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-blocker and Organophosphate Toxicity Mark Wahba Preceptor Dr. I. Vicas Core rounds March 25th, 2004 -blockers Teaching points • Recognize an overdose – “Toxidrome” • Management – What is most effective treatment? Facts • One of the most widely prescribed classes of drugs • Indications: – Supraventricular dysrhythmias, hypertension, angina, thyrotoxicosis, migraine, glaucoma, essential tremor Pharmacology Review Nervous System Peripheral Nervous System Efferent Division Autonomic System Parasympathetic Afferent Division Somatic System Sympathetic Central Nervous System Pharmacology Review • autonomic nerve fibres can be classified in two groups • based on the chemical nature of the neurotransmitters Autonomic Nerve Fibers Cholinergic Adrenergic Pharmacology review Adrenergic Receptors • Found in CNS and Sympathetic NS • Stimulated by Norepinephrine and Epinephrine • two classes of receptors in SNS – – • Stimulation of receptor results in activation of adenyl cyclase, conveting AMP to c-AMP which opens ion channels -Adrenergic Receptors and Agnonistic Response Receptors Location Response to Stimulation 1 Heart Heart rate and ectopy Contractility Kidney Renin secretion Airway (smooth muscle) Tone (relaxation) Peripheral vasculature Tone (relaxation) Liver gycogenolyis, gluconeogenesis 2 Selectivity • Nonselctive • 1 and 2 – – – – – – Propranolol Nadolol Timolol Pindolol Labetalol Sotalol • Selective • 1 – – – – Metoprolol Atenolol Esmolol Acebutolol Pharmacology • rapidly absorbed after oral ingestion • peak effect in 1-4 hours for regular release • Sustained release products may take up to 6 h to show effects and may last up to 72 h Pharmacology • large volume of distribution therefore Hemodialysis is often not effective • blood levels are not useful • Varying degrees of lipophilicity • high lipid solubility leads to a larger volume of distribution – drug penetrates into the CNS eg. propranolol Blocker overdose • • • • • • • • • • • Box 146-8. Manifestations and Complications of Blocker Overdose in Order of Decreasing Frequency * * 1. Bradycardia (65/90 cases) 2. Hypotension (64/90) 3. Unconsciousness (50/90) 4. Respiratory arrest or insufficiency (34/90) 5. Hypoglycemia (uncommon in adults) 6. Seizures (common only with propranolol, 16/90) 7. Symptomatic bronchospasm (uncommon) 8. VT or VF (6/90) 9. Mild hyperkalemia (uncommon) 10. Hepatotoxicity, mesenteric ischemia, renal failure (rare or single case reports) ------------------------------------------------------------------------ • • * Data in parentheses from Langemeijer JJM et al: Neth J Med 40:308, 1992. * VT, Ventricular tachycardia; VF, ventricular fibrillation. • Clinical Features • CV- most pronounced effect on CV system – Bradycardia and AV block, hypotension are hallmarks – QRS widening, vent dysrhythmias: VT, VF, torsade de pointes may occur – Direct agonistic effect on 1 receptors • CNS- unconsciousness, seizures – Hypoperfusion, hypoglycemia Clinical Features • Respiratory - Hypoxia – CHF or bronchospasm if hx of asthma • Metababolic - hypoglycemia – More common in children or people with diabetes – Is rarely severe Management • Airway • Breathing – Bronchospasm-antagonism of 2 receptors • Only an issue if asthmatic or COPD – Congestive Heart Failure- antagonism of 1 receptors • Rare, usualy bradycardia and hypotension • Circulation Frequency of desired therapeutic response when compared to treatment used table 5 Weinstein RS Recognition and management of poisoning with beta-adrenergic blocking agents. Ann Emerg Med Dec 1984; 13 1123-1131 Treatment Incrased HR (%) Increased BP (%) Total # of times used Glucagon 86 86 7 Epinephrine 67 50 6 Pacemaker 83 0 9 Isoproterenol 11 22 9 Dopamine 25 25 4 Atropine 22 0 9 Frequency of desired therapeutic response when compared to treatment used table 5 Weinstein RS Recognition and management of poisoning with beta-adrenergic blocking agents. Ann Emerg Med Dec 1984; 13 1123-1131 Treatment Incrased HR (%) Increased BP (%) Total # of times used Glucagon 86 86 7 Epinephrine 67 50 6 Pacemaker 83 0 9 Isoproterenol 11 22 9 Dopamine 25 25 4 Atropine 22 0 9 Management • Circulation • Fluids: 20-40ml/kg bolus crystalloid, may repeat • Atropine: 0.5mg for adults up to 3 mg, 0.02mg/kg for children (minimum 0.1 mg) – H/r has a poor effect on raising heart rate and BP Management • Glucagon: does not depend on -receptors for its action – increases intacellular cAMP through non-adrenergic pathways • has both inotropic and chronotropic effects • helps to counteract hypoglycemia • 2-10mg IV bolus. (Children 50mcg/kg) – Has 20min 1/2 life – May run an infusion of 2-5mg/h – Side effect is nausea and vomiting Management • Hyperinsulinemia-Euglycemia – based on an animal model – exact mechanism unclear • thought to be secondary to increased myocardial glucose utilization resulting from the high-dose insulin drips • Load with 1u/kg of insulin • Then infusion of insulin at 0.1-1.0 U/kg/hr • need glucose infusions +/or boluses to maintain euglycemia – Start with bolus of 2 ampules of D50 – monitor blood glucose levels closely: q1h Management • Vasopressors: epinephrine, dopamine, norepinephrine, isoproterenol – May need higher than average doses • Vent dysrhythmias: avoid 1A and 1C as they may potentiate AV block or prodysrhythmic effect. • Overdrive pace with pacemaker and MgSO4 for torsades de pointes Frequency of desired therapeutic response when compared to treatment used table 5 Weinstein RS Recognition and management of poisoning with beta-adrenergic blocking agents. Ann Emerg Med Dec 1984; 13 1123-1131 Treatment Incrased HR (%) Increased BP (%) Total # of times used Glucagon 86 86 7 Epinephrine 67 50 6 Pacemaker 83 0 9 Isoproterenol 11 22 9 Dopamine 25 25 4 Atropine 22 0 9 Management • Decontamination – Activated charcoal, can multidose b/c some -blockers undergo enterohepatic circulation – Whole bowel irrigation if delayed release preparation • Elimination – Hemodiaylsis unlikely to be beneficial • Find an antidote – Win Nobel prize here Treatment of -blocker Poisoning Modified from Rosens box 146-9 • Phase 1- Resuscitation -boluses of fluids, glucagon, HIE, atropine • Phase 2- Stabilization – Infusions of • Glucagon • Hyperinsulinemia-Euglycemia • Vasopressors • Early cardiac pacing Disposition • If asymptomatic after 8 hours, ? send to psych • If unstable may need ICU Medical/Legal Pitfalls from http://www.emedicine.com/emerg/topic59.htm • Failure to recognize beta-blocker toxicity as a cause of bradycardia and hypotension without a history of intentional overdose • Failure to administer activated charcoal because of missed diagnosis of beta-blocker intoxication • Administering ipecac syrup before the onset of sedation and seizures • Failure to adequately monitor a patient on multiple cardiac vasopressors (eg, use of Swan-Ganz catheter and/or arterial blood pressure monitoring) • Medically clearing a patient with beta-blocker toxicity before an 8- to 10-hour observation period • Failure to administer large enough doses of antidotes, including catecholamines, glucagon, calcium, and potentially insulin Organophosphates Teaching Points • Understand why the toxidrome occurs • Recognize the toxidrome • Recognize why early treatment with Pralidoxime is important History • Organophosphorous compounds and carbamates – Known as cholinesterase inhibitors • Pesticides and insecticides – Parathion, House hold insect sprays-Malathion Pharmacology Review • The autonomic nerve fibres can be classified in two groups • Based on the chemical nature of the neurotransmitters Autonomic Nerve Fibers Cholinergic Adrenergic Pharmacology review • The following use acetylcholine (ACh) as a neurotransmitter – post ganglionic fibres of the paraysmp NS – autonomic ganglia – preganglinonic fibres terminating in the adrenal medulla – Skeletal muscle – CNS not shown Cholinergic Receptors • Muscarinic • heart rate (vagal stimulation) • blood pressure by vasodilation • salivation • gut motlity • bronchial secretions • detrusor muscle tone • Nicotinic • heart rate and blood pressure ( NE from postgang symp neurons) • skeletal muscle activity Neurotransmission at cholinergic neurons 1. Synthesis of ACh Storage of ACh in vesicles Release of ACh Binding to the receptor Degredation of Ach 2. 3. 4. • 5. Acetylcholinesterase cleaves ACH to choline and acetate Recycling of ACh Organophosphates (OP) mechanism of toxicity • Inhibit the enzyme acetylcholinesterase (AChE) • Causes accumulation of excessive Ach • Overstimulation of the cholinergic receptors • How? – OPs covalently bind to AChE inactivating the enzyme “Aging” • Permanent binding of the OP to the AChE enzyme occurs in variable amounts of time 1. Covalent binding of OP with AChE 2. Inactivates the enzyme 3. AChE enzyme releases an alkyl group – • known as “aging” Loss of the alkyl group makes it impossible for chemical reactivators (pralidoxime) to break the bond between the OP and AChE – Military agents ‘age’ in minutes or seconds Carbamates • Also inhibit AChE – Medical carbamates: Physostigmine, edrophonium • Produce similar clinical effects • However, reactivation occurs much more quickly than with OPs b/c binding is reversible • Toxicity is brief and self-limited • Treatment with Pralidoxime is not required Exposure • Absorbed by inhalation, ingestion, cutaneously • Highly lipophilic • OPs are easily absorbed and stored in fat tissue • May lead to persistent toxicity lasting for days after exposure Clinical Presentation • May occur 1-2 h after exposure – Inhalational exposure • may be delayed – skin exposure – with agents that must undergo metabolism to their active form History and Physical • What agent were they • Muscarinic, Nicotinic exposed to? and CNS effects • How were they exposed? • Work: Protective equipment? Is it cleaned after each use? Frequency of exposure? Muscarinic Effects • Muscarninc effect causes parasympathetic hyperstimulation of end organs • “DUMBELS” – – – – – – – D - Defecation U - Urination M - Miosis B - Bronchospasm, Bronchorrhea, Bradycardia E - Emesis and Abdominal pain L - Lacrimation S - Salivation Nicotinic Effects • Nicotinic effect causes adrenal gland secretion of epi and NE • Days of the week – – – – – – M - Muscle cramps T - Tachycardia W - Weakness tH - Hypertension F - Fasiculations S - Sugar (hyperglycemia) CNS Effects • Agitation • Seizures • Coma • Other: pt may have a strong “garlicky” odor Classification of Organophosphate Poisoning • From: Tafuri & Roberts Organophosphate Poisoning Annals of emergency Medicine Feb 1987, 16, 2 193-202 • Latent poisoning • Clinical mainfestations: none • Serum cholinesterase: >50% of normal value Classification of Organophosphate Poisoning • Mild poisoning • Clinical mainfestations: fatigue, H/A, dizziness, paresthesias, N, V, diaphoresis, salivation, wheezing, abd pain, diarrhea, able to ambulate • Serum cholinesterase: 20-50% of normal value Classification of Organophosphate Poisoning • Moderate poisoning • Clinical mainfestations: previous sympt, generalized weakness, dysarthria, fasiculations, miosis, can’t ambulate • Serum cholinesterase: 10-20% of normal value Classification of Organophosphate Poisoning • Severe poisoning • Clinical mainfestations: marked miosis, loss of pupilary light reflex, fasiculaitons, flacid paralysis, respiratory distress, cyanosis, unconsciousness • Serum cholinesterase: <10% of normal value Laboratory evidence of poisoning • measure decreases in plasma pseudocholinesterase (PChE) and RBC AChE level • RBC AChE more reliable – 25% depression from baseline indicates exposure – Recovers within months of exposure • PChE sensitive but not specific (may be genetically low) – Recovers within weeks of exposure • However, wide interindividual variability • Most helpful in continuous monitoring – Workplace health surveillance program Treatment • Decontamination • Staff: must wear chemical protective clothing in grossly contaminated pts – Decontaminate in high flow ventilation room or outdoors – Wear nitrile or buyl rubber gloves, eyeshields, protective clothing Treatment • Patient: find out what they and caregivers have already done • Skin: remove all contaminated clothing and irrigate with copious amounts of fluid – Must permanently discard contaminated leather articles • Ingestion: activated charcoal Treatment • Airway • excessive salivation • vomiting • may require aggressive suctioning Treatment • Breathing • Bronchospasm and bronchorrhea hypoxia – “drown in their own secrections” • respiratory muscle dysfunction ventilatory support – Preceded by neck muscle weakness • Succinylcholine’s effects can be prolonged in presence of OP toxicity Atropine • Belladonna alkaloid • Antimuscarinic – No effect on nicotinic receptor • Competitive inhibitor of ACh – Competitively binds to muscarinic receptor preventing ACh from binding • Prevents bradycardia, bronchospasm, bronchorrhea Atropine • End-point of atropinization is drying of respiratory secretions – Primary cause of death is pt ‘drowning in their own secretions’ • 0.5-2mg IV repeat as needed • Large doses may be needed: 100-500mg IV/hour • If Atropine is used, must use pralidoxime Pralidoxime • Synthetic pyridinium compound • “Reactivates” inhibited AChE at both muscarinic and nicotinic receptors – Makes the enzyme active again • has a “charged group that approaches an anionic site on the AChE enzyme which displaces the OP and regenerates the enzyme” – Lippincott’s Illustrated Reviews Pharmacology 2nd ed. Harvey RA editor. Lippinocott-Raven New York Pralidoxmine • Reverses muscular weakness and fasiculations – 1-2g bolus (20-40mg/kg in children) over 30-60 min – or infusion of 200-500mg/h (5-10mg/kg/h in children) titrating to desired clinical response • Must give early before aging has occurred and enzyme is irreversibly bound Pralidoxime • The OP Fenthion will leach out of fat stores for days to weeks • Infusion may needed for several days – OP toxicity will continue until new ACh is synthesized by the body Treatment • • • • • Circulation If bradycardic atropine If hypotensive think dehydration fluid Treatment • Elimination • Dialysis not indicated b/c of large Vd • Body eventualy metabolizes the OP and it is excreted in the urine Treatment • Find an Antidote – Two parts 1. Atropine 2. Pralidoxime Treatment • General Management – BZD for agitation, seizures – ICU for ventilatory support – ECG, Foley, O2 sat monitor etc • Disposition: – Most pts that require medical intervention will be hospitalized and need observation for at least 24 hours Medical & Legal Pitfalls http://www.emedicine.com/emerg/topic346.htm • Failure to recognize cholinergic symptoms and delaying intervention may result in increased morbidity and mortality • Failure to adequately decontaminate the exposed patient may result in secondary contamination of others • Failure to consider the possibility of an intermediate syndrome or organophosphateinduced delayed neurotoxicity Real Life • Tokyo, Japan 1995 five containers of nerve agent Sarin place on Subway • 5000-6000 people exposed • 3227 evaluated in emergency departments • 493 admitted to hospitals • 12 died • 135 ambulance personnel developed symptoms • 33 hospitalized • Many hospital staff also required treatment • Neither ambulance personnel nor hospital staff had any protection Key Points • Protect staff from Contamination • Treat with Pralidoxime early to prevent aging Thanks Dr. Vicas References • • • • • • • • • • Poisoning & Drug Overdose 4th ed, Olson KR ed. Lange/Mcgraw Hill Toronto 2004 Rosen’s Lippincott’s Illustrated Reviews Pharmacology 2nd ed. Harvey RA editor. LippinocottRaven New York http://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98309/ANS/ANS_Intro/ANS_intro.html Emergency Medicine Reports / April 21/ 2003 / Chemical Warfare Agents Part II: Nerve Agents, Blood Agents, and Protective Gear Author: Charles E. Stewart Emergency Medicine Reports / May 24/ 1999 /Neuromuscular Transmission Failure in the ED: Recognition, Assessment, and Targeted Management of a Life-Threatening Disorder, Masood Haque, MD Weinstein RS Recognition and management of poisoning with beta-adrenergic blocking agents. Ann Emerg Med Dec 1984; 13 1123-1131 http://www.emedicine.com/emerg/topic59.htm http://www.emedicine.com/emerg/topic346.htm From: Tafuri & Roberts Organophosphate Poisoning Annals of emergency Medicine Feb 1987, 16, 2 193-202