cholinergic effects – Flashcards
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Brief anatomy of the parasympathetic nervous system
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The pre ganglionic fibres are long as the parasympathetic ganglion lies closer to the target organ. It releases Ach which act at nicotinic receptors. The post ganglionic neurone is shorter and released Ach which acts at muscarian receptors. Cranosacral outflow.
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What organs does the parasympathetic nervous system innervate?
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The rest and digest system. It causes relaxation of muscles and aids digestion.
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What effect does it have on the heart?
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it reduces the rate at which SAN produces APs therefore reduces the HR. Reduces the force of atrial muscle contraction. Has no effect on the ventricular muscle contraction. Reduces conduction velocity at the AV node- Atrioventricular block. M2 receptors involved.
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What effect does it have on the heart?
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it reduces the rate at which SAN produces APs therefore reduces the HR. Reduces the force of atrial muscle contraction. Has no effect on the ventricular muscle contraction. Reduces conduction velocity at the AV node- Atrioventricular block. M2 receptors involved.
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What effect does it have on Blood vessels?
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Doesnt innervate blood vessels. Except: Erectile tissue and salivary glands where it causes dilation of the vessels via M3 receptors.
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What effect does it have on Bronchi?
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Causes constriction and secretion from the glands via M3 receptors.
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What effect does it have on GI tracts?
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Increases smooth muscle motility. Dilation of sphincters and increased secretion from glands via M3 receptors. Vagus Nerve, S2-S4.
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What effects does it have on Bladder?
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contraction of the detrusor muscles and relaxation of the sphincter muscles via M3 receptors. S2-S4 pelvic splanic nerves.
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What effects does it have on the uterus?
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Variable effects on the uterus. Causes erection via M3 receptors. Vagus Nerve
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What effects does it have on the Eye?
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Causes constriction of the pupil by contracting the circular muscles. It causes contraction of ciliary muscles and relaxation of suspensory ligaments via M3. There is near accommodation. Also aids drainage of aqueous humour, closed angle glaucoma. Opens the canal of Schlemm and so reduces pressure. Oculomotor nerve.
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What effects does it have on sweat glands?
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No effect. Under sympathetic control. Ach at Muscarian receptors. Control via adrenal glands and adrenaline.
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What effects does it have on pilomotor?
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No effect.
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What effects does it have on salivary glands?
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secretion via M3 receptors. Glossopharyngeal nerve.
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What effects does it have on lacrimal glands?
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secretion via M3 receptors. Facial nerve.
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What effects does it have on kidney?
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No effect.
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What effects does it have on liver?
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No effect.
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How is Ach formed?
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It is formed by action of choline acetyltransferase. Which converts choline into acetyl choline by adding an acetyl group from acetyl CoA.
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How is Ach released?
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Ca ion influx causes depolarisation of the membrane which causes voltage gated calcium ion channels to move and fuse with the membrane releasing Ach by exocytosis.
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How is Ach release terminated?
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Ach is not taken up unmet abolished. There is a G protein involved which causes the closure of Ca ion channels through negative feedback loop. There are also Uptake 2 (low affinity) proteins which take up Ach but no Uptake 1 (high affinity). Cholinesterase in the synaptic cleft breaks down Ach into choline and ethanoic acid which is then taken up by the cell and removed into Ach. If the enzyme is inhibited it will cause an increase in Ach and increased stimulation of the target receptor.
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How do indirectly acting paraympatho-mimetics work?
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They block AchE so there is an increase in Ach which means that there would be an increase in stimulation of target receptor. E.g Neostigmine, Physostigmine, Edrophonium, Parathion. They have long lasting effects.
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What are the two types on cholinoreceptors and where are they found?
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Nicotinic (ligand-gated) receptors: Autonomic ganglia, Skeletal muscle Muscarinic (G-protein coupled) receptors: CNS, peripheral neurons, gastric parietal cells (M1), cardiomyocytes (M2), Visceral smooth muscle, secretory glands (M3). There are 5 known variants.
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What are the agonists and antagonists for Nicotinic Ach receptors?
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Agonists: Nicotine, lobeline Antagonists: Tubocararian, hexamethonium, Pancuronium There are different nicotinic receptors in muscular and neuronal system.
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What are the angonists and antagonists for the Muscarian receptors?
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Angonists: Muscarine, bethanecol, pilocarpine Antagonist: Atropine, Ipratropium, Pirenzepine. these are all receptor subtype specific.
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How do the Nicotinic Ach receptors work?
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The 2 molecules of Ach binds to it. The receptor undergoes a conformational shape change allowing the ionic flow of cations. It produces a EJP in the target cell. This leads to contraction of the muscle. Effect is terminated by unbinding of Ach. e.g skeletal muscle.
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How do the muscarian Ach receptors work?
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They are G protein linked.
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How does the G protein cycle operate?
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When the G protein linked receptor is activated, the alpha,gamma, beta, GDP complex binds to the receptor. The GDP is replaced by GTP. This causes dissociation of the alpha, beta, gamma, complex. The alpha GTP binds to an enzyme and activates it. Different alpha GTP complexes activate different enzymes. Gi and Ga activate adenylyl cyclase and produce cAMP and Gq/11 activate PLC producing DAG and IP3 from the hydrolysis of PIP2.
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What pathways are activated by M2 &4?
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Adenylate cyclase, Gi
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What pathways are activated by M1,3,5?
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PLC, Gq/11
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How is a decrease in BP achieved?
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Action potentials are sent down the Vagus nerve. Which releases Ach which acts on M2 receptors on the SAN. It causes a decrease in adenylate cyclase and a decrease in cAMP which then reduces the HR by reducing the spontaneous electrical impulses created by SAN and so cardiac output is reduced, hence BP. It reduces the conduction of electrical impulse through AV node and also decreases the force of atrial contraction. There are decreased pacemaker channels opened. Reduction in calcium ion channels opening, as there would be a reduction in activated PKA. Hyper polarised membrane due to opening of the K+ ion channels.
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How is arterial relaxation achieved?
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This DOES NOT normally happen in cells. This is due to circulating Ach after injection maybe. The Ach binds to M3 receptors. It causes the stimulation of NO synthase which causes Arginine to be converted into NO. This then diffuses and binds to gaunylyl cyclase to cause GTP to be converted to cGMP. This then causes the relaxation of smooth muscle. The receptor is found on the endothelial cells and NOT on smooth muscle itself.
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How is a reduced HR achieved?
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There is limited parasympathetic innervation to the heart. Vagus-SAN and atria. causes a reduction in the APs. Membrane potential is hyper polarised. Due to decreased Ca2+ being opened. K+ ion channels open to cause the hyper polarisation. The beta gamma unit of the G protein attaches to the K+ channels (which are open and are membrane independent), causing increased diffusion of K+ channels and increased hyper polarisation. This will prevent lots of VGCa ion channels from opening and so cause a reduction in contraction of muscle.
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How does atropine effect cholinoreceptors?
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It is a Muscarian receptor blocker. And so will reduce the effects. If you added increased Ach with atropine it will eventually lead to an increase in BP because it will lead to the sympathetic nervous system stimulation as it does not contain muscarinic receptors but does have nicotinic receptors in its system.
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What receptor is involved in contraction of GI tract?
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M3-Increased activation of PLC, increased [Ca+]
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What receptors is involved in contraction of bladder muscles?
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M3- Increased activation of PLC, increased [Ca+]
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What receptors are involved in constriction of the bronchi?
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M3- Increased activation of PLC, increased [Ca+]
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What are some of the clinical uses of directly acting parasympathomimetics?
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Pilocarpine is used to treat glaucoma and dry mouth. Used in sweat tests. Bethanecol occasionally used to aid bladder/ gastric emptying Succinylcholine high affinity nACHR agonist used in surgery- depolarising paralysis.
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What are some of the clinical uses of indirectly acting parasympathomimetics?
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AChE inhibitors such as TACRINE, DONEPEZIL or RIVASTIGMINE used in dementia Neuromuscular diseases such as MYASTHESIA GRAVIS or EATON-LAMBERT syndrome.
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Clinical uses of muscarian blockers?
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Premedication before anaesthesia to reduce secretions, sedation (hyoscine), prevent vagal effects In heart block to increase AV conduction Ophthalmology to produce mydriasis for examination Bronchodilatation in COPD Anti-spasmodic in GI colic Treatment of antiChE poisoning Motion sickness
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Clinical uses of nicotinic blockers?
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Muscle relaxants Direct nAchR blockers: tubocurarine, pancuronium, vecuronium, atacurium Depolarising blockers Direct nAchR agonists suxamethonium
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Clinical uses of nicotinic blockers?
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Muscle relaxants Direct nAchR blockers: tubocurarine, pancuronium, vecuronium, atacurium Depolarising blockers Direct nAchR agonists suxamethonium
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Clinical uses of nicotinic blockers?
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Muscle relaxants Direct nAchR blockers: tubocurarine, pancuronium, vecuronium, atacurium Depolarising blockers Direct nAchR agonists suxamethonium
