ANS Pharmacology and Cholinergic Drugs

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Autonomic Pharmacology

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Drugs acting on Autonomic Nervous System - “Autonomic Pharmacology” : 

Drugs acting on Autonomic Nervous System - “Autonomic Pharmacology” Dr. D. K. Brahma Department of Pharmacology NEIGRIHMS, Shillong

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Autonomic Drugs are very much Clinically Relevant

Goal ! : 

Goal ! To Learn about the drugs affecting the autonomic nervous system Be prepared to link mechanism of drug action with knowledge anatomy, physiology and neurobiology mainly of cardiovascular to predict effects of drugs

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Autonomic drugs are used for the treatment of Angina

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Autonomic drugs are used for the treatment of Heart Failure

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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

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+ 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 R

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+ 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

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+ 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

For a definite clinical outcome! : 

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 +

Organization ofNervous System - Recall : 

Organization ofNervous 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”

The Autonomic Nervous System : 

The Autonomic Nervous System ANS together with somatic motor pathways and neuroendocrine pathways, are the means whereby the central nervous system (CNS) sends commands to the rest of the body ANS - Functions below the level of consciousness 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 – the endocrine system , the other major system for control of Body function is more generalized

Somatic Vs Autonomic : 

Somatic Vs Autonomic

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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 &

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Like Somatic Nervous System, the ANS also consists of: Afferents Central connections Efferents

ANS Organization – Autonomic afferents : 

ANS Organization – Autonomic afferents Afferent fibers from visceral structures – are the first link in the reflex arcs of the autonomic system 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 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

ANS – Central connections : 

ANS – Central connections No Exclusive autonomic area in CNS Intermixing - somatic responses always are accompanied by visceral responses, and vice versa Sympathetic – Lateral and Posterior nuclei; Parasympathetic – Anterior and Medial nuclei Hypothalamus and STN - are the organs to regulate Highly integrated pattern of responses are organized in hypothalamus autonomic, endocrine, and behavioral components Limited patterned responses organized at - forebrain, brainstem, and spinal cord

ANS – Efferent fibres : 

ANS – Efferent fibres Motor limb Anatomically - 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

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Sympathetic Nervous System (Thoracolumbar Outflow) - paravertebral, prevertebral and terminal Parasympathetic: Craniosacral outflow

Sympathetic Vs Parasympathetic : 

Sympathetic Vs Parasympathetic SYMPATHETIC Fight or Flight Mydriasis, Bronchodilatation, Increase BP, HR, glucose, perfusion to skeletal muscles PARASYMPATHETIC Rest and Digest Miosis, decreased HR, BP, bronchia secretion, Insulin release, Digestion, excretion

Enteric Nervous System : 

Enteric Nervous System Considered 3rd Division of ANS Receives inputs from both sympathetic and parasympthetic systems But functions independently to regulate bowel movements, secretion ad absorption

Transmitters in Nervous system : 

Transmitters in Nervous system All preganglionic - Acetylcholine (Ach) - Both Sympathetic and Parasympathetic Post ganglionic Para sympathetic- Acetylcholine (Ach) Postganlionic Sympathetic - norepinephrine (NE, noradrenaline) Somatic (Muscle) - ACh

ANS Receptors - Gross : 

ANS Receptors - Gross Parasympathetic: Preganglionic: Nicotinic (NN) Ach Postganglionic: Muscarininic (M) Sympathetic: Preganglionic: Nicotinic (NN) Ach Postganglionic : Noradrenergic (NA) - ɑ and ß (alpha and beta) Adrenal medulla Preganglionic: Nicotinic (NN) Ach and Postganglionic - Adrenaline in blood stream

What Happens at the Effectors? : 

What Happens at the Effectors? NE from postganglionic sympathetics binds to Adrenergic Receptors ACh from postganglionic parasympathetics binds to Muscarinic Receptors ACh Muscarinic Receptor NE Adrenergic Receptor Sympathetic Parasympathetic

Neurotransmission : 

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.

Axonal Conduction : 

Axonal Conduction Impulse conduction: At rest, the interior of the typical mammalian axon is ~70 mV negative to the exterior - essentially due to high K+ potential permeability On arrival of electrical impulse – sudden rise in Na+ - depolarization (+20 mV) K+ moves according to conc. Gradient – ionic gradient normalized by Na+ K+ pump In response to depolarization to a threshold level, an action potential (AP) is initiated locally – sets up local current Tetrodotoxn, Saxitoxin and Batrachotoxin

Transmitter release : 

Transmitter release The transmitter (excitatory or inhibitory) – stored in vesicles Nerve impulse promotes fusion of vesicles with axonal membrane – fluidizes membrane Exocytosis of all contents (transmitter, enzymes and proteins) - Synaptogamin, synaptobrevin, neurexin, syntaxin, synaptophysin etc. – participate Feed back mechanism: Release is modulated by transmitter itself (ɑ2)– NA by NA, Dopamine, adenosine PG and enkephalin. Isoprenalin (beta-2) and angiotensin (AT1) – increases NA release ɑ2 and muscarinic agonists inhibit Ach release at NE junction

Neurohumoral transmission – contd. : 

Neurohumoral transmission – contd. Transmitter action on postjunctional membrane: Released transmitter – combines with specific receptors on postjunctional membrane and according to nature EPSP: increased permeability to cations (Ca+ and Na+) - depolarization IPSP: increased permeability to anions (Cl-) – stabilization or hyperpolarization Postjunctional activity: Nerve impulse, or contraction in muscles, or secretions Termination of transmitter action: Locally degraded (Ach) Taken back by axonal active uptake (NA) – carrier proteins like NET, DAT, SERT etc. Diffusion (NA)

Criteria of Neurohumoral transmitter : 

Criteria of Neurohumoral transmitter Should be present in presynaptic neurone along with enzymes synthesizing it Should be released in the medium following nerve stimulation Its application should produce responses identical to nerve stimulation Its effect should be antagonized or potentiated by other agents

Junctional Transmission Steps - Image : 

Junctional Transmission Steps - Image

Cotransmission : 

Cotransmission One Transmitter Model – over simplification Most PNS and CNS - Release more than one active substance Sympathetic – ATP, NPY, DA and ACh Parasympathetic – ATP, VIP and NO (Nitrergic nerves) Cotransmitters may – regulate primary transmitter release or act as alternative transmitter NANC: Demonstrated in gut, vas deferens, UT, salivary glands and BV – limited response evoked Guniea pig vas deferens – on stimulation of sympathetic nerve - 2 phase response by ATP followed by NA

Remember ! : 

Remember ! All preganglionic – Nicotinic (NN) Postganglionic parasympathetic – Muscarinic (M) Postganglionic Sympathetic – Noradrenergic (NA) - ɑ and ß types

NEXT CLASS : 

NEXT CLASS CHOLINERGIC DRUGS

Slide 34: 

Cholinergic System and Cholinergic Drugs

Sites of Cholinergic Transmission : 

Sites of Cholinergic Transmission Acetylcholine (Ach) is major neurohumoral transmitter at autonomic, somatic and central nervous system: All preganglionic sites (Both Parasympathetic and sympathetic) All Postganglionic Parasympathetic sites and sympathetic to sweat gland and some blood vessels Skeletal Muscles 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

Slide 36: 

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 Na+-dependent membrane choline cotransporter (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

Slide 37: 

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??

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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

True Vs Pseudo AChE : 

True Vs Pseudo AChE

Cholinergic receptors - 2 types : 

Cholinergic receptors - 2 types Muscarinic (M) and Nicotinic (N): Muscarinic (M) - GPCR Nicotinic (N) – ligand gated

Types of Cholinergic Transmission : 

Types of Cholinergic Transmission

Muscarinic Receptors ?? : 

Muscarinic Receptors ?? Selectively stimulated by Muscarine and blocked by Atropine – all are G-protein coupled receptors Primarily located in heart, eye, smooth muscles and glands of GIT Subsidiary M receptors are also present in ganglia for modulation – long lasting late EPSP Autoreceptors (M type) are present in prejunctional cholinergic Nerve endings also in adrenergic nerve terminals leading to vasodilatation when Ach is injected Blood vessels: All blood vessels have muscarninc receptors although no cholinergic innervations

Muscarinic Receptors - Subtypes : 

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

Muscarinic Receptors - Location : 

Muscarinic Receptors - Location M1: Autonomic ganglion Cells, Gastric glands 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

Muscarinic Receptor Subtypes : 

Muscarinic Receptor Subtypes

Acetylcholine (cholinergic receptors) – Muscarinic Receptors : 

Acetylcholine (cholinergic receptors) – Muscarinic Receptors Selectively stimulated by Muscarine and blocked by Atropine

Nicotinic (N) Receptors : 

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

Nicotinic Receptors - NM Vs NN : 

Nicotinic Receptors - NM Vs NN NM (Muscle type) Location: Skeletal Muscle end plates Function: Stimulate skeletal muscle (contraction) MOA: Postsynaptic and Excitatory (opening of cations Na+, K+ etc.) Agonists: ACh, carbachol (CCh), suxamethonium Selective stimulation by phenyl trimethyl ammonium (PTMA) Antagonists: tubocurarine, Atracurium, vecuronium and pancuronium NN (Ganglion type) Location: In autonomic ganglia of all type (ganglion type) – Sympathetic, Parasympathetic and also Adrenal Medulla Function: Depolarization and postganglionic impulse – stimulate all autonomic ganglia MOA: Opening of Na+, K+ and Ca+ channel opening Agonists: ACh, CCh, nicotine Selectively stimulated by Dimethyl phenyl piperazinium (DMPP) Antagonists: Trimethaphan, Mecamylamine and Hexamethonium

Question ? : 

Question ? A person is having severe cholinergic symptoms like vomiting, salivation and lacrimation etc. after accidental consumption of poisonous mushroom. What subtype of receptor is involved in the mediation of such reaction of Muscarine???? Answer: M3

Cholinergic Drugs or Cholinomimetic or Parasympathomimetics : 

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

Question…? : 

Question…? What side effects might you expect to see in a patient taking a cholinergic drug? Hint… Cholinergic = “Colon-Urgent”

Classifiction - Direct-acting (receptor agonists) : 

Classifiction - Direct-acting (receptor agonists) Choline Esters Natural: Acetylcholine (Ach) Synthetic: Methacholine, Carbachol and Bethanechol Alkaloids: Pilocarpine, Muscarine, Arecholine Synthetic: Oxotremorine

Cholinergic Drugs – Indirect acting : 

Cholinergic Drugs – Indirect acting Cholinesterase inhibitors or reversible anticholinesterases: Natural: Physostigmine Synthetic: Neostigmine, Pyridostigmine, Distigmine, Rivastigmine, Donepezil, Gallantamine, Edrophonium, Ambenonium, Demecarium Irreversible anticholinesterases: Organophosphorous Compounds (OPC) – Diisopropyl fluorophosphate (DFP), Ecothiophate, Parathion, malathion, diazinon (insecticides and pesticides) Tabun, sarin, soman (nerve gases in war) Carbamate Esters: Carbaryl and Propoxur (Baygon)

ACh actions – Muscarinic : 

ACh actions – Muscarinic 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) Blood Vessels: M3 Cholinergic innervations is limited – skin of face and neck - fall in BP and flushing But, M3 present in all type blood vessel – Vasodilatation by Nitric oxide (NO) release (PLc-IP3/DAG) Penile erection

Muscarinic action – contd. : 

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. Glands: M3 Increased secretions: sweating, salivation, lacrimation, tracheobronchial tree and gastric glands Pancratic and intestinal glands – less prominen Eye: M3 Contraction of circular fibres of Iris – miosis Contraction of Ciliary muscles – spasm of accommodation, increased outflow and reduction in IOP

Ach actions – Nicotinic : 

Ach actions – Nicotinic Autonomic ganglia: Both Sympathetic and parasympathetic ganglia are stimulated After atropine injection Ach causes tachycardia and rise in BP Skeletal muscle IV injection – no effect Application causes contraction of skeletal muscle 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), Congenital megacolon

Pilocarpine : 

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

Pilocarpine – contd. : 

Pilocarpine – contd. Used as eye drops in treatment of wide angle glaucoma to reduce IOP To reverse mydriatic effect of atropine 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 )

Pilocarpine in Glaucoma : 

Pilocarpine in Glaucoma Constriction of circular muscle of Iris Contraction of ciliary muscle Spasm of accomodation – fixed at near vision

Muscarine : 

Muscarine Alkaloid from mushroom Amanita muscaria Only muscarinic actions No clinical use Mushroom poisoning due to ingestion of poisonous mushroom Early onset mushroom poisoning (Muscarine type) Late onset mushroom poisoning Hallucinogenic type

Mushroom Poisoning : 

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.

Late Onset Mushroom Poisoning : 

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

Cholinergic Drugs – Indirect acting : 

Cholinergic Drugs – Indirect acting Cholinesterase inhibitors or reversible anticholinesterases: Natural: Physostigmine Synthetic: Neostigmine, Pyridostigmine, Distigmine, Rivastigmine, Donepezil, Gallantamine, Edrophonium, Ambenonium, Demecarium Tertiary amine N (lipid soluble) and quartenary N+ (lipid insoluble) Irreversible anticholinesterases: Organophosphorous Compounds (OPC) – Diisopropyl fluorophosphate (DFP), Ecothiophate, Parathion, malathion, diazinon (insecticides and pesticides) Tabun, sarin, soman (nerve gases in war) Carbamate Esters: Carbaryl and Propoxur (Baygon)

AChEs - MOA : 

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

AChEs - MOA : 

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

Anticholinesterases – Individual Drugs : 

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

Physostigmine : 

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

Physostigmine - uses : 

Physostigmine - uses Used as miotic drops to decrease IOP in Glaucoma To antagonize mydriatic effect of atropine To break adhesions between iris and cornea alternating with mydriatic drops Belladonna poisoning, TCAs & Phenothiazine poisoning Alzheimer’s disease- pre-senile or senile dementia Atropine is antidote in physostigmine poisoning. ADRs – CNS stimulation followed by depression

Neostigmine : 

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

Neostigmine – Uses and ADRs : 

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

Physostigmine Vs Neostigmine : 

Physostigmine Vs Neostigmine

Myasthenia gravis (Myo + asthenia) : 

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

Myasthenic crisis : 

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

Overall Therapeutic Uses – cholinergic drugs : 

Overall Therapeutic Uses – cholinergic drugs Myasthenia gravis: Edrophonium to diagnose and Neostigmine, Pyridostigmine & Distigmine to treat To stimulate bladder & bowel after surgery: Bethanechol, Carbachol, Distigmine. To lower IOP in chronic simple glaucoma: Pilocarpine, Physostigmine To improve cognitive function in Alzheimer’s disease: Rivastigmine, Gallantamine, Donepezil. Physostigmine in Belladonna poisoning Cobra Bite

Pharmacotherapy of Organophosphate Poisoning : 

Pharmacotherapy of Organophosphate Poisoning Complex effects – Muscarinic, Nicotinic and CNS Signs and symptoms: Irritationof eye, lacrmation, salivation, tracheo-bronchial secretions, colic, blurring of vision, defaecation and urination Fall in BP, tachy or bradycardia and CVS collapse Muscular fasciculations, weakness, and respiratory paralysis Irritability, disorientation, ataxia, tremor, convulsins and coma Treatment: Decontamination – gastric lavage if needed Airway maintenance – endotrachial intubation 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)

Cholinesterase Reactivators – Oximes : 

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 and 20-30 mg/kg/hour continuous IV infusion.

Summary : 

Summary 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

Slide 78: 

Khublei Shibun/Thank you

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