Introduction to Autonomic Pharmacology PDF

Introduction to Autonomic Pharmacology The Autonomic (and Somatic) Nervous Systems Dr. Peter Abel, Professor and Chair Department of Pharmacology and Neuroscience Criss III, Room 551 280-2983 [email protected]  Importance of the autonomi...

Introduction to Autonomic Pharmacology The Autonomic (and Somatic) Nervous Systems Dr. Peter Abel, Professor and Chair Department of Pharmacology and Neuroscience Criss III, Room 551 280-2983 [email protected]  Importance of the autonomic nervous system (ANS) The ANS maintains the bodies internal state (homeostasis) and thus regulates nearly every organ system in the body. Components of the ANS are the targets for autonomic drugs. Autonomic drugs are 10-15% of the top 200 drugs. Some drugs that are not autonomic drugs interact with the ANS to produce adverse and other effects. Divisions of the Nervous System Nerves to Skeletal Muscle Nerves to Smooth Muscle, Cardiac Tissue, Glands The Autonomic Nervous System (ANS)  Properties of the ANS Involuntary (automatic) control 2 neuron system Preganglionic nerves from CNS, myelinated, nerve terminal in ganglia. Sympathetic (Sym) and parasympathetic (PS) divisions – Sym = thoracic and lumbar – PS = cranial brain stem and sacral Synapse in ganglia. – Sym = sympathetic chain (paravertebral) ganglia, prevertebral ganglia – PS = terminal ganglia Postganglionic nerves from ganglion, nonmyelinated, innervate effector cells at the neuroeffector junction Peripheral Nerve Innervation of Effectors Parasympathetic Ganglia Innervate Sympathetic Ganglia Effectors Synapse Neuroeffector junction Neuromuscular junction Chromaffin Cells ACh = Acetylcholine, NE = Norepinephrine, Epi = Epinephrine  Somatic Motor System Voluntary control – usually of movement Innervates skeletal muscle Somatic motor nerves originate in CNS 1 neuron system Contraction of skeletal muscle Somatic motor nerves release acetylcholine (Ach) that acts on skeletal muscle in the neuromuscular junction. Peripheral Nerve Innervation of Effectors Parasympathetic Ganglia Innervate Sympathetic Ganglia Effectors Synapse Neuroeffector junction Neuromuscular junction Chromaffin Cells ACh = Acetylcholine, NE = Norepinephrine, Epi = Epinephrine  Parasympathetic Nerves originate from cranial and sacral regions Long preganglionic nerves Short postganglionic nerves Ganglia often near effector organ Acetylcholine (Ach) released from all preganglionic and postganglionic nerves. Functions to conserve energy: “Rest and Digest” Peripheral Nerve Innervation of Effectors Parasympathetic Ganglia Innervate Sympathetic Ganglia Effectors Synapse Neuroeffector junction Neuromuscular junction Chromaffin Cells ACh = Acetylcholine, NE = Norepinephrine, Epi = Epinephrine  Sympathetic Originate from thoracic and lumbar regions Short preganglionic nerves, long postganglionic nerves Ganglia near spinal cord Acetylcholine released from all preganglionic nerves Norepinephrine released from most postganglionic nerves Sympathetic cholinergic nerves – Sweat glands, etc. Sympathoadrenal Branch – Adrenal gland, releases the catecholamines epinephrine > norepinephrine from chromaffin cells. Functions to expend energy during stress: “Fight or Flight”  Review Peripheral Sites of Neurotransmitter (and Drug) Action Acetylcholine: ????????? Norepinephrine: ????????? Epinephrine: ?????????  Sites of Neurotransmitter Action Acetylcholine:  Sites of Neurotransmitter Action Norepinephrine: Epinephrine:  Peripheral Nerve Innervation of Effectors Parasympathetic Ganglia Innervate Sympathetic Ganglia Effectors Synapse Neuroeffector junction Neuromuscular junction Chromaffin Cells ACh = Acetylcholine – Activates Cholinergic Receptors NE = Norepinephrine, Epi = Epinephrine – Activates Adrenergic Receptors  Autonomic Receptors (Agonists and Antagonists) Cholinergic receptors (cholinoceptors): Acetylcholine Nicotinic (N) receptors – Nicotine NN (Neuronal) – Mecamylamine NM (Muscle) – Vecuronium Mucarinic (M) receptors – Methacholine, Atropine M1- M5 M1 – Pirenzepine  Peripheral Nerve Innervation of Effectors Parasympathetic Ganglia Innervate Sympathetic Ganglia Effectors Synapse Neuroeffector junction Neuromuscular junction Chromaffin Cells ACh = Acetylcholine – Activates Cholinergic Receptors NE = Norepinephrine, Epi = Epinephrine – Activates Adrenergic Receptors  Autonomic Receptors (Agonists and Antagonists) Adrenergic receptors (adrenoceptors): Epinephrine Alpha () receptors: Phentolamine 1 – Phenylephrine, Prazosin (1A, 1B, 1D) 2 – Clonidine (2A, 2B, 2C) Beta () receptors: Isoproterenol, Propranolol 1 – Dobutamine, Metoprolol 2 – Albuterol 3 – Mirabegron  Review Peripheral Location of Autonomic Receptors (Drug Targets) Nicotinic: ????????? Muscarinic: ????????? α and β: ?????????  Location of Autonomic Receptors Nicotinic: Muscarinic: α and β:  **M3 receptor releases nitric oxide that relaxes blood vessels a Minor actions are shown in brackets. b Receptor types: alpha = α, beta = ß, muscarinic = M. c Vascular smooth muscle in skeletal muscle blood vessels has minor sympathetic cholinergic dilator nerves. d Probably through presynaptic inhibition of parasympathetic activity. Low doses of epinephrine, or β2-selective agonists, decrease blood pressure. For epinephrine, this is called the “low dose effect” of epinephrine. **No nerves.  Patterns of autonomic innervation of effector organs Opposing dual (sympathetic/parasympathetic) innervation examples: SA node – Heart rate Iris – Pupillary diameter G.I. tract – Motility Urinary Bladder – Urine excretion Single innervation examples: Sympathetic Blood Vessels – Blood pressure, blood flow Metabolic – Glycogenolysis (liver), lipolysis Skin – Sweating, piloerection Dominant tone: Parasympathetic vs sympathetic 25  Cholinergic Release Acetylcholine Metabolism Acetylcholinesterase Action Cholinoceptors Agonists/Antagonists Muscarinic and Nicotinic Receptors  Adrenergic Release Valbenazine Removal Neuronal uptake - NE Transporter (NET) Metabolism Monoamine oxidase (MAO) Action Adrenoceptor Agonists/Antagonists α and β Receptors  Sensory Nerve Input - Baroreceptor Reflex Baroreceptors are sensory receptors that detect a change in blood pressure. They trigger sensory nerve reflex activity to counteract changes in blood pressure. Blood Pressure = Cardiac Output X Vascular Resistance Any drug that rapidly changes blood pressure  Sites of Neurotransmitter Action Acetylcholine: Neuromuscular junction Parasympathetic ganglia Sympathetic ganglia Parasympathetic neuroeffector junction Sympathetic cholinergic neuroeffector junction – sweat glands, etc. Adrenal medulla  Sites of Neurotransmitter Action Norepinephrine: Most sympathetic neuroeffector junctions Epinephrine: A hormone released from chromaffin cells in the adrenal gland. Catecholamine  Location of Autonomic Receptors Nicotinic: Parasympathetic ganglia Sympathetic ganglia Chromaffin cells Skeletal muscle Muscarinic: Effectors innervated by postganglionic parasympathetic nerves Effectors innervated by postganglionic sympathetic cholinergic nerves – sweat glands α and β: Most effectors innervated by postganglionic sympathetic nerves End  Cholinergic Agonists & Antagonists Charles S. Bockman, Ph.D. Creighton University School of Medicine  Peripheral Nervous System Controls Controls smooth & skeletal cardiac muscle muscle & glands Somatic Autonomi Nervous System c Nervous System One Two Neuron Neuron Efferent Efferent Lim Lim b b 2 Anatomy of Cranial Nerves (Brain & Brainstem) and Spinal Nerves (Cervical, Thoracic, Lumbar and Sacral) Effects Caused by Stimulation of the Parasympathetic Nervous System Eye - Iris muscle contraction: miosis Ciliary muscle contraction: Accommodation of focus for near vision Exocrine Glands - ↑ secretions lacrimation, rhinorrhea, salivation Heart - Bradycardia Lung - Bronchoconstriction GI Tract - ↑Gastric acid secretion ↑ Intestinal motility Urinary Bladder - Urination Penile and Clitoral Erection & Vaginal Lubrication  PARASYMPATHOMIMETICS (CHOLINOMIMETICS): Drugs that facilitate or mimic some or all of the actions of the parasympathetic nervous system. Muscarinic receptor agonists Anticholinesterases 5 Muscarinic receptor signal transduction 6  Big Ugly Table Sub- Other Locations Signaling Agonists Antagonists type names pathway M1 CNS Phospholipase C ACh Atropine M1 Enteric Nerves Muscarine Autonomic ganglia M2 Heart, nerves, ACh Atropine M2 (cardiac) smooth muscle ¯ Adenylyl cyclase, Muscarine CNS ­K channels M3 Exocrine glands, ­Phospholipase C ACh Atropine M3 (glandular) smooth muscle, endothelium Muscarine CNS CNS ACh Atropine M4 ¯ Adenylyl cyclase Muscarine CNS ­Phospholipase C ACh Atropine M5 Muscarine End plate Skeletal muscle ­Na+/K+ ACh NM receptor neuromuscular junction depolarizing ion Nicotine D-Tubocurarine channels Succinycholine Ganglionic Autonomic ganglia ­Na+/K+ ACh NN receptor Adrenal medulla depolarizing Nicotine Hexamethonium Mecamylamine CNS channels DMPP Muscarinic Receptor Agonists Choline esters: – Acetylcholine – Methacholine – Carbachol – Bethanechol Other synthetic – Cevimeline (M1 and M3 selective) Naturally occurring alkaloids – Muscarine – Arecoline – Pilocarpine  Structure–Activity Relationships Among Choline Esters Methylation: – Muscarinic selectivity – Slight cholinesterase resistance Carbamyl substitution: – Cholinesterase resistance  Naturally Occurring Alkaloids Muscarine – Poison from inocybe or clytocybe mushrooms – Selective for muscarinic receptors Pilocarpine – From pilocarpus plant – Not a substrate for cholinesterase – Selective for muscarinic receptors Arecoline – From betel nut – Not a substrate for cholinesterase – Selective for muscarinic receptors  Mechanism of Action Bind with high affinity and activate muscarinic receptors Mimic effects of endogenously released acetylcholine by parasympathetic nervous system: eye, lung, heart, GI, GU Specificity for muscarinic vs. nicotinic receptors varies Inactivation by cholinesterase varies Ocular Effects of Muscarinic Agonists Iris muscle contraction: miosis Ciliary muscle contraction: accommodation of focus for near vision  Cardiovascular Effects of Muscarinic Receptor Agonists Stimulate cardiac M2-muscarinic receptors – Bradycardia – Negative inotropy (slight) – Reduced A-V nodal conduction Stimulate vascular endothelial cells and stimulate NO release – Vasodilatation  Respiratory Effects of Muscarinic Receptor Agonists Bronchoconstriction – Inhaled methacholine for diagnosis of bronchial airway hyperreactivity Bronchial Glands - Increased mucous discharge  GI Effects of Muscarinic Receptor Agonists Sialorrhea – Use in Sjögrens Syndrome and radiation-induced xerostomia: pilocarpine, cevimeline Increased gastric and intestinal smooth muscle motility Relaxation of sphincters Increased gastric acid secretion  Genitourinary Effects of Muscarinic Receptor Agonists Contraction of detrusor muscle Relaxation of trigone and sphincter muscles - Bethanechol: stable to hydrolysis by AChE – Used to treat postoperative urinary retention  CNS Effects Muscarinic and nicotinic receptors widely distributed in brain Choline esters and pilocarpine do not significantly penetrate BBB Blocking central cholinergic receptors DOES produce functionally important effects  Other Effects Diaphoresis Lacrimal gland secretion  Mechanism of action of cholinomimetics Direct acting: bind to and activate muscarininc or nicotinic receptors Indirect acting: inhibit acetylcholinesterase and thereby prolong the action of acetylcholine (ACh) at the neuroeffector junction 19  Cholinesterase Inhibitors Acetylcholinesterase – Localized within junctions and synapses – Metabolizes/breaks down acetylcholine – Thus it terminates action of acetylcholine Butyrylcholinesterase – Found in plasma and on platelets – Substrate: circulating choline esters – Acetylcholine, succinylcholine 20  General Mechanism of Action Direct acting: agonists bind to and activate muscarinic cholinergic or nicotinic cholinergic receptors Indirect acting: inhibit acetylcholinesterase Prolongation of Acetylcholine’s Effects – Neuroeffector muscarinic cholinergic sites – Neuromuscular nicotinic cholinergic sites – Post synaptic nicotinic cholinergic receptors on autonomic ganglia  Available Cholinesterase Inhibitors Short duration – Edrophonium Intermediate duration – Neostigmine – Physostigmine – Pyridostigmine Long duration (irreversible) – Echothiophate (glaucoma & strabismus – Organophosphate pesticides (Malathion) and nerve agents (Sarin) (Antidote - reactivator: pralidoxime)  Pharmacological Effects Result from increased Ach concentration in junctions and synapses Muscarinic effects: same as for muscarinic agonists in eye, heart, gut bladder, lung. For example: Autonomic: “SLUD” syndrome – Salivation – Lacrimation – Urination – Defecation Nicotinic Receptor Mediated Effects of Cholinesterase Inhibitors Neuromuscular: Skeletal muscle effects: facilitation of voluntary contraction and tremor Depolarization block, paralysis and fasciculations 24  Depolarizing Block Results from persistent activation of Nm receptors – Initial intense activation of Nm causes depolarization w/ action potential – If signal is not terminated, response will quickly fade result in flaccid paralysis – Can be caused by acetylcholine (w/ cholinesterase inhibition) nicotine and succinylcholine Mechanism: Voltage-sensitive Na+ channels become refractory to stimulation  Therapeutic Use of Cholinesterase Inhibitors Myasthenia Gravis Reversal of neuromuscular blockade Atropine poisoning Alzheimer’s disease Myasthenia Gravis  Diagnosis of MG Initial signs and symptoms: lose of fine motor control in well-innervated muscles (fingers, face, eyelids, tongue) Diagnostic test: edrophonium (Tensilon) – rapid restoration of motor function  MG Treatment Neostigmine Pyridostigmine – Tablets – Liquid – Sustained release preparation Ambemonium  Additional Aspects of MG Myasthenic crisis – Sudden worsening of myasthenic symptoms – Caused by increased anti-Nm ab production Cholinergic crisis – Sudden worsening of myasthenic symptoms – Caused by depolarizing block  Additional Aspects of MG (cont.) Myasthenic crisis – worsening of myasthenic symptoms – Need to increase cholinesterase inhibition Cholinergic crisis – worsening of myasthenic symptoms – Need to decrease cholinesterase inhibition  Therapeutic Use of Cholinesterase Inhibitors Myasthenia Gravis Reversal of neuromuscular blockade Atropine poisoning Alzheimer’s disease  AchE Inhibitors and Reversal of Neuromuscular Blocking Drugs Neostigmine et al shorten duration of action of competitive neuromuscular blocking drugs (e.g., tubocurarine, vecuronium etc.) Mechanism: – Neuromuscular blocking drugs are competitive inhibitors of Nm receptors – AchE inhibitors increase junctional concentration of ACH, overcoming competitive inhibition.  Therapeutic Use of Cholinesterase Inhibitors Myasthenia Gravis Reversal of neuromuscular blockade Atropine poisoning Alzheimer’s disease  AchE Inhibitors and Reversal of Atropine Poisoning Atropine: Competitive muscarinic antagonist Cholinesterase inhibition increases junctional Ach concentration, competitively overcoming muscarinic blockade  Therapeutic Uses of Cholinesterase Inhibitors Myasthenia Gravis Reversal of neuromuscular blockade Atropine poisoning Alzheimer’s disease: – Tacrine – Donepezil – Galantamine – Rivastigmine Adverse Effects of Cholinesterase Inhibitors Similar to muscarinic receptor agonists: – Ocular: miosis, accommodation – Respiratory: bronchoconstriction, increased secretions – Cardiovascular: bradycardia, hypotension – GI: diarrhea, nausea, vomiting, sialorrhea – GU: urination – Diaphoresis Unique to cholinesterase inhibitors: – Muscle fasciculation, tremor – Flaccid paralysis, respiratory collapse (depolarizing block)  Adverse Effects (cont.) Cholinergic Crisis: overdose or rapid infusion Treatment: – Short or intermediate-acting: give atropine and supportive care (including respiratory support) – Organophosphorous inhibitor: atropine and slow infusion of pralidoxime (within 6 hours of exposure) Cholinesterase Inhibitors in Warfare VX - The nerve agent smeared onto the face of Kim Jong Nam, estranged half-brother of North Korean dictator Kim Jon Un, was administered in such a high dose it killed him within 20 minutes Sarin traces found in Syria chemical attack victims' blood, Turkey says  PARASYMPATHOLYTICS (ANTICHOLINERGICS): Drugs that reduce or inhibit some or all of the actions of the parasympathetic nervous system. Muscarinic receptor antagonists Ganglionic blocking drugs 41  Muscarinic Cholinergic Receptor Antagonists: Atropine Jimsonweed  Mechanism of Action Competitive antagonism of muscarinic receptors Pharmacological effects – Blockade of parasympathetic signals – Blockade of sympathetic signals mediated by muscarinic receptors – CNS action  Ocular Effects of Atropine Iris muscle relaxation: mydriasis Cycloplegia: loss of accommodation Decreased lacrimal gland secretion  Cardiovascular Tachycardia Mild increase in force of atrial contraction  Respiratory Effects of Atropine Bronchodilatation Inhibition of respiratory tract secretions Decreased ciliary mucous clearance in lung  GI Effects of Atropine Xerostomia Reduced gastric acid secretion Reduced GI motility Genitourinary Effects of Atropine Impaired micturation (M3 blocking effects) Blockade of detrusor contraction Contraction of trigone and sphincters  Drugs for Overactive Bladder/ Incontinence Oxybutynin M3-muscarinic cholinergic Darifenacin receptor antagonists Solifenacin Tolterodine Trospium Most frequent adverse effect is dry mouth. Sympathetic Effects of Atropine Inhibition of sweat gland secretion CNS Effects Sedation Antiemesis Amnesia  Therapeutic Uses of Muscarinic Cholinergic Antagonists in the CNS Motion sickness prophylaxis - Scopolamine Parkinson’s disease - Benztropine Antidote for poisoning by – Organophosphate insecticides – Nerve agents – Mushrooms  Therapeutic Uses of Muscarinic Cholinergic Antagonists in the Periphery Respiratory - Ipratropium/Tiotropium used via inhalation for asthma and COPD – Surgical adjunctive agent – drying mucous membranes of respiratory tract Ophthalmologic examination of the retina facilitated by mydriasis and cycloplegia Cardiovascular - Attenuate response of reflex vagal discharge during acute MI GI – Hyoscyamine, scopolamine in irritable bowel characterized by spasticity GU – Overactive bladder characterized by urinary urgency and incontinence Cholinergic poisoning- insecticides, nerve agents & mushrooms 51  Adverse effects Predictable Consequences of Muscarinic Receptor Blockade Ocular: blurred vision Cardiovascular: tachycardia GI: Xerostomia, constipation, dyspepsia CNS – Low doses: sedation – High doses: excitement, hallucinations, delirium & amnesia  Examples of Widely Used Drugs Associated with Cholinergic Burden Diphenhydramine Prescriptions for drugs tied to Amitryptiline cognitive decline 'Alarmingly High‘ despite the well-documented link Quetiapine between antimuscarinic agents and cognitive dysfunction in the elderly. Chlorpheniramine J Med Toxicol 6, 386-92, 2010. Olanzapine Doxylamine Cyclobenzaprine Trihexylphenidyl Datura stramonium: Locoweed, Devil’s Trumpet, Jimson Weed and Atropa belladonna/Deadly Nightshade  A detailed history revealed that 3-year old boy had touched and held a flower from an angel's trumpet plant (Panel B) and then rubbed his right eye. Angel's trumpet, a member of the genus brugmansia, is an ornamental plant from South America that is increasingly found worldwide and contains parasympatholytic alkaloids such as scopolamine, hyoscyamine and atropine. NEJM 367, 1341, 2012  Overdose Toxicity “Classic” symptoms: “Hot, red, dry and mad” – Dry as a bone – Red as a beet – Blind as a bat – Hot as a furnace – Mad as a hatter – Light sensitivity – Tachycardia Antidote: Physostigmine  Adrenergic Agonists Sympathomimetic Drugs Dr. Abel Department of Pharmacology and Neuroscience  Sympathomimetic Drugs (Adrenergic Agonists) - Sympathomimetic drugs - Mimic the effects caused by stimulation of the sympathetic nervous system. - Types of sympathomimetic drugs: 1. Direct Acting Sympathomimetic Drugs Directly bind to and active adrenergic receptors. 2. Indirect Acting Sympathomimetic Drugs Increase the amount of endogenous norepinephrine available to stimulate adrenergic receptors. 3. Mixed Acting Sympathomimetic Drugs Has both direct and indirect acting mechanisms. a Minor actions are shown in brackets. b Receptor types: alpha = α, beta = ß, muscarinic = M. c Vascular smooth muscle in skeletal muscle blood vessels has minor sympathetic cholinergic dilator nerves. d Probably through presynaptic inhibition of parasympathetic activity. Low doses of epinephrine, or β2-selective agonists, decrease blood pressure. For epinephrine, this is called the “low dose effect” of epinephrine.  Adrenergic receptors and responses Arteries and Veins Low doses of epinephrine decrease blood pressure. This is called the “low dose effect” of epinephrine.  Prototype Direct Acting Sympathomimetic Drugs Epinephrine Epinephrine Epinephrine Epinephrine Norepinephrin Norepinephrine Norepinephrine e Isoproterenol Isoproterenol a1 a2 ß1 ß2 β3 Phenylephrine Brimonidine Dobutamine Albuterol Mirabegron Salmetertol Clonidine Relative versus absolute receptor selectivity of adrenergic receptor agonists.  Sympathomimetic drugs Epinephrine, norepinephrine (α, β) - Endogenous, metabolized by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). Given by injection. Isoproterenol (β1, β2) – Synthetic drug. Phenylephrine, midodrine (α1)– Synthetic drugs. Brimonidine, oxymetazoline, tetrahydrozoline, (α2) - Synthetic, applied locally, peripheral acting. Clonidine, guanfacine (α2) - Synthetic, act in CNS. Dobutamine (β1)– Synthetic. Albuterol– terbutaline, formoterol, salmeterol, (β2)– Synthetic. Mirabegron – Synthetic drug, new. β3 - adrenergic receptor agonist. Dopamine - Endogenous, stimulates dopamine receptors, 1- receptors, - receptors and releases norepinephrine. Theoretical use of sympathomimetic drugs in patients with asthma. Effects of Drugs on Intact Systems  Sensory Input - The Baroreceptor Reflex Baroreceptor sensory nerves trigger reflex activity which changes in blood pressure. BP = CO X PVR Baroreceptor Reflex Blood Pressure – Baroreceptor: Heart Rate Blood Pressure Blood Pressure - Baroreceptor: Heart Rate Blood Pressure  Other Sympathomimetic Drugs Indirect acting sympathomimetic drugs – Drugs that release norepinephrine from sympathetic nerves. Amphetamines and related drugs (methylphenidate, phentermine). Tyramine. >> – Drugs that block the neuronal uptake of norepinephrine. Tricyclic antidepressants (imipramine), serotonin -norepinephrine reuptake inhibitors (duloxetine), cocaine. Mixed acting sympathomimetic drugs – Ephedrine, pseudoephedrine.  NE Releasing Drugs NE NET Amphetamine etc.  H Indirect Acting Drugs Amphetamine, related drugs (methylphenidate, phentermine) and tyramine. These drugs/agent cause release of norepinephrine from sympathetic nerves. Foods containing moderate to high tyramine content Cheese – cheddar, brie, mozzarella Meat – sausages (bologna, bratwurst) Fruit – figs, raisins (depends on ripeness) Beverages – beer, red wine Other – soy sauce, yogurt Drug Interaction - Tyramine or norepinephrine releasing drugs plus phenelzine or other monoamine oxidase inhibitors can be dangerous when used together. My Summer Vacation  NE Releasing Drugs + MAO Inhibitors Drug Contraindication: Tyramine or Phenelzine X X norepinephrine releasing drugs plus monoamine oxidase inhibitor drugs, NET NE such as Phenelzine, can cause nervousness, anxiety, hypertensive Amphetamine etc. Tyramine etc. crisis, arrhythmias, stroke. Phenelzine X  Other Sympathomimetic Drugs Indirect acting sympathomimetic drugs – Drugs that release norepinephrine from sympathetic nerves. Amphetamines and related drugs (methylphenidate, phentermine). Tyramine. – Drugs that block the neuronal uptake of norepinephrine. Tricyclic antidepressants (imipramine), serotonin -norepinephrine reuptake inhibitors (duloxetine), cocaine. >> Mixed acting sympathomimetic drugs NE Uptake Blockers X  Other Sympathomimetic Drugs Indirect acting sympathomimetic drugs – Drugs that release norepinephrine from sympathetic nerves. Amphetamines and related drugs (methylphenidate, phentermine). Tyramine. – Drugs that block the neuronal uptake of norepinephrine. Tricyclic antidepressants (imipramine), serotonin -norepinephrine reuptake inhibitors (duloxetine), cocaine. Mixed acting sympathomimetic drugs – Ephedrine, pseudoephedrine.  Mixed Acting Drugs Pseudoephedrine Ephedrine  Major Therapeutic Uses Cardiovascular – Cardiac Arrest, Shock, Arrhythmias, Hypotension Respiratory – Bronchoconstriction, Nasal Congestion Genitourinary – Overactive Bladder, Preterm Labor Allergic Reactions – Severe allergy “CNS” – Attention Deficit Hyperactivity Disorder, Depression, Obesity  Cardiovascular Shock Cardiac Arrest - Epinephrine - Norepinephrine - Dopamine - Dobutamine β1 α1  Cardiovascular Hypotension – Ephedrine, α1 Phenylephrine α1 α1 Arrhythmias - Phenylephrine  E Respiratory Nasal Congestion- Pseudoephedrine, phenylephrine, Bronchoconstriction- oxymetazoline Albuterol, salmeterol β2 β2 α1 α2  Genitourinary β2 β3 β3 β2 Preterm Labor- Overactive Bladder- Terbutaline Mirabegron Severe allergic reactions -Anaphylaxis Due to insect bites, foods or drugs. Causes bronchoconstriction, shortness of breath, hypotension, edema (glottis), swelling, rash. Emergency: Epinephrine i.m. or nasal spray. Duration ≈ 20 minutes. CNS - Appetite Suppression - Obesity Phentermine + topiramate (Qsymia®) Increases monoamine neurotransmitters (dopamine, norepinephrine, serotonin) in the CNS.  Adverse Effects and Precautions Cardiovascular – 1,(↑2) Palpitations, tachycardia, arrhythmias, cardiac ischemia Use care with arrhythmias, hyperthyroidism, coronary artery disease – 1+ 2 Increased blood pressure, reduced tissue blood flow Use care with hypertension, diabetes mellitus Genitourinary – 1 Urinary retention CNS – Stimulation (indirect > mixed > direct acting) Skeletal Muscle – 2 Tremor Others 25 End  Adrenergic Antagonists Adrenergic Blocking Drugs Dr. Peter Abel, Professor and Chair Department of Pharmacology and Neuroscience Criss III, Room 551 280-2983 [email protected]  Adrenergic Blocking Drugs These drugs block responses caused by adrenergic nerve stimulation. Types of adrenergic blocking drugs – Adrenergic Receptor Blocking Drugs (Adrenergic Receptor Antagonists). Bind to adrenergic receptors but do not stimulate the receptor to cause a response. – Adrenergic Neuron Blocking Drugs. These drugs inhibit the activity of adrenergic nerves.  Sites of Action of Blocking Drugs Peripheral CNS Neuron Neuron Blockers Blockers Receptor Blockers Sympathetic  Receptor Selectivity of Receptor Blockers CARVEDILOL CARVEDILOL CARVEDILOL 3rd Generation PROPRANOLOL PROPRANOLOL 1st Generation NADOLOL NADOLOL PINDOLOL PINDOLOL PHENTOLAMINE PHENTOLAMINE PHENOXYBENZAMIE PHENOXYBENZMINE a1 a2 ß1 ß2 TAMSULOSIN (a1A) YOHIMBINE METOPROLOL TERAZOSIN ATENOLOL 2nd Generation  Adrenergic Receptor Blockers Carvedilol - Other drugs = nebivolol. labetalol. Blocks > 1 adrenergic receptor type. Vasodilator β blockers. 3rd Gen. Propranolol, Pindolol - Other drugs = nadolol, timolol, carteolol. Pindolol has intrinsic sympathomimetic activity. Nonselective β blockers. 1st Gen. Phentolamine, Phenoxybenzamine- In contrast to other adrenergic receptor blocking drugs, phenoxybenzamine causes an irreversible blockade of -adrenergic receptors. Terazosin, Tamsulosin- Other drugs = prazosin, doxazosin. Metoprolol, Atenolol - Other drugs = esmolol (iv only), acebutolol, betaxolol. Cardioselective β blockers. 2nd Gen. Beta blockers end in “lol” or “olol”, α1 blockers end in “osin”. Responses to Receptor Blockers  Cardiovascular Effects of -Blockers “Epinephrine Reversal” “Epinephrine Reversal” – Reversing epinephrine from a vasoconstrictor to a vasodilator by blocking α receptors. Therapeutic use of α Blockers Hypertension Benign Prostatic Hyperplasia Peripheral Vascular Disease Impotence – Peripheral vasodilation CNS action Hypertension – Terazosin, etc. Block α1 adrenoceptors on vascular smooth muscle. Inhibit sympathetic nerve mediated vasoconstriction. BP = PVR x CO Benign Prostatic Hyperplasia (BPH) α1A α1A α1A α1A Tamsulosin, etc. (α1A subtype selective)  Peripheral Vascular Disease - Raynaud’s Phenomenon Raynaud’s Phenomenon – Excessive vasoconstriction to cold. Prazosin  Impotence – Phentolamine, Yohimbine Some doctors already use phentolamine (Vasomax®) as an injection, shown here on a grapefruit. Yohimbine Yohimbie - Can cause insomnia, anxiety, palpitations, tachycardia, chest pain, sweating, blurred vision, heart attacks and seizures.  Adverse Effects of α Blockers Cardiovascular – Orthostatic (Postural) Hypotension – “First Dose Effect”: dizziness, fainting on standing – Reflex tachycardia, palpitations: caution with arrhythmias, angina pectoris – Fluid retention, weight gain, peripheral edema: caution in edema, hypertension Genital/Urinary – Inhibition of ejaculation Other – Dizziness, drowsiness, constipation/diarrhea  1-2 Therapeutic use of  Blockers Hypertension Angina Pectoris Arrhythmias Chronic Congestive Heart Failure Glaucoma Migraine Muscle tremor Others  Hypertension – Atenolol etc. Antihypertensive mechanisms: ↓ Cardiac output BP = PR x CO CO = HR x SV β1 ↓ Renin-Angiotensin BP = PR x CO Β1 ↓ Renin CNS effect? ↓ Angiotensin II Angina Pectoris - Metoprolol etc. Angina pectoris is characteristic chest discomfort associated with β1 myocardial ischemia. O2 Demand > O2 Supply β1 Arrhythmias – Atenolol etc. Supraventricular Tachycardia (SVT), Atrial Fibrillation, etc. Chronic Congestive Heart Failure Carvedilol etc. Chronic congestive heart failure leads to reduced cardiac output. Carvedilol and other β blockers are used in heart failure (HFrEF).  Glaucoma Glaucoma is an elevated Timolol (Timoptic) and intraocular pressure. other β-blocker drugs reduce aqueous humor formation. β Essential Tremor – Propranolol Migraine Headache - Propranolol Migraine headache prevention.  Adverse Effects of  Blockers Central Nervous System – Lethargy, depression, fatigue, vivid dreams – with lipophilic beta blockers (metoprolol etc.) Respiratory – Wheezing and bronchoconstriction in asthma - with nonselective beta blockers Cardiac – Cardiac suppression, bradycardia, AV node block - use care with cardiac arrhythmias, bradycardia Rebound effects with acute drug withdrawal – Angina, hypertension, arrhythmias  Adrenergic Blocking Drugs Types of adrenergic blocking drugs – Adrenergic Receptor Blocking Drugs (Adrenergic Receptor Antagonists). Bind to adrenergic receptors but do not stimulate the receptor to cause a response. – Adrenergic Neuron Blocking Drugs. These drugs inhibit the activity of adrenergic nerves. Central acting α2 agonists inhibit sympathetic nerve outflow - Clonidine, guanfacine, lofexidine Stimulate 2- adrenergic receptors in the brain. Clonidine, etc. ↓ sympathetic nerve outflow to the heart and blood vessels. ↓ blood pressure and heart rate. May cause an initial, transient increase in blood pressure. Neurotransmitter Storage Blockers Reserpine, Valbenazine Inhibits the vesicular monoamine transporter Reserpine (VMAT) on storage vesicle Reserpine Valbenazine X Blocks transport of norepinephrine and dopamine into the vesicle The storage vesicle becomes depleted of norepinephrine/dopamine and less is released The response to nerve stimulation is reduced 25  Adrenergic Neuron Blockers Use of centrally acting α2 agonists: – Clonidine (hypertension, pain), guanfacine (ADHD), alcohol/nicotine/opiate withdrawal (lofexidine), etc. Adverse Effects – sedation, altered sleep, impaired ejaculation, dry mouth Use of neurotransmitter storage blockers: – Reserpine – retired. – Valbenazine blocks uptake of dopamine into nerve storage vesicles in the CNS to reduce dopamine release. Used to treat tardive dyskinesia, a movement disorder caused by antipsychotic drugs. Adverse Effects End