Autonomic Nervous System Pharmacology and Cholinergics (updated 2016) - drdhriti


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An updated PowerPoint presentation on Autonomic Pharmacology and Cholinergics suitable for UG MBBS level Medical students

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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 2016) - drdhriti

    1. 1. Autonomic Nervous System - “Autonomic Pharmacology” Dr. D. K. Brahma Department of Pharmacology NEIGRIHMS, Shillong
    2. 2. Autonomic Drugs are very much Clinically Relevant
    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. Autonomic drugs are used for the treatment of Angina
    5. 5. Autonomic drugs are used for the treatment of Heart Failure
    6. 6. Autonomic drugs are used for the treatment of High Blood Pressure • Autonomic drugs also used for treatment of - Anaphylactic shock - Septic shock - Benign prostatic hypertrophy - Alzheimer’s disease - Asthma
    7. 7. + Drug A increases activity of organ O Autonomic Pharmacology is Practical Nerves to organ O release neurotransmitter N, and N increases the activity of organ O Mimic transmitters Drug A enhances release of neurotransmitter N by acting on receptors of N
    8. 8. + Drug A decreases activity of organ O Autonomic Pharmacology Nerves to organ O release neurotransmitter N, and N increases the activity of organ O Block transmitters Drug A blocks receptors for neurotransmitter N
    9. 9. + Atropine blocks Ach receptors (muscarinic) 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 Acetylcholine (Ach) and increase intestinal motility
    10. 10. For a definite clinical outcome! Sympathetic nerves release Noradrenaline (NA) and increase Blood Pressure Propranolol blocks Receptors (β-adrenergic) that respond to NA Propranolol blocks β-adrenergic receptors and decreases Blood Pressure +
    11. 11. The autonomic nervous system maintains the internal environment of the body – HOMEOSTASIS • Role of ANS in homeostasis links to specific target organs - (Circulation, respiration, digestion, temperature regulation and some endocrine secretion) • In contrast – endocrine system is more generalized • ANS in periphery – nerve, ganglia and plexuses innervates heart, glands, other smooth muscles and visceral organs
    12. 12. 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”
    13. 13. AUTONOMIC NERVOUS SYSTEM • SYMPATHETIC – Fight or Flight • PARASYMPATHETIC – Rest and Digest
    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 LimbPostganglionic Preganglionic smooth &
    15. 15. Somatic Vs Autonomic Somatic Autonomic 1. Organ supplied Skeletal Muscle All other organs 2. Distal most synapse Within CNS Outside CNS in ganglia 3. Nerve fibres Myelinated Preganglionic – Myelinated Postganglionic – Non-myelinated 4. Peripheral plexus formation Absent Present 5. Efferent Transmitter Acetylcholine Acetylcholine and Noradrenaline 6. Effect of Nerve section Paralysis and atrophy Activity maintained – no atrophy
    16. 16. ANS Organization – Autonomic afferents • Afferent fibers from visceral structures – are the first link in the reflex arcs of the autonomic system • Most visceral reflexes are mediated through the central nervous system (CNS) • Information on the status of the visceral organs is transmitted to the CNS through the cranial nerve (parasympathetic) visceral sensory system and the spinal (sympathetic) visceral afferent system • Cell bodies are located in the sensory ganglia of Cranial Nerves and the dorsal root ganglion of Spinal Nerves - mixed and nonmyelinated Nerves • The cranial visceral sensory - mechanoreceptor and chemosensory information – 4 cranial nerves - V, VII, IX and X – Carries from face, head, toungue, palate, carotid body, oesophagus, thoracic and abdominal visceral organs except pelvic • The spinal visceral system - temperature and tissue injury of mechanical, chemical, or thermal origin: – Sensory afferents from all viscera at thoracic level – Muscle chemosensations – at all spinal level • Pelvic sensory responses at S2-S4 level
    17. 17. ANS – Central connections • No Exclusive autonomic area in CNS • Intermixing - somatic responses always are accompanied by visceral responses, and vice versa • Autonomic reflexes can be elicited at the level of the spinal cord - sweating, blood pressure alterations, vasomotor responses to temperature changes, and reflex emptying of the urinary bladder, rectum, and seminal vesicles. • Hypothalamus and STN - is the organ to regulate – Highly integrated pattern of responses are organized in hypothalumus • Many autonomic centres are located in mid brain, medulla – limited pattern responses • Sympathetic – Lateral and Posterior nuclei; Parasympathetic – Anterior and Medial nuclei
    18. 18. ANS – Efferent fibres • Motor limb – Sympathetic and Parasympathetic • Most organs receive both innervations • Functionally antagonistic of each other • EXCEPTIONS: – Most Blood vessels, sweat glands, spleen and hair follicles – Sympathetic – Gastric and pancreatic glands, cilliary muscles – Parasympathetic • Overall – depends on the tone at particular moment (summation) • Exception: Atrial fibres – ERP reduced by both
    19. 19. Sympathetic Nervous System (Thoracolumb ar Outflow) - paravertebr al, prevertebral and terminal Parasympathetic: Craniosacral outflow
    20. 20. Transmitters and Receptors - General • Neurotransmitter – All preganglionic and postganglionic Parasympathetic – Acetylcholine (Ach) – Postganglionic sympathetics – norepinephrine (NE, noradrenaline) • Somatic: Nicotinic (NM) ACh type of receptor – NM: musculoskeletal junction • Autonomic: 1. Parasympathetic: • Preganglionic: Nicotinic (NN) Ach • Postganglionic: Muscarininic (M) 2. Sympathetic: • Preganglionic: Nicotinic (NN) Ach • Postganglionic : Noradrenergic (NA) - ɑ and ß (alpha and beta) • Adrenal medulla (NN) Preganglionic and Postganglionic - Adrenaline in blood stream
    21. 21. Enteric Nervous System • Considered 3rd Division of ANS – Control activities of the GI tract are controlled locally – Afferent sensory neurons and a number of motor nerves and interneurons – Organized by Auerbach`s plexus or myenteric plexus and Meissner`s plexus or submucous plexus • Myenteric plexus – contraction and relaxation • submucous plexus – secretory and absorptive function • Parasympathetic as a whole is excitatory (pre and post ACH) while sympathetic is relaxant (preganglionic Ach inhibition) • Stimulation of these neurones causes release of – ACh, NE, VIP, ATP, Substance P, 5-HT etc.
    22. 22. Enteric Nervous System
    23. 23. Neurotransmission • Understanding the steps of chemical mediation of nerve impulses is important – exploited pharmacologically • Conduction refers to the passage of an impulse along an axon or muscle fiber • Transmission (Neurohumoral) transmission means the transmission of message across synapse and neuroeffector junctions by release of humoral (chemical) messages • Initially junctional transmission was thought to be Electrical • But, Dale (1914) and Otto Loewi (1921) provided direct proof of humoral transmission – vagusstoff and acceleranstoff • Many Neurohumoral transmitters identified: Acetylcholine, noradrenalin, Dopamine, 5-HT, GABA, Purines, Peptides etc.
    24. 24. Axonal Conduction • At rest, the interior of the typical mammalian axon is ~70 mV negative to the exterior • Essentially a K+ Nernst potential based • These ionic gradients are maintained by the Na+, K+-ATPase • In response to depolarization to a threshold level, an action potential (AP) is initiated locally • The AP consists of two phases: • rapid increase in the permeability of Na+ • rapid inactivation of the Na+ channel and the delayed opening of a K+ channel • Tetrodotoxn, Saxitoxin and Batrachotoxin
    25. 25. Junctional Transmission - Steps • Arrival of the AP at the axonal terminals initiates a series of events that trigger – transmission of excitatory or inhibitory: 1. Release of stored Transmitter (prejunctional regulation) – • Cotransmission: enzymes, other proteins, and cotransmitters (e.g.,ATP, NPY) • autoreceptors and heteroreceptors - M2 and M4 and ɑ2A, ɑ2B and ɑ2C 2. Combination of the transmitter with postjunctional receptors and production of the postjunctional potential • EPSP and IPSP 3. Initiation of postjunctional activity 4. Termination of transmitter action – NET, SERT, DT
    26. 26. Junctional Transmission Steps - Image
    27. 27. Sites of Cholinergic Transmission Acetylcholine (Ach) is major neurohumoral transmitter at autonomic, somatic and central nervous system: 1. All preganglionic sites (Both Parasympathetic and sympathetic) 2. All Postganglionic Parasympathetic sites and sympathetic to sweat gland and some blood vessels 3. Skeletal Muscles 4. CNS: Cortex Basal ganglia, spinal chord and others Parasympathetic Stimulation – Acetylcholine (Ach) release at neuroeffector junction - biological effects Sympathetic stimulation – Noradrenaline (NA) at neuroeffector junction - biological effects
    28. 28. Cholinergic Transmission – Synthesis: • Cholinergic neurons contain large numbers of small membrane-bound vesicles (containing ACh) concentrated near the synaptic portion of the cell membrane • ACh is synthesized in the cytoplasm from acetyl-CoA and choline by the catalytic action of Choline acetyltransferase (ChAT) • Acetyl-CoA is synthesized in mitochondria, which are present in large numbers in the nerve ending • 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 The action of the choline transporter is the rate-limiting step in ACh synthesis 1000-50000 and 300000
    29. 29. Cholinergic Transmission – Release: • 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 • Release is dependent on extracellular Ca2+ and occurs when an action potential reaches the terminal and triggers sufficient influx of Ca2+ ions • The increased Ca2+ concentration "destabilizes" the storage vesicles by interacting with special proteins associated with the vesicular membrane (VAMPs and SNAP- synaptosome associated protein) Fusion of the vesicular membranes with the terminal membrane results in exocytotic expulsion of ACh into the synaptic cleft • 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??
    30. 30. Cholinergic Transmission: Destruction • After release - ACh molecules may bind to and activate an ACh receptor (cholinoceptor) • Eventually (and usually very rapidly), all of the ACh released will diffuse within range of an acetylcholinesterase (AChE) molecule • AChE very efficiently splits ACh into choline and acetate, neither of which has significant transmitter effect, and thereby terminates the action of the transmitter. • 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. • Another cholinesterase with a lower specificity for ACh, butyrylcholinesterase [pseudo cholinesterase], is found in blood plasma, liver, glial, and many other tissues
    31. 31. True Vs Pseudo AChE 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 Function Termination of Ach action Hydrolysis of Ingested Esters Inhibition More sensitive to Physostigmine More sensitive to Organophosphates
    32. 32. Cholinergic receptors - 2 types • Muscarinic (M) and Nicotinic (N): Muscarinic (M) - GPCR Nicotinic (N) – ligand gated
    33. 33. Muscarinic Receptors ?? 1. Selectively stimulated by Muscarine and blocked by Atropine – all are G-protein coupled receptors 2. Primarily located in heart, eye, smooth muscles and glands of GIT 3. Subsidiary M receptors are also present in ganglia for modulation – long lasting late EPSP 4. Autoreceptors (M type) are present in prejunctional cholinergic Nerve endings – also in adrenergic nerve terminals leading to vasodilatation when Ach is injected 5. Blood vessels: All blood vessels have muscarninc receptors although no cholinergic innervations
    34. 34. Muscarinic Receptors - Subtypes • Pharmacologically - M1, M2, M3, M4 and M5 • M4 and M5 are present in certain areas of Brain and regulate other neurotransmitters • M1, M3 and M5 fall in one class, while M2 and M4 in another class • However - M1, M2 and M3 are major ones and present in effector cell and prejunctional nerve endings in CNS • All subtypes have little agonist selectivity but selective antagonist selectivity • Most organs usually have more than one subtype but one subtype predominates in a tissue
    35. 35. Muscarinic Receptors - Location • M1: Ganglion Cells and Central Neurons (cortex, hippocampus, corpus striatum) – Physiological Role: Mediation of Gastric acid secretion and relaxation of LES (vagal) • Learning, memory and motor functions • M2: Cardiac Muscarinic receptors – Mediate vagal bradycardia – Also auto receptors in cholinergic nerve endings • M3: Visceral smooth muscles, glands and vascular endothelium. Also Iris and Ciliary muscles
    36. 36. 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 Methacholine Bethanechol Antagonists Pirenzepine Methoctramine & Triptramine Darifenacin Transducer IP3/DAG and PLA2 increase – Ca++ and PG K+ channel opening and decresed cAMP IP3/DAG and PLA2 increase – Ca++ and PG
    37. 37. Acetylcholine (cholinergic receptors) – Muscarinic Receptors • Selectively stimulated by Muscarine and blocked by Atropine M1 M2 M3 Ganglia and CNS Heart Glands and Smooth Muscles
    38. 38. Nicotinic (N) Receptors • Nicotinic receptors: nicotinic actions of ACh are those that can be reproduced by the injection of Nicotine (Nicotiana tabacum) – Can be blocked by tubocurarine and hexamethonium • ligand-gated ion channels – activation results in a rapid increase in cellular permeability to Na+ and Ca++ resulting - depolarization and initiation of action potential
    39. 39. Nicotinic Receptors - NM Vs NN NM (Muscle type) 1. Location: Skeletal Muscle end plates 2. Function: Stimulate skeletal muscle (contraction) 3. MOA: Postsynaptic and Excitatory (increases Na+ and K+ permeability) 4. Agonists: ACh, carbachol (CCh), suxamethonium – Selective stimulation by phenyl trimethyl ammonium (PTMA) 5. Antagonists: tubocurarine, Atracurium, vecuronium and pancuronium NN (Ganglion type) 1. Location: In autonomic ganglia of all type (ganglion type) – Sympathetic, Parasympathetic and also Adrenal Medulla 2. Function: Depolarization and postganglionic impulse – stimulate all autonomic ganglia 3. MOA: Excitatory – Na+, K+ and Ca+ channel opening 4. Agonists: ACh, CCh, nicotine – Selectively stimulated by Dimethyl phenyl piperazinium (DMPP) 5. Antagonists: Trimethaphan, Mecamylamine and Hexamethonium
    40. 40. Cholinergic Drugs or Cholinomimetic or Parasympathomimetics Drugs producing actions similar to Acetylcholine by – 1) interacting with Cholinergic receptors or 2) increasing availability of Acetylcholine at these sites
    41. 41. Question…? • What side effects might you expect to see in a patient taking a cholinergic drug? • Hint… Cholinergic = “Colon-Urgent”
    42. 42. Classifiction - Direct-acting (receptor agonists) • Choline Esters – Natural: Acetylcholine (Ach) – Synthetic: Methacholine, Carbachol and Bethanechol • Alkaloids: Pilocarpine, Muscarine, Arecholine – Synthetic: Oxotremorine
    43. 43. Cholinergic Drugs – Indirect acting • Cholinesterase inhibitors or reversible anticholinesterases: 1. Natural: Physostigmine 2. Synthetic: Neostigmine, Pyridostigmine, Distigmine, Rivastigmine, Donepezil, Gallantamine, Edrophonium, Ambenonium, Demecarium • Irreversible anticholinesterases: 1. Organophosphorous Compounds (OPC) – Diisopropyl fluorophosphate (DFP), Ecothiophate, Parathion, malathion, diazinon (insecticides and pesticides) 2. Tabun, sarin, soman (nerve gases in war) 3. Carbamate Esters: Carbaryl and Propoxur (Baygon)
    44. 44. ACh actions – Muscarinic 1. Heart: M2 – SA node hyperpolarization (decrease in rate of diastolic depolarizaton) - reduction in impulse generation and Bradycardia – AVN and PF – RP is increased – slowing of conduction – partial/complete heart block – Atrial fibres: Reduction in force of contraction and RP in fibers abbreviated – Atrial fibrillation and flutter – nonuniform vagal innervations and variation in intensity of effect on RP in diferent atrial fibres – Decrease in ventricular contractility (less prominent) 2. Blood Vessels: M3 – Cholinergic innervations is limited – skin of face and neck – But, M3 present in all type blood vessel – Vasodilatation by Nitric oxide (NO) release – fall in BP and flushing – Penile erection
    45. 45. Muscarinic action – contd. 3. Smooth Muscles: M3 - All are contracted – Abdominal cramps, diarrhoea – due to increased peristalsis and relaxed sphincters – Voiding of Bladder – Bronchial SM contraction – dyspnoea, attack of asthma etc. 4. Glands: M3 – Increased secretions: sweating, salivation, lacrimation, tracheobronchial tree and gastric glands – Pancratic and intestinal glands – less prominen 5. Eye: M3 – Contraction of circular fibres of Iris – miosis – Contraction of Ciliary muscles – spasm of accommodation, increased outflow and reduction in IOP
    46. 46. Ach actions – Nicotinic 1. Autonomic ganglia: – Both Sympathetic and parasympathetic ganglia are stimulated – After atropine injection Ach causes tachycardia and rise in BP 2. Skeletal muscle – IV injection – no effect – Application causes contraction of skeletal muscle 3. CNS: – Does not penetrate BBB – Local injection in CNS – complex actions (Acetylcholine is not used therapeutically – non specific) Bethanecol Uses: Postoperative and postpartum urinary obstruction, neurogenic bladder and GERD (10-40 mg oral)
    47. 47. Pilocarpine • Alkaloid from leaves of Jaborandi (Pilocarpus microphyllus) • Prominent muscarinic actions • Profuse salivation, lacrimation, sweating • Dilates blood vessels, causes hypotension • High doses: Rise in BP and tachycardia (ganglionic action) • On Eyes: produces miosis and spasm of accommodation • Lowers intraocular pressure (IOP) in Glaucoma when applied as eye drops • Too toxic for systemic use – CNS toxicity • Diaphoretic (?), xerostomia and Sjögren’s syndrome
    48. 48. Pilocarpine – contd. 1. Used as eye drops in treatment of wide angle glaucoma to reduce IOP 2. To reverse mydriatic effect of atropine 3. To break adhesion between iris and cornea/lens alternated with mydriatic • Pilocarpine nitrate eye drops ( 1 to 4% ) • Atropine used as antidote in acute pilocarpine poisoning ( 1- 2 mg IV 8 hrly )
    49. 49. Pilocarpine in Glaucoma • Constriction of circular muscle of Iris • Contraction of ciliary muscle • Spasm of accomodation – fixed at near vision
    50. 50. Muscarine • Alkaloid from mushroom Amanita muscaria • Only muscarinic actions • No clinical use • Mushroom poisoning due to ingestion of poisonous mushroom 1. Early onset mushroom poisoning (Muscarine type) 2. Late onset mushroom poisoning 3. Hallucinogenic type
    51. 51. Mushroom Poisoning • Early Onset Mushroom Poisoning: Occurs ½ to 1 hour – Symptoms are characteristic of Muscarinic actions – Inocybe or Clitocybe – severe cholinergic symptoms like vomiting, salivation, lacrimation, headache, bronchospasm, diarrhoea bradycardia, dyspnoea, hypotension, weakness, cardiovascular collapse, convulsions and coma – Antidote is Atropine sulphate ( 2-3 mg IM every hrly till improvement) • Hallucinogenic type: due to Muscimol or ibotenic acid present in A. muscria. Blocks muscarinic receptors in brain and activate amino acid receptors. No specific treatment – Atropine is contraindicated.
    52. 52. Late Onset Mushroom Poisoning • Occurs within 6 - 15 hours • Amanita phylloides (deadly nightcap)– due to peptide toxins – Inhibit RNA polymerase II and therefore mRNA synthesis • Irritability, restlessness, nausea, vomiting, bloody diarrhoea ataxia, hallucination, delirium, sedation, drowsiness and sleep – Kidney, liver and GIT mucosal damage • Maintain blood pressure, respiration • Inj. Diazepam 5 mg IM • Atropine contraindicated as it may cause convulsions and death - penicillin, thioctic acid and silibinin (antidote?) • Gastric lavage and activated charcoal
    53. 53. Cholinergic Drugs – Indirect acting • Cholinesterase inhibitors or reversible anticholinesterases: 1. Natural: Physostigmine 2. Synthetic: Neostigmine, Pyridostigmine, Distigmine, Rivastigmine, Donepezil, Gallantamine, Edrophonium, Ambenonium, Demecarium Tertiary amine N (lipid soluble) and quartenary N+ (lipid insoluble) • Irreversible anticholinesterases: 1. Organophosphorous Compounds (OPC) – Diisopropyl fluorophosphate (DFP), Ecothiophate, Parathion, malathion, diazinon (insecticides and pesticides) 2. Tabun, sarin, soman (nerve gases in war) 3. Carbamate Esters: Carbaryl and Propoxur (Baygon)
    54. 54. AChEs - MOA • Normally Acetylcholinesterase (AchE) hydrolyses Acetylcholine • The active site of AChE is made up of two subsites – anionic and esteratic • The anionic site serves to bind a molecule of ACh to the enzyme • Once the ACh is bound, the hydrolytic reaction occurs at a second region of the active site called the esteratic subsite • The AChE itself gets acetylated at serine site • Acetylated enzyme reacts + water = acetic acid and choline • Choline - immediately taken up again by the high affinity choline uptake system presynaptic membrane Glutamate and histidine Tryptophan
    55. 55. AChEs - MOA • Anticholinesterases also react with the enzyme ChEs in similar fashion like Acetylcholine • Carbamates – carbamoylates the active site of the enzyme • Phosphates – Phosphorylates the enzyme • Both react similar fashion covalently with serine • 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) • But, Phosphorylated (irreversible) reacts extremely slowly or not at all – takes more time than synthesis of fresh enzyme – Sometimes phosphorylated enzyme losses one alkyl group and become resistant to hydrolysis – aging • Edrophonium and tacrine reacts only at anionic site – short acting while Organophosphates reacts only at esteratic site
    56. 56. Anticholinesterases – Individual Drugs • 2 (two) important clinically used drugs – – Physostigmine – lipid soluble, ganglion acting and less action in skeletal muscle • Also organophosphates – Neostigmine – lipid insoluble, skeletal muscle acting
    57. 57. Physostigmine • Alkaloid from dried ripe seed (Calabar bean) of African plant Physostigma venenosum • Tertiary amine, lipid soluble, well absorbed orally and crosses BBB • Hydrolyzed in liver and plasma by esterases • Long lasting action (4-8 hours) • It indirectly prevents destruction of acetylcholine released from cholinergic nerve endings and causes ACh accumulation • Muscarinic action on eye causing miosis and spasm of accommodation on local application • Salivation, lacrimation, sweating and increased tracheobronchial secretions • Increased heart rate & hypotension
    58. 58. Physostigmine - uses 1. Used as miotic drops to decrease IOP in Glaucoma 2. To antagonize mydriatic effect of atropine 3. To break adhesions between iris and cornea alternating with mydriatic drops 4. Belladonna poisoning, TCAs & Phenothiazine poisoning 5. Alzheimer’s disease- pre-senile or senile dementia 6. Atropine is antidote in physostigmine poisoning. ADRs – CNS stimulation followed by depression
    59. 59. Neostigmine • Synthetic reversible anticholinesterase drug • Quaternary ammonium compound and lipid insoluble • Cannot cross BBB • Hydrolysed by esterases in liver & plasma • Short duration of action (3-5 hours) • Direct action on nicotinic (NM) receptors present in neuromuscular junction (motor end plate) of skeletal muscle • Antagonises (reverses) skeletal muscle relaxation (paralysis) caused by tubocurarine and other competitive neuromuscular blockers • Stimulates autonomic ganglia in small doses - Large doses block ganglionic transmission • No CNS effects
    60. 60. Neostigmine – Uses and ADRs • Used in the treatment of Myasthenia Gravis to increase muscle strength • Post-operative reversal of neuromuscular blockade • Post-operative complications – gastric atony paralytic ileus, urinary bladder atony • Cobra snake bite • Produces twitchings & fasciculations of muscles leading to weakness • Atropine is the antidote in acute neostigmine poisoning
    61. 61. Physostigmine Vs Neostigmine 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
    62. 62. Myasthenia gravis (Myo + asthenia) • Autoimmune disorder affecting 1 in 10,000 population (?) – reduction in number of NM receptors • Causes: Development of antibodies directed to Nicotinic receptors in muscle end plate – reduction in number by 1/3rd of NM receptors – Structural damage to NM junction • Symptoms: Weakness and easy fatigability – ptosis to diaphragmatic paralysis • Treatment: – Neostigmine – 15 to 30 mg. orally every 6 hrly – Adjusted according to the response – Pyridostigmine – less frequency of dosing – Other drugs: Corticosteroids (prednisolone 30-60 mg /day) • Azathioprin and cyclosporin also Plasmapheresis
    63. 63. Myasthenic crisis • Acute weakness and respiratory paralysis – Tracheobronchial intubation and mechnical ventilation – Methylprednisolone IV with withdrawal of AChE – Gradual reintroduction of AChE – Thymectomy • The problem – overtreatment Vs actual disease (opposite treatments) – Diagnosis by various tests – Tensilon Test – Injection of Edrophonium – 2 mg (observe) – after half a minute 8 mg (observe) • In MG – symptoms will improve • In overtreatment – symptoms worsen
    64. 64. Overall Therapeutic Uses – cholinergic drugs 1. Myasthenia gravis: Edrophonium to diagnose and Neostigmine, Pyridostigmine & Distigmine to treat 2. To stimulate bladder & bowel after surgery: – Bethanechol, Carbachol, Distigmine. 3. To lower IOP in chronic simple glaucoma: – Pilocarpine, Physostigmine 4. To improve cognitive function in Alzheimer’s disease: Rivastigmine, Gallantamine, Donepezil. 5. Physostigmine in Belladonna poisoning 6. Cobra Bite
    65. 65. Pharmacotherapy of Organo[hosphate Poisoning • Signs and symptoms: 1. Irritationof eye, lacrmation, salivation, tracheo-bronchial secretions, colic, blurring of vision, defaecation and urination 2. Fall in BP, tachy or bradycardia and CVS collapse 3. Muscular fasciculations, weakness, and respiratory paralysis 4. Excitement, tremor, convulsins and coma • Treatment: – Decontamination – gastric lavage if needed – Airway maintenance – Supportive measures – for BP/fluid and electrolyte – Specifc antidote – Atropine – 2mg IV every 10 minutes till dryness of mouth or atropinization (upto 200 mg/day)
    66. 66. Cholinesterase Reactivators - Oximes • Pralidoxime (2-PAM) and Obidoxime Diacetyl monoxime (DAM) • Oximes have generic formula R-CH=N-OH • Provides reactive group OH to the enzymes to reactivate the phosphorylated enzymes – million times faster • PAM: – Quaternary Nitrogen of PAM gets attaches to Anionic site of the enzyme and reacts with Phosphorous atom at esteratic site – Forms Oxime-phosphonate complex making esteratic site free – Not effective in Carbamate poisoning – Dose: 1-2 gm IV slowly maximum 12 gms/24 hrs
    67. 67. Summary • Biosynthesis of Acetylcholine • Distribution of Muscarinic and Nicotinic receptors • Classification of Anticholinesterases • Mechanism of action of Anticholinesterases and Aging • Action of cholinomimetics on eye • Physostigmine Vs Neostigmine • Myasthenia gravis • Neostigmine and its uses • Use of Edrophonium • Oximes • Alzheimer`s disease drug names
    68. 68. Khublei Shibun/Thank you