Autonomic Nervous System Pharmacology and Cholinergics (updated 2011) - 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, vesicle-associated membrane protein (VAMP) family, SNAP - Soluble NSF Attachment Protein ( N-ethylmaleimide-sensitive factor)
  • A site on a neuron that binds the neurotransmitter released by that neuron, which then regulates the neuron's activity.
  • Phenyl trimethyl ammonium
  • Autonomic Nervous System Pharmacology and Cholinergics (updated 2011) - drdhriti

    1. 1. Autonomic Nervous System - “Autonomic Pharmacology” Department of Pharmacology NEIGRIHMS, Shillong
    2. 2. 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 –
    3. 3. The autonomic nervous system maintains the internal environment of the body – called HOMEOSTASIS Role of ANS in homeostasis links to target organs - (Cardivascular System, smooth muscle of GI and glands)
    4. 4. + Drug A decreases activity of organ O Autonomic Pharmacology is Practical Nerves to organ O release neurotransmitter N , and N increases the activity of organ O Mimic or Block transmitters Drug A blocks receptors for neurotransmitter N
    5. 5. + Atropine blocks muscarinic receptors and decreases intestinal motility Atropine blocks muscarinic cholinergic receptors that respond to ACh Understanding actions of drugs that influence the autonomic nervous system allows prediction of their effects! Parasympathetic nerves release ACh and increase intestinal motility
    6. 6. For a definite clinical outcome! Sympathetic nerves release Noradrenaline and increase Blood Pressure Propranolol blocks β -adrenergic receptors that respond to NA Propranolol blocks β -adrenergic receptors and decreases Blood Pressure
    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 – Recall
    13. 13. Organization of Nervous System - Recall 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. Controls skeletal muscle Controls cardiac muscle & glands Peripheral Nervous System Somatic Nervous System Autonomic Nervous System One Neuron Efferent Limb Two Neuron Efferent Limb Postganglionic Preganglionic smooth &
    15. 15. Recall Differences - Somatic Vs ANS
    16. 16. ANS - Organization <ul><li>Autonomic afferents: </li></ul><ul><ul><li>Mixed and nonmyelinated Nerves </li></ul></ul><ul><ul><li>Cell bodies are located in the dorsal root ganglion of Spinal Nerves and the sensory ganglia of Cranial Nerves </li></ul></ul><ul><ul><li>Mainly mediate visceral pain </li></ul></ul><ul><ul><li>Also reflexes from CVS, visceral and respiratory </li></ul></ul>
    17. 17. Organization of ANS – Central Connections <ul><li>No Exclusive autonomic area in CNS </li></ul><ul><li>Intermixing and integration of somatic and ANS occurs </li></ul><ul><li>Hypothalamus is the organ to regulate </li></ul><ul><li>Sympathetic – Lateral and Posterior sympathetic </li></ul><ul><li>Parasympathetic – Anterior and Medial </li></ul><ul><li>Many autonomic centres are located in mid brain medulla </li></ul>
    18. 18. Organization of ANS – Efferent fibres <ul><li>Motor limb – Sympathetic and Parasympathetic </li></ul><ul><li>Most organs receive both innervations </li></ul><ul><li>Functionally antagonistic of each other </li></ul><ul><li>Overall – depends on the tone at particular moment </li></ul><ul><ul><li>EXCEPTIONS: </li></ul></ul><ul><ul><li>Most Blood vessels, sweat glands and hair follicles – Sympathetic </li></ul></ul><ul><ul><li>Gastric and pancreatic glands, cilliary muscles - Parasympathetic </li></ul></ul>
    19. 19. 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><ul><ul><li>Next slide – </li></ul></ul><ul><ul><li>Distriibution: </li></ul></ul>
    20. 20. 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
    21. 21. 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
    22. 23. Epinephrine (+) Fatty Acid Release (-) Intestinal Motility (+) Glycogenolysis (+) ACTH & TSH (+) Mental Alertness (+) Muscle Contraction & Efficiency (+) Dilates Airways (+) Cardiac Output ADRENAL MEDULLA Chromaffin Cells
    23. 24. 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
    24. 25. 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>
    25. 26. Enteric Nervous System
    26. 27. 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 identified: Acetylcholine, noradrenalin, Dopamine, 5-HT, GABA, Purines, Peptides etc. </li></ul>
    27. 28. 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>
    28. 29. Impulse conduction across synapse
    29. 30. 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. 31. 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. 32. Cotransmission <ul><li>Peripheral and central Neurons 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. 35. Sites of Cholinergic Transmission <ul><li>Acetylcholine (Ach) is major neurohumoral transmitter at autonomic, somatic and central nervous system: </li></ul><ul><li>All preganglionic sites (Both Parasympathetic and sympathetic) </li></ul><ul><li>All Postganglionic Parasympathetic sites and sympathetic to sweat gland and some blood vessels </li></ul><ul><li>Skeletal Muscles </li></ul><ul><li>CNS: Cortex Basal ganglia, spinal chord and others </li></ul><ul><li>Parasympathetic Stimulation – Acetylcholine (Ach) release at neuroeffector junction - biological effects </li></ul><ul><li>Sympathetic stimulation – Noradrenaline (NA) at neuroeffector junction - biological effects </li></ul>
    33. 36. <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 Choline 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>
    34. 37. <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>
    35. 38. <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>
    36. 39. Differences between 2 AChEs True AChE Pseudo AChE Distribution All cholinergic sites, RBCs, gray matter Plasma, liver, Intestine and white matter Action on: Acetycholine Methacholine Very Fast Slower Slow Not hydrolyzed Inhibition More sensitive to Physostigmine More sensitive to Organophosphates Function Termination of Ach action Hydrolysis of Ingested Esters
    37. 40. Cholinergic receptors - 2 types <ul><li>Muscarinic (M) and Nicotinic (N): </li></ul>Muscarinic (M) - GPCR Nicotinic (N) – ligand gated
    38. 41. Acetylcholine (cholinergic receptors) – Muscarinic Receptors <ul><li>Selectively stimulated by Muscarine and blocked by Atropine – all are G-protein coupled receptors </li></ul><ul><li>Primarily located in heart, 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 – also in adrenergic nerve terminals leading to vasodilatation when Ach is injected </li></ul><ul><li>Blood vessels: All blood vessels have muscarninc receptors although no cholinergic innervations </li></ul>Amanita muscaria
    39. 42. Muscarinic Receptors - Subtypes <ul><li>Pharmacologically - M1, M2, M3, M4 and M5 </li></ul><ul><li>M4 and M5 are present in certain areas of Brain and regulate other neurotransmitters </li></ul><ul><li>M1, M3 and M5 fall in one class, while M2 and M4 in another class </li></ul><ul><li>However till today, M1, M2 and M3 are major ones and present in effector cell and prejunctional nerve endings in CNS </li></ul><ul><li>All subtypes have little agonist selectivity but selective antagonist selectivity </li></ul><ul><li>Most organs usually have more than one subtype but one subtype predominates in a tissue </li></ul>
    40. 43. Muscarinic Receptors - Location <ul><li>M1: Ganglion Cells and Central Neurons (cortex, hippocampus, corpus striatum) </li></ul><ul><ul><li>Physiological Role: Mediation of Gastric acid secretion and relaxation of LES </li></ul></ul><ul><ul><ul><li>Learning, memory and motor functions </li></ul></ul></ul><ul><li>M2: Cardiac Muscarinic receptors </li></ul><ul><ul><li>Mediate vagal bradycardia </li></ul></ul><ul><ul><li>Also auto receptors in cholinergic nerve endings </li></ul></ul><ul><li>M3: Visceral smooth muscles, glands and vascular endothelium. Also Iris and Ciliary muscles </li></ul>
    41. 44. 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
    42. 45. Acetylcholine (cholinergic receptors) – Muscarinic Receptors <ul><li>Selectively stimulated by Muscarine and blocked by Atropine </li></ul>M1 M2 M3 Ganglia Heart Glands and Smooth Muscles
    43. 46. Nicotinic (N) Receptors <ul><li>Nicotinic receptors: nicotinic actions of ACh are those that can be reproduced by the injection of Nicotine (Nicotiana tabacum) </li></ul><ul><ul><li>Can be blocked by tubocurarine and hexamethonium </li></ul></ul><ul><li>ligand-gated ion channels </li></ul><ul><ul><li>activation results in a rapid increase in cellular permeability to Na+ and Ca++ resulting - depolarization and initiation of action potential </li></ul></ul>
    44. 47. Nicotinic (N M and N N ) Receptor - comparison <ul><li>N M (Muscle type) </li></ul><ul><li>Location: Skeletal Muscle end plates </li></ul><ul><li>Function: Stimulate skeletal muscle (contraction) </li></ul><ul><li>MOA: Postsynaptic and Excitatory (increases Na+ and K+ permeability) </li></ul><ul><li>Agonists: ACh, carbachol (CCh), suxamethonium </li></ul><ul><ul><li>Selective stimulation by phenyl trimethyl ammonium (PTMA) </li></ul></ul><ul><li>Antagonists: tubocurarine, hexamethonium </li></ul><ul><li>N N (Ganglion type) </li></ul><ul><li>Location: In autonomic ganglia of all type (ganglion type) – Sympathetic, Parasympathetic and also Adrenal Medulla </li></ul><ul><li>Function: Depolarization and postganglionic impulse – stimulate all autonomic ganglia </li></ul><ul><li>MOA: Excitatory – Na+, K+ and Ca+ channel opening </li></ul><ul><li>Agonists: ACh, CCh, nicotine </li></ul><ul><ul><li>Selectively stimulated by phenyl piperazinium (DMPP) </li></ul></ul><ul><li>Antagonists: mecamylamine, trimetaphan </li></ul>
    45. 48. Sites of Cholinergic transmission and types of Receptors Site Types Selective agonist Selective antagonist All Postganglionic Parasympathetic Postganglionic sympathetic to sweat gland & BV 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
    46. 49. Ganglia Concept - summary
    47. 50. 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. 51. Classification - 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. 52. 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. 53. 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. 54. Ach actions - Muscarinic <ul><li>Heart: M 2 </li></ul><ul><ul><li>Hyperpolarization of SA node, reduction in impulse generation and Bradycardia </li></ul></ul><ul><ul><li>RP in SAN and PF increased but atrial muscles fibers abbreviated </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: M 3 </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. 55. Muscarinic action – contd. <ul><li>3. Smooth Muscles: M 3 </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: M 3 </li></ul><ul><ul><li>Increased secretions: sweating, salivation, lacrimation, tracheobronchial tree and gastric glands </li></ul></ul><ul><li>Eye: M 3 </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. 56. 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><ul><li>Bethanecol Uses: Postoperative and postpartum urinary obstruction, neurogenic bladder and GERD (10-40 mg oral) </li></ul>
    54. 57. 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: </li></ul><ul><ul><li>it produces miosis by contraction of circular muscles of iris </li></ul></ul><ul><ul><li>Contraction of cilliary muscles </li></ul></ul><ul><ul><ul><li>spasm of accommodation - fixed for near vision </li></ul></ul></ul><ul><ul><ul><li>Increased outflow of AH </li></ul></ul></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. 58. 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. 59. 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>Mushroom poisoning due to ingestion of poisonous mushroom </li></ul><ul><li>= Early onset mushroom poisoning (Muscarine type) </li></ul><ul><li>= Late onset mushroom poisoning (neurogenic) </li></ul>
    57. 60. Early Onset Mushroom Poisoning <ul><li>Occurs ½ to 1 hour </li></ul><ul><li>Symptoms are characteristic of Muscarinic actions </li></ul><ul><li>Inocybe or Clitocybe – severe cholinergic symptoms like vomiting, salivation, lacrimation, headache, bronchospasm, diarrhoea bradycardia, dyspnoea, hypotension, weakness, cardiovascular collapse, convulsions and coma </li></ul><ul><li>Antidote is Atropine sulphate ( 2-3 mg IM every hrly till improvement) </li></ul><ul><li>Hallucinogenic type: due to Muscimol or ibotenic acid present in A. muscria. Blocks muscarinic receptors in brain and activate mio acid receptors. No specific treatment – Atropine is contraindicated. </li></ul>Volvariella volvacea
    58. 61. Late Onset Mushroom Poisoning <ul><li>Occurs within 6-15 hours </li></ul><ul><li>Amanita phylloides – due to peptide toxins – Inhibit RNA and protein synthesis </li></ul><ul><li>Irritability, restlessness, nausea, vomiting, bloody diarrhoea ataxia, hallucination, delirium, sedation, drowsiness and sleep – Kidney, liver and GIT mucosal damage </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>
    59. 62. Cholinesterase Inhibitors “ ANTICHOLINESTERASES”
    60. 63. Cholinesterase inhibitors - Classification <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. 64. Overall … <ul><li>Most reversible Anti-ChEs are Carbamic acid compounds – Physostigmine, Neostigmine, pyridostigmine and Edrophonium </li></ul><ul><ul><li>Physostigmine is tertiary amine (has tertiary amino N radical) – lipid soluble </li></ul></ul><ul><ul><li>Neostigmine – Quarternary amine (has tertiary amino N radical) - lipid insoluble </li></ul></ul><ul><ul><li>Exception: Tacrine – Acridine derivative </li></ul></ul><ul><li>Most Irreversible Anti-ChEs contain Phosphoric acid – ORGANOPHOSPHATES – highly lipid soluble </li></ul><ul><ul><li>A few Irreversible Anti-ChEs are lipid soluble Carbamates - Carbaryl and Propoxur </li></ul></ul>
    62. 65. AChEs - MOA <ul><li>Acetylcholinesterase is the primary target </li></ul><ul><li>Normally Acetylcholine - binds to the enzyme's active site and is hydrolyzed, yielding free choline and the acetylated enzyme </li></ul><ul><ul><li>The active site has t wo subsites – anionic and esteratic </li></ul></ul><ul><ul><li>The anionic site serves to bind a molecule of ACh to the enzyme </li></ul></ul><ul><ul><li>Once the ACh is bound at anioic site, the hydrolytic reaction occurs at a second region of the active site - esteratic subsite </li></ul></ul><ul><ul><li>AChE itself gets acetylated by acetylation of serine site </li></ul></ul><ul><ul><li>Acetylated enzyme reacts with water to form Acetic acid and choline (Bond splits) </li></ul></ul>
    63. 66. Anti-ChEs (MOA) – contd. <ul><li>Anticholinesterases also react with the enzyme ChEs in similar fashion like Acetylcholine </li></ul><ul><ul><li>Carbamates – carbamylates the active site of the enzyme </li></ul></ul><ul><ul><li>Phosphates – Phosphorylates the enzyme </li></ul></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. 67. Anti-ChEs (MOA) – contd.
    65. 68. If You Want to Know More … Please follow the coming Slides!
    66. 69. Hydrolysis of acetylcholine by AChE Trp 86 Esteratic site Ser 203 Phe 338 Anionic site Glu 327 His 440
    67. 70. Hydrolysis of acetylcholine by AChE Trp 86 Esteratic site Ser 203 Phe 338 Anionic site Glu 327 His 440
    68. 71. Hydrolysis of acetylcholine by AChE Trp 86 Esteratic site Ser 203 Phe 338 Anionic site choline Glu 327 His 440
    69. 72. Hydrolysis of acetylcholine by AChE Trp 86 Esteratic site Ser 203 Phe 338 Anionic site Glu 327 His 440
    70. 73. Hydrolysis of acetylcholine by AChE Trp 86 Esteratic site Ser 203 Phe 338 Anionic site acetate Glu 327 His 440
    71. 74. Na + Ca 2+ Acetylcholinesterase Pharmacologic manipulation of AChE: No inhibition Presynaptic neuron Postsynaptic target Muscarinic Receptor ACH ACH Choline Acetate ACH ACH ACH ACH ACH ACH ACH ACH ACH Action Potential
    72. 75. Na + Ca 2+ Acetylcholinesterase Pharmacologic manipulation of AChE: Inhibition by drugs Presynaptic neuron Postsynaptic target Muscarinic Receptor ACH ACH ACH ACH ACH ACH ACH ACH ACH ACH ACH ACH ACH ACH ACH ACH ACH Action Potential
    73. 76. Anti-ChEs – Pharmacological Actions <ul><li>Qualitatively similar to directly acting cholinergics, but quantitatively different – two important clinically used drugs: </li></ul><ul><ul><li>Lipid soluble agents (physostigmine) – more muscarinic and CNS effects (stimulate ganglia) – less skeletal muscle effect </li></ul></ul><ul><ul><li>Lipid insoluble ones like Neostigimine – more skeletal muscle effect, stimulate ganglia but less muscarinic effect </li></ul></ul><ul><li>Ganglia: Stimulates ganglia through muscarinic receptors, but high doses may cause persistent depolarization of Nicotinic receptors and block transmission </li></ul><ul><li>CVS: Complex action – muscarinic-bradycardia, ganglionic-tachycardia etc. </li></ul><ul><li>Skeletal Muscle: Repetitive firing – twitching and fasciculation </li></ul><ul><ul><li>High doses – persistent depolarization and NM blockade </li></ul></ul>
    74. 77. 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>
    75. 78. 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>
    76. 79. 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>
    77. 80. 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>
    78. 81. 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
    79. 82. Therapeutic Uses – cholinergic drugs <ul><li>Myasthenia gravis: </li></ul><ul><ul><li>Edrophonium to diagnose </li></ul></ul><ul><ul><li>Neostigmine, Pyridostigmine & Distigmine to treat </li></ul></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>
    80. 83. 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>Dose requirement may fluctuate time to time – adjustment required </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><ul><ul><li>Plasmapheresis </li></ul></ul>
    81. 84. Myasthenia Gravis - Images
    82. 85. Myasthenic crisis <ul><li>Acute weakness and respiratory paralysis </li></ul><ul><ul><li>Tracheobronchial intubation and mechanical 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><ul><li>Edrophonium is used for diagnosis of Myasthenic crisis (disease itself) and cholinergic crisis (overdose of Anti-ChE) </li></ul><ul><ul><li>Improvement of symptoms – myasthenic crisis </li></ul></ul><ul><ul><li>Worsening – Cholinergic crisis </li></ul></ul>
    83. 86. 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>
    84. 87. 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>
    85. 88. 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>
    86. 89. 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 has a quaternary Nitrogen – gets attached to Anionic site of the enzyme - unoccupied in Organophosphorous poisoning </li></ul></ul><ul><ul><li>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>Available as 500 mg/20 ml infusion or 1 gm/vial for infusion </li></ul></ul><ul><ul><li>Injected slow IV - 1-2gm </li></ul></ul>
    87. 90. Khublei Shibun / Thank you

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