Anticonvulsants for poisoning by the organophosphorus compound soman: pharmacological mechanisms.

Exposure to high doses of organophosphorus nerve agents such as soman, even with carbamate pretreatment, produces a variety of toxic cholinergic signs, including secretions, convulsions and death. Evidence suggests that soman-induced convulsions may be associated with postexposure brain neuropathology. The purpose of this study was to investigate the pharmacologic mechanism of action of soman-induced convulsions and of anticonvulsant drugs. Various classes of compounds were evaluated for their efficacy in preventing soman-induced convulsions in rats pretreated with the oxime HI-6 to increase survival time, along with various doses of the test compounds (IM) either in the absence or presence of atropine sulfate (16 mg/kg, IM) 30 minutes prior to a soman challenge dose (180 micrograms/kg, SC; equivalent to 1.6 x LD50) that produced 100% convulsions. Without atropine sulfate, only tertiary anticholinergics (scopolamine, trihexyphenidyl, biperiden, benactyzine, benztropine, azaprophen and aprophen), caramiphen, carbetapentane and MK-801 were effective anticonvulsants. In the presence of atropine sulfate, the benzodiazepines (diazepam, midazolam, clonazepam, loprazolam and alprazolam), mecamylamine, flunarizine, diphenylhydantoin, clonidine, CGS 19755 and Organon 6370 studied were effective. We have examined the possibility that diazepam may exert some of its anticonvulsant effects through cholinergic mechanisms and found that a reduced release of ACh into synapses after diazepam and atropine treatment may account for diazepam's anticonvulsant activity against soman. We also found that at anticonvulsant doses biperiden and trihexyphenidyl each significantly reversed the effects of soman on striatal levels of DOPAC and HVA, the metabolites of dopamine, and have concluded that in addition to actions on muscarinic receptors, the anticonvulsant effects of these anticholinergics in soman poisoning may be partially related to their actions on the striatal dopaminergic system. These findings allow us to postulate that central muscarinic cholinergic mechanisms are primarily involved in eliciting the convulsions following exposure to soman and that subsequent recruitment of other excitatory neurotransmitter systems and loss of inhibitory control may be responsible for sustaining the convulsions and for producing the subsequent brain damage. Future studies to confirm these neuropharmacological mechanisms are proposed.

Anesthetic management of conray toxicity.

Conray (meglumine iothalamate), the contrast media frequently used in shuntograms for diagnosing malfunctioning ventriculo-peritoneal shunts, will occasionally cause severe muscular spasms and seizures. In this article, the authors describe anesthetic and critical care management of a case with this complication.

Factors in the lethality of i.v. phencyclidine in conscious dogs.

1. Pretreatment were pancuronium prevented convulsions and hyperthermia, but had no effect on acidemia or changes in cardiovascular parameters after intravenous (i.v.) infusion of phencyclidine (PCP). 2. While dogs survived higher amounts of PCP, they failed to regain spontaneous respiratory function. 3. Mechanical ventilation alone increased the mean lethal dose/time of PCP and reduced the effects of PCP on arterial systolic pressure, cardiac output, and PCO2. 4. EKG showed ventricular arrhythmias, which progressed to death. 5. Phenytoin pretreatment plus respiratory assistance increased the lethal dose and reduced PCP effects on cardiovascular parameters, body temperature, and cardiac rhythm. 6. Blocking of convulsions prevented hyperthermia and acidemia; respiratory support reduced circulatory effects, but respired dogs then died, at higher doses, from a primary myocardial toxicity of PCP.