Carbamates Organophosphates and Riot Agents

Organophosphates

  • Agents
    • Dimethyl: azinphos-methyl, demeton-s-methyl, dichlorvos, dimethoate, fenitrothion, malathion, oxydemeton-methyl, parathion-methyl
    • Diethy: Chlorpyrifos, diazinon, disulfoton, ethion, parathion, quinalphos
    • diMethyl More important to give 2-paM
  • Exposure
    • Dermal exposure with the concentrated product or for prolonged periods of time.
    • Volatility contributes to exposure: Dichlorvos > malathion
    • Distributed in fat, liver, kidney, salivary gland => redistribute out, can have prolonged effects.
    • Phosphorothioates (diethyl) may have delayed onset due to activation
  • Clinical Manifestations
    • PNS (muscarinic), CNS, Nicotinic. Onset within 5 minutes but always within 12 hours.
      • Initial symptoms may be simply exhaustion and fatigue/weakness. Followed by n/v/d, sweating, hypersalivation. Miosis
  • Clinical Toxicology
    • Oxon phosphorylates the serine hydroxyl group at the active site of AChE
    • Partial dealkylation of this serine hydroxyl group renders AChE renders the enzyme inactive and cannot be reactivated = AGING
    • Rate of spontaneous reactivation faster with diETHYL. So aging a bigger risk with diMETHYL
    • Must give 2pam within 2-4 hr of Dimethoxy; 48 hours after diethoxy
    • Bronchorrhea: neuronal and nonneuronal cholinergic stimulation of the mucous glands, cilia, and cells producing ciliary fluid.
      • Bronchconstriction-> M3 stimulation
    • Atropine start with 2 mg
    • 2-PAM 30mg/kg, repeat q6 or infusion of 8-10 mg/kg/hr. Continue for as long as atropine is required.
    • Diazepam/Midazolam – can give phenytoin for seizures
  • Notes
    • Phosphates (P=0) are biologically active
    • Phosphorothioates (P=S) must be bioactivated to the corresponding metabolite (“thion” to “oxon”)
    • Activated by oxidative desulfuration by CYP450 (among other things)
    • OP Delayed Neuropathy (1-4 weeks), phosphorylation and subsequent aging of > 70% of neuropathy target esterase (NTE) [distinct from AChE] – > linked to methamidophos
    • Intermediate syndrome
    • Recurrent cholinergic signs 24-96 hrs after exposure. Oximes can prevent IS
    • Delayed neuropsychiatric effects – following long term, low-level exposures (occupational hazard)
    • BuChE falls first, followed by RBC AChE
      • RBC AChE: (1) more accurately reflects CNS AChE (2) Also more accurate at low hematocrits (3) takes weeks to recover

Carbamates

  • Agents
    • SALAD-> dithiocarbamates (fungicides= maneb, zineb, thiram) resemble disulfiram; metam sodium degrades to methyl-isothiocyanate
    • Aldicarb, bendiocarb, benfuracarb, butoxycaroxim, carbosulfan, carbofuran, carbaryl, ethiofencarb, methomyl, theiocarb, oxamyl, pirimicarb, propoxur, thiodicarb, thiofanox
  • Exposure
    • Undergo 2 phase biotransformation:
    • Phase 1 hydrolysis by nonspecific carboxylesterases or oxidation
    • Phase 2 conjugative reactions
    • Most carbamates DO NOT CROSS BBB
    • Exposure via skin, inhalation, ingestion
  • Clinical Manifestations/Toxicology
    • Carbamates are hydrolyzed in alkali -> decon strategy
    • Inhibit AChE by carbamylation of serine hydroxyl residue at the active site. Activity is restored after spontaneous hydrolysis of the carbamylated enzyme.
    • Lab measurement is not helpful due to rapid course of toxicity. Blood samples must be kept frozen -> slows spontaneous decarbamylation of AChE
    • Atropine, 2-PAM just like with OPs
  • Notes
    • Seizures are rare due to limited penetration into the CNS. So when they occur are usually due to hypoxia
    • Not commonly associated with delayed neurological sequelae since they are short-acting.
    • Gastric lavage NOT RECOMMENDED due to coformulation with hydrocarbons and risk of pneumonitits.

TOCP (tri-ortho cresyl phosphate)

Riot control/incapacitating agents

  • Lacrimators (All have RAPID onset):
    • CN (Chloroacetophenone)-Chemical Mace
    • CS (Chlorobenzilidine malononitrile)-Capsaicin
    • CR (Dibenzoxazepine)
    • DM (Adamsite)
  • Clinical Manifestations
    • Vesication if severe/high dose

Incapacitating agent

  • Agents
    • 3-quinudclidinyl benzilatate (BZ)
      • DELAYED onset (HOURS) – 25x more centrally potent than atropine (Central anticholinergic toxidrome)
    • Super potent opioids
    • PS- Chloropicrin (nitrochloroform)
    • 10-chloro-5,10-dihydrodiphenarsazine (DM)
      • Induces vomiting

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Carbamates Organophosphates and Riot Agents