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 -blocker and Organophosphate Toxicity

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  1. -blocker and Organophosphate Toxicity Mark Wahba Preceptor Dr. I. Vicas Core roundsMarch 25th, 2004

  2. -blockers

  3. Teaching points • Recognize an overdose • “Toxidrome” • Management • What is most effective treatment?

  4. Facts • One of the most widely prescribed classes of drugs • Indications: • Supraventricular dysrhythmias, hypertension, angina, thyrotoxicosis, migraine, glaucoma, essential tremor

  5. PharmacologyReview

  6. PharmacologyReview • autonomic nerve fibres can be classified in two groups • based on the chemical nature of the neurotransmitters

  7. 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

  8.  -Adrenergic Receptors and Agnonistic Response

  9. Nonselctive 1 and 2 Propranolol Nadolol Timolol Pindolol Labetalol Sotalol Selective 1 Metoprolol Atenolol Esmolol Acebutolol Selectivity

  10. 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

  11. 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

  12.  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.

  13. 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

  14. Clinical Features • Respiratory - Hypoxia • CHF or bronchospasm if hx of asthma • Metababolic - hypoglycemia • More common in children or people with diabetes • Is rarely severe

  15. 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

  16. Frequency of desired therapeutic response when compared to treatment usedtable 5 Weinstein RS Recognition and management of poisoning with beta-adrenergic blocking agents. Ann Emerg Med Dec 1984; 13 1123-1131

  17. Frequency of desired therapeutic response when compared to treatment usedtable 5 Weinstein RS Recognition and management of poisoning with beta-adrenergic blocking agents. Ann Emerg Med Dec 1984; 13 1123-1131

  18. 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

  19. 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

  20. 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

  21. 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

  22. Frequency of desired therapeutic response when compared to treatment usedtable 5 Weinstein RS Recognition and management of poisoning with beta-adrenergic blocking agents. Ann Emerg Med Dec 1984; 13 1123-1131

  23. 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

  24. Treatment of -blocker PoisoningModified 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

  25. Disposition • If asymptomatic after 8 hours, ? send to psych • If unstable may need ICU

  26. 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

  27. Organophosphates

  28. Teaching Points • Understand why the toxidrome occurs • Recognize the toxidrome • Recognize why early treatment with Pralidoxime is important

  29. History • Organophosphorous compounds and carbamates • Known as cholinesterase inhibitors • Pesticides and insecticides • Parathion, House hold insect sprays-Malathion

  30. PharmacologyReview • The autonomic nerve fibres can be classified in two groups • Based on the chemical nature of the neurotransmitters

  31. 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

  32. 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 Cholinergic Receptors

  33. Neurotransmission at cholinergic neurons • Synthesis of ACh Storage of ACh in vesicles • Release of ACh • Binding to the receptor • Degredation of Ach • Acetylcholinesterase cleaves ACH to choline and acetate • Recycling of ACh

  34. 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

  35. “Aging” • Permanent binding of the OP to the AChE enzyme occurs in variable amounts of time • Covalent binding of OP with AChE • Inactivates the enzyme • 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

  36. 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

  37. 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

  38. 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

  39. 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 History and Physical

  40. 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

  41. 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)

  42. CNS Effects • Agitation • Seizures • Coma • Other: pt may have a strong “garlicky” odor

  43. 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

  44. 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

  45. 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

  46. 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

  47. 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

  48. 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

  49. 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

  50. Treatment • Airway • excessive salivation • vomiting • may require aggressive suctioning