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Cholinergic Pharmacology and Cholinergic Drugs 2017

Muscarine is an alkaloid found in the Amanita muscaria mushroom that causes only muscarinic effects. It can cause profuse salivation, lacrimation, sweating, blood vessel dilation and hypotension, miosis, and spasm of accommodation in the eyes. Mushroom poisoning may occur due to ingestion of poisonous mushrooms containing toxins like muscarine, amatoxins, or gyromitrins. Early onset poisoning features muscarinic symptoms like excessive sweating and salivation within 1-2 hours.

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CHOLINERGIC SYSTEM AND CHOLINERGIC DRUGS Dr. D. K. Brahma Associate Professor of Pharmacology NEIGRIHMS, Shillong
SympatheticVs Parasympathetic • SYMPATHETIC Fight or Flight • Increase BP & HR, glucose, perfusion to skeletal muscles, Mydriasis, Bronchodilatation • PARASYMPATHETIC Rest and Digest • Miosis, decreased HR, BP, bronchia secretion, Insulin release, Digestion, excretion
Sympathetic Nervous System (Thoracolumbar Outflow) - paravertebral, prevertebral and terminal Parasympathetic: Craniosacral outflow
Sites of CholinergicTransmission - Summary 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
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
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??
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 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 actio Hydrolysis of Ingested Esters Inhibition More sensitive to Physostigmine More sensitive to Organophosphates
Cholinergic receptors - 2 types • Muscarinic (M) and Nicotinic (N): Muscarinic (M) - GPCR Nicotinic (N) – ligand gated
Types of Cholinergic Transmission Site Receptor type Selective agonist Selective antagonist All postganglionic Parasympathetic and few postganglionic sympathetic to sweat gland some blood vessels Muscarinic Muscarine Atropine Ganglionic both symp. and parasymp. Nicotinic (NN) DMPP Heaxamethonium Skeletal Muscle Nicotinic (NM) PTMA D-tubocurarine CNS cortex, basal ganglia, spinal chord etc. Muscarinic Nicotinic Muscarine Carbachol Atropine d-tubocurarine
Muscarinic Receptors ?? 1. Selectively stimulated by Muscarine and blocked by Atropine – all are G- protein coupled receptors 2. Primarily located in autonomic effector cells in heart, eye, smooth muscles and glands of GIT and CNS 3. Subsidiary M receptors are also present in ganglia for modulation – long lasting late EPSP 4. Autoreceptors (M type) are present in postganglionic prejunctional cholinergic Nerve endings – inhibits ACh release 1.also in adrenergic nerve terminals (inhibits NA release) leading to vasodilatation when ACh is injected 5. Blood vessels: All blood vessels have muscarninc receptors although no cholinergic innervations – EDRF – SM relaxation -Vasodilatation
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 cells and prejunctional nerve endings in Peripheral organs and 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 • 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 • CNS –Tremor, analgesia • M3: Visceral smooth muscles, glands and vascular endothelium. Also Iris and Ciliary muscles
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 Depolarization (late EPSP) & Histamine release & acid secretion, relaxation of LES, CNS learning and motor functions Less impulse generation, less velocity of conduction, decreased contractility, less ACh release (auto) Visceral SM contraction, glandular secretions, Constriction of pupil, contraction of Cilliary muscle and vasodilatation (EDRF - NO)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 increase – Ca++ and PG synthesis
Acetylcholine (cholinergic receptors) – Muscarinic Receptors M1 M2 M3 Ganglia, gastric gland and CNS Heart Cholinergic Nerves Visceral Smooth Muscles, Iris and cilliary muscle Selectively stimulated by Muscarine and blocked by Atropine
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 • TWOTypes: NM and NN – based on location
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 (opening of cations Na+, K+ etc.) 4. Agonists: ACh, carbachol (CCh), suxamethonium – Selective stimulation by phenyl trimethyl ammonium (PTMA) 1. 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; Adrenal Medulla – Catecholamine release 3. MOA: Opening of Na+, K+ and Ca+ channel opening 4. Agonists: ACh, CCh, nicotine – Selectively stimulated by Dimethyl phenyl piperazinium (DMPP) 1. Antagonists: Trimethaphan, Mecamylamine and Hexamethonium
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 ….. ???? • Answer: M3
Question…? • What side effects might you expect to see in a patient taking a cholinergic drug? • Hint… • = “Colon-Urgent” ….Cholinergic
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
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 • Cholinesterase inhibitors or reversible anticholinesterases: 1. Natural: Physostigmine 2. Synthetic: Neostigmine, Pyridostigmine, Distigmine, Rivastigmine, Donepezil, Gallantamine, Edrophonium, Ambenonium, Demecarium 1.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)
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, APD increase – 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) 1. BloodVessels: 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. 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
Ach actions – Nicotinic 1. Autonomic ganglia: – Both Sympathetic and parasympathetic ganglia are stimulated – After atropine injection ACh causes tachycardia and rise in BP 1. 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), Congenital megacolon
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. 1. Used as eye drops in treatment of narrow 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 )
Pilocarpine in Glaucoma • Constriction of circular muscle of Iris • Contraction of ciliary muscle • Spasm of accommodation – fixed at near vision
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
Mushroom Poisoning • After the ingestion of mushrooms that contain toxins • Thousands of species of mushrooms, but only 100 species of mushrooms cause symptoms • 15-20 mushroom species are potentially lethal when ingested • As a result of misidentification of the mushroom by an amateur • Toxins: Amatoxin, Gyromitrins (monomethylhydrazine), Muscarine, Muscimol & ibotenic acid, Nephrotoxins (norleucine), Myotoxins, Immunoactive toxins, Hemolytic toxins and GI irritants
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 contraindicated.
Late Onset Mushroom Poisoning • Occurs within 6 - 15 hours • Amanita phylloides (deadly nightcap), Galerina– due to peptide toxins – Inhibit RNA and protein 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 DELAYED ONSETType (more than 24 Hours) – Nephrotoxic syndromes
Cholinergic Drugs – Indirect acting • Cholinesterase inhibitors or reversible anticholinesterases: 1. Natural: Physostigmine 2. Synthetic: Neostigmine, Pyridostigmine, Distigmine, Rivastigmine, Donepezil, Gallantamine, Edrophonium, Ambenonium, Demecarium 3. Acridine: Tacrine 1.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) Carbamates
AChEs - Chemistry • Either esters of Carbamic acid or derivative of Phosphoric acid • Carbamates: R1 – Nonpolar tertiary amino N – physostigmine (lipid soluble); Others – R1 quartenary amino N+ (lipid insoluble) • Organophosphates: All are highly lipid soluble except ecothiophate Carbamates Organophosphates
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 • Anticholinesterases also react with the enzyme ChEs in similar fashion like Acetylcholine • Carbamates – carbamylate the active site of the enzyme • Phosphates – Phosphorylate 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 react only at anionic site – short acting while Organophosphates react only at esteratic site
Anticholinesterases – Pharmacological actions • 2 (two) important clinically used drugs – – Physostigmine – Muscarinic and CNS action, lipid soluble, ganglion acting and less action in skeletal muscle • Also organophosphates – Neostigmine – lipid insoluble, skeletal muscle acting, stimulate ganglia, less muscarinic effect • Ganglia: Stimulate ganglia – muscarinic action – less prominent action • CVS: Complex; Muscarinic – bradycardia and hypotension; Ganglionic action – stimulation – increase HR and BP; Medullary centre – stimulation followed by depression …overall unpredictable • Skeletal Muscle: Ach is not quickly destroyed – rebinds to same receptors – repetitive firing – twitching and fasciculation; increases force of contraction in muscles
Physostigmine • Alkaloid from dry ripened 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) • Penetrates cornea readily on local application in eye - 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 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
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 • 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 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
Other Drugs • Pyridostigmine: Same as Neostigmine - less potent but longer acting • Edrophonium: Same as Neostigmine – shorter duration of action (1- - 30 minutes) – diagnostic use in MG • Tacrine: Acts like edrophonium, lipid soluble, crosses BBB – increases brain ACh – symptomatic improvement in Alzheimer`s disease (AD) • Rivastigmine, donepezil, galantamine – all used in AD
Myasthenia gravis (Myo + asthenia) • Autoimmune disorder affecting 1 in 10,000 population (?) – reduction in number of NM receptors • Symptoms: Weakness and easy fatigability – ptosis to diaphragmatic paralysis • 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
Myasthenia gravis – other drugs • 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) – immunosuppression • Inhibits production of NR antibodies and may increase synthesis or NRs • Azathioprin and cyclosporin also Plasmapheresis
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 – overtreatmentVs actual disease (opposite treatments) – Diagnosis by various tests – TensilonTest – Injection of Edrophonium – 2 mg (observe) – after half a minute 8 mg (observe) • In MG – symptoms will improve • In overtreatment – symptoms worsen
OverallTherapeutic 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. 1. To lower IOP in chronic simple glaucoma: – Pilocarpine, Physostigmine 1. To improve cognitive function in Alzheimer’s disease: Rivastigmine, Gallantamine, Donepezil. 2. Physostigmine in Belladonna poisoning 3. Cobra Bite
Pharmacotherapy of Organophosphate Poisoning • Complex effects – Muscarinic, Nicotinic and CNS • 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. Irritability, disorientation, ataxia, tremor, convulsins and coma • Treatment: 1. Decontamination and termination of further exposure – gastric lavage if needed 2. Airway maintenance – endotrachial intubation 3. Supportive measures – for BP/fluid and electrolyte 4. Specifc antidote – Atropine – 2mg IV every 10 minutes till dryness of mouth or atropinization (upto 200 mg/day)
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 • Distribution of Muscarinic and Nicotinic receptors • Classification of Anticholinesterases • Mechanism of action of Anticholinesterases and Aging • Action of cholinomimetics on eye • PhysostigmineVs Neostigmine • Myasthenia gravis • Neostigmine and its uses • Use of Edrophonium • Organophosphate poisoning • Oximes
Khublei Shibun/Thank you