Cholinesterase inhibitors act by blocking the active site of acetylcholinesterase (AChE). Organophosphates form a covalent phosphate linkage at the enzyme active site. Enzyme regeneration occurs by either de novo synthesis, hydrolysis of the serine–organophosphorus bond, or oxime regeneration. However, over 24 to 48 hours, most phosphorylated molecules age or become resistant to reactivation by oxime therapy. Carbamates are reversible inhibitors of AChE, occupying (but not modifying) the catalytic region of the enzyme. AChE activity is restored when the carbamate spontaneously leaves the enzyme’s active site [5]. AChE inhibitors such as tacrine, rivastigmine, donepezil, and galantamine have been used for treatment of Alzheimer’s dementia. The characteristics and treatment of exposure to these products is covered at the end of this chapter.

Inhibition of AChE allows the neurotransmitter acetylcholine to accumulate and remain active in the synapse, resulting in sustained depolarization of the postsynaptic neuron or effector organ. This effect occurs in the central nervous system (CNS) as well as at muscarinic sites in the peripheral nervous system, nicotinic sites in the sympathetic and parasympathetic ganglia, and nicotinic sites at the neuromuscular junction. In general, effects at muscarinic sites are sustained, whereas nicotinic sites are stimulated and then depressed (hyperpolarization block). Signs and symptoms of cholinergic toxicity typically appear when 60% to 80% of cholinesterase activity has been inhibited [6]. The pharmacologic and toxicologic effects of acetylcholinesterase inhibitor are an extension of their mechanism of action (Table 128.1).

In addition to acute cholinergic effects, organophosphates cause two other toxic effects. Intermediate syndrome (IMS) is a recurrence of weakness that occurs hours to days after a serious organophosphate exposure [7]. Some authors have suggested that IMS is caused by inadequate oxime therapy when serum organophosphate concentrations remain elevated due to redistribution, altered metabolism, or decreased clearance [8]. It is also possible that IMS is due to desensitization block with downregulation and eventual decrease in the nicotinic receptor activity. Since the nicotinic receptor has five subunits, there is probably significant polymorphism at this receptor affecting clinical response [9].

The second noncholinergic effect is organophosphorus-induced delayed peripheral neuropathy (OPIDN). This is a delayed peripheral neuropathy, which appears to be mediated by a membrane-bound specific “neuropathy target esterase.” Organophosphates that have been associated with OPIDN are aryl organophosphorus esters that contain either a pentavalent phosphorus atom (type I, including derivatives of phosphoric, phosphonic, and phosphoramidic acids, or phosphorofluoridates) or a trivalent phosphorus atom (type II or phosphorus acid derivatives). This neuropathy primarily involves motor fibers. Histologic analysis shows progressive neuronal degeneration, beginning with axonal swelling followed by demyelination, axonal degeneration, and neuronal cell body death and Wallerian degeneration or “dying back” phenomenon [10].

Excessive acetylcholine produces symptoms of muscarinic and nicotinic excess. These clinical effects are outlined in Table 128.2. One mnemonic used to describe the muscarinic toxidrome is DUMBELS (diarrhea, urination, miosis, bronchospasm, emesis, lacrimation, salivation). Miosis may be the most sensitive marker for moderate or severe exposure to a acetylcholinesterase inhibitor [11]. Lacrimation, rhinorrhea, salivation, and profuse sweating are common in moderate to severe poisoning. Abdominal cramping, diarrhea, and vomiting are very common with severe poisoning. Fasciculations are typically observed in severe overdoses.

Respiratory failure is a common cause of death from acetylcholinesterase inhibitor poisoning [2]. Cholinergic excess has direct deleterious effects on the respiratory center; causes bronchial muscle spasm and noncardiogenic pulmonary edema with exuberant mucus production; and severe respiratory muscle impairment. Respiratory failure may be further complicated by aspiration.

Cardiac toxicity has been increasingly described as a complication of organophosphate poisoning. There are three phases of reported toxicity including a brief period of intense sympathomimetic tone, a period of enhanced parasympathetic activity, and corrected QT (QTc) interval prolongation with potential for torsade de pointes. Prolongation of the QTc is a marker of severity and patients with a QTc greater than 440 milliseconds require higher doses of atropine and have a higher mortality than those a QTc less than 440 milliseconds [12]. Electrocardiographic abnormalities including nonspecific ST-T changes, tachydysrhythmias, bradydysrhythmias, and polymorphic (torsade de pointes) ventricular tachycardia have been reported [13]. The effect on blood pressure is variable. Patients poisoned with dimethoate have an initial benign course but develop refractory hypotension and cardiogenic shock within 36 to 48 hours [2].

The CNS effects of cholinergic poisoning include altered mental status seizures and coma [2]. Dystonias and choreoathetoid movements have also been observed [14]. Less severe
acute manifestations include anxiety, agitation, emotional lability, headaches, insomnia, tremor, difficulty in concentrating, slurred speech, ataxia, and hyperreflexia or hyporeflexia. In some cases, acute organophosphate poisoning may produce longer-lasting neuropsychiatric sequelae [15]. This has been labeled the chronic organophosphorus-induced neuropsychiatric disorder (COPIND). These problems seem most severe after serious acute intoxications and usually resolve within 1 year [15].

Cholinergic signs and symptoms typically begin minutes to hours after exposure [2]. Symptom onset is rarely more than 12 hours after exposure. Onset may be delayed for lipophilic compounds (e.g., fenthion, dichlofenthion, leptophos) [2] or compounds that require hepatic metabolism to a more toxic intermediate (e.g., parathion is metabolized to paraoxon) [16]. Progressive or prolonged symptoms raise the suspicion of continued absorption of the poison.

Life-threatening cholinergic symptoms from organophosphate toxicity generally abate within 1 to 3 days, although many cases requiring weeks of intensive care are reported [17]. Symptoms usually resolve within 12 to 48 hours after exposure to carbamates and other reversible cholinesterase inhibitors [18].

The intermediate syndrome, characterized by weakness of neck muscles, motor cranial nerves, proximal limb muscles, and respiratory muscles, but without prominent muscarinic findings beginning 24 to 96 hours after the onset of poisoning and lasting 4 to 18 days has been described [8]. An early clinical indication of this syndrome is that affected patients are unable to lift their heads up from their beds [17].