Cholinergic drugs

This presentation covers an introduction to Autonomic Nervous System.. only enough to understand the actions of cholinergic and anticholinergic drugs. This presentation does not include anticholinergic drugs.

1. Cholinergic drugs For BNS 1 st Year Dr. Pravin Prasad 1st Year Resident, MD Clinical Pharmacology Maharajgunj Medical Campus 27 th December, 2015 ( Poush 12, 2072), Sunday

2. Nervous System: Overview

3. Autonomic Nervous System: Organization

4. Sympathetic vs Parasympathetic NS Sympathetic NS Parasympathetic NS Thoracolumbar outflow Most ganglions are nearer to vertebral column Shorter preganlionic fibres Craniosacral outflow Ganglions are within or near to target organ Longer preganglionic fibers Preganglionic NT: Acetylcholine Preganglionic NT: Acetylcholine Postganlionic NT: Norepinephrine (Noradrenaline); Acetylcholine at some sites Postganglionic NT: Acetylcholine; Nitric oxide at some sites

5. Cholinoceptors Muscarinic (G Protein Coupled Receptor) Selective Agonist: Muscarine Antagonist: Atropine Five Subtypes: M 1 -M 5 M 1 , M 3 , M 5 : excitatory Nicotinic (Ligand gated cation channel) Selective Agonist: Nicotine Antagonist: d- tubocurarine Two subtypes: N N & N M Usually excitatory

6. Cholinergic Transmission Site Type of Receptor Selective Agonist Selective Antagonist All postganglionic parasympathetic( parasym ). Few postganglionic sympathetic ( sym ) 1 Muscarinic Muscarine Atropine Ganglia (sym. & parasym .) Adrenal Medulla Nicotinic (N N ) Dimethyl Phenyl Piperazinium (DMPP) Hexamethonium Skeletal Muscles Nicotinic (N M ) Phenyl Trimethyl Ammonium (PTMA) d- tubocurarine CNS (cortex, basal ganglia, spinal cord, others) Muscarinic Muscarine/ Oxotremorine Atropine Nicotinic Carbachol d- tubocurarine

7. Cholinergic Transmission Synthesised from Acetyl CoA and Choline in presence of Choline Acetyl Transferase Stored in vesicles Released when impulses arrives by exocytosis Degraded by Acetylcholinesterase ( AChE )

8. Muscarinic Cholinoceptors Features M1 M2 M3 Location & Function Autonomic ganglia: depolarization 1 Gastric glands: increased secretion CNS (learning, memory, motor function) Heart: Decrease rate, force Nerve endings: Decrease ACh release CNS: tremor, analgesia Visceral smooth muscle: contraction Visceral smooth muscle: contraction Iris: constriction of pupil Ciliary muscle: contraction 2 Exocrine glands: secretion Vascular endothelium: vasodilatation Nature G q protein coupled G i /G protein coupled G q protein coupled Transducer mechanism IP 3 /DAG – increase Ca ++ PLA 2 increasd – PG synthesis K+channel opening, decreased cAMP IP 3 /DAG – increase Ca ++ PLA 2 increasd – PG synthesis Agonists Oxotremorine , MCN 343A Methacholine Bethanechol Antagonists Pirenzepine , Telenzepine Methotramine , Triptiramine Solifenacin , Darifenacin

9. Nicotinic Cholinoceptors Features N M N N Location & Function Neuromuscular junction: depolarization of muscle end plate – contraction of skeletal muscle Autonomic ganglia: depolarization –postganglionic impulse Adrenal medulla: catecholamine release CNS: site specific excitation or inhibition Nature Intrinsic ion channel, pentamer of α 2 β ε or γ and δ , each with 4 transmembrane segments Intrinsic ion channel, pentamer of only α or α , β subunit, each with 4 transmembrane segments Transducer mechanism Opening of cation channels (Na + K + ) Opening of cation (Na + K + Ca ++ ) channels Agonists PTMA, nicotine DMPP, nicotine Antagonists Tubocurarine , α - Bungarotoxin Hexamethonium , Trimethaphan

10. Cholinergic (Cholinomimetic / Parasympathomimetic) Drugs Cholinergic Agonists Anti- cholinesterases Choline esters Alkaloids Reversible Irreversible Acetylcholine Pilocarpine Carbamates : Physostigmine , Neostigmine, Pyridostigmine , Edrophonium , Rivastigmine , Donepezil, Galantamine Carbamates : Carbaryl , Propoxur Methacholine Arecoline Organophosphates : Dyflos , Echothiophate , Malathion, Diazinon , Tabun , Sarin, Soman Carbachol Muscarine Bethanechol Acridine : Tacrine

11. Muscarinic Actions of Cholinergic Agonists (ACh) Organ Receptor Involved Mechanism Effect Heart M 2 Hyperpolarization of SA Node Bradycardia, cardiac arrest M 2 Increased Refractory Period at AV node and His-Purkinje Fibres Delayed conduction, Prolonged P-R interval, Heart Block Blood Vessels PLc – IP3/DAG mediated EDRF (NO release): Vasodilation Fall in BP, flushing M 3 Vasoconstriction Release of NO – dilatation of cavernous sinus Erection of penis

12. Muscarinic Actions of Cholinergic Agonists (ACh) Organ Receptor Involved Mechanism Effects Smooth Muscle M 3 + M 2 Increased tone and peristalsis of GIT, sphincters relaxed Abdominal cramps, evacuation of bowels M 3 Increased peristalsis in ureters, detrusor contracts, trigone & sphincter relaxes Voiding of bladder M 3 Constriction of bronchial muscles Bronchospams , dyspnoea, asthamatic attack

13. Muscarinic Actions of Cholinergic Agonists (ACh) Organ Receptor Involved Mechanism Effects Glands M 3 + M 2 Increased secretion Salivation, sweating, lacrimation, increased tracheobronchial and gastric secretions Eyes M 3 Contraction of circular muscle of iris Miosis Contraction of ciliary muscle Blurring of near vision, increased aqueous outflow, decreased intra ocular pressure in glaucomatous eye

14. Nicotinic Actions of Cholinergic Drugs (ACh) Organ Receptor Involved Mechanism & Effects Autonomic Ganglia N N Stimulation of sym. & parasym . ganglia (higher doses) Skeletal Muscles N M Iontophoreic application of ACh to muscle end plate: contraction of fibres Intra-arterial injection: twitching and fasciculations

15. CNS Action of ACh Intravenous injection: No central effects Direct injection into brain: arousal response followed by depression Complex neurological and behavioural effects

16. Drug interactions Synergism Antagonism Anticholinesterases: potentiation Atropine, Atropine like substances Methacholine: potentiation (lesser extent) Adrenaline Carbachol , bethanechol : additive

17. Choline esters: Uses and Side Effects Uses: Rarely used (evanescent and non selective action) Bethanechol : non-obstructive urinary retention, neurogenic bladder Side effects: Belching, colic Involuntary urination/defecation Flushing, sweating Fall in BP Bronchospasm

18. Cholinomimetic Alkaloids Pilocarpine Source: Pilocarpus microphyllus Prominent muscarinic actions; ganglionic action via M 1 receptors CVS Effects: Small dose – fall in BP (muscarinic, ?M 2 ) Higher dose – rise in BP and tachycardia (ganglion mediated; M 1 ) Eyes: Local application – penetrates cornea, miosis, ciliary muscle contraction, fall in intraocular tension (M 3 ) Use: As Miotics ( counteract mydriatics used for refraction, along with mydriatics to prevent/break adhesions), In open angle glaucoma , S/E: marked sweating, salivation, increased secretions

19. Arecholine Source: betel nut Areca catechu Muscarinic as well as Nicotinic actions No therapeutic use Cholinomimetic Alkaloids

20. Muscarine Source: mushrooms Amanita muscaria , Inocybe sps . Only muscarinic actions Not used therapeutically, has toxicological importance Cholinomimetic Alkaloids

21. Mushroom Poisoning Early type (Muscarinic) Hallucinogenic Type Late type ( Phalloidin ) Toxic principle Inocybe and related sps . Muscimol ; isoxazole ( A. muscaria ) Peptide toxin of A. phalloides , Galerina Mechanism Blocks M receptors in CNS Inhibit RNA and protein synthesis Features Muscarinic Hallucinogenic, central manifestations Damage to GIT, liver, kidney Presentation Within an hour of eating After hours of ingestion Treatment Atropine Nonspecific, Atropine contraindicated Supportive

22. Anti- cholinesterases ( AChE ) Inhibits Cholinesterases ( ChE )  protects ACh from hydrolysis  cholinergic effects Some have additional direct action on Nicotinic receptors

23. AChE : Mechanism of Action Normally, after showing its activity, ACh is degraded by hydrolysis by Cholinesterase( ChE ) into choline and acetic acid Hydrolysis of AChEs is either slow (carbamates, about 30 mins) or extremely slow (organophosphates, days), hence the enzyme ChE is rendered inactive  normal ACh at the junction cannot be hydrolysed  prolonged action of ACh (cholinomimetic action) Hydrolysis after ageing not possible, new ChE needs to be formed

24. AChE : Pharmacological Actions Due to amplification of endogenous Ach Intensity of action on muscarinic, nicotinic and CNS varies among different agents Characteristics Example Muscarinic Nicotinic CNS Ganglia Skeletal Muscle Lipid soluble Physostigmine , organophosphates +++ + Less prominent +++ Lipid insolube Neostigmine Less prominent + +++ none

25. AChE : Pharmacological Actions Ganglia : stimulation at low dose, blockade at high dose Stimulation via M1 receptors High dose: persistent depolarization  depletion of ACh  blockade of transmission CVS: complex, unpredictable effects Muscarinic: bradycardia, hypotension; Ganglionic: tachycarida , hypertension Action on medullary centres(stimulation then depression), ganglion blockade at high doses Skeletal Muscles: twitching and fasciculations at low dose, weakness and paralysis at high dose Prolonged action of ACh on motor end plates and prejunctional fibres twitching and fasciculations High dose: persistent depolarization  neuromuscular transmission blockade  weakness and paralysis CNS : general arousal at low dose, excitement, confusion at high dose Lipophilic agent: generalised alerting response, improved cognition in Alzheimer’s Disease Higher doses: excitement, mental confusion, disorientation, tremors, convulsions, coma

26. AChE : Pharmacokinetics Physostigmine : Rapid absorption (oral, parenteral, topical in eye) Crosses BBB, central effects Metabolism by hydrolysis Neostigmine : Poor oral absorption (20-30 times parenteral dose) Does not cross BBB, cornea Partially hydrolysed and partially excreted unchanged in urine Organophosphates : Absorbed from all sites Hydrolysed and oxidised and then excreted

27. AChE:Uses As Miotic Glaucoma : Increases tone of ciliary muscle and sphincter pupillae  opening of trabeculae  intra ocular tension ( iot ) falls in open angle glaucoma Pilocarpine – rapid and short lasting (4-6hrs), 6-8hrly instillation required; fluctuation of iot in between seen, S/E: diminution of vision especially in dim light, spasm of accommodation, brow pain; nausea, diarrhoea, sweating, bronchospasm with higher concentration; also used in combination for angle closure glaucoma Physostigmine 0.1% - supplement pilocarpine Reversal of mydriasis after refraction Prevent/break adhesions (iris-lens, iris-cornea): in conjunction with mydriatics

28. AChE:Uses Myasthenia gravis(MG): Treatment Neostigmine 15 mg orally 6 hrly , adjusted according to response, dose requirement fluctuates in accordance to remission and exacerbation Pyridostigmine Atropine if muscarinic side effects seen, cholinergic weakness/crisis if dose adjustment not adequate Diagnostic Tests Ameliorative Test : Inj Edrophonium 2mg i.v. (test dose) followed by 8 mg i.v. after 30-60 sec. reversal of weakness and short lasting improvement of strength: + ve for MG Provocative Test : hazardous – not performed Demonstration of anti-NR antibodies in plasma or muscle biopsy specimen

29. Myasthenic crisis Acute weakness of respiratory muscles Management Tracheal intubation and mechanical ventilation Plasmapheresis Methyl prednisolone pulse therapy Withheld AChE for 2-3 days then introduced gradually Duration 1-3 weeks

30. Myasthenic crisis vs Cholinergic Crisis Myasthenic Crisis Cholinergic Crisis Deficiency of ACh activity Excess of ACh activity Exacerbation of Myasthenia gravis Overdose of AChE Symptoms: weakness Improvement seen on injection of edrophonium 2mg i.v. No improvement or worsening seen on injecting edrophonium 2 mg i.v. T/t: respiratory support, plasmapheresis, corticosteroids T/t: stop AChE , supportive management