Genitalia Sublingual/Submaxillary & Parotid Gland Pilomotor Muscles Sweat Glands Blood Vessels Sympathetic Nervous System (Thoracolumbar Outflow) Paravertebral Ganglia Prevertebral Ganglia
    20. 20. Epinephrine (+) Fatty Acid Release (-) Intestinal Motility (+) Glycogenolysis (+) ACTH & TSH (+) Mental Alertness (+) Muscle Contraction & Efficiency (+) Dilates Airways (+) Cardiac Output ADRENAL MEDULLA Chromaffin Cells
    21. 21. Sympathetic Parasympathetic Origin Dorso-lumber (T1 to L2 or 3) Craniosacral (S2-4) Distribution Wide Head, neck and trunk Ganglia Away from Organ supplied On or close to the organ Postganglionic fibers Long Short Pre and post fiber ratio 1:20 to 1:100 1:1 or 1: 2 Transmitter Noradrenalin Acetylcholine Duration Long and wider action Ach – rapid destroy Function Tackling stress and emergency Assimilation of food and conservation of energy
    22. 22. Enteric Nervous System <ul><li>Considered 3 rd Division of ANS </li></ul><ul><ul><li>Auerbach`s plexus or myenteric plexus </li></ul></ul><ul><ul><li>Meissner`s plexus or submucous plexus </li></ul></ul><ul><li>Stimulation of these neurones causes release of – Ach, NE, VIP, ATP, Substance P, 5-HT etc. </li></ul><ul><li>May be excitatory or inhibitory in Nature </li></ul>
    23. 23. Enteric Nervous System
    24. 24. Neurohumoral Transmission <ul><li>Neurohumoral transmission means the transmission of message across synapse and neuroeffector junctions by release of humoral (chemical) messages </li></ul><ul><li>Initially junctional transmission was thought to be Electrical </li></ul><ul><li>But, Dale (1914) and Otto Loewi (1921) provided direct proof of humoral transmission – vagusstoff and acceleranstoff </li></ul><ul><li>Many Neurohumoral transmitters re identified: Acetylcholine, noradrenalin, Dopamine, 5-HT, GABA, Purines, Peptides etc. </li></ul>
    25. 25. Neurohumoral Transmission - Steps <ul><li>Impulse Conduction </li></ul><ul><ul><li>Tetrodotoxin and saxitoxin </li></ul></ul><ul><li>Transmitter Release </li></ul><ul><li>Transmitter release on postjunctional membrane </li></ul><ul><ul><li>EPSP and IPSP </li></ul></ul><ul><li>Postjunctional activity </li></ul><ul><li>Termination of transmitter action </li></ul><ul><ul><li>NET, SERT, DT </li></ul></ul>
    26. 26. What is a synapse? A synapse is a junction between two neurones across which electrical signals pass. The human body contains up to 500 trillion synapses. presynaptic cell postsynaptic cell
    27. 27. Release of neurotransmitters When a nerve impulse arrives at the end of one neurone it triggers the release of neurotransmitter molecules from synaptic vesicles. synaptic vesicle neurotransmitter molecules
    28. 28. Continuing the impulse The neurotransmitters diffuse across the synaptic cleft and bind with receptors on the next neurone, triggering another impulse. nerve impulse receptor synaptic cleft
    29. 29. Ach Ach Ach Ach NE Ach EPI/NE Ach Ach Somatic Sympathetic Sympathetic Sympathetic Para- sympathetic Postganglionic Fiber: Adrenergic Postganglionic Fiber: Cholinergic Adrenal Gland Motor Fiber Sweat Glands Smooth Muscle Cardiac Cells Gland Cells Smooth Muscle Cardiac Cells Gland Cells Skeletal Muscle Preganglionic Fiber: Cholinergic Ganglion Ganglion Ganglion
    30. 30. Cholinergic and Adrenergic System <ul><li>Accordingly: </li></ul><ul><ul><li>Cholinergic Drugs, i.e., they act by releasing acetylcholine </li></ul></ul><ul><ul><ul><li>But also utilize nitric oxide (NO) or peptides for transmission </li></ul></ul></ul><ul><ul><li>Noradrenergic (commonly called &quot;adrenergic&quot;) Drugs - act by releasing norepinephrine (NA) </li></ul></ul>
    31. 31. Cotransmission <ul><li>Peripheral and central Neurones release more than one active substance when stimulated </li></ul><ul><li>In ANS, besides Ach and NA – neurones elaborate Purines (ATP, adenosines), Peptides (VIP) or NPY, substance P, NO, enkephalins etc. </li></ul><ul><li>ACH and VIP, ATP with both Ach and NA </li></ul><ul><li>Stored in same neurones, but distinct vesicles – ATP and NA in same vesicle </li></ul><ul><li>NANC – gut, vas deferens, urinary tract, salivary glands and certain blood vessels . </li></ul>
    32. 32. Cholinergic System and Drugs
    33. 33. Cholinergic Transmission <ul><li>Acetylcholine (Ach) is major neurohumoral transmitter at autonomic, somatic and central nervous system: </li></ul><ul><li>The important sites of Acetylcholine as Neurohumoral transmitters are: </li></ul><ul><ul><li>All Postganglionic and few postganglionic sympathetic to sweat glands and some blood vessels – Muscarinic </li></ul></ul><ul><ul><li>All preganglionic (Para and sympathetic) i.e. ganglia and Adrenal medulla - Nicotinic (N N ) </li></ul></ul><ul><ul><li>Skeletal Muscle – Nicotinic (N M ) </li></ul></ul><ul><ul><li>Central Nervous System (cortex, basal ganglia and spinal chord) – Muscarinic and Nicotinic </li></ul></ul>
    34. 35. <ul><li>Cholinergic Transmission: </li></ul><ul><li>Cholinergic neurons contain large numbers of small membrane-bound vesicles (containing ACh) concentrated near the synaptic portion of the cell membrane </li></ul><ul><li>ACh is synthesized in the cytoplasm from acetyl-CoA and choline by the catalytic action of acetyltransferase (ChAT) </li></ul><ul><li>Acetyl-CoA is synthesized in mitochondria, which are present in large numbers in the nerve ending </li></ul><ul><li>Choline is transported from the extracellular fluid into the neuron terminal by a sodium-dependent membrane carrier (carrier A). This carrier can be blocked by a group of drugs called hemicholiniums </li></ul><ul><ul><li>The action of the choline transporter is the rate-limiting step in ACh synthesis </li></ul></ul>
    35. 36. <ul><li>Cholinergic Transmission: </li></ul><ul><li>Synthesized, ACh is transported from the cytoplasm into the vesicles by an antiporter that removes protons (carrier B). This transporter can be blocked by vesamicol </li></ul><ul><li>Release is dependent on extracellular Ca2+ and occurs when an action potential reaches the terminal and triggers sufficient influx of Ca2+ ions </li></ul><ul><li>The increased Ca2+ concentration &quot;destabilizes&quot; the storage vesicles by interacting with special proteins associated with the vesicular membrane (VAMPs) </li></ul><ul><li>Fusion of the vesicular membranes with the terminal membrane results in exocytotic expulsion of ACh into the synaptic cleft </li></ul><ul><li>The ACh vesicle release process is blocked by botulinum toxin through the enzymatic removal of two amino acids from one or more of the fusion proteins. Black widow spider </li></ul>
    36. 37. <ul><li>Cholinergic Transmission: </li></ul><ul><li>After release - ACh molecules may bind to and activate an ACh receptor (cholinoceptor) </li></ul><ul><li>Eventually (and usually very rapidly), all of the ACh released will diffuse within range of an acetylcholinesterase (AChE) molecule </li></ul><ul><li>AChE very efficiently splits ACh into choline and acetate , neither of which has significant transmitter effect, and thereby terminates the action of the transmitter. </li></ul><ul><li>Most cholinergic synapses are richly supplied with AChE; the half-life of ACh in the synapse is therefore very short. AChE is also found in other tissues, eg, red blood cells. </li></ul><ul><li>Another cholinesterase with a lower specificity for ACh, butyrylcholinesterase [pseudo cholinesterase], is found in blood plasma, liver, glial, and many other tissues </li></ul>
    37. 38. Differences between 2 AChEs True AChE Pseudo AChE Distribution All cholinergic sites, RBCs, gray matter Plasma, liver, Intestine and white matter Action on ACh Very Fast Slow Inhibition More sensitive to Physostigmine More sensitive to Organophosphates Function Termination of Ach action Hydrolysis of Ingested Esters
    38. 39. Cholinergic receptors - 2 types <ul><li>Muscarinic (M) and Nicotinic (N) </li></ul>Muscarinic (M) - GPCR <ul><li>Nicotinic (N) – ligand gated </li></ul>
    39. 40. Sites of Cholinergic transmission Site Types Selective agonist Selective antagonist <ul><li>All Postganglionic Parasympathetic </li></ul><ul><li>Postganglionic sympathetic to sweat gland & BV </li></ul>Muscarinic Muscarine Atropine Ganglia (Both Para and sympathetic and also Adrenal Medulla N N DMPP Hexamethonium Skeletal Muscle N M PTMA Curare CNS Muscarinic Muscarine Oxotremorine Atropine
    40. 41. Cholinergic receptors – Muscarinic (M) and Nicotinic (N) <ul><li>Nicotinic receptors: </li></ul><ul><ul><li>nicotinic actions of ACh are those that can be reproduced by the injection of Nicotine </li></ul></ul><ul><ul><li>and also can be blocked by tubocurarine and hexamethonium </li></ul></ul><ul><ul><li>ligand-gated ion channels </li></ul></ul><ul><ul><li>activation results in a rapid increase in cellular permeability to Na+ and Ca++ </li></ul></ul><ul><ul><li>results in depolarization and initiation of action potential </li></ul></ul>
    41. 42. Nicotinic (N M and N N ) Receptor Locations <ul><li>N M (Muscle type) and N N (Ganglion type) </li></ul><ul><li>NM (Muscle type): at neuromuscular junctions of skeletal muscle : </li></ul><ul><ul><li>Postsynaptic and Excitatory (increases Na+ and K+ permeability) </li></ul></ul><ul><ul><li>Stimulate skeletal muscle (contraction) </li></ul></ul><ul><ul><li>Agonists: ACh, carbachol (CCh), suxamethonium </li></ul></ul><ul><ul><li>Selective stimulation by phenyl trimethyl ammonium (PTMA) </li></ul></ul><ul><ul><li>Antagonists: tubocurarine, hexamethonium </li></ul></ul><ul><li>N N type: In autonomic ganglia of all type (ganglion type) – Sympathetic, Parasympathetic and also Adrenal Medulla </li></ul><ul><ul><li>Depolarization and postganglionic impulse – stimulate all autonomic ganglia </li></ul></ul><ul><ul><li>Excitatory – Na+, K+ and Ca+ channel opening </li></ul></ul><ul><ul><li>Agonists: ACh, CCh, nicotine </li></ul></ul><ul><ul><li>Selectively stimulated by phenyl piperazinium (DMPP) </li></ul></ul><ul><ul><li>Antagonists: mecamylamine, trimetaphan </li></ul></ul>
    42. 43. Muscarinic (M) Receptors Amanita muscaria
    43. 44. Acetylcholine (cholinergic receptors) – Muscarinic Receptors <ul><li>Selectively stimulated by Muscarine nd blocked by Atropine </li></ul><ul><li>G-protein coupled receptors </li></ul><ul><li>Primarily located in heart, blood vessels, eye, smooth muscles and glands of GIT </li></ul><ul><li>Subsidiary M receptors are also present in ganglia for modulation </li></ul><ul><li>Autoreceptors (M type) are present in prejunctional cholinergic Nerve endings </li></ul>
    44. 45. Muscarinic Receptors - Subtypes <ul><li>M1, M2, M3, M4 and M5 </li></ul><ul><li>M1, M2 and M3 are major ones and present in effector cell and prejunctional nerve endings in CNS </li></ul><ul><li>M4 and M5 are present in certain areas of Brain and regulate other neurotransmitters </li></ul><ul><li>All subtypes have little agonist selectivity but selective antagonist selectivity </li></ul>
    45. 46. Muscarinic Receptor Subtypes M1 M2 M3 Location Autonomic ganglia, Gastric glands and CNS Heart and CNS SMs of Viscera, Eye, exocrine glands and endothelium Functions EPSP & Histamine release & acid secretion with CNS learning and motor functions Less impulse generation, less velocity of conduction, decreased contractility, less Ach release Visceral SM contraction, Constriction of pupil, contraction of Cilliary muscle and vasodilatation Agonists Oxotremorine and MCN and MCN-343A Methacholine Bethanechol Antagonists Pirenzepine Methoctramine & Triptramine Darifenacin
    46. 47. Acetylcholine (cholinergic receptors) – Muscarinic Receptors <ul><li>Selectively stimulated by Muscarine and blocked by Atropine </li></ul>M1 M2 M3 Ganglia Heart Glands and SM
    47. 48. Cholinergic Drugs or Cholinomimetic or Parasympathomimetics Drugs producing actions similar to Ach – by interacting with Cholinergic receptors or by increasing availability of Ach at these sites.
    48. 49. Classifiction - Direct-acting (receptor agonists ) <ul><li>Choline Esters </li></ul><ul><ul><li>Natural: Acetylcholine </li></ul></ul><ul><ul><li>Synthetic: Methacholine, Carbachol and Bethanechol. </li></ul></ul><ul><li>Alkaloids: pilocarpine, muscarine, arecholine </li></ul><ul><ul><li>Synthetic: Oxotremorine </li></ul></ul>
    49. 50. Cholinergic Drugs – Indirect acting <ul><li>Cholinesterase inhibitors or reversible anticholinesterases: </li></ul><ul><ul><li>Natural: Physostigmine </li></ul></ul><ul><ul><li>Synthetic: neostigmine, pyridostigmine, distigmine, rivastigmine, donepezil, gallantamine, edrophonium, ambenonium, demecarium </li></ul></ul><ul><li>Irreversible anticholinesterases: </li></ul><ul><ul><li>Organophosphorous Compounds (OPC) – Diisopropyl fluorophosphate (DFP), Ecothiophate, Parathion, malathion, diazinon (insecticides and pesticides) </li></ul></ul><ul><ul><li>Tabun, sarin, soman (nerve gases in war) </li></ul></ul><ul><ul><li>Carbamate Esters Carbaryl and Propoxur (Baygon) </li></ul></ul>
    50. 51. Question… <ul><li>What side effects might you expect to see in a patient taking a cholinergic drug? </li></ul><ul><li>Hint… Cholinergic = “Colon-Urgent” </li></ul>
    51. 52. Ach actions - Muscarinic <ul><li>Heart: M2 </li></ul><ul><ul><li>Hyperpolarization of SA node, reuction in impulse generation and Bradycardia </li></ul></ul><ul><ul><li>Slowing of AV conduction and His-purkinje fibres – partial or complete block </li></ul></ul><ul><ul><li>Atrial fibrillation and flutter – nonuniform vagal innervations </li></ul></ul><ul><ul><li>Decrease in ventricular contractility </li></ul></ul><ul><li>Blood Vessels: M3 </li></ul><ul><ul><li>Cholinergic innervations is limited – skin of face and neck </li></ul></ul><ul><ul><li>But, M3 present in all type blood vessel – Vasodilatation by Nitric oxide (NO) release </li></ul></ul><ul><ul><li>Penile erection </li></ul></ul>
    52. 53. Muscarinic action – contd. <ul><li>3. Smooth Muscles: M3 </li></ul><ul><ul><li>Abdominal cramps, diarrhoea – due to increased peristalsis and relaxed sphincters </li></ul></ul><ul><ul><li>Voiding of Bladder </li></ul></ul><ul><ul><li>Bronchial SM contraction – dyspnoea, attack of asthma etc. </li></ul></ul><ul><li>Glands: M3 </li></ul><ul><ul><li>Increased secretions: sweating, salivation, lacrimation, tracheobronchial tree and gastric glands </li></ul></ul><ul><li>Eye: M3 </li></ul><ul><ul><li>Contraction of circular fibres of Iris – miosis </li></ul></ul><ul><ul><li>Contraction of Ciliary muscles – spasm of accommodation, increased outflow and reduction in IOP </li></ul></ul>
    53. 54. Ach actions - Nicotinic <ul><li>Autonomic ganglia: </li></ul><ul><ul><li>Both Sympathetic and parasympathetic ganglia are stimulated </li></ul></ul><ul><ul><li>After atropine injection Ach causes tachycardia and rise in BP </li></ul></ul><ul><li>Skeletal muscle </li></ul><ul><ul><li>IV injection – no effect </li></ul></ul><ul><ul><li>Application causes contraction of skeletal muscle </li></ul></ul><ul><li>CNS: </li></ul><ul><ul><li>Does not penetrate BBB </li></ul></ul><ul><ul><li>Local injection in CNS – complex actions </li></ul></ul><ul><li>(Acetylcholine is not used therapeutically) </li></ul>
    54. 55. Pilocarpine <ul><li>Alkaloid from leaves of Pilocarpus microphyllus </li></ul><ul><li>Prominent muscarinic actions </li></ul><ul><li>Profuse salivation, lacrimation, sweating </li></ul><ul><li>Dilates blood vessels, causes hypotension </li></ul><ul><li>On Eyes it produces miosis and spasm of accommodation </li></ul><ul><li>Lowers intraocular pressure (IOP) in Glaucoma when applied as eye drops </li></ul><ul><li>Too toxic for systemic use </li></ul>
    55. 56. Pilocarpine – contd. <ul><li>Used as eye drops in treatment of narrow angle and wide angle glaucoma to reduce IOP </li></ul><ul><li>Used to reverse mydriatic effect of atropine </li></ul><ul><li>To break adhesion between iris and cornea/lens alternated with mydriatic </li></ul><ul><li>Pilocarpine nitrate eye drops ( 1 to 4% ) </li></ul><ul><li>CNS toxicity after systemic use </li></ul><ul><li>Atropine used as antidote in acute pilocarpine poisoning ( 1-2 mg IV 8hrly ) </li></ul>
    56. 57. Pilocarpine – Mechanism in Eye Causes opening up of trabecular pores and increased drainage
    57. 58. Muscarine <ul><li>Alkaloid from mushroom Amanita muscaria </li></ul><ul><li>Only muscarinic actions </li></ul><ul><li>No clinical use </li></ul><ul><li>Cause mushroom poisoning due to ingestion of poisonous mushroom </li></ul><ul><li>= Early onset mushroom poisoning </li></ul><ul><li>= Late onset mushroom poisoning (neurogenic) </li></ul>
    58. 59. Early Onset Mushroom Poisoning <ul><li>Occurs ½ to 1 hour. </li></ul><ul><li>Muscaria cause mild cholinergic symptoms like nausea, vomiting, salivation, lacrimation, headache, bronchospasm, diarrhoea </li></ul><ul><li>ntidote is Atropine sulphate (0.5-I mg IM twice daily) </li></ul><ul><li>Inocybe or Clitocybe – severe cholinergic symptoms like bradycardia, dyspnoea, hypotension, weakness, cardiovascular collapse, convulsions and coma </li></ul><ul><li>Antidote is Atropine sulphate ( 2-3 mg IM hrly till </li></ul><ul><li>improvement ) </li></ul>Volvariella volvacea
    59. 60. Late Onset Mushroom Poisoning <ul><li>Occurs within 6-15 hours </li></ul><ul><li>Amanita phylloides – irritability, restlessness, nausea, vomiting, ataxia, hallucination, delirium, sedation, drowsiness and sleep. </li></ul><ul><li>Maintain blood pressure, respiration </li></ul><ul><li>Inj. Diazepam 5 mg IM </li></ul><ul><li>Atropine contraindicated as it may cause convulsions and death </li></ul><ul><li>Gastric lavage and activated charcoal </li></ul>
    60. 61. Cholinesterase inhibitors: <ul><li>Reversible anticholinesterases (Carbamates): </li></ul><ul><ul><li>Natural: Physostigmine </li></ul></ul><ul><ul><li>Synthetic: Neostigmine, pyridostigmine, distigmine, rivastigmine, donepezil, gallantamine, edrophonium, ambenonium, demecarium </li></ul></ul><ul><li>Irreversible anticholinesterases: </li></ul><ul><ul><li>Organophosphorous Compounds (OPC) – Diisopropyl fluorophosphate (DFP), Ecothiophate, Parathion, malathion, diazinon (insecticides and pesticides) </li></ul></ul><ul><ul><li>Tabun, sarin, soman (nerve gases in war) </li></ul></ul><ul><ul><li>Carbamate: Carbaryl and Propoxur (Baygon) </li></ul></ul>
    61. 62. AChEs - MOA <ul><li>Acetylcholinesterase (AchE) is an enzyme, which hydrolyses Acetylcholine </li></ul><ul><li>The active site of AChE is made up of two subsites – anionic and esteratic </li></ul><ul><li>The anionic site serves to bind a molecule of ACh to the enzyme </li></ul><ul><li>Once the ACh is bound, the hydrolytic reaction occurs at a second region of the active site called the esteratic subsite </li></ul><ul><li>The AChE itself gets acetylated at serine site </li></ul><ul><li>Acetylated enzyme reacts with water to produce acetic acid and choline </li></ul><ul><li>Choline is then immediately taken up again by the high affinity choline uptake system on the presynaptic membrane </li></ul>
    62. 63. Hydrolysis of ACh
    63. 64. Anti-ChEs (MOA) – contd. <ul><li>Anticholinesterases also react with the enzyme ChEs in similar fashion like Acetylcholine </li></ul><ul><li>Carbamates – carbamylates the active site of the enzyme </li></ul><ul><li>Phosphates – Phosphorylates the enzyme </li></ul><ul><li>Carbamylated (reversible inhibitors) reacts with water slowly and the esteratic site is freed and ready for action – 30 minutes (less than synthesis of fresh enzyme) </li></ul><ul><li>But, Phosphorylated (irreversible) reacts extremely slowly or not at all – takes more time than synthesis of fresh enzyme </li></ul><ul><ul><li>Sometimes phosphorylated enzyme losses one alkyl group and become resistant to hydrolysis – aging </li></ul></ul><ul><li>Edrophonium and tacrine reacts only at anionic site while Organophosphates reacts only at esteratic site </li></ul>
    64. 65. Cholinesterase inhibitors – contd.
    65. 66. Anticholinesterases – Individual Drugs <ul><li>2 (two) important clinically used drugs – </li></ul><ul><ul><li>Physostigmine – lipid soluble, ganglion acting and less action in skeletal muscle </li></ul></ul><ul><ul><ul><li>Also organophosphates </li></ul></ul></ul><ul><ul><li>Neostigmine – lipid insoluble, skeletal muscle acting </li></ul></ul>
    66. 67. Physostigmine <ul><li>Alkaloid from dried ripe seed (Calabar bean) of African plant Physostigma venenosum </li></ul><ul><li>Tertiary amine, lipid soluble, well absorbed orally and crosses BBB </li></ul><ul><li>Hydrolyzed in liver and plasma by esterases. </li></ul><ul><li>Long lasting action (4-8 hours) </li></ul><ul><li>Reversible anticholinesterase drug </li></ul><ul><li>It indirectly prevents destruction of acetylcholine released from cholinergic nerve endings and causes ACh accumulation </li></ul><ul><li>Muscarinic action on eye causing miosis and spasm of accommodation on local application </li></ul><ul><li>Antagonises mydriasis and cycloplegia produced by atropine and anticholinergic drugs </li></ul><ul><li>Salivation, lacrimation, sweating and increased tracheobronchial secretions. </li></ul><ul><li>Increased heart rate & causes hypotension </li></ul>
    67. 68. Physostigmine - uses <ul><li>Used as miotic drops to decrease IOP in Glaucoma </li></ul><ul><li>To antagonise mydriatic effect of atropine </li></ul><ul><li>To break adhesions between iris and cornea alternating with mydriatic drops </li></ul><ul><li>Belladonna poisoning, TCAs & Phenothiazine poisoning </li></ul><ul><li>Alzheimer’s disease- pre-senile or senile dementia. </li></ul><ul><li>Atropine is antidote in physostigmine poisoning. </li></ul><ul><li>ADRs – CNS stimulation followed by depression. </li></ul>
    68. 69. Neostigmine <ul><li>Synthetic reversible anticholinesterase drug. </li></ul><ul><li>Quaternary ammonium compound and lipid soluble. </li></ul><ul><li>Cannot cross BBB </li></ul><ul><li>Hydrolysed by esterases in liver & plasma </li></ul><ul><li>Short duration of action (3-5 hours) </li></ul><ul><li>Direct action on nicotinic (NM) receptors present in neuromuscular junction (motor end plate) of skeletal muscle </li></ul><ul><li>Antagonises (reverses) skeletal muscle relaxation (paralysis) caused by tubocurarine and other competitive neuromuscular blockers </li></ul><ul><li>Stimulates autonomic ganglia in small doses </li></ul><ul><li>Large doses block ganglionic transmission </li></ul><ul><li>No CNS effects </li></ul>
    69. 70. Neostigmine – Uses and ADRs <ul><li>Used in the treatment of Myasthenia Gravis to increase muscle strength </li></ul><ul><li>Post-operative reversal of neuromuscular blockade </li></ul><ul><li>Post-operative complications – gastric atony paralytic ileus, urinary bladder atony </li></ul><ul><li>Cobra snake bite </li></ul><ul><li>Produces twitchings & fasciculations of muscles leading to weakness </li></ul><ul><li>Atropine is the antidote in acute neostigmine poisoning </li></ul>
    70. 71. Physostigmine and Neostigmine - Summary Physostigmine Neostigmine Source Natural Synthetic Chemistry Tertiary amine Quaternary ammonium compound Oral absorption Good Poor CNS action Present Absent Eye Penetrates cornea Poor penetration Effect Ganglia Muscle Uses Miotic Mysthenia gravis Dose 0.5-1 mg oral/parenteral 0.1-1% eye drop 0.5-2.5 mg IM/SC 15-30 mg orally Duration of action 4-6 Hrs 3-4 Hrs
    71. 72. Therapeutic Uses – cholinergic drugs <ul><li>Myasthenia gravis: Edrophonium to diagnose and Neostigmine, Pyridostigmine & Distigmine to treat </li></ul><ul><li>To stimulate bladder & bowel after surgery: </li></ul><ul><ul><li>Bethanechol, Carbachol, Distigmine. </li></ul></ul><ul><li>To lower IOP in chronic simple glaucoma: </li></ul><ul><ul><li>Pilocarpine, Physostigmine </li></ul></ul><ul><li>To improve cognitive function in Alzheimer’s disease: Rivastigmine, Gallantamine, Donepezil. </li></ul><ul><li>Physostigmine in Belladonna poisoning </li></ul>
    72. 73. Myasthenia gravis <ul><li>Autoimmune disorder affecting 1 in 10,000 population </li></ul><ul><li>Causes: Development of antibodies directed to Nicotinic receptors in muscle end plate – reduction in number by 1/3 rd of NM receptors </li></ul><ul><ul><li>Structural damage to NM junction </li></ul></ul><ul><li>Symptoms: Weakness and easy fatigability </li></ul><ul><li>Treatment: </li></ul><ul><ul><li>Neostigmine – 15 to 30 mg orally every 6 hrly </li></ul></ul><ul><ul><li>Adjusted according to the response* </li></ul></ul><ul><ul><li>Pyridostigmine – less frequency of dosing </li></ul></ul><ul><ul><li>Other drugs: Corticosteroids (prednisolone 30-60 mg /day) </li></ul></ul><ul><ul><ul><li>Azathioprin and cyclosporin also Plasmapheresis </li></ul></ul></ul>
    73. 74. Myasthenic crisis <ul><li>Acute weakness and respiratory paralysis </li></ul><ul><ul><li>Tracheobronchial intubation and mechnical ventilation </li></ul></ul><ul><ul><li>Methylprednisolone IV with withdrawal of AChE </li></ul></ul><ul><ul><li>Gradual reintroduction of AChE </li></ul></ul><ul><ul><li>Thymectomy </li></ul></ul>
    74. 75. Snake venom Poisoning <ul><li>Asian Cobra Bite </li></ul><ul><li>Symptoms are similar to Myasthenia gravis </li></ul><ul><li>Atropine sulfate 0.6 mg IV slowly – to counteract Muscarinic action </li></ul><ul><li>Edrophonium chloride (Tensilon) - 10 mg IV over 2 minutes – reversal of occulomotor and respiratory paralysis </li></ul>
    75. 76. AChE Poisoning (Organophopsphorous Poisoning) <ul><li>Poisoning may be – Occupational, accidental, Suicidal </li></ul><ul><li>Symptoms: </li></ul><ul><ul><li>Fall in BP, bradycardia or tachycardia, cardiac arrhythmia and vascular collapse </li></ul></ul><ul><ul><li>Irrittion of Eye, lacrimation, salivation, colic, involuntary defection, breathlessness, blurring of vision </li></ul></ul><ul><ul><li>Muscular fasciculations and weakness </li></ul></ul><ul><ul><li>Death due to respiratory paralysis – peripheral and central </li></ul></ul>
    76. 77. Principles of Treatment <ul><li>Remove soiled clothes </li></ul><ul><li>Wash soiled skin and eyes </li></ul><ul><li>Prone Positioning and clear mouth and throat </li></ul><ul><li>Intubation of airway </li></ul><ul><li>Gastric lavage </li></ul><ul><li>Atropine: All cases of AChE poisoning, 2mg IV every `10 minutes – continue till atropinization occurs </li></ul><ul><li>Cholinesterase reactivators: Oximes </li></ul>
    77. 78. Cholinesterase Reactivators - Oximes <ul><li>Pralidoxime (2-PAM), Obidoxime Diacetyl monoxime (DAM) </li></ul><ul><li>Oximes have generic formula R-CH=N-OH </li></ul><ul><li>Provides reactive group OH to the enzymes to reactivate the phosphorylated enzymes </li></ul><ul><li>PAM: </li></ul><ul><ul><li>Quaternary Nitrogen of PAM gets attaches to Anionic site of the enzyme and reacts with Phosphorous atom at esteratic site </li></ul></ul><ul><ul><li>Forms Oxime-phosphonate complex making esteratic site free </li></ul></ul><ul><ul><li>Not effective in Carbamate poisoning </li></ul></ul><ul><ul><li>Dose: 1-2 gm IV slowly </li></ul></ul>
    78. 79. Khublei Shibun/Thank you
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