-blocker and Organophosphate Toxicity

Mark WahbaPreceptor Dr. I. Vicas

Core roundsMarch 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

PharmacologyReview

Parasympathetic Sympathetic

Autonomic System Somatic System

Efferent Division Afferent Division

Peripheral Nervous System Central Nervous System

Nervous System

PharmacologyReview

• autonomic nerve fibres can be classified in two groups

• based on the chemical nature of the neurotransmitters

Cholinergic Adrenergic

Autonomic Nerve Fibers

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

Kidney

Heart rate and ectopy Contractility

Renin secretion

2 Airway (smooth muscle)

Peripheral vasculature

Liver

Tone (relaxation)

Tone (relaxation)

gycogenolyis, gluconeogenesis

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 9Isoproterenol 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 9Isoproterenol 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 7Epinephrine 67 50 6Pacemaker 83 0 9Isoproterenol 11 22 9Dopamine 25 25 4Atropine 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

PharmacologyReview

• The autonomic nerve fibres can be classified in two groups

• Based on the chemical nature of the neurotransmitters

Cholinergic Adrenergic

Autonomic Nerve Fibers

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

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

2. Release of ACh 3. Binding to the receptor4. Degredation of Ach

• Acetylcholinesterase cleaves ACH to choline and acetate

5. 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 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

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 exposed to?

• How were they exposed?

• Work: Protective equipment? Is it cleaned after each use? Frequency of exposure?

• Muscarinic, Nicotinic and CNS effects

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

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

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. Atropine2. 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 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

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. 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