[yorkiegirl2]

Organophosphate/Carbamate Toxicity
Organophosphate and carbamate compounds are widely employed for control of external parasites in dogs and cats and for control of insects in the home and garden. Cats are relatively susceptible to acute toxicosis by the organophosphate compound chlorpyrifos [123]. Toxicosis may develop following ingestion of liquid concentrates or granules of these compounds or from excessive skin/hair coat dusting or painting [63]. Organophosphates and carbamates are acetylcholine esterase (ChE) enzyme inhibitors: -organophosphates are irreversible inhibitors of the enzyme, whereas carbamates are reversible inhibitors of ChE. This results in an accumulation of the neurotransmitter acetylcholine, causing:

overstimulation of the parasympathetic nervous system and subsequent development of muscarinic signs, e.g., salivation, lacrimation, urination, and defecation (SLUD), as well as pronounced gastrointestinal sounds, bradycardia, and pupillary constriction,
nicotinic signs associated with skeletal muscle stimulation, e.g., muscle fasciculations, tremors, twitching, spasms that may result in a stiff gait or rigid stance, and eventually weakness and paralysis, and
variable involvement of the central nervous system due to central cholinergic overstimulation (anxiety, restlessness, hyperactivity, anorexia, and generalized seizures).

The role of various serum and liver esterases in the pathogenesis of acute organophosphate toxicosis remains to be determined [63]. Death from asphyxia may result from severe central respiratory depression, bronchial fluid accumulation and bronchoconstriction. Clinical signs occur usually within minutes or hours. It has been reported that toxicity by the organophosphate compound, fenthion (Spotton®, Prospot®) usually results in a predominance of nicotinic signs (with no muscarinic signs), including muscle tremors, muscle weakness (particularly the neck muscles), and collapse after exercise [124]. In experimental intoxication with dichlorvos, muscle hemorrhage and necrosis was noted and was believed to be secondary to continual muscle fasciculations/contractions and possibly to the metabolic disturbances (metabolic acidosis and tissue hypoxia) produced in muscle as a result of ChE inhibition [125]. The myopathy associated with organophosphate toxicosis seems to be associated with excessive entry of calcium ions into muscle cells [126]. In a clinical report, acute polymyopathy in a 7 year old German Shepherd dog was attributed to the muscular hypertonia, tremors and seizures which developed during the acute phase of carbamate poisoning [127]. After two days of generalized muscular rigidity, the dog adopted a characteristic fetal position thought to be explained by the imbalance between the injuries to the extensor and flexor muscles. The polymyopathy, the diagnosis of which was based on EMG findings, myoglobinuria, and elevated serum muscle enzymes (muscle biopsy was normal), resolved gradually over the course of a week. A delayed neurotoxicity may occur in cats days or weeks after minimal exposure to organophosphates. In an experimental study, cats developed clinical signs of delayed neurotoxicity 16 to 18 days after di- isopropylfluorophosphate injection [128]. A histologic survey of the central and peripheral nervous systems revealed that the topographic distribution of axonal degeneration was characteristic of a dying-back neuropathy. In teased- fiber preparations from the left recurrent laryngeal nerve, the axonal degeneration that was initially focal and nonterminal subsequently spread in a somatofugal direction to involve the entire distal axon. Nerve fiber varicosities and paranodal demyelination preceded the axonal degeneration. The varicosities were associated ultrastructurally with intra-axonal and/or intramyelinic vacuoles, along with accumulations of axonal agranular reticulum [129]. Neurotoxic esterase is considered to be the target enzyme in the production of organophosphorus-induced delayed neurotoxicity (OPIDN) [130,131]. Affected animals manifest signs of a neuropathic syndrome. Dogs appear to be relatively resistant to delayed neurotoxicity [132]. Clinical signs associated with carbamate toxicity are likely to be less severe and shorter in duration [63]. ChE activity in domestic animals has been recommended as a potential biomonitor for nerve agent and other organophosphate exposure [133]. In this regard, it should be noted that physostigmine is a reversible ChE inhibitor and has a short duration of action. It crosses the blood-brain barrier readily; hence, it is a centrally acting carbamate. Pretreatment with physostigmine rapidly improves the incapacitating effects of organophosphate intoxication in various animal species [134]. Physostigmine carbamylates to a portion of ChE enzyme and thus protects the enzyme from irreversible binding with organophosphate.
Diagnosis is suggested by historical data, clinical signs and response to therapy. Whole blood cholinesterase levels can be determined using several substrates, including acetyl-, butyryl- and propionylthiocholine [217]. Red blood cell ChE levels reduced by 25% or more will confirm exposure [11]. At post mortem examination, brain tissue submitted for ChE activity is the most definitive diagnostic measure available for lethal organophosphate toxicosis [123]. Atropine, a muscarinic cholinolytic agent, at a dosage of 0.2 to 0.4 mg/kg body weight, IV, slowly over 5 minutes, usually results in a dramatic cessation of muscarinic signs within 3 to 5 minutes. Repeated administration of atropine, SC or IV, at lower dosages is often required, especially in cats. Atropine blocks the effects of accumulated acetylcholine at muscarinic parasympathetic nerve endings. However, it does not affect the skeletal muscle (nicotinic) signs. Repeated doses of atropine can be given using one-half the initial dose. Overatropinization can cause tacchyarrhythmias, pyrexia, behavioral excitation and signs of delirium. Additionally, a ChE-reactivating oxime, such as pralidoxime chloride (2-PAM, Protopam Chloride) may be used to counter the nicotinic cholinergic signs. This compound acts by forming a relatively non-toxic complex with the organophosphate compound that can be excreted in urine, and also reactivates acetylcholine esterase. 2-PAM works best in the presence of atropine, the dose of which may be reduced when 2-PAM is used (e.g., 0.04 to 0.4 mg/kg once, or as needed). The dose of 2-PAM (given as a 10% solution) is 10 to 20 mg/kg for cats and 40 mg/kg for dogs, given IV slowly, or with fluids over a 30 minute period [11]. Signs of muscle weakness and fasciculations usually disappear within 30 minutes. If signs remain, repeat the dosage within an hour and then give every 8 hours, for 24 to 48 hours, or until recovery. Treatment with 2-PAM should begin within 24 to 48 hours and this agent may be especially beneficial in animals exposed to fenthion and chlorpyrifos with their slow rate of elimination [11]. The dose can be reduced in animals that are severely depressed, weak and anorectic one or more days after exposure. Oximes are of not benefit in treating carbamate toxicosis and may worsen the animal's condition. Orally administered activated charcoal in cats and dogs (0.5 to 4.0 gm/kg), in combination with a saline cathartic (e.g., 70% sorbitol), will help reduce absorption following ingestion of organophosphate/carbamate compounds. Seizures in cats and dogs may be controlled using diazepam (2.5 to 5.0 mg/kg IV as needed) or a barbiturate such as phenobarbital (10 to 20 mg/kg IV as needed). Supportive care is very important, especially in cats, and includes monitoring for hypo- and hyperthermia, oral or parenteral potassium supplementation if hypokalemia is detected, and parenteral fluid, electrolyte and nutritional support (e.g., hand-feeding, tube-feeding, or use of pharyngostomy tubes) [123]. Such care may extend over several weeks.
Diphenhydramine (Benadryl®) may be effective in treating organophosphate-induced neuromuscular weakness in dogs and cats, that is refractory to other forms of therapy [135,136]. Initial treatment should be initiated IV or IM (IM only in cats) at 4 mg/kg every 4 to 6 hours until clinical improvement occurs, followed by oral treatment at 4 mg/kg, tid. Diphenhydramine blocks the nicotinic and muscarinic effects of compounds such as fenthion (Spotton®). Experimental studies have shown that early and prolonged treatment using a high-dose regimen of methylprednisolone prevented the development of OPIDN in cats [137].
Variations in clinical presentations may occur with organophosphate compounds. In one report, two cats with chronic exposure (3 weeks) to chlorpyrifos (Dursban®), an organophosphate available as a soil insecticide and a parasiticide for use on cattle, presented with paraparesis, generalized hyperesthesia, anorexia, depressed postural reactions and bilaterally dilated pupils that were partially responsive to light stimulation [138]. It was considered that both cats lacked muscarinic signs but showed evidence of nicotinic and central nervous system stimulation. Serum ChE activity was low in both cats and electromyographic studies revealed presence of fibrillation potentials and high frequency discharges, especially in more distal muscles of the pelvic limbs. Administration of 2-PAM, 20 mg/kg, IV, bid, for 5 or 6 treatments, as well as atropine sulfate, 0.05 mg/kg, SC, every 6 hours for 2 days, resulted in complete clinical recovery. Interestingly, diazepam induced signs of acute organophosphate toxicity (miotic pupils, hypersalivation, generalized muscle fasciculations, and depression) in both cats - the mechanism of action was not determined.