Organophosphorus and Carbamate Insecticides

Organophosphorus and Carbamate Insecticides

Toxicology of Selected Pesticides, Drugs, and Chemicals 0195-5616/90 $0.00 + .20 Organophosphorus and Carbamate Insecticides James D. Fikes, DVM, M...

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Toxicology of Selected Pesticides, Drugs, and Chemicals

0195-5616/90 $0.00

+ .20

Organophosphorus and Carbamate Insecticides James D. Fikes, DVM, MS*

The use of chemicals is a major and often valuable component of insect control. Over 900 compounds are formulated in 25,000 registered insecticidal formulations in the United States, with annual production in excess of 500,000 tons. 61 Insecticides have benefited the quality of life of man by controlling insect parasites and vectors of diseases and by increasing agricultural productivity. Clearly, such uses of insecticides will continue in the foreseeable future. Currently, organophosphorus (OP) and carbamate compounds are some of the most widely used insecticides, making it inevitable that accidental or inappropriate exposure of pets to these compounds will occur and, on occasion, produce toxicosis. Although the compounds themselves differ in structure (Fig. 1), OP and carbamate insecticide toxicoses are discussed together because of similar mechanisms of action, clinical signs, diagnosis, and treatment. There are, however, some important differences between the two categories that influence the duration of action, the nature of some of the effects, and the therapy needed.

INCIDENCE OP and carbamate toxicoses commonly occur. In 1987, the Illinois Animal Poison Information Center (IAPIC) received 1315 calls concerning OP or carbamate insecticide exposures of cats and dogs. 62 Of these, 28 per cent were categorized as exposures only, 29 per cent as doubtful toxicoses, and 32 per cent as suspected toxicoses and 11 per cent as toxicoses. These calls represented 2192 animals at risk, with 61 per cent exhibiting clinical signs at the time of the call. Thus, veterinarians should be familiar with OP and carbamate insecticide toxicoses in order to include the syndromes in differential diagnoses, when appropriate, and to initiate appropriate therapy when poisoning occurs.

MECHANISM OF ACTION Carbamate and OP insecticides are inhibitors of cholinesterase (ChE) activity (Fig. 2). Cholinesterase enzymes in animals can be divided into 'Postdoctoral Fellow, Department of Pathology, Michigan State University, East Lansing, Michigan \'eterinary Clinics of North America: Small Animal Practice-Yo!. 20, No. 2, March 1990

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Figure l. General formula for carbamate (A) and organophosphorus insecticides (B).

"true cholinesterase," also termed acetylcholinesterase (AChE), and pseudocholinesterase. 40 AChE is commonly found in nervous tissue, red blood cells, and muscle tissue and has a high specific affinity for the neurotransmitter substance acetylcholine (ACh). Pseudocholinesterase is found in plasma, liver, pancreas, and nervous tissue and can hydrolyze a variety of esters, including ACh. 3 Acetylcholine serves as a neurotransmitter (1) at autonomic ganglia of both sympathetic and parasympathetic nervous systems; (2) between postganglionic parasympathetic nerve fibers and cardiac muscle, smooth muscle, and exocrine glands; (3) at neuromuscular junctions of the somatic nervous system (Fig. 3); and (4) at cholinergic synapses in the central nervous system (CNS). In response to the arrival of an action potential, ACh is released from the presynaptic membrane into the synaptic cleft and binds to the postsynaptic cholinergic receptor (muscarinic or nicotinic), producing depolarization of the postsynaptic membrane. Thus, depending upon location in the body, the depolarization may propagate a nerve impulse or stimulate either a motor end-plate of a voluntary muscle or another effector organ (gland, pupil, blood vessel, or other smooth muscle). 1 Acetylcholinesterase terminates the stimulatory effect of ACh by rapidly hydrolyzing ACh within the junctional space. Carbamate and OP insecticides bind to the ChE enzyme, thereby inhibiting its normal hydrolytic activity (see Fig. 2). With AChE activity inhibited, ACh accumulates at the postsynaptic receptor, producing prolonged depolarization of effector organs. Depolarization initially causes stimulation; with prolonged depolarization, however, there may be inadequate repolarization, so that subsequent presynaptic action potentials may have little or no postsynaptic effect.

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Figure 2. Scheme of interactions of carbamate and organophosphorus (OP) insecticides with acetylcholinesterase (Enzyme-OH). Spontaneous reactivation is extremely slow with OP insecticides, almost nonexistent after aging, and slow with carbamate insecticides. l = Reversible formation of Michaelis enzyme-substrate complex; 2 = phosphorylation or carbamy-

lation of a serine moiety on the cholinesterase molecule, with the loss of a leaving group (X) from the insecticide; 3 = reactivation reaction-reactivation rates are dependent upon the physical characteristics of the inhibitor-enzyme complex, as well as the addition of oximes, which help reactivate phosphorylated AChE; 4 = "aging"-involves loss of an R-OP bond; A·= carbamate or OP insecticide.

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OPs are generally considered irreversible inhibitors of ChE activity, whereas carbamates are slowly reversible inhibitors. 43 Aging is a timedependent chemical change in certain OP insecticides that results in extremely tight binding to ChE, 20 such that it is essentially irreversible, even in the presence of oxime reversal agents such as 2-PAM.

TOXICITY Depending upon chemical structure and formulation, the toxicity of carbamate and OP insecticides can vary from only slightly to extremely toxic. Many OP compounds used as insecticides today contain the thiono ( = S) moiety rather than the oxon ( = 0) moiety (see Fig. 1). In the parent form, the thiono type OPs characteristically are not potent inhibitors of ChE but require metabolic activation to form the active oxon analogues, a process that occurs primarily through the action of mixed function oxidase Sympathetic

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Figure 3. Schematic representation of the peripheral nervous system effects of cholinesterase-inhibiting insecticides. Following exposure to a toxic dose of a carbamate or OP insecticide, acetylcholine (ACh) accumulates at the autonomic nervous system ganglia, postganglionic cholinergic neuron-effector organ synapses, and neuromuscular junctions of the somatic neurons. Parasympathetic stimulation results in miosis, bradycardia, secretion of exocrine glands (lacrimal, salivary, bronchial, gastric, and pancreatic), hyperactivity of gastrointestinal smooth muscle, and bronchial constriction. Cholinergic stimulation at sympathetic ganglia enhances the release of catecholamines from the adrenal gland. Sympathetic adrenergic stimulation produces mydriasis, tachycardia, decreased gastrointestinal motility, bronchodilation, and vasoconstriction. The degree to which either the sympathetic or parasympathetic systems predominate during toxicosis depends upon the type, dose, and rate of absorption of the compound, as well as individual animal physiologic factors. ACh = acetylcholine; N = norepinephrine; E = epinephrine; mus = muscarinic cholinergic receptor; nic = nicotinic cholinergic receptor.

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(MFO) enzymes. The liver contains the greatest capacity for bioactivation; however, other organs such as the lung and brain also have some activating capacity, 46 which may be of significance, since such tissues are target organs of OP insecticides. Besides bioactivation processes, enzymes of detoxification are also present in the liver, and, experimentally, the liver has been shown to have a net detoxification effect with some 0Ps. 6 ° Carbamate insecticides and some OPs are direct inhibitors of ChE (i.e., they do not require metabolic activation). Recent or concurrent administration of several drugs may potentially increase an animal's susceptibility to OP or carbamate toxicosis. Drugs having neuromuscular blocking capabilities or those that compete for target esterases may increase susceptibility. These drugs include phenothiazine, procaine, magnesium ion, inhaled anesthetics, and depolarizing neuromuscular blocking agents such as succinylcholine and decamethonium. 23 Antibiotics such as the aminoglycosides (streptomycin, dihydrostreptomycin, neomycin, kanamycin, gentamicin), polypeptides (polymyxin A and B, colistin), clindamycin, and lincomycin may also have neuromuscular blocking effects. 23 • 5° Central nervous system depressants may also potentiate OP and carbamate insecticide toxicosis through synergistic pharmacodynamic actions and/or indirectly, through pharmacologic effects such as respiratory depression. 66 Drugs in this group include phenothiazine tranquilizers, benzodiazepines, reserpine, meprobamate, ethanol, and barbiturates. Because of these potential drug-insecticide interactions, when a patient has been recently exposed to aChE-inhibiting insecticide, it may be necessary to delay elective surgeries, to avoid use of inhalant anesthetics, to use an alternate sedative/preanesthetic, or to select a different antibiotic. Conversely, a clinician may need to use a non-ChE-inhibiting insecticide (i.e., pyrethrins) to control parasites if a patient is already being administered a medication that could potentially render it more susceptible to OP or carbamate insecticide toxicosis. Cimetidine, an H 2-antihistamine used for gastrointestinal ulcer therapy, is also an inhibitor of hepatic MFO activity in laboratory animals and humans. Experimental evidence indicates that cimetidine potentiates the toxicity of parathion in rats, apparently by slowing its metabolism. 42 Ranitidine, also an H 2 -antagonist, apparently does not affect MFOs as does cimetidine49 and, therefore, may be preferred in a patient in whom metabolic clearance of an insecticide may be of concern. Simultaneous exposure to more than one ChE inhibitor may also enhance OP and carbamate toxicity. Previous treatment of an animal with a ChE inhibitor may produce a significant inhibition of ChE activity without producing a toxicosis. However, additional exposure to a seemingly low dose of aChE inhibitor may block the remaining functional ChE, resulting in toxicosis. This may occur when owners use two or more ChE inhibitors, often without recognizing their common mechanism of action (i.e., topical fenthion for flea control or a dichlorvos anthelmintic, followed by dipping with a carbamate or OP insecticide). Diet is another factor that may influence toxicity. Rations deficient in protein lowered the LD 50 of carbaryl in rats 7 and decreased the hepatic detoxification of malaoxon in chickens. 19 To the author's knowledge, the

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only reference in the literature that confirms the clinical relevance of these experimental observations pertains to malathion use in poultry production. However, it seems likely that other clinical scenarios could develop in which malnutrition or other causes of protein malassimilation (such as pancreatic insufficiency, parasitism, or intestinal malabsorption) would render an animal more susceptible to toxicosis from a ChE-inhibiting insecticide. CLINICAL SIGNS Following an exposure to a toxic dose of a carbamate or OP insecticide, the onset of clinical signs is usually fairly rapid (minutes to a few hours). This can vary greatly, however, depending upon the absorption, distribution, metabolism, elimination, and AChE affinity of the insecticide involved. Experience of the IAPIC and from human case reports indicates that with some insecticides, especially lipophilic OPs, the onset of signs may be delayed up to 4 days and can persist for several weeks 16 ; for example, a delayed onset of clinical signs may occur in cats following topical exposure to the lipophilic OP insecticide, chlorpyrifos. 21 Signs may change from mild to serious and life-threatening in a short period of time if there has been sufficient exposure. Owing to variation in individual animal response and the number of OP and carbamate insecticide formulations available, not all poisoned animals exhibit the same signs, nor do all inhibitors of ChE consistently produce similar or even typical syndromes. The earliest signs noted with OP or carbamate insecticide toxicosis are usually of the muscarinic type. These may include hypersalivation, lacrimation, urination, GI hypermotility, defecation, diarrhea, increased respiratory sounds from bronchoconstriction and/or excessive bronchial secretions, bradycardia, and miosis. Muscarinic signs may be attenuated or completely masked by sympathetic stimulation (mediated by stress or ganglionic stimulation via AChE inhibition), which tends to produce opposite effects (i.e., mydriasis, tachycardia, etc.). Nicotinic neuromuscular signs may soon follow the muscarinic signs and include muscle stiffness, fasciculations, tremors, weakness, and paralysis. Signs attributable to the accumulation of ACh at cholinergic receptors in the CNS may include restlessness, anxiety, hyperactivity, seizures, and profound mental depression. Death is commonly attributed to respiratory failure, resulting most often from inhibition of central (medullary) respiratory drive, as well as from excessive bronchial secretions and bronchospasm (all regarded as muscarinic sites of action), potentially coupled with depolarizing blockade at the neuromuscular junctions (a nicotinic site), which further impairs diaphragm and intercostal muscle contraction. 45• 51 No one site of action is consistently responsible for death, and when one type of effect (i.e., muscarinic) is controlled, another (i.e., nicotinic neuromuscular paralysis) may become life-threatening or lethal in response to continued absorption or redistribution of the insecticide. Some OP compounds also interact with "Y-aminobutyric acid (GABA) receptors and protein of the nonsynaptic, voltage-dependent Cl- channels. 22

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The ability to bind to either or both of these proteins appears to be variable among the OP insecticides tested. The evidence suggestive of interference with GABAergic transmission by OP compounds is supported by paraoxoninduced decreases in brain GABA concentrations32 and by reductions of OP-induced seizures with benzodiazepinesY Further research is needed to determine the clinical significance of these effects on GABAergic neurotransmission.

DELAYED NEUROPATHY A toxic effect infrequently encountered and associated with exposure to certain OP insecticides is termed organophosphorus ester-induced delayed neuropathy (OPIDN). Onset is generally delayed for 7 to 21 days following exposure. The syndrome is not associated with inhibition of ChE. Instead, OPIDN appears to be related to inhibition of neuropathy target esterase (NTE) 29 with aging of the OP molecule on this enzyme. 30 Although carbamate compounds can potentially bind to NTE, the lack of aging capability renders them nonneurotoxic and even potentially protective. 28 Delayed neuropathy has been demonstrated experimentally in several small animal species such as dogs, cats, rabbits, and guinea pigs. 29 Generally, younger animals are less severely affected than adults. 30 Delayed neuropathy signs may include weakness, ataxia, and conscious proprioceptive deficits, all primarily affecting the hindlimb. This may potentially progress to paralysis, which, in severe cases, may also involve the forelimbs. A histologic lesion is generally characterized as a symmetrical, distal, primary axonal degeneration in the central and peripheral nervous system, with secondary myelin degeneration.

OTHER NONCHOLINERGIC EFFECTS OF OPs The following section may be of value when one is attempting to interpret biochemical, neurochemical, or morphologic changes associated with exposure to toxicosis produced by an OP or carbamate insecticide. The significance of noncholinergic effects in toxicoses remains unclear in most cases. Changes noted may simply represent an animal's normal response to an altered homeostatic level, rather than a direct effect of the insecticide. Clinical Pathologic Parameters Changes in clinical pathologic parameters are frequently nonspecific. An increase in packed cell volume (PCV), serum glutamic oxaloacetic transaminase (SCOT), and creatine phosphokinase (CPK) activities were noted during experimentally induced acute OP toxicosis in dogs. 56 Snow56 speculated that the increase in PCV was due to a combination of splenic contraction and dehydration, and the increases in SCOT and CPK were secondary to muscle damage from fasciculations and/or muscle necrosis (see section on Lesions). Elevated serum amylase activity secondary to pan-

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creatic injury and parasympathetic stimulation has been reported in association with OP toxicosis in humans 17• 25• 41 and has been experimentally reproduced in animals. 17 Hyperglycemia following exposure to OP and carbamate compounds has been reported in humans45 and rats. 31 • 48 Clement11 attributed the hyperglycemia to catecholamines released from the adrenal medulla following sympathetic stimulation and an increase in circulating glucocorticoids, which decrease peripheral glucose utilization. Hypokalemia has been noted in humans 26 and cats poisoned with OPs and may be secondary to alterep intracellular versus extracellular potassium concentrations, as mediated by circulating catecholamines. 26 Hematologic changes noted in humans during OP toxicosis included leukocytosis with or without a left shift. 45

TERATOGENICITY The teratogenic potential of some OP and carbamate insecticides has been examined, using various (primarily rodent) animal species. 53 Teratogenic effects have been reported in rodents exposed to fenthion, 8 demeton, 8 and trichlorfon. 58 In most species, the teratogenic dose is near the maternally toxic dose. However, the teratogenic dose of carbaryl in· Beagles, at 12.5 to 50 mg!kg given daily throughout gestation, was less than one tenth the doses of 125 mg!kg or greater, which were toxic to adult females. 55 The increased sensitivity to teratogenesis was attributed to the failure of the Beagles to biotransform carbaryl to !-naphthol, a major metabolite of other species. 64 Whether 0 ther breeds are equally sensitive is unknown. Fenchlorphos was reported to be teratogenic and embryotoxic to blue foxes 4 and teratogenic in rabbits, 44 producing, in particular, an increase in major skeletal malformations and cerebellar hypoplasia. 44 Cerebellar hypoplasia has also been reported in piglets following maternal exposure to trichlorfon. 6• 35

HORMONAL INFLUENCES Elevations of plasma corticosterone (the primary glucocorticoid produced by the adrenal of rodents) have been documented in rats and mice following toxic doses of OP compounds.U Other endocrine effects noted following acutely toxic doses of the OP "nerve gas" soman in rats include an increase in thyroxine and triiodothyronine, with a decrease in plasma ACTH and plasma testosterone. 11

LESIONS Lesions associated with OP or carbamate insecticide toxicoses are inconsistently observed and generally nonspecific. When lesions occur, they are related primarily to the pulmonary effects of the involved agent. Pulmonary changes may include bronchoconstriction, increased bronchial

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secretions, occasional rupture oflatge bronchi, pulmonary emphysema, and pulmonary edema. 57 · 59 Anoxic type hemorrhage may be present if the syndrome is prolonged. Petechial hemorrhage may be present, especially if seizures have occurred. Other reported lesions include pancreatitis in dogs following diazinon toxicosis 18 and enteritis in dogs, speculated to result from reduced mesenteric blood flow and intestinal ischemia following dichlorvos exposure. 34 A myopathy apparently dependent on "a critical degree and duration of AChE inhibition" 63 and mediated by accumulation of ACh at neuromuscular junctions has been documented in rats 33 and dogs 56 exposed to toxic doses of OP compounds. Kibler33 speculated that the syndrome potentially could be produced by all inhibitors of AChE. Among muscles commonly affected are the diaphragm (the most susceptible muscle group) and intercostal muscles; and dysfunction of these muscles as the result of necrosis could contribute to respiratory failure during acute toxicosis. 33

DIAGNOSIS History A history of recent, potentially excessive exposure to a carbamate or OP insecticide should alert a veterinarian to consider these compounds in the differential diagnosis. Signs With the wide variety of OP and carbamate insecticides currently available, and considering variation among individual animals of the same species, it is possible that an animal may not exhibit "typical" signs but rather a combination of mixed peripheral muscarinic and nicotinic as well as brain-related signs. The response of an animal to the administration of atropine can be helpful in establishing a preliminary diagnosis. Failure of a preanesthetic dose of atropine (0.02 mg/kg, intravenously) to produce the usual anticholinergic signs such as tachycardia and mydriasis would be suggestive of toxicosis from a ChE inhibitor. Cholinesterase Assays The determination of ChE activity in blood, plasma, serum, and brain is routinely performed by many laboratories to establish exposure to a ChE inhibiting compound. However, some laboratories may not routinely perform ChE assays on samples from domestic animals and, therefore, may lack established "normal ranges." Thus, additional samples from animals not exposed during the previous 6 to 8 weeks to a carbamate or OP insecticide may be needed to help establish a range of basal ChE activity. Whole blood containing the anticoagulant suggested by the laboratory should be refrigerated while stored and shipped, and serum and plasma should be stored and submitted frozen. One half of the brain should be removed as soon as possible postmortem and frozen. The other half can be fixed in formalin for histologic examination.

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Although not a uniformly reliable indicator, a decrease to 50 per cent or more of normal ChE activity in samples from mammals, 39 birds, 9• 70 and fish 65 generally indicates significant inhibition, and for most cases of poisoning, ChE is commonly less than 25 per cent of normal activity. 39 Normal brain ChE activity of avian species is generally higher than that of mammals. 5 The ChE inhibition produced by carbamate insecticides generally involves a weaker, more labile binding than with OP compounds, potentially resulting in spontaneous reactivation of the ChE enzyme, sometimes with return to the normal range of activity. Samples from a suspected carbamate toxicosis must therefore be rapidly (1) collected, (2) frozen, (3) transported to the laboratory (while maintained in a frozen state), and (4) analyzed. Insecticide Identification

Several laboratories are available that can analyze samples in an attempt to identify a specific insecticide. Carbamate and OP insecticide concentrations decrease in body tissues fairly quickly following exposure; however, in the event of a suspected toxicosis, samples should be saved (frozen) for possible identification of the insecticide involved. Samples to be saved include vomitus and potentially exposed hair (ante mortem), stomach contents, liver, body fat, and skin with subcutaneous tissue if a topical exposure is suspected (postmortem). The suspected source of exposure (product container, contaminated food, water, etc.) should also be saved. A laboratory should be consulted prior to submission of samples to identify their analytical capabilities and to obtain guidance with regard to sample selection and handling. Care must be taken to avoid cross-contamination from suspected source materials to specimens from animals. TREATMENT

Effects on small animals exposed to toxic amounts of OP or carbamate insecticides may range from asymptomatic, to peracute life-threatening dyspnea and seizures, to persistent depression and anorexia; therefore, therapy must be tailored to the needs of the individual patient. Drugs that appear to be contraindicated in 0 P or carbamate insecticide toxicosis include morphine, theophylline, and theophylline-ethylenediamine. 27 Other medications can potentially enhance the toxicity of OP and carbamate insecticides and should be used with caution and only when necessary in association with a toxicosis (see previous section on Toxicity). Because of the potential seriousness of OP and carbamate insecticide toxicoses, familiarity with an appropriate treatment protocol is a necessity (Table 1). During the initial evaluation, it is important to assess the patient rapidly and initiate measures to sustain life, such as establishing a patent airway and controlling seizures (see Beasley and Dorman, Management of Toxicoses). Generally, atropine is given early on, in order to restore centrally mediated respiratory drive, to minimize bronchial constriction and secretions, and to counteract bradycardia. Nevertheless, in some hypoxic patients, the initial administration of 0 2 (i.e., before atropine)

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Table 1. Summary of Therapy Recommendations for Organophosphorus or Carbain{lte Insecticide Toxicosis* 1: · Sta,bilize the animal and control its seizures if necessary (with diazepam or a barbiturate) and provide 0 2 support and mechanical ventilation as needed. ~· Atropine sulfate (0.1 to 0.2 mg/kg) is ·given as needed. One fourth of the initial dose is given intravenously and the remainder intramuscularly or subcutaneously. Take care to avoiq OV!Jratropinization. Animals do not die from constricted pupils or hypersalivation; therefore, maintenance of open airways and control of bradycardia and CNS dysfunction are the primary goals of atropine therapy. 3. Pralidoxime chloride (Protopam chloride, 2-PA.M, Ayerst Laboratory, New York, NY) for OP toxicoses at 20 mg/J
should be considered to improve tissue oxygenation and minimize the risk of atropine-induce~ 'ventricular fibrillation. 67 Atropinecinduced ventricular fibrillation has· been documented in dogs exposed to the OP compound TEPP. 67 A d~ci~ion on whether to give atropine immediately or wait until respiration has improved must 'be based on medical judgment. It is hoped that few animals wUl be presented in such an advanced state of toxicosis that atropine caqnot be given immediately. · Atropine sulfate is capable of crossing the blooq-brain barrier. It is used to alleviate the muscarinic effects of AChE inhibition and can be especially important in relieving respiratory distress. The atropine dose tange presented in Table 1 should be considered as a guideline. The amount, frequency, and duration of atropine therapy required must be varied, depending on the response of the individual animal. Also, the ChE jnhibitor involved and the route and severity of exposure greatly influence the requirement for atropine therapy. Initial atropine administration and su~sequent closings should not be "reflex acts" in response to exposure to acholinesterase inhibitor but should be based mi the presence of significant plinical signs such as dyspnea related to respiratory paralysis, hypersecretions and/or bronchospasm, or bradycardia. Possible detrimental sequelae associated with overatropinization indude intestinal stasis, tachycardia, delirium, and hyperthermia. 2 Atropine has little or no effect at nicotinic receptors. Therefore, when used alone, it does not counteract OP insecticide-associated neuromuscular paralysis. Synthetic muscarinic blocking agents such as the positively charged amines, methyl atropine nitrate, propantheline, and glycopyrrolate, have been synthesized in an effort to enhance the blocking activity at se\ective muscarinic sights and to diminish the ability to cross the blood-brain barrier, thereby reducing some of the undesirable (centrally mediated) side effects of atropine. 2 However, because these compouncls are unlikely to cross the bloocl-brain barrier in significant amounts, 2 they are generally not indicated for OP or carbamate toxicosis, since the central effects of the

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excessive ACh would not be blocked. Glycopyrrolate, because of its peripheral antisialorreal activity, coupled with its relatively lesser cardiac effects, potentially could be used in a patient exhibiting persistent hypersalivation without additional signs. 54 Cholinergic antagonists with more rapid access to the CNS than atropine are being studied for their use in acute anti-ChE toxicosis. 38 Pralidoxime chloride (Protopam chloride, 2-PAM, Ayerst Laboratory, New York, NY) should be administered in an effort to regenerate AChE, thereby relieving nicotinic signs such as muscle weakness and tremors associated with OP toxicosis. Oximes such as 2-PAM work best when combined with atropine. The oximes function by interacting with the OPChE complex to free the ChE enzyme and by interacting directly with OP compounds to form a complex that is excretable via the urine. 23 Many OP insecticides have chemical structures that allow them to change or "age" once bound to ChE, producing an even tighter bond with the enzyme (see Fig. 2). 20 Aging renders ChE reactivating oximes such as 2-PAM ineffective because of the increased affinity of the OP compound for the enzyme receptor site. Therefore, to provide maximal benefit, 2-PAM should be administered as soon as possible following exposure. However, even if the initiation of treatment is delayed and clinical signs have been present for an extended period of time, 2-PAM therapy should still be started and continued until the patient is asymptomatic or no improvement in nicotinic signs (e.g., a decrease in muscle tremors, weakness, or paralysis) is seen after 24 to 36 hours of 2-PAM therapy. Oxime reactivators are generally unnecessary in carbamate toxicoses, since inhibition is rapidly reversible. Evidence that 2-PAM may be contraindicated for carbaryl toxicosis exists in two reports indicating a reduction in the protective effects of atropine associated with the concomitant administration of 2-PAM. 10 • 52 The contraindication in carbaryl poisoning should not necessarily be extended to all other carbamate insecticides. 15 Therefore, if in doubt as to whether a poisoning is due to an OP or a carbamate but signs suggest a cholinesterase inhibitor, 2-PAM should be used and clinical signs observed closely, while efforts to identify the cause of the problem continue. The use of diphenhydramine as a therapy for OP or carbamate toxicosis is considered controversial at this time. Diphenhydramine appeared to counteract in the dog some of the nicotinic effects produced by fenthion, an OP insecticide. 12 Clemmons 12 suggested that diphenhydramine may be an effective adjunct to therapy for OF-poisoned animals that fail to respond to atropine and oxime reversal agents. It was suggested that the effective dose of diphenhydramine for dogs should be titrated but was usually 1 to 4 mg/kg PO every 6 to 8 hours. 13 If this agent is used, attention should be paid to clinical response to avoid inducing mental depression, especially when high doses of atropine have also been given. 13· 24 The predilection of lipophilic compounds, especially some OPs, for adipose tissue may result in significant concentrations of parent compound accumulating in body fat with subsequent release into the blood through a dynamic equilibrium. 16• 69 This depot may act as a source of continued exposure to an animal, even though exposure from the initial route may

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have been terminated. This could necessitate prolongation of therapy to counteract signs and prevent relapse. 36 For most toxicoses, detoxification measures should be initiated as soon as the patient is stabilized. Judgment is needed to avoid the use of detoxification measures that may create an undue stress or risk of aspiration of gastric contents. When feasible, activated charcoal (with a saline or osmotic cathartic, unless diarrhea is present) should be administered to decrease gastrointestinal absorption, and topically exposed animals should be bathed with a suitable detergent (see Beasley and Dorman, Management of Toxicoses). Supportive care may be the most overlooked component in the management of OP or carbamate toxicoses. Body temperature should be monitored and regulated as necessary. Patients with profound muscle tremors and/or seizures may have elevated body temperatures, whereas animals exhibiting mental depression may develop hypothermia. Electrolyte and acid-base status should also be monitored. Correcting acidosis with sodium bicarbonate was shown to improve survival rate in dogs following experimentally induced OP toxicosis. 14 Parenteral fluids may be necessary to compensate for fluid losses from vomiting, diarrhea, hypersalivation, and decreased intake. The choice of fluids depends on the electrolyte needs of the patient and what is readily available. Provided the patient is not hypotensive, initial fluid therapy should be directed toward restoration of total body water and electrolyte balance. If hypotension is present after atropinization, larger volumes of fluids may be indicated. If anorexia should persist, it may be necessary to force feed or tube feed animals in order to provide caloric and electrolyte requirements. When an animal is resistant to forced or tube feeding or the risk of aspiration is high, as in a severely debilitated patient, a pharyngostomy tube may enable safer and more efficient feeding. Hemoperfusion (HP) and hemodialysis (HD) are currently being utilized in the therapy for OP toxicosis of humans 69 and, experimentally, in animals. 47 More water-soluble compounds may be removed by HD; however, the greatest benefit would most likely come from HP (dialysis of blood against activated charcoal). 47

REFERENCES l. Adams HR: Introduction to the autonomic nervous system. In Booth NH, McDonald LE (eds): Veterinary Pharmacology and Therapeutics. Ames, Iowa State University Press, 1988, pp 73-90 2. Adams HR: Cholinergic pharmacology: Autonomic drugs. In Booth NH, McDonald LE (eds): Veterinary Pharmacology and Therapeutics. Ames, Iowa State University Press, 1988, pp 117-136 3. Augustinsson KB: Assay methods for cholinesterase. In Glick D (ed): Methods of Biochemical Analysis, Vol 5. London, lnterscience Publishers Inc, 1957, pp 1-63 4. Berge GN, Nafstad I: Teratogenicity and embryotoxicity of orally administered fenchlorphos in blue foxes. Acta Vet Scand 24:99-112, 1983 5. Blakley BR, Skelley KW: Brain cholinesterase in animals and birds. Vet Hum Toxicol 30:329-331, 1988

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