Organophosphates/Carbamates

Epidemiology

  • xxxx

Agents

Organophosphate Pesticides

  • General Comments
    • Many of These Agents Have a Petroleum or Garlic-Like Odor
  • Chlorpyrifos
    • Sold Under the Brane Name Baygon
    • Used in Cockroach/Insect Baits
  • Diazinon
    • Developed in 1952 to Replace Use of the Pesticide DDT
    • Heavily Used in the 1970’s-1980’s
  • Diclorvos (DDVP)
    • Sold Under the Brand Name Vapona
    • Commercially Available Since 1961
  • Ethion
    • Fifteen Victims were Accidentally Poisoned with this Agent in 2005 After Ingesting Ethion-Contaminated Food in a Ceremony in Magrawa, India
  • Malathion (Carbophos, Maldison, Mercaptothion) (see Malathion, Malathion)
    • Listed as a Probable Carcinogen Associated with Prostate Cancer by the American Cancer Society
    • Used in Head Lice Shampoos
  • Parathion
    • Sold Under the Brand Name Folidol

Organophosphate Nerve Gases (Militarized Organophosphates)

  • Sarin (see Sarin, Sarin)
    • Used in Iran-Iraq War (During the 1980’s)
    • Used in Tokyo Subway Attack by the Religious Sect, Aum Shinrikyo (in 1995)
  • Soman
  • Tabun
    • Used in Iran-Iraq War
  • VX Nerve Agent (see VX Nerve Agent, VX Nerve Agent)

Carbamate Pesticides

  • Aldicarb
    • Sold Under the Brand Name Temik
  • Ambenonium
    • Sold Under the Brand Name Mytelase
  • Carbaryl
    • Sold Under the Brand Name Sevin
  • Bendiocarb
    • Sold Under the Brand Names Ficam and Turcam
  • Propoxur
    • Sold Under the Brand Name Baygon

Medical Carbamates

  • Donepezil (Aricept) (see Donepezil, Donepezil)
    • Used to Treat Alzheimer’s Disease
  • Ecthiopate
    • Used to Treat Glaucoma
  • Edrophonium (Tensilon, Enlon) (see Edrophonium, Edrophonium)
    • Used to Treat Myasthenia Gravis
  • Galantamine
    • Used to Treat Alzheimer’s Disease
  • Neostigmine (Prostigmin, Vagostigmin) (see Neostigmine, Neostigmine)
    • Used to Treat Colonic Pseudo-Obstruction, Elapid Envenomation, and Prolonged Neuromuscular Blockade
  • Physostigmine (Antilirium) (see Physostigmine, Physostigmine)
    • Used to Treat Antimuscarinic (Anticholinergic) Intoxication and Glaucoma
  • Pyridostigmine (Mestinon) (see Pyridostigmine, Pyridostigmine)
    • Used to Treat Myasthenia Gravis and Prolonged Neuromuscular Blockade
  • Rivastigmine (Exelon) (see Rivastigmine, Rivastigmine)
    • Used to Treat Alzheimer’s Disease
  • Tacrine (Cognex) (see Tacrine, Tacrine)
    • Used to Treat Alzheimer’s Disease

Exposure

Routes of Exposure

  • Skin: organophosphates/carbamates are both well-absorbed
  • Lungs: organophosphates/carbamates are both well-absorbed
  • Gastrointestinal (GI) Tract: organophosphates/carbamates are both well-absorbed
  • Injection

Chemistry/Pharmacology

Chemistry

  • Organophsophates Contain Carbon and Derivatives of Phosphoric Acid
    • Organophosphates are Irreversible Acteylcholinesterase Inhibitors
    • “Aging”: the acetylcholinesterase-organophosphate compound undergoes a conformational change over time, resulting in irreversible binding and resistance to reactivation by antidotes (such as oximes)
    • Dimethyl Compounds: these compounds undergo rapid aging, mandating early initiation of oxime therapy
    • Diethyl Compounds: these compounds may have delayed toxicity and therefore, may require prolonged therapy
  • Carbamates are Derived from Carbamic Acid
    • Carbamates are Reversible Acteylcholinesterase Inhibitors: they spontaneously hydrolyze from the cholinesterase enzymatic site within 48 hrs

Organophosphates and Carbamates are Red Blood Cell Acteylcholinesterase Inhibitors

  • Acteylcholinesterase Inhibition Results in Accumulation of Acetylcholine at Nicotinic/Muscarinic Synapses and Neuromuscular Junction
  • Organophosphates Also Inhibit Plasma Cholinesterase (aka Pseudocholinesterase) and Neuropathy Target Esterase (NTE)
    • The Clinical Consequences of these Interaction are Unclear
  • Organophosphates and Carbamates are Structurally Distinct, But Have Similar Clinical/Toxicologic Manifestations
    • Carbamate Intoxication Tends to Be Shorter in Duration than that of Organophosphates (Assuming Equivalent Doses), But the Mortality Rates with Both Exposures are Similar

Clinical Effects

  • Muscarinic Effects
    • SLUDGE/BBB Mnemonic
      • Salivation
      • Lacrimation
      • Urination
      • Defecation
      • Gastric Emesis
      • Bronchorrhea
      • Bronchospasm
      • Bradycardia
    • DUMBELS Mnemonic
      • Defecation
      • Urination
      • Miosis
      • Bronchorrhea/Bronchospasm/Bradycardia
      • Emesis
      • Lacrimation
      • Salivation
  • Nicotinic Effects
    • Cardiovascular
      • Hypertension
      • Sinus Tachycardia
    • Neurologic
      • Areflexia
      • Ataxia
      • Twitching/Fasciculations
      • Weakness/Paralysis
    • Pulmonary
      • Acute Respiratory Failure
      • Bronchospasm
      • Laryngospasm
  • Central Nervous System Effects (Mediated by Muscarinic and Nicotinic Receptors in Brain)
    • Altered Mental Status
      • Obtundation-Coma
    • Anxiety
    • Agitation
    • Seizures
    • Tremor

Metabolism

  • Organophosphates Undergo Mostly Hepatic Metabolism (Slowly)
    • Oxidative Metabolites (Paroxon/Maloxone) are Active, These are Subsequently Hydrolyzed to Inactive Metabolites
  • Carbamates Undergo Rapid Elimination by Serum Cholinesterases and Hepatic Metabolism
    • Duration of Carbamate Toxicity is Therefore, Generally Shorter and Less Severe than with Organophosphates

Diagnosis

Arterial Blood Gas (ABG) (see Arterial Blood Gas, Arterial Blood Gas)

  • Useful to Diagnose Metabolic Acidosis and Respiratory Acidosis: their presence correlates with severity of symptoms and mortality

Urine Toxicology Screen

  • May Detect These Agents

Chest X-Ray/Chest CT (see Chest X-Ray, Chest X-Ray and Chest Computed Tomography, Chest Computed Tomography)

  • Useful to Rule Out Aspiration Pneumonia, ARDS, etc

Bronchoscopy (see Bronchoscopy, Bronchoscopy)

  • May Be Required to Rule Out Airway Injury

Red Blood Cell Acetylcholinesterase Activity (see Red Blood Cell Acetylcholinesterase Activity, Red Blood Cell Acetylcholinesterase Activity)

  • Rationale
    • Acute Intoxication
      • Red Blood Cell Acetylcholinesterase Activity Provides a Direct Assessment of the Degree of Toxicity
      • Sequential Assessment May Be Used to Monitor the Effectiveness of Oxime Therapy
    • Chronic/Occupational Exposure:
      • Red Blood Cell Acetylcholinesterase Activity May Be Used Diagnostically
  • Availability: less readily available in most hospital laboratories
  • Interpretation
    • Usually Decreased to <50% Normal in Acute Organophosphate Intoxication
    • May Be Normal in Carbamate Intoxication: due to reversible binding of these agents
    • Etiology of Falsely-Decreased RBC Cholinesterase Activity
      • Antimalarial Drugs
      • Hemoglobinopathies
      • Drawing Blood in Oxalate Blood Tubes
      • Pernicious Anemia

Plasma Pseudocholinesterase (see Plasma Pseudocholinesterase, Plasma Pseudocholinesterase)

  • More Readily Available from Hospital Laboratories, But Does Not Correlate Well with the Severity of Toxicity: not clinically useful to guide therapy

Clinical Manifestaions

Acute Toxicity

General Comments

  • Onset of Symptoms: effects generally occur within 30 min-2 hrs after exposure
    • Latency of Symptoms is Related to Route of Exposure
      • Respiratory/Oral Exposure: symptoms usually develop within 3 hrs
      • Dermal Exposure: symptoms may be delayed up to 12 hrs later
    • Latency of Symptoms is Related to Lipophilicity of the Agent
      • Lipohilic Agents (Dichlofenthion, Fenthion, Malathion) are Associated with Delayed Onset of Symptoms (Up to 5 Days in Some Cases): may be related to delayed distribution from fat stores

Cardiovascular Manifestations

Gastrointestinal/Genitourinary Manifestations

Neurologic Manifestations

  • Altered Mental Status (see Altered Mental Status, Altered Mental Status)
    • Pharmacology: due to involvement of muscarinic/nicotinic receptors in the central nervous system
    • Clinical
  • Agitation (see Agitation, Agitation)
    • Pharmacology: due to involvement of muscarinic/nicotinic receptors in the central nervous system
  • Anxiety (see Anxiety, Anxiety)
    • Pharmacology: due to involvement of muscarinic/nicotinic receptors in the central nervous system
  • Areflexia (see Hyporeflexia, Hyporeflexia)
    • Pharmacology: nicotinic
  • Ataxia (see Ataxia, Ataxia)
    • Pharmacology: nicotinic
  • Seizures (see Seizures, Seizures)
    • Pharmacology: due to involvement of muscarinic/nicotinic receptors in the central nervous system
  • Tremor (see Tremor, Tremor)
    • Pharmacology: due to involvement of muscarinic/nicotinic receptors in the central nervous system
  • Twitching/Fasciculations (see Fasciculations, Fasciculations)
    • Pharmacology: nicotinic
    • Clinical: fasciculations are strongly suggestive of cholinergic intoxication
  • Weakness/Paralysis (see xxxx, xxxx)
    • Pharmacology: nicotinic

Pulmonary Manifestations

Other Manifestations

Intermediate (Neurologic) Toxicity

General Comments

  • Epidemiology
    • Occurs in 10-40% of Cases
      • Risk Appears to Be Related to Exposure to a Highly Fat Soluble Organophosphate Agent or Inadequate Therapy with Pralidoxime (Przegl Lek, 1995) [MEDLINE]
      • Rarely Occurs with Carbamate Exposure
    • Occurs 24-96 hrs After Exposure
  • Diagnosis
  • Prognosis
    • Usually Resolves Completely within 2-3 Weeks

Neurologic Manifestations

Delayed/Long-Term Neurologic Toxicity

Neurologic Manifestations

  • Difficulties with Abstraction
  • Memory Loss (see Memory Loss, Memory Loss)
  • Organophosphate-Induced Delayed Polyneuropathy (OPIDN) (see Peripheral Neuropathy, Peripheral Neuropathy)
    • Epidemiology
      • Associated with Chlorpyrifos, Leptophos, Malathion, Merphos, Mipafox,Trichlorfon, and Triorthocresyl Phosphate (TOCP),
      • Rarely Seen with Carbamate Exposure
      • Risk of OPIDN is Independent of the Severity of the Initial Acute Toxicity
    • Physiology
      • Inhibition of Neuropathy Target Esterase (NTE) Found in Brain, Peripheral Nerves, and Lymphocytes: enzyme normally functions to degrade esters within the cell
    • Diagnosis
    • Clinical
      • Initial Transient, Painful Stocking-Glove Distribution Parasthesias
      • Subsequent Symmetrical Motor Polyneuropathy with Flaccid Lower (Ascending to Upper) Extremity Weakness
        • Mild Sensory Deficits
        • Distal Muscle Groups are Predominantly Affected with Relative Sparing of Proximal Muscle Groups/Neck Muscles/Cranial Nerves
    • Prognosis
      • Recovery May Take Up to 1 Year
      • Severe Cases May Manifest Permanent Upper Motor Neuron Syndrome with Lower Extremity Spasticity
  • Parkinson’s Disease (see Parkinson’s Disease, Parkinsons Disease)

Chronic Organophosphate Exposure

Pulmonary Manifestations


Treatment of Acute Toxicity

Decontamination

  • Evacuate from Site of Exposure: to prevent further contact
  • Remove and Discard Contaminated Clothing
  • Wash Skin with Soap and Water
  • Ocular Irrigation

Forced Emesis

  • Contraindicated

Gastric Lavage (see Gastric Lavage, Gastric Lavage)

  • Indications
    • Organophosphate/Carbamate Ingestion within the Prior 1 hr: although has no clear impact on morbidity/mortality
  • Technique
    • Perform Only in Intubated Patient After Atropine and Oxime Therapy is Initiated

Activated Charcoal (see Activated Charcoal, Activated Charcoal)

  • Indications
    • Organophosphate/Carbamate Ingestion within the Prior 1 hr: administration is unlikely to be effective after 1 hr (Lancet, 2008) [MEDLINE]
  • Contraindications
    • Avoid Use of Activated Charcoal in Patients Who are Not Intubated
  • Administration
    • Dose: 1 g/kg (maximum dose: 50 g) PO

Treatment of Seizures (see Seizures, Seizures)

Atropine (see Atropine, Atropine)

  • Pharmacology: muscarinic receptor antagonist
    • Less Effective for Central Nervous System Effects
    • Ineffective for Nicotinic Effects (in Particular Neuromuscular Dysfunction): as atropine does not bind to nicotinic receptors
  • Administration
    • Diagnostic Test Dose: 1 mg IV
    • Treatment Dose: 2-5 mg IV
      • Escalate Dose q3-5 min Until Clinical Effect (Mucosal Drying, Decreased Secretions, Decreased Wheezing) is Observed
      • Some Cases Require Multiple Doses or Prolonged Infusion Over a Period of Days (Severe Intoxications May Require Up to Hundreds of Milligrams Over Several Days)
      • Heart Rate and Pupillary Size Should Not Be Used as Treatment Endpoints: tachycardia and mydriasis are not contraindications to atropine
    • Atropine Autoinjector (Atropen): available for lay person administration in cases of nerve agent/pesticide exposure
  • Clinical Efficacy
    • Open Label Trial of Atropine in Organophosphate Intoxication (J Med Toxicol, 2012) [MEDLINE]
      • Incremental Atropine Bolus Dosing with Infusion Decreased Mortality Rate (and Decreased Atropine Toxicity) in Organophosphate Intoxication, as Compared to Standard Atropine Bolus Dosing with Infusion

Ipratropium Bromide (Atrovent) (see Ipratropium Bromide, Ipratropium Bromide)

  • Pharmacology
    • Short-Acting Muscarinic Antagonist (SAMA)
  • Indications
    • Bronchospasm

Pralidoxime (2-PAM) (see Pralidoxime, Pralidoxime)

  • Pharmacology: reactivates cholinesterases
    • Effective for Treating Both Muscarinic and Nicotinic Effects
    • Less Effective for Central Nervous System Effects
  • Indications
    • Any Patient with Evidence of Cholinergic Toxicity in the Setting of Organophosphate/Carbamate Intoxication
    • Patient with Neuromuscular Dysfunction in the Setting of Organophosphate/Carbamate Intoxication
    • Patients with Exposure to Organophosphates/Carbamates Known to Cause Delayed Neurotoxicity
      • Early Oxime Therapy May Be Beneficial to Prevent the Intermediate (Neurologic) Toxicity Syndrome or OPIDN
  • Administration
    • Bolus Dosage: give at least 30 mg/kg (usually 2 g) IV slowly over 30 min (may repeat in 30 min, as required
      • Always Given with Concomitant Atropine to Prevent Worsening of Symptoms Due to Transient Oxime-Induced Acetylcholinesterase Inhibition
      • If Administered Intramuscular: 600 mg IM (may repeat, as required, to max dose: 1800 mg)
    • Continuous Infusion (as Required for Severe Intoxication): 8 mg/kg/hr
  • Adverse Effects
    • Cardiac Arrest (see Cardiac Arrest, Cardiac Arrest): usually associated with rapid infusion
    • Muscle Weakness: due to transient acetylcholinesterase inhibition as pralidoxime binds to the enzyme
  • Monitor
    • Red Blood Cell Acetylcholinesterase Activity Can Be Serially Assayed to Monitor the Effectiveness of Oxime Therapy

Respiratory Support

  • Endotracheal Intubation/Mechanical Ventilation (see Mechanical Ventilation-General, Mechanical Ventilation-General)
    • Early Intubation is Often Required
    • Avoid Succinylcholine for Rapid Sequence Intubation (RSI) (see Succinylcholine, Succinylcholine): due to the fact that succinylcholine is metabolized by acetylcholinesterase (which is inhibited by organophosphates) and there is a risk of prolonged paralysis
    • Nondepolarizing Neuromuscular Blockers (Rocuronium, etc) May Be Less Effective at Standard Doses (Due to Competitive Inhibition at the Neuromuscular Junction: increased doses may be required

Corticosteroids (see Corticosteroids, Corticosteroids)

  • May be beneficial in Acute Respiratory Distress Syndrome (ARDS), But are Unproven

Prognosis

  • Predictors of Outcome (QJM, 2008) [MEDLINE]
    • Glasgow Coma Score
      • Patients with GCS ≤13 Need Intensive Monitoring
      • However, the Identity of the Agent Should Be Considered, Since Half of the Patients Who Died From Fenthion Poisoning Only Had Mild Symptoms at Presentation
    • International Program on Chemical Safety Poison Severity Score (IPCS PSS)
  • APACHE II and SAPS-II Scoring Have Been Demonstrated to Outperform the Poison Severity Score (PSS) in Terms of Predicting Outcome (Clin Toxicol-Phila, 2013) [MEDLINE]

References

  • Intermediate syndrome in acute fenitrothion poisoning. Przegl Lek. 1995;52(5):271 [MEDLINE]
  • QTc prolongation indicates a poor prognosis in patients with organophosphate poisoning. Am J Emerg Med. Sep 1996;14(5):451-3
  • The Tokyo subway sarin attack: disaster management, Part 3: national and international responses. Acad Emerg Med. 1998 Jun;5(6):625-8 [MEDLINE]
  • Weapons of mass destruction events with contaminated casualties: effective planning for health care facilities. JAMA. 2000;283(2):242-249 [MEDLINE]
  • Organic insecticides. Anaesth Intensive Care. Feb 2000;28(1):11-21
  • The prevalence of pancreatitis in organophosphate poisonings. Hum Exp Toxicol. 2002;21(4):175 [MEDLINE]
  • Acute renal failure from organophospate poisoning: a case of success with haemofiltration. Hum Exp Toxicol. 2003;22(3):165 [MEDLINE]
  • The clinical and electrophysiological features of a delayed polyneuropathy developing subsequently after acute organophosphate poisoning and it’s correlation with the serum acetylcholinesterase. Electromyogr Clin Neurophysiol. 2003;43(7):421 [MEDLINE]
  • Changes in the hemodynamic state of patients with acute lethal organophosphate poisoning. Vet Hum Toxicol. 2004;46(1):5 [MEDLINE]
  • Clinical review: Tokyo – protecting the health care worker during a chemical mass casualty event: an important issue of continuing relevance. Crit Care. 2005 Aug;9(4):397-400. Epub 2005 Feb 17 [MEDLINE]
  • Continuous pralidoxime infusion versus repeated bolus injection to treat organophosphorus pesticide poisoning: a randomised controlled trial. Lancet. Dec 16 2006;368(9553):2136-41
  • Acid-base interpretation can be the predictor of outcome among patients with acute organophosphate poisoning before hospitalization. Am J Emerg Med. Jan 2008;26(1):24-30
  • The spectrum of intermediate syndrome following acute organophosphate poisoning: a prospective cohort study from Sri Lanka. PLoS Med. 2008 Jul 15;5(7):e147. doi: 10.1371/journal.pmed.0050147 [MEDLINE]
  • Predicting outcome in acute organophosphorus poisoning with a poison severity score or the Glasgow coma scale. QJM. 2008 May;101(5):371-9. Epub 2008 Mar 4 [MEDLINE]
  • Multiple-dose activated charcoal in acute self-poisoning: a randomised controlled trial. Lancet. 2008;371(9612):579 [MEDLINE]
  • Evaluation of the Test-mate ChE (cholinesterase) field kit in acute organophosphorus poisoning. Ann Emerg Med. Dec 2011;58(6):559-564.e6
  • Open-label randomized clinical trial of atropine bolus injection versus incremental boluses plus infusion for organophosphate poisoning in Bangladesh. J Med Toxicol. 2012;8(2):108 [MEDLINE]
  • Organophosphate poisoning-induced acute renal failure. Pediatr Emerg Care. 2013 May;29(5):646-7 [MEDLINE]
  • Performance of clinical scoring systems in acute organophosphate poisoning. Clin Toxicol (Phila). 2013 Nov;51(9):850-4. Epub 2013 Sep 26 [MEDLINE]
  • Organophosphate and carbamate poisoning. Emerg Med Clin North Am. 2015;33(1):133-151 [MEDLINE]