Cholinergic Drugs Overview
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This document provides an overview of cholinergic drugs, which act on the parasympathetic nervous system. It begins with an introduction to cholinergic transmission and the discovery of acetylcholine. It describes the different types of cholinoceptors and their locations. The document then discusses the pharmacological actions of direct and indirect cholinergic drugs. It provides examples of therapeutic uses for various drugs in conditions like glaucoma and myasthenia gravis. Screening methods for cholinergic drugs are also summarized. The document concludes by stating that cholinergic pharmacology is an established field but further research is still needed for cognitive enhancing drugs.
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Cholinergic Drugs Overview
- 1. CHOLINERGIC DRUGS (PARASYMPATHOMIMETIC DRUGS) (CHOLINOMIMETIC DRUGS) Dr Prasheeta V Praviraj 2nd year MD Pharmacology Rangaraya Medical College 9/6/2016 1
- 2. CONTENTS • INTRODUCTION • PHARMACOLOGICAL ACTIONS • THERAPEUTIC USES • PHARMACOTHERAPY OF GLAUCOMA • PHARMACOLOGY OF MYASTHENIA GRAVIS • PHARMACOTHERAPY OF OP POISONING • SCREENING METHODS • CONCLUSION • REFERENCES 9/6/2016 2
- 3. INTRODUCTION • Autonomic nervous system for a long time occupied centre stage in pharmacology of chemical transmission. • 1869 - Actions of Muscarine & Atropine • 1905 - Actions of Nicotine & Curare : Langley • 1921 - Loewi “Vagustoff” : Frog heart • 1930 – Dale : leech dorsal muscle : Ach • Dale’s Principle : A mature neuron releases the same neurotransmitter at all of its synapses. 9/6/2016 3
- 4. CHOLINOCEPTORS 9/6/2016 4 Receptor Location Mechanism NM Neuromuscular junction Ion channel NN Autonomic ganglia Adrenal medulla CNS Ion channel
- 5. MUSCARINIC RECEPTORS 9/6/2016 5 Receptors Locations Mechanism M1 ANS , CNS Gq M2 Heart ,ganglia Gi M3 Smooth muscle ,glands, vascular endothelium Gg M4 CNS Gi M5 CNS Gq
- 7. CHOLINERGIC DRUGS Cholinergic Drugs Direct acting Muscarinic Nicotinic Indirect acting Organophosphates (Very long acting) 9/6/2016 7 Edrophonium (short acting) AlkaloidsCholine esters Carbamates (intermediate )
- 8. DIRECTLY ACTING CHOLINERGIC DRUGS • Choline esters: Acetylcholine Methacholine Carbachol Bethanechol • Natural alkaloids: Pilocarpine Muscarine Arecoline Nicotine • Synthetic agonists: Cevemiline Varenicline Oxotremorine Tremorine 9/6/2016 8
- 9. INDIRECTLY ACTING CHOLINERGIC DRUGS REVERSIBLE • Carbamates- Physostigmine , Neostigmine, Pyridostigmine , Edrophonium , Rivastigmine , Donepezil, Galantamine • Acridine-Tacrine IRREVERSIBLE • Organophophates – Dyflos , Echothiophate , Parathion Malathion , Diazinon , Tabun, Sarin , Soman • Carbamates – Carbaryl , Propoxur 9/6/2016 9
- 10. PHARMACOLOGIC ACTIONS • NICOTINIC ACTIONS 9/6/2016 10 ORGAN SYSTEM EFFECT/ACTION Central nervous system Complex stimulatory effects Autonomic nervous system Sympathetic and Parasympathetic ganglia stimulated Skeletal muscle Contraction
- 11. • MUSCARINIC ACTIONS 9/6/2016 11 ORGAN SYSTEM ACTIONS EYE Sphincter pupillae Ciliary muscle Miosis Cyclospasm , accomodation of near vision HEART SA node Atria AV node Ventricles Negative chronotropy Negative ionotropy Negative dromotropy Negative ionotropy BLOOD VESSELS Dilatation via release of EDRF from endothelium(NO) BRONCHI Bronchoconstriction GI TRACT Motility Sphincter Increases peristalisis Relaxation URINARY BLADDER Detrusor Trigone & sphincter Contraction Relaxation GLANDS Increases secretion
- 12. THERAPEUTIC USES CHOLINE ESTER -Bethanechol • Totally resistant to hydrolysis by both true and pseudocholinesterase 1. Reverse postop atony of bladder & combat urinary retention in neurogenic bladder 2. To revert post-op paralytic ileus & expel gases prior to X-ray 3. As an alternative to pilocarpine in Xerostomia • Contraindications 1. Hyperthyroidism 2. Bronchial asthma 3. Peptic ulcer 4. Myocardial infarction 9/6/2016 12
- 13. 9/6/2016 13 NATURAL ALKALOIDS-Pilocarpine •Pilocarpus jaborandi •Crosses blood brain barrier 1. Open angle glaucoma 2. Counteract mydriasis produced by atropine 3. Break adhesions in iridocyclitis 4. As a sialogogue in xerostomia • Side effects: Pulmonary edema SYNTHETIC DRUGS- Tremorine and Oxotremorine • investigative research tool- Parkinsonism model Cevemiline- Sjogrens syndrome • Side effect: decrease in central field visual acuity
- 14. Nicotine • Plant alkaloid – Nicotiana tobaccum • Fatal dose of nicotine=40mg • Psychic dependence • Smoking cessation therapy: nicotine patches, chewing gums , Varenicline • partial agonist at NN receptor and α4β2 • Act on mesolimbic – dopamine system ; reduce craving • Side effects: nausea, headache, insomnia Tetramethyl Ammonium(TMA) Dimethyl Piperazinium • Synthetic compounds –pharmacological tool 9/6/2016 14
- 15. ANTICHOLINESTERASES NATURAL ALKALOIDS-Physostigmine • Physostigma venonosum 1. Ophthalmic uses similar to pilocarpine 2. Belladona/atropine poisoning –specific antidote SYNTHETIC COMPOUNDS • Donot cross blood brain barrier • Direct agonistic action on Nm receptor Neostigmine & Pyridostigmine : Myasthenia gravis Postoperative decurarization Cobra bite Demecarium: Glaucoma Distigmine: Paralytic ileus Edrophonium: Paroxysmal Atrial & Supraventricular Tachycardia Tensilon test 9/6/2016 15
- 16. • Echothiophate : resistant cases of glaucoma • Malathion : Pediculosis treatment • Alzheimers disease and Anticholinesterase : Marked decrease in choline acetyltransferase and loss of cholinergic neurons, originate from nucleus basalis in the forebrain and project to the frontal cortex and hippocampus and play critical role learning ,memory & cognition . (APP) • -Tacrine: first drug used for Alzheimers not currently used- highly hepatotoxic • Donepezil, Rivastigmine, Galantamine: newer reversible anticholinesterase better penetration into CNS better tolerated than tacrine-less toxic • Clinical results with all these drugs are modest • Palliative treatment of mild to moderate form of AD9/6/2016 16
- 17. DRUG DOSAGE DONEPEZIL 5mg once daily (evening) 10mg after 4 weeks RIVASTIGMINE 1.5mg BD 3mg BD after 2 weeks GALANTAMINE 4mg BD 8mg after 1 week 9/6/2016 17 Transdermal rivastigmine patch: 24 hours – improves patient compliance Side effects: Diarrhoea , Nausea , Vomitting , Increased urination
- 19. GROUPS DRUGS MECHANISM OF ACTION Directly acting cholinomimetic PILOCARPINE Ciliary muscle contraction Pupillary constriction Reversible anticholinesterase PHYSOSTIGMINE DEMECARIUM Opening of trabecular meshwork Irreversible anticholinesterase ECHOTHIOPHATE ISOFLUROPHATE Increased drainage of aqueous humor Beta blockers TIMOLOL , LEVOBUNOLOL BETAXOLOL ,CARTEOLOL Reduce aqueous humor formation from ciliary epi. Nonselective alpha agonists EPINERPHNE DIPIVEFRINE Increases uveoscleral outflow Selective alpha 2 agonists APRACLONIDINE BRIMONIDINE Increase uveoscleral outflow Carbonic anhydrase inhibitors ACETAZOLAMIDE DORZOLAMIDE BRINZOLAMIDE Reduce aqueous humor production –dec HCO3 formation Hypertonic Solutions MANNITOL GLYCEROL Intraocular dehydration Prostaglandins LATANOPROST BIMATOPROST Increases uveoscleral outflow9/6/2016 19
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- 21. Pharmacotherapy of Myasthenia Gravis 9/6/2016 21 Autoimmune disorder characterised by progressive weakening of skeletal muscle. - Antibodies against Nm receptors - Diagnosis: Tensilon test : Myasthenic crisis Cholinergic crisis -
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- 23. Pharmacotherapy of OP poisoning • Occupational , accidental , suicidal 9/6/2016 23 MUSCARINIC NICOTINIC CENTRAL EFFECTS Salivation Muscle fasciculatons Irritability Lacrimation Muscle weakness Disorientation Urination Respiratory paralysis Unsteadiness Defecation Tremor Gastric secretions Ataxia Bronchospasm Convulsions Reflex tachycardia Coma
- 24. • If poisoning is through skin, remove clothing and wash the skin with soap and water. • If consumed by oral route, gastric lavage is given. • Maintain BP and maintain patent airway. • Drug of choice is atrophine IV. 2mg every 10 minute till pupil dilates. • Maximum dose is 50 – 100 mg. • Careful monitoring of symptoms due to delayed absorptions of OP compounds. • ChE reactivators – Pralidoxime, Obidoxime, Diacetyl Monoxime are given. • This oxime compounds combines with ChE organophosphate complex release the binding and set free AchE enzymes. 9/6/2016 24
- 25. SCREENING METHODS IN VIVO METHODS IN VITRO METHODS 1) Cat model for Anticholinesterase activity 1) Guinea pig ileum 2)Rat blood pressure model 2)Isolated eye of rodents 3) Mydriasis test in rabbits 3) In-vitro assay for anticholinesterase activity 4)Intestinal spasmolytic activity in mice 4) Isolated frog rectus muscle 5)Continuous cystometry in rats 5) Rat isolated aorta model 6)Guinea pig bronchospasm model 6) Guinea pig trachea model 7) Guinea pig isolated heart model 9/6/2016 25
- 26. CONCLUSION • Cholinergic pharmacology is a relatively mature field with a number of receptor selective agents • There are two major classes of cholinoceptors – Nicotinic and Muscarinic • But still there is a need for muscarinic tissue specific receptor subtype agents development • Also nicotinic receptor subunit diversity in CNS can spur the development of more selective agents that modulate their activity • Currently available AChE inhibitors are not very effective , hence further research is required for cognitin enhancing effectsof the drug. 9/6/2016 26
- 27. REFERENCES • Achilles J Pappano ; Cholinoceptor activating and cholinesterase inhibiting drugs;Betram G Katzung , Anthony J Trevor ;Basic and Clinical Pharmacology 13th edition ,Chapter 7;Pg105-120 • Alireza Atri , Michael S Chang , Gay R Strichatz ;Cholinergic Neurotransmission; Golan; Principles of Pharmacology;3rd edition ;Chapter 9; Pg 110-130 • Kevin M O’ Shaughnessy ; Cholinergic and anti mucarinic mechanisms and drugs; Peter bennett ,Morris J Brown, Pankaj Sharma ; Chapter 22 ; Pg 372-378 • Robert.B.Rafta ; Netter’s Illustrated Pharmacology ; Upated edition ;chapter 2; Pg 41 • Harrisons manual of medicine;18thedition;section 14;Neurology;chapter 206; Myasthenis gravis; Pg1302-1306 • S.K.Gupta, Drug screening methods, 2nd edition, Drugs acting on Peripheral nervous system , Chapter 23 , Pg 354-361 • Richard G Fiscella , Timothy S Lesar ; Deepak K Edward :Dipiro ;Pharmacotherapy A Pathophysiologic Approach ;Chapter 97 ; Glaucoma;Pg1551-1563 9/6/2016 27
- 28. • Goodman and gilman;12th edition; The Pharmacological Basis of Therapeutics ;Section II; Neuropharmacolgy ; Chapter 8-9 ; Neurotransmission ; pg 259 • Sharma and Sharma ; Principles of Pharmacology ; drugs affrcting parasympathetic nervous system; chapter 11;pg 128-135 • K.D.Tripathi :Essentials of Medical Pharmacology;6th edition; Cholinergic system and Drugs; Chapter 7; pg 93- 105 9/6/2016 28
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