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    1. 1. Pharmacology-1 PHL 351, Parasympathetic Nervous System Abdelkader Ashour, Ph.D. 5 th Lecture
    2. 2. Muscarinic agonists None - - ++ Oxotremorine Glaucoma - - ++ Pilocarpine None † - - +++ Muscarine Bladder* and Gl hypotonia - - +++ Bethanechol None ++ + +++ Methacholine None - +++ ++ Carbachol None +++ +++ +++ Acetylcholine     Nic Musc     Clinical uses Hydrolysis by AChE Receptor specificity Structure Drug
    3. 3. Nicotinic Agonists <ul><li>Nicotine is the most commonly encountered nicotinic agonist. </li></ul><ul><li>It is a tertiary amine found in the leaves of the tobacco plant. </li></ul><ul><li>It is sufficiently lipid-soluble to be absorbed across the skin. </li></ul><ul><li>It is responsible for the addicting properties of tobacco. </li></ul><ul><li>Nicotine has a greater affinity for neuronal than for skeletal muscle nicotinic receptors </li></ul><ul><li>Nicotine's actions are complex. </li></ul><ul><ul><li>At low dosages it stimulates ganglionic nicotinic receptors (cause marked activation of these nicotinic receptors and initiate action potentials in postganglionic neurons) thus enhancing both sympathetic and parasympathetic neurotransmission </li></ul></ul><ul><ul><ul><li>The initial response therefore often resembles simultaneous discharge of both the parasympathetic and the sympathetic nervous systems. </li></ul></ul></ul><ul><ul><ul><li>In the case of the cardiovascular system, the effects of nicotine are chiefly sympathomimetic on blood vessels, and parasympathomimetic on the heart </li></ul></ul></ul><ul><ul><ul><li>In the GI and urinary tracts, the effects are largely parasympathomimetic </li></ul></ul></ul><ul><ul><li>As nicotine dosages increase, there is stimulation of nicotinic receptors in many other sites </li></ul></ul><ul><ul><li>At high dosages, nicotine possesses some antagonist effect at nicotinic receptors </li></ul></ul><ul><ul><ul><li>Prolonged exposure results in depolarizing blockade of the ganglia </li></ul></ul></ul>
    4. 4. Nicotinic Agonists, Ganglion Stimulants <ul><li>The mild alerting action of nicotine absorbed from inhaled tobacco smoke is the best-known of these effects. </li></ul><ul><li>In larger concentrations, nicotine induces tremor, emesis, and stimulation of the respiratory center. At still higher levels, nicotine causes convulsions, which may terminate in fatal coma. </li></ul><ul><li>Most nicotinic receptor agonists affect both ganglionic and motor end plate receptors, but nicotine and lobeline (a plant derivative similar to nicotine) affect ganglia preferentially </li></ul><ul><li>In spite of the smaller ratio of nicotinic to muscarinic receptors in the brain, nicotine and lobeline have important effects on the brainstem and cortex. </li></ul><ul><li>The lethal effects on the central nervous system, and the fact that nicotine is readily absorbed, form the basis for the use of nicotine as an insecticide. </li></ul><ul><li>These drugs are not used clinically, but only as experimental tools. They cause complex peripheral responses associated with generalized stimulation of ALL autonomic ganglia (sympathetic & parasympathetic) </li></ul>
    5. 5. Nicotinic Antagonists, Ganglionic Blockers <ul><li>The primary receptors at ganglia are cholinergic receptors of the nicotinic (N N ) type. </li></ul><ul><li>Nearly all effects are predictable from the knowledge that ganglionic blockers reduce transmission in all autonomic ganglia, both sympathetic and parasympathetic. </li></ul><ul><li>In some sites, sympathetic activation seems to predominate over parasympathetic, while in other sites, the opposite is true. </li></ul><ul><li>Ganglionic blockade thus &quot;uncovers&quot; the predominant system. This class of drugs is now rarely used. </li></ul><ul><li>Example: trimetaphan </li></ul><ul><li>Mediators and Effects of Ganglionic Blockade on Organ Systems </li></ul><ul><ul><li>Tissue Predominant System/Ganglionic Blockade Effect </li></ul></ul><ul><ul><li>Arterioles Sympathetic/(Vasodilation </li></ul></ul><ul><ul><li>Veins Sympathetic/Vasodilation </li></ul></ul><ul><ul><li>Heart Parasympathetic/Tachycardia </li></ul></ul><ul><ul><li>Iris Parasympathetic/Mydriasis </li></ul></ul><ul><ul><li>Ciliary muscle Parasympathetic/Cycloplegia </li></ul></ul><ul><ul><li>Gastrointestinal tract Parasympathetic/Hypomotility </li></ul></ul><ul><ul><li>Urinary bladder Parasympathetic/Urinary retention </li></ul></ul><ul><ul><li>Salivary glands Parasympathetic/Xerostomia </li></ul></ul><ul><ul><li>Sweat glands Sympathetic cholinergic /Anhidrosis </li></ul></ul>
    6. 6. Nicotinic Antagonists, Skeletal Muscle Relaxants (drugs that block neuromuscular transmission) <ul><li>Since skeletal muscle contraction is elicited by nicotinic (Nm) cholinergic mechanisms, it has similarities to nicotinic neurotransmission at the autonomic ganglia. </li></ul><ul><li>Two different kinds of functional blockade may occur at the neuromuscular endplate, and hence clinically used drugs fall into two categories: </li></ul><ul><ul><li>Non-depolarizing blocking agents: antagonists at the nAChR (i.e. they act by blocking nAChR </li></ul></ul><ul><ul><li>Depolarizing blocking agents: agonists at the nAChR (i.e., they act by stimulating the nAChR) </li></ul></ul><ul><li>Non-depolarizing neuromuscular blocking drugs: </li></ul><ul><ul><li>They act as competitive antagonists at the ACh receptors of the endplate </li></ul></ul><ul><ul><li>Tubocurarine is a prototype for this class of drugs. </li></ul></ul><ul><ul><li>Blockade by these agents (such as tubocurarine, pancuronium, and doxacurium) can be reversed by increasing the amount of ACh in the synaptic cleft, for example, by the administration of a cholinesterase inhibitor </li></ul></ul>
    7. 7. <ul><li>Depolarizing neuromuscular blocking drugs: </li></ul><ul><ul><li>They stimulate the nicotinic endplate receptor to depolarize the neuromuscular endplate </li></ul></ul><ul><ul><li>This initial depolarization is accompanied by transient twitching of the skeletal muscle (fasciculation). </li></ul></ul><ul><ul><li>With continued agonist effect, the skeletal muscle tone cannot be maintained, and, therefore, this continuous depolarization results in a functional muscle paralysis (flaccid paralysis; muscles are weak and have little or no tone). </li></ul></ul><ul><ul><li>Thus, the effects of a depolarizing neuromuscular blocking agent move from a continuous depolarization (phase I) to a gradual repolarization (as the sodium channel closes) with resistance to depolarization (phase II) </li></ul></ul>Nicotinic Antagonists, Skeletal Muscle Relaxants (drugs that block neuromuscular transmission) <ul><ul><li>Succinylcholine (suxamethonium ) is a prototype for this class of drug. It has a shorter half-life (5-10 minutes) and must be given by continuous infusion if prolonged paralysis is required. </li></ul></ul><ul><ul><li>An important aspect of succinylcholine is its hydrolysis by pseudocholinesterase </li></ul></ul><ul><ul><ul><li>In patients with pseudocholinesterase deficiency, succinylcholine half-life is greatly prolonged, and such patients may suffer from prolonged apnoea and they may regain control of their skeletal muscles slowly after a surgical procedure. This is the most serious complication of pseudocholinesterase deficiency </li></ul></ul></ul>