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The Parasympathetic Nervous System

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The Parasympathetic Nervous System مادة اﻻدوية املرحلة الثالثة أ.م.د. حسام الدين سامل 2017-2016 FUNCTIONS OF THE PARASYMPATHETIC NERVOUS SYSTEM • Protects the retina from excess light • Decreases heart rate • Promotes glandular secretions • Promotes the emptying of hollow organs • Promotes the conservation of energy • Promotes rest and repair • Physiologically antagonizes the sympathetic nervous system DUAL INNERVATION AT MOST SITES CONCEPT OF DOMINANCE IN THE AUTONOMIC NERVOUS SYSTEM • The sympathetic nervous system dominates at some sites • The parasympathetic nervous system dominates at other sites PARASYMPATHETIC INNERVATION FROM THE BRAIN PARASYMPATHETIC INNERVATION FROM THE SACRAL CORD CHOLINERGIC FIBER • There is always sufficient choline in the blood so it is never a problem. Acetyl choline A is a daughter molecule that is transported to vesicles in the nerve membrane. When action potential travels down the fiber, there is an uptake of calcium and the vesicles fuse with the membrane and acetylcholine is released. As a result, acetylcholine is able to act on muscarinic or nicotinic receptors. Acetylcholinesterase rapidly metabolizes acetylcholine into choline and acetic acid and choline is taken up. Hardly any of it gets a chance to diffuse away from the active site and get into the bloodstream. AGENTS AFFECTING CHOLINERGIC TRANSMISSION • Hemicholinium • Latrotoxin • Botulinus toxin • Calcium • Physostigmine • Atropine • d-Tubocurarine • Hemicholinium – blocks choline uptake, thereby blocking synthesis of Ach. These compounds are poisonous and not used for any therapeutic purpose • Latrotoxin is a toxin from the black widow spider that produces an explosive release of Ach, causing muscular spasm. • Botulinus toxin is a toxin that is able to bind to the neuron and interferes with the trafficking proteins as they come together to promote the fusing of the vesicles to the membrane. • Calcium is involved in the vesicular release. Its uptake is important in the fusion of vesicles to membrane of neuron. • Physostigmine is an example of a drug that affects cholinergic transmission by increase Ach in the plasma at the synaptic cleft, inhibiting acetylcholinesterase and Ach concentrations in the synaptic cleft will increase and rebind to muscarinic and nicotinic receptors. This drug is considered an inhibitor of acetylcholinesterase and these type drugs are only effective where you have cholinergic innervation. • Atropine is a drug that blocks muscarinic actions of Ach. • D-Tubocurarine blocks the nicotinic actions, which are primarily at the endplate of the neuromuscular junction. Higher doses of this do tend to block nicotinic receptors at the autonomic ganglion. WHAT ACETYLCHOLINE DOES • Promotes transmission in postganglionic autonomic fibers • Promotes release of epinephrine and norepinephrine from the adrenal medulla • Promotes transmission in skeletal muscle fibers • Promotes the functions of the parasympathetic nervous system at cardiac muscle, smooth muscles and glands NEURONAL INNERVATION TO ORGANS NICOTINIC RECEPTORS • Nicotinic receptors areTwo subtypes – NN subtype is present on cell body of postganglionic autonomic neuron – NM subtype is present at the endplate of the neuromuscular junction MUSCARINIC RECEPTORS Several subtypes: M1 M2 M3…….. M1 in autonomic ganglia , gastric tissue. M2 in cardiac fibers M3 smooth muscles , glands PARASYMPATHETIC FUNCTION AT ORGANS SITES • Gastrointestinal tract increases tone and motility – Longitudinal muscles contraction – Circular muscles contraction – Sphincter muscles relaxed to allow emptying of hollow organs • Bile duct increased tone and motility • Gall bladder increased tone and motility • Urinary tract increased tone and motility – Ureters – Detrusor muscle of the bladder – Trigone RELAXED – Sphincter muscle of the bladder RELAXED • Bronchial smooth muscles respond to presence of Ach by constriction • Lacrimal glands tearing • Pharyngeal glands secretion • Salivary glands copious secretion of saliva • Mucus glands – Respiratory tract secretion – Esophagus secretion of glands • Intestinal glands • Gastric glands • Pancreas foodstuff also causes secretion of hormones (cause secretion of trypsin and chymotrypsin enzymes aiding in digestion) as PNS causes secretion of fluids PARASYMPATHETIC CONTROL OF THE CARDIOVASCULAR SYSTEM • SA Node reduction in rate of diastolic depolarization • Atrial muscle decreased refractory period, decreased force of contraction • AV node increased refractory period, decreased impulse flow • Purkinje fibers reduced impulse flow • Ventricles decrease in force of contraction • Blood vessels vasodilation, causing fall in peripheral vascular resistance • M2 is found in the cardiac muscles. • SA node pacemaker of the heart so if it is slowed down, heart rate will decrease • Ach has negative chronotropic effect (decreases rate of heart) and negative ionotropic effect (decreases force of contraction). A decrease in force of contraction is primarily at atrial muscle. • M3 is found in blood vessels. ACETYLCHOLINESTERASE • Sites of location – Cholinergic neurons – Cholinergic synapses – Neuromuscular junction Substrates Acetylcholine is the best substrate ORGANOPHOSPHATE INHIBITORS OF AChE • Their action promoting accumulation of ACh at the NN nicotinic receptor is the basis for their toxicity, but actions at muscarinic receptors contribute to their toxic actions as well • Inhibition of AChE by these agents is irreversible – New enzyme synthesis is required for recovery of enzyme function Hydrolysis of the AChE-phosphorylated is extremely slow, in the order of days. The phosphorylated enzyme is considered to be irreversibly inhibited, and recovery of function is in the order of days. THERAPEUTIC USES OF INHIBITORS OF ACETYL CHOLINESTERASE • Glaucoma (wide angle) • Atony of the bladder • Atony of the gastrointestinal tract • Intoxication by antimuscarinic agents • Intoxication by tricyclic antidepressants (TCA’s) or phenothiazines (use physostigmine) • Myasthenia gravis e.g: • Physostigmine atropine intoxication • Neostigmine Myasthenia gravis • Pyridostigmine Myasthenia gravis • Recovery of neuromuscular function after competitive blockade of NN receptor of skeletal muscle fibers as neostigmine • Alzheimer’s disease as : Tacrine Donepezil Rivastigmine Galantamine • SOME ORGANOPHOSPHATE INHIBITORS OF ACETYLCHOLINESTERASE • Tetraethylpyrophosphate • Echothiophate (N+) • Diisopropylflurophosphate (DFP) • Sarin nerve gas • Soman nerve gas • Tabun nerve gas • Malathion insecticide, only one still used, even in homes • Parathion insecticide • Diazinon insecticide • Chlorpyrifos insecticide used in the home? • Many others ORGANOPHOSPHATES AS NERVE GAS AGENTS IN CHEMICAL WARFARE • Extremely volatile agents such as sarin, tabun, soman, and agent VX may be used as nerve agents in chemical warfare. • Accumulation of ACh at cholinergic receptors produces effects reflecting stimulation of cardiac muscle, smooth muscles and glands. Suchs effects would be identical to those cause by muscarine poisoning. • Bradycardia and hypotension occurs. However, in some cases, tachycardia may be observed, due to intense sympathetic discharge in response severe hypoxemia. • Irreversible inhibition of acetylcholinesterase by these agents produces accumulation of ACh at the end plate of skeletal muscle fibers. This in turn leads to depolarizing blockade of the NM nicotinic receptor. Skeletal muscle paralysis occurs. Movement is impossible. The diaphragm is also paralyzed. The individual eventually dies due to respiratory paralysis. • Pralidoxime, atropine, and removal of the person from the source of exposure are all to be employed in cases of posioning MUSCARINIC RECEPTOR BLOCKING AGENTS • ACETYLCHOLINE IS AN AGONIST AT BOTH MUSCARINIC AND NICOTINIC RECEPTORS • THE NICOTINIC ACTIONS OF ACETYLCHOLINE REMAIN WHEN MUSCARINIC RECEPTORS ARE BLOCKED MUSCARINIC RECEPTOR BLOCKADE DOES NOT AFFECT GANGLIONIC TRANSMISSION Autonomic ganglia: -Nicotinic sites -Muscarinic sites Muscarinic receptor blockade prevents generation of the IPSP and the sEPSP but not the fEPSP Muscarinic receptor blockade does not interfere with transmission at autonomic ganglionic sites, the adrenal medulla, or skeletal muscle fibers. Sympathetic adrenergic functions are not affected. In dual innervated organs, muscarinic receptor blockade allows sympathetic dominance • PHARMACOLOGY OF MUSCARINIC RECEPTOR BLOCKADE/ATROPINE .
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