-blocker and Organophosphate Toxicity
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Transcript of -blocker and Organophosphate Toxicity
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-blocker and Organophosphate Toxicity
Mark WahbaPreceptor Dr. I. Vicas
Core roundsMarch 25th, 2004
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-blockers
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Teaching points
• Recognize an overdose– “Toxidrome”
• Management– What is most effective treatment?
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Facts
• One of the most widely prescribed classes of drugs
• Indications:– Supraventricular dysrhythmias, hypertension,
angina, thyrotoxicosis, migraine, glaucoma, essential tremor
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PharmacologyReview
Parasympathetic Sympathetic
Autonomic System Somatic System
Efferent Division Afferent Division
Peripheral Nervous System Central Nervous System
Nervous System
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PharmacologyReview
• autonomic nerve fibres can be classified in two groups
• based on the chemical nature of the neurotransmitters
Cholinergic Adrenergic
Autonomic Nerve Fibers
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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
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-Adrenergic Receptors and Agnonistic Response
Receptors Location Response to Stimulation
1 Heart
Kidney
Heart rate and ectopy Contractility
Renin secretion
2 Airway (smooth muscle)
Peripheral vasculature
Liver
Tone (relaxation)
Tone (relaxation)
gycogenolyis, gluconeogenesis
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Selectivity
• Nonselctive 1 and 2
– Propranolol– Nadolol– Timolol– Pindolol– Labetalol– Sotalol
• Selective 1
– Metoprolol– Atenolol– Esmolol– Acebutolol
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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
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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
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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.
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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
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Clinical Features
• Respiratory - Hypoxia– CHF or bronchospasm if hx of asthma
• Metababolic - hypoglycemia– More common in children or people with
diabetes
– Is rarely severe
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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
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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 9Isoproterenol 11 22 9
Dopamine 25 25 4
Atropine 22 0 9
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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 9Isoproterenol 11 22 9
Dopamine 25 25 4
Atropine 22 0 9
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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
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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
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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
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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
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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 7Epinephrine 67 50 6Pacemaker 83 0 9Isoproterenol 11 22 9Dopamine 25 25 4Atropine 22 0 9
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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
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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
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Disposition
• If asymptomatic after 8 hours, ? send to psych
• If unstable may need ICU
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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
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Organophosphates
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Teaching Points
• Understand why the toxidrome occurs• Recognize the toxidrome• Recognize why early treatment with
Pralidoxime is important
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History
• Organophosphorous compounds and carbamates– Known as cholinesterase inhibitors
• Pesticides and insecticides– Parathion, House hold insect sprays-Malathion
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PharmacologyReview
• The autonomic nerve fibres can be classified in two groups
• Based on the chemical nature of the neurotransmitters
Cholinergic Adrenergic
Autonomic Nerve Fibers
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Pharmacologyreview
• 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
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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
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Neurotransmission at cholinergic neurons
1. Synthesis of ACh Storage of ACh in vesicles
2. Release of ACh 3. Binding to the receptor4. Degredation of Ach
• Acetylcholinesterase cleaves ACH to choline and acetate
5. Recycling of ACh
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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
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“Aging”
• Permanent binding of the OP to the AChE enzyme occurs in variable amounts of time
1. Covalent binding of OP with AChE2. Inactivates the enzyme3. 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
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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
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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
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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
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History and Physical
• What agent were they exposed to?
• How were they exposed?
• Work: Protective equipment? Is it cleaned after each use? Frequency of exposure?
• Muscarinic, Nicotinic and CNS effects
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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
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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)
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CNS Effects
• Agitation• Seizures• Coma
• Other: pt may have a strong “garlicky” odor
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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
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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
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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
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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
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Laboratoryevidence 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
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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
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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
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Treatment
• Airway• excessive salivation• vomiting• may require aggressive suctioning
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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
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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
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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
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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
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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
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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
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Treatment
• Circulation• If bradycardic • atropine• If hypotensive • think dehydration fluid
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Treatment
• Elimination• Dialysis not indicated b/c of large Vd• Body eventualy metabolizes the OP and it is
excreted in the urine
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Treatment
• Find an Antidote– Two parts
1. Atropine2. Pralidoxime
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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
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Medical & Legal Pitfallshttp://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 organophosphate-induced delayed neurotoxicity
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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
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Key Points
• Protect staff from Contamination• Treat with Pralidoxime early to prevent
aging
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Thanks Dr. Vicas
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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. Lippinocott-
Raven New York• http://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98-309/A
NS/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