Organophosphorus (OP) compounds and carbamates, also known as cholinesterase inhibitors, are widely used pesticides. These agents, which comprise thousands of structurally related substances, are responsible for a large number of suicidal or accidental poisonings, with the greatest mortality (an estimated 200,000 deaths per year) in rural areas of developing countries.
During the 1930s, German military scientists synthesized numerous OP compounds, including parathion and several highly potent chemical warfare agents (eg, GA [tabun], GB [sarin], and GD [soman]; see Warfare Agents–Chemical and Table II–57). Because these chemical weapons affect the autonomic nervous system, they are sometimes referred to as “nerve agents.” Terrorist attacks in Japan (1994 and 1995) affected thousands of urban civilians who were exposed to the OP compound sarin.
Carbamates, although less deadly than OP agents, are used frequently as pesticides, fungicides, herbicides, rodenticides, and medications (eg, pyridostigmine) to treat neurologic disorders such as myasthenia gravis.
Mechanism of toxicity
Organophosphorus compounds inhibit two enzymes: acetylcholinesterase (AChE), found in synaptic junctions and in red blood cells (RBCs), and butyrylcholinesterase, also known as pseudocholinesterase (PChE) or plasma cholinesterase, found in the blood. Each of these enzymes breaks down acetylcholine.
Blockade of AChE is the most clinically significant effect of OPs and carbamates because this leads to the accumulation of excessive amounts of acetylcholine at muscarinic receptors (found on various cholinergic secretory cells), at nicotinic receptors (located on skeletal neuromuscular junctions and autonomic ganglia), and in the CNS.
Permanent inhibition of AChE (“aging”) may occur when there is covalent binding by the OP to the enzyme. The rate of aging is highly variable, from several minutes to days, depending on the route of exposure as well as the specific OP. Dimethyl OP compounds (eg, dimethoate) generally age more quickly than diethyl agents (eg, chlorpyrifos), and lipophilic OP compounds can be released into the systemic circulation from fat stores for many days to weeks following exposure, prolonging both the duration of clinical toxicity and the aging window. Antidotal treatment with an oxime (see “Pralidoxime”) is considered beneficial only if administered before aging occurs.
Carbamates also inhibit the AChEs and lead to accumulation of acetylcholine, with similar acute clinical effects.
CNS effects from carbamates are often less pronounced because they have more difficulty crossing the blood-brain barrier.
Carbamates do not “age” the AChE enzyme, and toxicity is therefore usually more brief and self-limited than with the OP compounds.
Patients with myasthenia gravis and related neurologic disorders may be at increased risk for carbamate-induced cholinergic toxicity because they are frequently prescribed
or related “-stigmine” compounds.
Aldicarb is relatively more potent and is translocated systemically by certain plants (eg, melons) and concentrated in their fruit. An acute outbreak of poisoning occurred in California in 1985 after ingestion of watermelons that had been grown in a field previously sprayed with aldicarb. The use of an imported rodenticide (Tres Pasitos, “three little steps”) led to an epidemic of aldicarb poisoning ...