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Drugs Unit 2 Introduction to the Autonomic Nervous System Nervous System CNS PNS Autonomic Sympathetic Somatic Parasympathetic 2 Ion Diffusion Key to neurophysiology Dependent upon: Concentration gradient Electrical gradient Modified by: ‘Gated ion channels’ 3 Where Does Diffusion Take the Ion? Na+ 150 mM K+ 5 mM ClHigh Exterior I N Na+ 15 mM O U T K+ 150 mM ClLow Cell Interior 4 Major Networks of CNS Motor Systemvoluntary musculoskeletal movement Extra Pyramidal System (EPS) – controls fine movements (defective in Parkinson’s disease) Autonomic Nervous System (ANS)controls fight/flight and rest/digest body actions Reticular Activating Systemresponsible for maintenance of consciuosness and alertness Limbic Systemresponsible for control of emotions/happiness etcetera 5 Organization of the Nervous System: Reticular Activating System Key Regulatory Functions: CV, respiratory systems Wakefulness Clinical Link: Disturbances in the RAS are linked to sleep-wake disturbances Radiation Fibers Thalamus Visual Inputs Reticular Formation Ascending Sensory Tracts 6 Organization of the Peripheral Nervous System Three major divisions: EFFERENT AFFERENT Somatic (motor) Autonomic Sensory Sympathetic and Parasympathetic AFFERENT Sensory EFFERENT Parasympathetic Sympathetic Motor Parasympathetic 7 Preganglionic Nerves Sympathetic and Parasympathetic preganglionic fibres release Acetylcholine (ACh) ACh has two types of receptors: Muscarinic and Nicotinic Postganglionic nerves have Nicotinic receptors Sympathetic Parasympathetic ACh 8 Postganglionic Nerves Sympathetics release Norepinephrine Parasympathetics release ACh Norepinephrine binds to adrenergic Sympathetic Parasympathetic receptor ACh binds to Muscarinic receptors ACh NE 9 Autonomic Nervous System (ANS) Definition Involuntary or visceral nervous system Function Mostly with little conscious awareness of its activity Regulate and integrate the body’s internal functions Integrate parts of the CNS and PNS to react to changes in the internal and external environment 10 Bodily Functions Regulated by the ANS Blood pressure Heart rate Respiration Body temperature Water balance Urinary excretion Digestive functions 11 12 Classifications of the Receptor Sites Reacting With Sympathetic NeurotransmittersNorepinephrine and Epinephrine α alpha-receptors alpha1- (Peripheral vasculature) alpha2- (Brain vasculature) β beta-receptors beta1- (Heart) beta2- (Lungs) 13 14 What do these receptors do? Alpha 1 Vasoconstriction, ↑ BP, ↑ tonus of sphincter muscles Alpha 2 Inhibit norepinephrine, insulin release Beta 1 Tachycardia, ↑ lipolysis, ↑ myocardial contractility Beta 2 Vasodilation, bronchodilation, insulin release 15 Location and Function of Alpha1 Receptors Blood vessels Cause vasoconstriction and increase peripheral resistance, raising blood pressure Iris Cause pupil dilation Urinary bladder Cause the increased closure of the internal sphincter 16 Location and Function of Alpha2 Receptors Nerve membranes Act as modulators of norepinephrine release Beta cells in the pancreas Help to moderate the insulin release stimulated by sympathetic nervous system activation 17 Location and Function of Beta1 Receptors Cardiac tissue Can stimulate increased myocardial activity and increased heart rate Responsible for increased lipolysis or breakdown of fat for energy in peripheral tissues 18 Location and Function of Beta2 Receptors Smooth muscle in blood vessels Stimulation leads to vasodilation Bronchi Stimulation leads to bronchodilation Periphery Increased muscle and liver breakdown of glycogen and increased release of glucagon Uterine muscle Results in relaxed uterine smooth muscle 19 Sympathetic NS Drugs Predictable response based on knowledge of affects of adrenergic receptor stimulation Each receptor may be: Stimulated (sympathomimetic) Inhibited (sympatholytic) (‘blocker’) 20 Alpha1 Agonists Profound vasoconstriction Increases afterload & blood pressure when given systemically Decreases drug absorption & bleeding when given topically 21 Alpha- and Beta-Adrenergic Agonists and Their Indications Dobutamine (Dobutrex): Congestive heart failure Dopamine (Intropin): Shock Ephedrine (Pretz-D): Seasonal rhinitis; hypotensive episodes Epinephrine (Adrenalin, Sus-Phrine): Shock; prolongs effects of regional anesthetic Norepinephrine (Levophed): Shock; cardiac arrest 22 Alpha-Specific Adrenergic Agonists (Alpha-Agonists) Definition Drugs that bind primarily to alpha-receptors rather than to beta-receptors Drugs in this class Phenylephrine (Neo-Synephrine, Allerest, AK-Dilate, and others) Midodrine (ProAmantine) Clonidine (Catapres) 23 Beta1 Agonists Increases heart rate, contractility, and conductivity 24 Beta-Specific Adrenergic Agonists and Their Indications Isoproterenol (Isuprel) Treatment of shock, cardiac standstill, and heart block in transplanted hearts; prevention of bronchospasm during anesthesia; inhaled to treat bronchospasm Ritodrine (Yutopar) Management of preterm labor (uterine beta receptors – relaxes pregnant uterus on stimulation) 25 Adrenergic Blocking Agents Adrenergic Blocking Agents Definition Called sympatholytic drugs because they lyse, or block, the effects of the SNS Therapeutic and adverse effects Related to their ability to react with specific adrenergic receptor sites without activating them Action Prevent norepinephrine from activating the receptor 27 Alpha- and Beta Blocking Agents and Their Indications Carvedilol (Coreg): Hypertension, congestive heart failure (adult) 28 Selective Alpha1- Blocking Agents* Doxazosin (Cardura): Used to treat hypertension; also effective in the treatment of benign prostatic hypertrophy Prazosin (Minipress): Used to treat hypertension, alone or in combination with other drugs Terazosin (Hytrin): Used to treat hypertension as well as BPH Tamsulosin (Flomax) and alfuzosin (Uroxatral): Used only in the treatment of BPH *Inhibits peripheral vasoconstriction *Used for hypertension 29 Indications for Beta- Blocking Agents Treating cardiovascular problems Hypertension Angina Migraine headaches Preventing reinfarction after MI 30 Focus on the Beta-Blocker Prototype: Propranolol (Inderal) Indications: Treatment of hypertension, angina pectoris, supraventricular tachycardia, tremor; prevention of reinfarction after MI; prophylaxis of migraine headache; management of situational anxiety NON SELECTIVE- Blocks both Beta 1 and Beta 2 receptors And Timolol 31 Adverse Effects of BetaBlocking Agents GI upset CNS changes Respiratory problems CV effects Loss of libido Impotence 32 Selective (blocks ONLY) Beta1- Blocking Agents Advantage Do not usually block beta2-receptor sites, including the sympathetic bronchodilation Preferred for patients who smoke or have asthma, obstructive pulmonary disease, or seasonal or allergic rhinitis Uses Hypertension, angina, some cardiac arrhythmias 33 Selective Beta1- Blocking Agents and Their Indications Acebutolol (Sectral): Hypertension and premature ventricular contractions Atenolol (Tenormin): MI, chronic angina, and hypertension Metoprolol (Lopressor):MI, chronic angina, and hypertension 34 Word of the Day: SYMPATHOMIMETIC (Agonist) Adrenergic drug which acts directly on adrenergic receptor, activating or stimulating it SYMPATHOLYTIC (Antagonist) Anti-Adrenergic drug which acts directly on adrenergic receptor, blocking it 35 Cholinergic Neurons (Parasympathetic-Acetylcholine) Na+ Choline Acetylation Ca++ Acetylcholinesterase Receptor 36 Cholinergic Receptors Muscarinic receptors come in 5 subtypes M1, M2, M3, M4, M5 Found in different locations Research is on-going to identify specific agonists and antagonists Nicotinic receptors come in 2 subtypesNn – neurosynaptic receptor (autonomic) Nm – muscular motor endplates (voluntary) 37 Drugs 2 Cholinergic Agents Cholinergic Agonists Acetylcholine Bethanechol Carbachol Pilocarpine 39 General Effects of Cholinergic Agonists Decrease heart rate and cardiac output Decrease blood pressure Increases GI motility and secretion Pupillary constriction 40 Cholinergic Agonists Cholinergic agents cause SLUDGE! HINT! These effects are predictable by knowing PNS physiology (slide 22) Salivation Lacrimation Urination Defecation Gastric motility Emesis 41 Results of Parasympathetic Nervous System Stimulation Increased motility and secretions in the GI tract- diarrhea / belly cramps Decreased heart rate and contractility- bradycardia Constriction of the bronchi, with increased secretion- wheezing Relaxation of the GI and urinary bladder sphincters- urination (P is for Peeing) Pupillary constriction – (MIOSIS- useful in glaucoma therapy) 42 Cholinergic Neurons Na+ Choline Acetylation Ca++ Acetylcholinesterase Receptor 43 Types of Cholinergic Agonists Direct-acting cholinergic •Indirect acting cholinergic agonists Occupy receptor sites for ACh on the membranes of the effector cells of the postganglionic cholinergic nerves Cause increased stimulation of the cholinergic receptor agonists React with the enzyme acetylcholinesterase and prevent it from breaking down the ACh that was released from the nerve Causes increased stimulation of the ACh receptor sites 44 Examples of Direct-Acting Cholinergic Agonists and Their Indications Bethanechol (Duvoid, Urecholine) Treat urinary retention; neurogenic bladder atony Diagnose and treat reflux esophagitis Carbachol (Miostat); pilocarpine (Pilocar) Induce miosis or pupil constriction Relieve intraocular pressure of glaucoma Perform certain surgical procedures 45 Indirect-Acting Cholinergic Agonists (Useful in Myasthenia Gravis) Do not react directly with ACh receptor sites React chemically with acetylcholinesterase in the synaptic cleft to prevent it from breaking down Ach ACh released from the presynaptic nerve accumulates, stimulating the ACh receptors Bind reversibly to acetylcholinesterase, so effects will pass with time 46 Myasthenia Gravis Definition Chronic muscular disease caused by a defect in neuromuscular transmission Autoimmune disease; patients make antibodies to ACh receptors, causing gradual destruction of them Symptoms Progressive weakness and lack of muscle control with periodic acute episodes 47 Acetylcholinesterase Inhibitors ‘Indirect’ Used to Treat Myasthenia Gravis Neostigmine (Prostigmine): Has a strong influence at the neuromuscular junction Pyridostigmine (Regonol, Mestinon): Has a longer duration of action than neostigmine Ambenonium (Mytelase): Available only in oral form; cannot be used if patient is unable to swallow tablets Edrophonium (Tensilon, Enlon): Diagnostic agent for myasthenia gravis 48 Alzheimer’s Disease A progressive disorder involving neural degeneration in the cortex Leads to a marked loss of memory and of the ability to carry on activities of daily living Cause of the disease is not yet known There is a progressive loss of ACh-producing neurons and their target neurons 49 Drugs Used to Treat Alzheimer’s Disease Tacrine (Cognex) First drug to treat Alzheimer’s dementia Galantamine (Reminyl) Used to stop progression of Alzheimer’s dementia Rivastigmine (Exelon) Available in solution for swallowing ease Donepezil (Aricept) Has once-a-day dosing 50 Adverse Effects of Acetylcholinesterase Inhibitors ENHANCE parasympathetic effec6ts: Bradycardia Hypotension Increased GI secretions and activity Increased bladder tone Relaxation of GI and genitourinary sphincters Bronchoconstriction Pupil constriction 51 Cholinergic Drugs Bethanechol (Duvoid, Neostigmine Urecholine) Treat urinary retention; neurogenic influence at the neuromuscular junction (Prostigmine): Has a strong bladder atony Diagnose and treat reflux esophagitis Pyridostigmine (Regonol, Carbachol (Miostat); Ambenonium (Mytelase): pilocarpine (Pilocar) Induce miosis or pupil constriction Relieve intraocular pressure of Mestinon): Has a longer duration of action than neostigmine Available only in oral form; cannot be used if patient is unable to swallow tablets Edrophonium (Tensilon, glaucoma Enlon): Diagnostic agent for Perform certain surgical procedures myasthenia gravis 52 Drugs 2 Anticholinergic Agents Anticholinergic Drugs Action Used to block the effects of acetylcholine Lyse, or block effects of the PNS; also called parasympatholytic agents 54 Anticholinergic Drugs Decrease GI activity and secretions (treat ulcers) Decrease parasympathetic activities to allow the increase in sympathetic activity 55 Anticholinergics/ Parasympatholytics Derived from the plant Belladonna Block only the muscarinic effectors in the PNS and cholinergic receptors in the SNS (sweat glands) Act by competing with acetylcholine for the muscarinic acetylcholine receptor sites Do not block the nicotinic receptors Have little or no effect at the neuromuscular junction 56 Types of Anticholinergic Agents and Their Indications Atropine Blocks parasympathetic effects in many situations Dicyclomine (Antispas, Dibent, and others) Relaxes GI tract; treats hyperactive or irritable bowel Glycopyrrolate (Robinul) Adjunct in the treatment of ulcers Propantheline (Pro-Banthine) Adjunct in the treatment of ulcers 57 Actions of Atropine Depresses salivation and bronchial secretions Dilates the bronchi Inhibits vagal responses in the heart Relaxes the GI and genitourinary tracts Inhibits GI secretions Causes mydriasis (Dilated pupils) Causes cycloplegia (Blurring) 58 Adverse Effects of Atropine Hot Hotas asHell Hell Blurred vision Blind Mydriasis (Dilated pupils) Blindas asaaBat Bat Cycloplegia Dry Dryas asaaBone Bone Photophobia Red Redas asaaBeet Beet Palpitations, bradycardia Mad as aaHatter Mad as Hatter Dry mouth, altered taste perception Urinary hesitancy and retention Decreased sweating; predisposition to heat prostration 59 Warning Signs That Patients Should Report to the Health Care Team Eye pain Skin rash Fever Rapid heartbeat Chest pain Difficulty breathing Agitation or mood changes Impotence 60 Effects of Blocking the Parasympathetic System Increase in heart rate Decrease in GI activity Decrease in urinary bladder tone and function Pupil dilation Cycloplegia (unable to focus) 61 Types of Anticholinergic Agents and Their Indications Atropine Blocks parasympathetic effects in Depresses salivation and many situations bronchial secretions Dicyclomine (Antispas, Dibent, and others) Dilates the bronchi Relaxes GI tract; treats hyperactive Inhibits vagal responses in or irritable bowel the heart Propantheline (Pro-Banthine) Relaxes the GI and Adjunct in the treatment of ulcers Hot Hotas asHell Hell Blind Blindas asaaBat Bat Dry Dryas asaaBone Bone Red Redas asaaBeet Beet Mad Madas asaaHatter Hatter genitourinary tracts Inhibits GI secretions Causes mydriasis (Dilated pupils) Causes cycloplegia (Blurring) 62 FACTS TO REMEMBER! ANS is an efferent system Has 2 major divisions: Sympathetic and Parasympathetic There are differences between the two divisions in terms of anatomy/ physiology/ neurotransmitters ANS is involuntary and is responsible for maintaining Internal environment Sympathetic: Alpha 1 and 2/ Beta 1 and 2 receptors/ Norepinephrine (NE) is the neurotransmitter at target sites Parasympathetic: Nicotinic and Muscarinic receptors/ Acetylcholine neurotransmitter 63 Drugs 2 Drugs Acting on the Upper Respiratory Tract Drugs That Affect the Respiratory System Antitussives Block the cough reflex Decongestants Decrease the blood flow to the upper respiratory tract and decrease the overproduction of secretions Antihistamines Block the release or action of histamine that increases secretions and narrows airways 65 Drugs That Affect the Respiratory System Expectorants Increase productive cough to clear airways Mucolytics Increase or liquefy respiratory secretions to aid clearing of airways 66 Antitussives Definition Drugs that suppress the cough reflex by acting directly on the medullary cough center of the brain Traditional antitussives Codeine (generic only) (Robatussin) Hydrocodone (Hycodan) Dextromethorphan (Benylin and many others) 67 Decongestants Definition Cause local vasoconstriction Decrease the blood flow to the irritated and dilated capillaries of the mucous membranes lining the nasal passages and sinus cavities Types Usually adrenergics or sympathomimetics 68 Types of Topical Nasal Decongestants Ephedrine (Kondon’s Nasal) Oxymetazoline (Afrin, Allerest, and others) Phenylephrine (Coricidin and many others) Tetrahydrozoline (Tyzine) Xylometazoline (Otrivin) phenylephrine (Neo-Synephrine®) pseudoephedrine (Sudafed®, Actifed®) 69 Types of Topical Nasal Steroid Decongestants Beclomethasone (Beclovent and others) Budesonide (Rhinocort) Dexamethasone (Decaderm and others) Flunisolide (AeroBid and others) Fluticasone (Flovent) Triamcinolone (Kenacort) 70 Antihistamines Found in multiple OTC preparations Designed to relieve respiratory symptoms and to treat allergies Act by blocking the effects of histamine Bring relief to patients suffering from itchy eyes, swelling, congestion, and drippy nose 71 Antihistamines: Histamine receptors H1 receptors (Skin, Resp. tract) Vasodilation Increased capillary permeability Bronchoconstriction Other histamine receptors (Brain) Sedation H2 receptors (Gastric) Increase gastric acid secretion (Zantac®), etc) 72 Antihistamine Agents First generation Sedation chlorpheniramine (Chlor-Trimeton®) diphenhydramine (Benadryl®) clemastine (Tavist®) promethazine (Phergan®) Second generation No sedation fexofenadine (Allegra®) cetirizine (Zyrtec®) loratadine (Claritin®) 73 Mucolytics Action Break down mucus in order to aid the high-risk respiratory patient Administration Nebulization or direct instillation into the trachea Types Acetylcysteine (Mucomyst and others) Dornase alfa (Pulmozyme) 74 Indications for Mucolytics Patients who have difficulty coughing up secretions Patients who develop atelectasis Patients undergoing diagnostic bronchoscopy Postoperative patients Patients with tracheostomies 75 Cough medications -Recap Antitussives Decrease cough reflex Opioids codeine & hydrocodone Non-opioids dextromethorphan benzonatate (Tessalon®) Expectorants guaifenesin may work others are doubtful Mucolytics Decreases viscocity acetlycysteine (Mucomyst®) hypertonic saline 76 Drugs 2 Drugs Used to Treat Obstructive Pulmonary Disorders Changes in the Airway With COPD 78 Antiasthma Drugs The problem: Narrowing of the respiratory passages Normal The causes: Bronchiole smooth muscle constriction mucous production Narrowed Bronchiole 79 Asthma Drugs The Solutions: Bronchodilators Adrenergic agonists (β2) Terbutaline, salmeterol, albuterol Cholinergic Antagonists Ipratropium Theophylline Why has this been replaced with other drugs? 80 Asthma Drugs (continued) Anti inflammatories Cromolyn – mast cell stabilizer Corticosteroids Inhaled: beclamethasone Systemic: prednisone Side effects? 81 Drugs to Treat COPD The Problem: Chronic, irreversible airflow obstruction Variety of causes The Solutions: β2 agonists- Terbutaline, salmeterol, albuterol Theophylline glucocorticoids 82 Xanthines (Theophylline) Come from a variety of sources Include caffeine and theophylline Once the main choice for treatment of asthma and bronchospasm Relatively narrow margin of safety; interact with many other drugs No longer considered the first-choice bronchodilators 83 Asthma therapy Bronchodilators (Sympathomimetics) Anticholinergics Anti-inflammatory Agents Leukotriene Antagonists Mast cell stabilizers 84 Bronchodilators ß2 agonists albuterol (Proventil®), metaproterenol (Alupent®) terbutaline (Breathair®) Nonselective epinephrine (Adrenalin®) Methylxanthines theophylline (TheoDur®) aminophyllin, (Aminophylline®) Anticholinergics ipratropium bromide (Atrovent®) 85 Anti-inflammatory Agents Glucocorticoids inhaled oral injected beclomethasone (Beclovent®) flucticasone (Flovent®) prednisolone (Deltasone®) Mast cell Stabilizer methylprednisolone (Solu-Medrol®) dexamethasone(Decadron®) cromolyn (Nasalcrom®, Intal®) Leukotriene Antagonists zafirlukast (Accolate®) zileuton (Zyflo®) 86 Leukotriene Receptor Antagonists Action Developed to act more specifically at the site of the problem associated with asthma Drugs in this class Zafirlukast (Accolate) (first one developed) Montelukast (Singulair) Zileuton (Zyflo) 87 “long-acting beta 2-adrenergic agonists” (LABA) Advair (combination of salmeterol and fluticasone) “may increase the chance of severe asthma episodes, and death when those episodes occur.”FDA warning 88