Download - ACES: CV Drugs / Pesticides
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20 November 2013
CHAPTER 150
CHAPTER 161
CV Drug Toxicity
Pesticides
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1. Which of the following poisoning-
antidote therapeutic pairings is correct?
A.Anticholinergic-atropine
A.Beta-blocker- octreotide
A.Calcium-channel blocker-insulin
A.Digoxin-Calcium
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2. A 70 year-old patient with a history of CHF on digoxin
presents with weakness. Which is correct with regard to
her EKG?
A. EKG findings suggest the emergent need for
digiFAB
B. EKG findings are most likely due to ischemia
C. EKG findings are expected with therapeutic
digoxin levels.
D. EKG findings are diagnostic of chronic vs. acute
digoxin toxicity
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3. A 29 year old patient is brought in to the ED
by EMS in full cardiac arrest. The medics found
an empty bottle of digoxin next to his bed.
What is the most appropriate initial dose of DigiFab for this patient?
A. 2 Vials
B. 4-6 Vials
C. 10 Vials
D. 20 Vials
E. It needs to be calculated
based on the digoxin level.
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4. Which of the following is correct
regarding Beta Blocker overdose?
A. Beta blocker overdose universally causes
AV block.
B. Seizures and obtundation are seen more
often with propanolol compared to
metroprolol.
C. Octreotide is an important component of
treatment
D. Unlike calcium channel blocker toxicity,
high-dose insulin/glucose is not effective for beta-blocker toxicity.
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5. High dose insulin treatment in beta-blocker overdose increases
cardiac output primarily by increasing heart rate.
• A. True
• B. False
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6. Which is correct regarding the EKG? • A. This EKG shows a common finding in acute digoxin
toxicity.
• B. Salvage treatment should include administering of intravenous lipid emulsion (ILE).
• C. This EKG is highly suggestive of Class I sodium channel blockade (TCA, beta blocker (sotalol)
• D. This EKG is diagnostic for Digoxin Toxicity
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7. Which statement is not correct with regard
to the theoretical mechanism-of-action of
intravenous lipid emulsion (ILE) therapy for
beta blocker overdose?
A. Directly activates cardiac calcium
channels.
B. Acts as a “sink” for lipid-soluble beta
blockers
C. Provides a substrate for cardiac myocytes.
D. Activates Adenyl cyclase by a C-AMP
process.
E. It would be appropriate to use in a massive
propanolol overdose.
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8. Which calcium channel blocker has the highest fatality rate after
overdose? • A. Diltiazem
• B. Verapamil
• C. Nifedipine
• D. Nicardipine
• E. Bepridil
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9. Which is correct regarding the clinical endpoint for atropine administration in
Organophosphate toxicity?
A. Pupillary dilatation @ 10mm is the best endpoint.
B. Heart rates exceeding 140 are a relative contraindication to continued atropine administration.
C. Drying of airway secretions is always the best clinical endpoint.
D. Total bolus dosing should never exceed 200 mg .
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10. Which is true with regard to intubation of a patient with a significant
organophosphate exposure?
• A. Succinylcholine in OGP is associated with malignant hyperthermia.
• B. Succinylcholine will cause a worsening of airway secretion production.
• C. Succinylcholine is contraindicated in OGP.
• D. Succinylcholine’s activity lasts longer than that of rocuronium.
• E. There is little risk of exposure to ED staff during airway management.
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Which painting does not have any connection to a cardiotoxic
medication? A.
B.
D. C.
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1. Which of the following
poisoning-antidote therapeutic pairings is correct?
A.Anticholinergic-atropine
A.Beta-blocker- octreotide
A.Calcium-channel blocker-insulin
A.Digoxin-Calcium
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1. Which of the following
poisoning-antidote therapeutic pairings is correct?
A.Anticholinergic-atropine
A.Beta-blocker- octreotide
A.Calcium-channel blocker-insulin
A.Digoxin-Calcium
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Which painting does not have any connection to a cardiotoxic
medication? A.
B.
D. C.
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Cardiovascular Drugs
David E. Slattery, MD
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Digoxin Toxicity
• Derived from Digitalis lanata (Foxglove plant)
• Drug looking for an indication
– 1797
• Most common cause of preventable iatrogenic cardiac arrests
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Na/K ATPase & Ca2+ exchanger
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Pharmacologic Effects
• Inotrope
– Increased contractility due to increase intracellular calcium concentrations
• Parasympathomimetic
– Decreased AV Conduction
– Due to increased vagal efferent activity
– Slowed ventricular rate in afib
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Digoxin at Toxic levels
• Paralysis of Na/K ATPase
– Hyperkalemia
• SA Nodal blockade
• AV nodal blockade
• Increased sensitivity of SA node to catecholamines
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Digoxin effects on Pukinje fibers
• Decreased resting potential (slowed phase 0)
• Decreased action potential duration
– Increased sensitivity to electrical stimuli
• Enhanced automaticity (increased phase 4 repolarization)
Most common manifestation of Digoxin toxicity= Increased PVC’s
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NB! Digoxin can produce any dysrhythmia or conduction block
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Digoxin Toxicity
• Elimination half-life
– Digoxin=36 hours; multi-dose charcoal not effective
– Digitoxin=7 days; multi-dose charcoal very effective
• Highly protein bound
– Dialysis is not effective
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2. A 70 year-old patient with a history of CHF on digoxin
presents with weakness. Which is correct with regard to
her EKG?
A. EKG findings suggest the emergent need for
digiFAB
B. EKG findings are most likely due to ischemia
C. EKG findings are expected with therapeutic
digoxin levels.
D. EKG findings are diagnostic of chronic vs.
acute digoxin toxicity
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2. A 70 year-old patient with a history of CHF on digoxin
presents with weakness. Which is correct with regard to
her EKG?
A. EKG findings suggest the emergent need for
digiFAB
B. EKG findings are most likely due to ischemia
C. EKG findings are expected with therapeutic
digoxin levels.
D. EKG findings are diagnostic of chronic vs.
acute digoxin toxicity
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EKG - Digoxin • Causes increased automaticity with
conduction block (PAT with block)
• Therapeutic levels may cause – T wave depression
– ST down sloping (Salvador Dali moustache)
– QT shortened
• Toxic levels – PVCs (most common dysrhythmia)
– Sinus / AV node blocks
– AV dissociation
– SVT (especially with blocks)
– Sinus bradycardia
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Paroxysmal Atrial Tachycardia with Block
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Aflutter with block
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Clinical Manifestations
• Acute Toxicity: – GI: Nausea and vomiting – CNS: Headache, dizziness, confusion, coma – Cardiac: bradyarrhythmias SVT with block – Electrolytes- potassium elevated
• Chronic Toxicity – Hx: elderly patients taking diuretics – GI: nausea and vomiting – Cardiac: Almost any arrhythmia, Ventricular are
common. – Potassium normal or low
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Elderly patient with altered mental status and cardiac arrhythmia
• Think Digoxin toxicity
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Putting it all together
http://manicgrandiosity.blogspot.com
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NB! Indications for Fab Fragments
• Ventricular dysrhythmias (beyond PVC’s)
• Hemodynamically significant bradycardia unresponsive to atropine
• Potassium >5.0
• Worsening rhythm disturbances/rapidly rising K+
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3. A 29 year old patient is brought in to the ED
by EMS in full cardiac arrest. The medics found
an empty bottle of digoxin next to his bed.
What is the most appropriate initial dose of DigiFab for this patient?
A. 2 Vials
B. 4-6 Vials
C. 10 Vials
D. 20 Vials
E. It needs to be calculated
based on the digoxin level.
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3. A 29 year old patient is brought in to the ED
by EMS in full cardiac arrest. The medics found
an empty bottle of digoxin next to his bed.
What is the most appropriate initial dose of DigiFab for this patient?
A. 2 Vials
B. 4-6 Vials
C. 10 Vials
D. 20 Vials
E. It needs to be calculated
based on the digoxin level.
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Calculation of DigiFab dosing
• Step 1: Calculate total body-load (TBL)
– TBL= amt ingested (mg) x 0.80
– TBL= dig level (ng/ml)x 5.6 x wt (kg)
1,000
Step 2: Calculate # vials of DigFab
1 vial=40 mg DigFab
Number of vials= TBL/0.5
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Simple math!
# Vials = Dig level (ng/ml)X wt (kg) 100
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Empiric Administration
• Acute with indications
– 10 vials over 30 minutes
• Chronic
– 4-6 vials
• Cardiac arrest
– 20 vials undiluted IV bolus
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Digoxin Toxicity Treatment
• IV Access • Continuous monitoring • Activated Charcoal • Bradyarrhythmias
– Atropine – DigiFAB – Pacing (external; avoid transvenous pacing) –
• Ventricular arrhythmias – Digifab – Magnesium – Lidocaine (1-1.5 mg/kg IV bolus followed by 1-4 mg/min) and/or phenytoin (15-20 mg/kg)
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Summary
• Think of dig toxicity in any patient with GI or visual disturbances and new onset dysrhythmia or conduction abnormality
• Use DigFab before pacing or other antidysrhythmics
• Hyperkalemia best definitively treated with digfab
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4. Which of the following is
correct regarding Beta Blocker
overdose?
A. Beta blocker overdose universally causes
AV block.
B. Seizures and obtundation are seen more
often with propanolol compared to
metroprolol.
C. Octreotide is an important component of
treatment
D. Unlike calcium channel blocker toxicity,
high-dose insulin/glucose is not effective for beta-blocker toxicity.
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4. Which of the following is
correct regarding Beta Blocker
overdose?
A. Beta blocker overdose universally causes
AV block.
B. Seizures and obtundation are seen more
often with propanolol compared to
metroprolol. C. Octreotide is an important component of
treatment
D. Unlike calcium channel blocker toxicity,
high-dose insulin/glucose is not effective for beta-blocker toxicity.
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Beta Blocker toxicity
• Initially used to treat dysrhythmias
• Antihypertensive effects discovered later
• Used for – SV dysrhythmias
– HTN
– Angina
– Thyrotoxicosis
– Migraine
– Glaucoma
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Pathophysiology
• Competitively inhibit endogenous catecholamines at beta-adrenergic receptors.
• Beta 1 blockade – Blocks inotropy, dromotropy (conduction)
chronotropy
• Beta 2 blockade – Blocks Vascular smooth muscle relaxation and
vasodilation
– Inhibits gluconeogenesis
– Inhibits release of Free fatty acids
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Unique Characteristics.
• Cardioselctivity (atenolol, metoprolol, esmolol= lower mortality in OD)
• Membrane stabilization (Na channel blockade)
• Lipophilicity
• Intrinsic sympathomimetic
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Glucagon MOI
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Beta Blocker Pharmacokinetics
• Rapidly absorbed
• Peak effect 1-4 hours
• Hemodialysis not effective except for “ANTS”
– Acebutolol
– Atenolol
– Nadolol
– Timolol
– Sotalol
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Manifestations of complications
• Bradycardia and Hypotension
• Unconscious
• Respiratory arrest
• Hypoglycemia (uncommon in adults)
• Others: seizures, VT/VF, mild hyperkalemia
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Propanolol
• Non-selective
• Most fatalities
• Lipophilic and readily crosses BB barrier
– Altered mental status
– Seizures
• Hypoglycemia common in children
NB!
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Sotalol
• Class III (K ch) and Class II (beta blockers) antidysrhythmic
• Torsades de pointes
• Dialyzable (Remember ANTS)
• QT prolongation
– Sotalol
– Acebutolol
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Treatment • Phase I:
– Fluids – Atropine – Calcium – Glucagon
• Phase II: – High-dose insulin/glucose (inotrope) – Glucagon – Pressors (epi, NE, isoproterenol) – Consider dialysis of lipophilic beta blockers – Pacing /SWAN-Ganz
• Phase III: Salvage – Intravenous fat emulsion – IAB pump – LVAD
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Glucagon
• Inotropic and chronotropic effects not dependent on beta receptors
– Stimulates C-AMP
• Helps counteract hypoglycemia
• Dose: 5-10 mg IV bolus (0.1 mg/kg)
– Followed by response dosing (over 1 hour)
– Short half-life (20 minutes)
• Less effective than insulin-glucose
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5. High dose insulin treatment in beta-blocker overdose increases
cardiac output primarily by increasing Heart rate.
• A. True
• B. False
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5. High dose insulin treatment in beta-blocker overdose increases
cardiac output primarily by increasing Heart rate.
• A. True
• B. False
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5. High dose insulin treatment in beta-blocker overdose increases
cardiac output primarily by increasing Heart rate.
• A. True
• B. False
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High Dose Insulin-Glucose
• HDI is a potent inotrope – Optimizing of the use of carbohydrates
– And modulation of IC calcium
• NB! Improve in CO due more to increase in stroke volume vs. HR
• 1U/kg Bolus
• 1 -10 U/kg/hr drip
• Preceded with amp D50 and followed by D10 or D25 drip.
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Adjuncts for specific agents
• Sodium Bicarb
– Use for QRS widening
• Propanolol
• Sotalol
• Magnesium
– Prolonged QT interval
• Sotalol
• Acebutelol
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6. Which is correct regarding the EKG? • A. This EKG shows a common finding in acute digoxin
toxicity.
• B. Salvage treatment should include administering of intravenous lipid emulsion (ILE).
• C. This EKG is highly suggestive of Class I sodium channel blockade (TCA, beta blocker (sotalol)
• D. This EKG is diagnostic for Digoxin Toxicity
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6. Which is correct regarding the EKG? • A. This EKG shows a common finding in acute digoxin
toxicity.
• B. Salvage treatment should include administering of intravenous lipid emulsion (ILE).
• C. This EKG is highly suggestive of Class I sodium channel blockade (TCA, beta blocker (sotalol)
• D. This EKG is diagnostic for Digoxin Toxicity
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Bi-directional Ventricular Tachycardia Rare but specific for dig toxicity
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7. Which statement is not correct with regard
to the theoretical mechanism-of-action of
intravenous lipid emulsion (ILE) therapy for
beta blocker overdose?
A. Directly activates cardiac calcium
channels.
B. Acts as a “sink” for lipid-soluble beta
blockers
C. Provides a substrate for cardiac myocytes.
D. Activates Adenyl cyclase by a C-AMP
process.
E. It would be appropriate to use in a massive
propanolol overdose.
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7. Which statement is not correct with regard
to the theoretical mechanism-of-action of
intravenous lipid emulsion (ILE) therapy for
beta blocker overdose?
A. Directly activates cardiac calcium
channels.
B. Acts as a “sink” for lipid-soluble beta
blockers
C. Provides a substrate for cardiac myocytes.
D. Activates Adenyl cyclase by a C-AMP
process. E. It would be appropriate to use in a massive
propanolol overdose.
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Intravenous Fat emulsion
• Lipid sink
• Optimization of cardiac metabolism
– Provides substrate for myocytes
– Free fatty acids
• Direct activation of cardiac calcium channels
• Dose: 1.5 ml/kg 20% solution over 3 minutes, then drip at 0.25ml/kg/min
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Calcium channel blocker toxicity
• Earliest
– Verapamil Nifedipine
• Many indications
– Antihypertensive
– SV tachy
– Hypertrophic cardiomyopathy
– Migraine prophylaxsis
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Calcium channel blockers
• Rapidly absorbed
• Peak effect earliest with nifedipine
• Highly protein bound not conducive to dialysis
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8. Which calcium channel blocker has the highest fatality rate after
overdose? • A. Diltiazem
• B. Verapamil
• C. Nifedipine
• D. Nicardipine
• E. Bepridil
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8. Which calcium channel blocker has the highest fatality rate after
overdose? • A. Diltiazem
• B. Verapamil
• C. Nifedipine
• D. Nicardipine
• E. Bepridil
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Pathophysiology
• Block slow L-type calcium channels
– Coronary and peripheral vasodilation
– Reduction of contractility
– Slow AV conduction
• NB! Verapamil
– Deadliest, severe vasodilation and myocardial depression
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Calcium channel blocker toxicity
• Hypotension • Bradycardia • All degrees of AV block • Nifedipine (Dihydropyridines)
– Reflex tachycardia
• No QRS widening is seen. • Pulmonary edema • Lethargy, confusion, seizures • Metabolic: hyperglycemia, lactic acidosis, mild
hyperkalemia.
NB!
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Treatment Phase I:
IV fluids
Calcium
atropine
No data to support glucagon.
Phase II:
Calcium
HDI
Pressors
Pacing
Phase III:
Intravenous Fat Emulsion
LVAD
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Ca Channel blocker toxitiy Pediatric PEARLS
• Seizures are more common
• Death is rare
• Refractory shock can be treated with IABP
• Verapamil IV is contraindicated for SVT in infants.
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Know these two
• Nifedipine
– Single pill can kill a child
– Shortest onset
– Has Reflex tachycardia
• Verapamil
– Highest fatality rates
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Nitrates/Nitrites
• Know – Nitroprusside (renal failure patients)
– PDI contraindication • Viagra et al
– Found in rural well water
– Patients with G-6PD deficiency= hemolysis
• Methemoglobinemia – Treatment methylene blue 1-2 mg IV over 5
minutes
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9. Which is correct regarding the clinical endpoint for atropine administration in
Organophosphate toxicity?
A. Pupillary dilatation @ 10mm is the best endpoint.
B. Heart rates exceeding 140 are a relative contraindication to continued atropine administration.
C. Drying of airway secretions is always the best clinical endpoint.
D. Total bolus dosing should never exceed 200 mg .
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9. Which is correct regarding the clinical endpoint for atropine administration in
Organophosphate toxicity?
A. Pupillary dilatation @ 10mm is the best endpoint.
B. Heart rates exceeding 140 are a relative contraindication to continued atropine administration.
C. Drying of airway secretions is always the best clinical endpoint.
D. Total bolus dosing should never exceed 200 mg .
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Pesticides
• Organophosphates
– Highly lipid soluble
– Rapidly absorbed through skin
• Metabolites are ACHesterase inhibitors
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Autonomic Nervous system
Muscarinic Nicotinic
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Muscarinic vs. Nicotinic
• Muscarinic – Not an ion channel
– G-protein-coupled receptor
– Activate ion channels via second messenger system.
– Blocked by atropine
• Nicotinic – Ion gated channel
– Post-synaptic neuromuscular junction
– Ach causes Na entry and leads to depolorization.
– Stimulation (tremor, seizures, temp, etc)
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Muscarinic Receptors • Gland excretion • Smooth muscle
relaxation
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Nicotinic Receptors
• Skeletal muscle hyperstimulation
• Fasciculations
• Twitches
• Seizures
• Muscle fatigue and paralysis
• Delayed resp failure
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Cholinesterase inhibitors can result in :
• Tachycardia, bradyardia
• Hypertension or hypotension
• Mydriasis, miosis
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OGP Aging
• Irreversible conformational change when OGP bound to cholinesterase enzyme
• Becomes irreversible
• Varies with agent
• Importance of 2PAM
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OGP Aging
• Irreversible conformational change when OGP bound to cholinesterase enzyme
• Becomes irreversible
• Varies with agent
• Importance of 2-PAM (give regardless of time from ingestion)
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Diagnosis
• Clinical syndrome
• Cholinesterase levels
– RBC
– Plasma-these decrease first
• RBC cholinesterase levels correlate best with ACH activity at nerve terminal.
• RBC cholinesterase recovers slowly
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10. Which is true with regard to intubation of a patient with a significant
organophosphate exposure?
• A. Succinylcholine in OGP is associated with malignant hyperthermia.
• B. Succinylcholine will cause a worsening of airway secretion production.
• C. Succinylcholine is contraindicated in OGP.
• D. Succinylcholine’s activity lasts longer than that of rocuronium.
• E. There is little risk of exposure to ED staff during airway management.
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10. Which is true with regard to intubation of a patient with a significant
organophosphate exposure?
• A. Succinylcholine in OGP is associated with malignant hyperthermia.
• B. Succinylcholine will cause a worsening of airway secretion production.
• C. Succinylcholine is contraindicated in OGP.
• D. Succinylcholine’s activity lasts longer than that of rocuronium.
• E. There is little risk of exposure to ED staff during airway management.
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Management
• 1. Decontamination
– Remove clothes, soap and water
• 2. Supportive Care
– Airway management (rocuronium better choice)
• 3. Reversal of ACH excess at muscarinic sites
• 4. reversal of toxin binding at active sites on the ACH molecule
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Treatment
• Atropine 1-2 mg IV and double dose q 5 minutes until secretions dry
• Patients may need 200-300 mg
• Follow with continuous infusion:
• 5-100 mg/hr
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2-PAM
• Pralidoxime
• Regenerates ACHesterase complex and restores ACHesterase activity at nicotinic and muscarinic sites.
• Dose: 1-2 g IV over 30 minutes repeat q 4 hours
• Benzodiazepines for seizures
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Carbamates
• Differentiated from OGP by short half-life
• Reversible inhibition
• Lasts ~48 hours
• Symptoms – Twitching, hyperdynamic, rhabdo, altered MS
• Treatment – Decontamination
– Cooling measures
– Benzos
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Phenols
• DNP
• Insecticides, herbicides
• Absorbed through skin
• Uncouple oxidative phosphorylation
• Hyperthermic, tachycardia, diaphoresis
• TX: early skin decon; control body temp, fluids, glucose, supportive care.
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Summary
• Decon all!
• Patients die from airway compromise
• V/S and pupil findings variable
• 2-PAM should be given if you are giving atropine
• Rapid cooling and glucose the most important therapies for phenol toxicity
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