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University of Hawai‘i Hilo Pre- Nursing Program NURS 203 – General AUTONOMIC NERVOUS SYSTEM Pharmacology Danita Narciso Pharm D 1 LEARNING OBJECTIVES Understand the basic function of the autonomic nervous system (ANS) Know the neurotransmitters and receptors of each branch of the autonomic nervous system Understand if a tissue or organ is being activated by a certain branch of the ANS what the resulting action would be Understand how these two systems work in concert for daily living and situation of fight or flight 2 AUTONOMIC NERVOUS SYSTEM – WHERE IT FITS IN Nervous System Central Peripheral Somatic Autonomic (Skeletal Muscle) Parasympathetic Sympathetic Brain (cholinergic) ACh (adrenergic) NE Spinal Cord Nicotinic Alpha Beta α1, α2 β1, β2 Muscarinic 3 AUTONOMIC NERVOUS SYSTEM Fight or Flight Adrenergic Rest & Digest Norepinephrine Cholinergic Acetylcholine 4 AUTONOMIC NERVOUS SYSTEM – WHERE IT FITS IN Nervous System Central Peripheral Somatic Autonomic (Skeletal Muscle) Parasympathetic Sympathetic Brain (cholinergic) ACh (adrenergic) NE Spinal Cord Nicotinic Alpha Beta α1, α2 β1, β2 Muscarinic 5 AUTONOMIC NERVOUS SYSTEM (ANS) Parasympathetic NS Nicotinic Muscarinic Peripheral Sympathetic NS Alpha Autonomic Beta Nerves Parasympathetic Sympathetic Carrying ACh (cholinergic) ACh (adrenergic) NE Cholinergic Carrying NE Nicotinic Beta Adrenergic Alpha α1, α2 β1, β2 Muscarinic 6 AUTONOMIC NERVOUS SYSTEM (ANS) 7 AUTONOMIC NERVOUS SYSTEM (ANS) Ganglion: Group of nerve cell bodies. Connects pre and post ganglionic nerves. 8 AUTONOMIC NERVOUS SYSTEM (ANS) 9 AUTONOMIC NERVOUS SYSTEM (ANS) 10 AUTONOMIC NERVOUS SYSTEM (ANS) Preganglionic PNS ACh Preganglionic SNS ACh Post ganglionic Post ganglionic PNS SNS ACh NE 11 ACTIONS OF THE ANS - SNS Think fight or flight Dilate pupils Let in more light to see the bear Inhibit salivation This is no time to be hungry Relax airways Increase O2 intake Increase heart rate ….. 12 ACTIONS OF THE ANS - PNS Think rest and digest Constrict pupils Lessened sense of awareness Stimulate saliva Let’s eat Constrict bronchi Don’t need extra oxygen Decrease heart beat Rest easy 13 ANS – NEUROTRANSMITTER TRANSMISSION Cholinergic and adrenergic transmission – from start to finish Synthesis Storage Release Action Inactivation 14 ANS – CHOLINERGIC TRANSMISSION Synthesis & Storage Choline acetyltra nsferase 15 ANS – CHOLINERGIC TRANSMISSION -100 CELL 16 ANS – CHOLINERGIC TRANSMISSION Propagation 17 ANS – CHOLINERGIC TRANSMISSION 18 ANS – CHOLINERGIC TRANSMISSION Hey look, exocytosis! 19 ANS – ADRENERGIC TRANSMISSION Synthesis Nerve terminal Neurotransmitter Adrenal medulla Hormone Epi and NE 20 ANS – ADRENERGIC TRANSMISSION 21 ANS – ADRENERGIC TRANSMISSION Alpha receptors - excitatory Alpha 1 Postsynaptic nerve Constrict Vascular smooth muscle, prostate, pupillary dilator muscle Alpha 2 Presynaptic nerve Inhibit SNS outflow Platelets, adrenergic and cholinergic nerve terminals, some vascular smooth muscle, and fat cells 22 ANS – ADRENERGIC TRANSMISSION Beta receptors – inhibitory Beta 1 – heart Postsynaptic Increase rate & increase force of contraction Beta 2 – lungs Postsynaptic Relax & increase glucose Lungs, liver, & vascular smooth muscle 23 ANS – ADRENERGIC TRANSMISSION Turning off the SNS Reuptake Monoamine oxidase (MOA) Catechol-o-methyltransferase (COMT) 24 AUTONOMIC NERVOUS SYSTEM - SUMMARY The 2 branches of the ANS are the SNS and PNS The PNS and SNS balance each other out in terms of daily activities Each of these systems has its own set of NTs and receptors with actions that promote its cause and attenuate the cause of its brother system 25 QUESTIONS 26 LEARNING OBJECTIVES – CHOLINERGIC AGONISTS Know the receptor location and neurotransmitter involved in direct acting and indirect acting drugs of the cholinergic agonist class Know the physiologic results of the activation or inhibition of those receptors Know the dosage forms involved in nicotine replacement therapy (NRT) Know the toxic effects of cholinergic agonists & acetylcholinesterase inhibitors 27 CHOLINERGIC AGONIST Remember, acetylcholine is the neurotransmitter for all preganglionic nerve fibers. Parasympathomimetic Even those of the sympathetic Receptors nervous system. Nicotinic Ganglia, adrenal medulla, skeletal muscle, brain Muscarinic Cardiac and smooth muscle, gland cells, and nerve terminals 28 CHOLINERGIC AGONIST INDIRECT ACTING – Direct vs. Indirect acting cholinergic agonists Acetylcholinesterase inhibitor M PRESYNAPTIC NEURON POST SYNAPTIC DIRECT NEURON ACTING N 29 MUSCARINIC RECEPTORS Muscarinic receptors Eye (lacrimal gland), saliva gland, heart, lungs, GI tract, gallbladder, bladder, AND sweat glands (sympathetic effect) AND vascular smooth muscle (no PNS innervation) 30 MUSCARINIC AGONISTS – DIRECT ACTING ADRs: Cardiovascular Bethanechol Hypotension, flushing, tachycardia CNS Headache, malaise, seizure Dermatology Brand name: Urecholine Sweating Use: Ease urinary retention in the GI neurogenic bladder Abd. cramps, diarrhea, burping, rumbly Dosage form: Oral tablet tummy, nausea, salivation, vomiting Distribution: Poorly absorbed and poorly GU: distributed to CNS, concentrates in GI tract Urinary urgency and bladder Ophthalmic MOA: Increase bladder muscle tone, Miosis & lacrimation stimulated gastric motility Respiratory Onset/Duration: 30-90 min/~1 hr (up to Bronchoconstriction/asthma 6 hrs) Overdose: Treat with atropine 31 MUSCARINIC AGONIST– DIRECT ACTING ADRs: Cardiovascular Pilocarpine flushing CNS Brand name: Salagen (oral)/Isopto Headache Carpine (ophthalmic) Dermatology Use: Xerostomia (cancer tx/sjogrens), Rash, itching glaucoma GI Dosage form: Tablet/solution & gel Nausea Distribution: Well absorbed and GU: distributes into the CNS Urinary frequency MOA: Increased salivation/miosis, Ophthalmic decreased intraocular pressure Double vision & lacrimation Onset/Duration: 10-60 min/ 4-8 hrs (up Respiratory to 12 hrs) Rhinitis Excretion: Kidney 32 NICOTINIC RECEPTORS Nicotinic receptors Ganglia, adrenal medulla, skeletal muscle, and neuronal cells in the CNS CNS effects At therapeutic doses – mild alerting effect At increased to toxic doses – tremor, stimulation of respiratory center, convulsions, & coma Neuromuscular junction At therapeutic doses – contraction of muscle At increased to toxic doses – disorganized twitching, contraction of entire muscle, & paralysis Peripheral nervous system Activation of the SNS and PNS at the same time Cardiovascular effects – mostly SNS effects GI tract – mostly PNS effects 33 NICOTINIC AGONISTS – DIRECT ACTING Nicotine (NRT) Varenicline (Chantix) Use: Smoking cessation Use: Smoking cessation Dosage forms: Tablets – Can be dispensed in Dosage forms: Next slide monthly packs Distribution: Well absorbed, not affected by Distribution: Lipophilic, distributes well to tissues food, 90% bioavailability Onset/duration: Fast/24 hour – depends of Onset: Peak 3-4 hours dosage form Half-life: 24 hours Metabolism: Liver Excretion: Urine 92% unchanged drug Excreted: Kidney ADR’s: CNS – HA, insomnia, abnormal dreams, ADRs: Depends on dosage form – headache, suicide ideation, depression (can lead to d/c) nausea, throat irritation, cough, dyspepsia GI: Nausea and vomiting Toxicity: Very toxic. Lethal doses seen at 30-60 mg (5 cigarettes) 34 NRT – DOSAGE FORMS 35 CHOLINERGIC AGONIST – INDIRECT ACTING Neostigmine GI & GU disorders: Post operative ileus, congenital Myasthenia gravis: Pyridostigmine megacolon, urinary retention, Autoimmune disease that reflux esophagitis Ambenonium degrades nicotinic receptors from autoantibodies causing Physostigmine Antimuscarinic overdose: Plants, severe muscle weakness. atropine, 1st generation antihistamines, Tacrine & tricyclic antidepressants. Physostigmine completes with the Donepezil antimuscarinic agent. Only used with Alzheimer’s disease: Degradation of high fever or supraventricular cholinergic nerves in CNS causing memory Rivastigmine tachycardia loss and cognitive function decline Causes not known: Efficacy of these drugs is Galantamine modest and doses and use are limited by adverse effects. 36 ACETYLCHOLINESTERASE INHIBITOR EFFECTS Type of Lower doses Higher doses effects Autonomic Nicotinic receptor activation *Both SNS and PNS are activated but the effects of the PNS prevail. effects o SNS & PNS effects Patient will present with bradycardia, reduced cardiac output, variable o Decreased HR and BP blood pressure, severe bronchospasm, reduced respiratory function. Muscarinic receptor activation SLUDGE o Miosis/impaired vision o Salivation, lacrimation, urination, diarrhea, GI upset, emesis o Bronchospasm/increased secretions DUMBELS o Sweating/salivation o Diaphoresis & diarrhea, urination, miosis, o Nausea/vomiting bradycardia/bronchospasm/bronchorrhea, emesis, lacrimation, o Diarrhea/abd cramps salivation o Urination Central NS Nicotinic & muscarinic receptor activation Nicotinic & muscarinic receptor activation effects o Anxiety/confusion o Tremors/seizures o Tremors o Coma o Depression of respiratory center Motor Nicotinic receptor activation on skeletal muscle Nicotinic receptor activation on skeletal muscle effects o Muscle twitching and weakness o Paralysis o Respiratory failure 37 ACETYLCHOLINESTERASE INHIBITOR OVERDOSE Lethal – due to respiratory effects Usually due to poisoning, chemical warfare, insecticides (organophosphates) Route – skin or lungs. First signs – Ocular symptoms followed by respiratory symptoms Treatment Ventilation ATROPINE Pralidoxime (reactivated enzymes) 38 QUESTIONS 39 LEARNING OBJECTIVES – CHOLINERGIC ANTAGONISTS