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Cholinergic Blockade

Physiology and Pharmacology

QuestionAnswer
Two types of cholinergic receptor mAChR - G-protein coupled receptors nAChR - ligand gated ion channels
Effects of ACh on its receptors - Dale Arterial pressure recorded. ACh causes decrease due to vasodilation then causes bradycardia - muscarinic effects Atropine (mAChR antagonist) prevents this Much larger dose of ACh causes rise in bp, tachycardia - nicotinic effects
Methods to classify receptors Pharmacological - selective agonists/antagonists Biochemical/molecular - genes, mRNA, protein Structural - X-ray crystallography or electron microscopy In silico - mathematical modelling of quantitative structure-activity relationships
Pharmacological classification Classification into muscarinic and nicotinic types ACh binds to both Muscarine only binds to muscarinic Nicotine only binds to nicotinic Antagonists - atropine (muscarinic) and Tubocurarine (nicotinic)
Structural classification Purification of nAChRs have identified subtypes Crystal structure reveal the ligand binding domain of nicotinic receptors
Toxins affecting release of ACh Alpha-latrotoxin - massive release and depletion of vesicles Botulism toxin - block of release. Used to treat blepharospasm, salivary drooling, auxiliary hyperhidrosis, achalasia and for cosmetic reasons
Effect of snake toxins on AChRs E.g. bungarotoxin and cobratoxin Bind tightly to nAChR at NMJ causing paralysis Very selective Useful for identifying nAChR Used in studies of NMJ Cobra venom contains proteins used to treat MS, Herpes, retroviruses and other studies
Mechanism of drugs affecting cholinergic transmission Influence cholinergic transmission by acting on the release and destruction of ACh Enhance cholinergic transmission by blocking AChE Acting on postsynaptic AChR as agonists or antagonists
Subdivisions of drugs affecting cholinergic transmission Muscarinic agonists/antagonists Ganglion-stimulated drugs Ganglion blocking drugs Neuromuscular blocking drugs Anticholinesterase/ other drugs enhancing transmission
Muscarinic agonists All closely mimic effects of parasympathetic nerve stimulation Apart from ACh, they all act more potently on mAChR with the exception of Carbachol Bethanechol - treatment of bladder and gastrointestinal hypotonia Pilocarpine - Treatment of glaucoma
Effects of muscarinic agonists Cardiovascular - decreased heart rate, decreases cardiac output Smooth muscle - generally contraction Exocrine glands - increased secretions
Clinical use of parasympathomimetic Glaucoma Suppression of atrial tachycardia (rare use)
Use of muscarinic agonists for treatment of glaucoma Abnormally raised interocular pressure leads to glaucoma Muscarinic agonists e.g. pilocarpine constrict the pupil and improve drainage Atropine, cyclopentolate and other antagonists cause dilation but reduce drainage through canal of schlemm
Muscarinic Antagonists M1 - pirenzepine - stomach and salivary glands M2 - Gallamine - heart M3 - Darifenacin - smooth muscle Less subtype specific antagonists include atropine, hyoscine and cyclopentolate
Effects of muscarinic antagonists Atropine and hyoscine are naturally occurring compounds Inhibition of secretions Tachycardia Pupillary dilation Relaxation of smooth muscle
Clinical use of antimuscarinic drugs Atropine - treatment of bradycardia Tropicamide - to dilate pupils Ipratropium - asthma Pirenzepine - decrease gut motility and decrease secretions Darifenacin - urinary incontinence Hyoscine - motion sickness
Ganglion Stimulants Most nAChR agonists act on either neuronal (ganglionic and CNS) nAChR or on striated muscle receptors E.g. Nicotine (Autonomic ganglia and CNS) Lobeline (Autonomic ganglia) Suxamethonium (NMJ)
Ganglion blocking drugs Hexamethonium (autonomic ganglia) - blocks transmission First effective hypertensive agent now not used due to side effects
Neuromuscular blocking drugs Can act either presynaptically - inhibiting ACh synthesis or release or postsynapticly - blocking receptors or continuous activation of ACh receptors
Depolarising muscle relaxants ACh receptor agonists - generate an action potential Cannot be metabolised by AChE so give prolonged binding and extended depolarisation of the end plate As it continues to bind the endplate cannot repolarise giving a phase 1 block
Suxamethonium Only depolarising blocking drug used short duration (broken down by plasma esterase) Given by injection, reaches receptors at NMJ since not broken down by AChE Causes flaccid paralysis Used to relax larynx during intubation
How does Suxamethonium work Repeated activation of receptors causes depolarisation Maintained depolarisation leads to inactivation of voltage gates Na channels essential for an AP Neuromuscular transmission is blocked as AP can no longer be initiated
Non-depolarising muscle relaxants Act as competitive antagonists Bind to ACh receptors but do not open them Prevent AXh from binding so EPPs do not develop
Nicotinic receptor antagonists Tubocurarine - prototypical non-depolarising neuromuscular blocker Vecuronium - NMJ Mecamylamine - ganglia
Muscle relaxation during surgery Competitive antagonists bind to ACh receptors so binding of ACh is reduced Block transmission when over 80% of receptors are occupied by an antagonist Vecuronium and Atracurium often used
How can neuromuscular blockade be overcome Competitive antagonists are reversed by neostigmine This inhibits AChE so more ACh molecules reach the receptors
Cholinesterase inhibitors Only work if there is release of ACh Act on skeletal muscle (reverse blockade, diagnosis/treatment of myasthenia gravis), CNS (treatment of Alzheimer's) and eye (treatment of glaucoma) E.g. neostigmine and physostigmine Includes many insecticides
Use of cholinesterase inhibitors in Myasthenia Gravis Cause - autoantibodies bind to skeletal nAChR Symptoms - muscle weakness and rapid muscle fatigue Diagnosis - Edrophonium test (short acting AChEI should produce muscle recovery) Treatment - Neostigmine
Cholinesterase inhibitors in Alzheimer's Disease Cause - genetic and poorly understood Symptoms - progressive dementia Diagnosis- exclusion of other causes e.g. vascular, depression, hyperthyroidism Treatment - anticholinesterases and nicotinic allosteric potentiating ligands (Rivastigmine)
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