?-blocker and Organophosphate Toxicity

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
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
9
Selectivity

• Nonselctive
• ?1 and ?2
• Propranolol
• Nadolol
• Timolol
• Pindolol
• Labetalol
• Sotalol

• Selective
• ?1
• Metoprolol
• Atenolol
• Esmolol
• Acebutolol

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 40308, 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
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
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
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
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
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
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
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

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
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

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 gt50 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, cant 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 lt10 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

51
Treatment

• Breathing
• Bronchospasm and bronchorrhea ? hypoxia
• drown in their own secrections
• respiratory muscle dysfunction ? ventilatory
  support
• Preceded by ? neck muscle weakness
• Succinylcholines effects can be prolonged in
  presence of OP toxicity

52
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

53
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

54
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
• Lippincotts Illustrated Reviews Pharmacology 2nd
  ed. Harvey RA editor. Lippinocott-Raven New York

55
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

56
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

57
Treatment

• Circulation
• If bradycardic?
• atropine
• If hypotensive ?
• think dehydration ? fluid

58
Treatment

• Elimination
• Dialysis not indicated b/c of large Vd
• Body eventualy metabolizes the OP and it is
  excreted in the urine

59
Treatment

• Find an Antidote
• Two parts
• Atropine
• Pralidoxime

60
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

61
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

62
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

63
Key Points

• Protect staff from Contamination
• Treat with Pralidoxime early to prevent aging

64
Thanks Dr. Vicas
65
References

• Poisoning Drug Overdose 4th ed, Olson KR ed.
  Lange/Mcgraw Hill Toronto 2004
• Rosens
• Lippincotts Illustrated Reviews Pharmacology 2nd
  ed. Harvey RA editor. Lippinocott-Raven New York
• http//www.ovc.uoguelph.ca/BioMed/Courses/Public/P
  harmacology/pharmsite/98-309/ANS/ANS_Intro/ANS_int
  ro.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