Understanding the manifestations and treatment of poisoning by nerve agents such as sarin or soman — cholinergic toxins — can be somewhat difficult initially because the actions of the neurotransmitter acetylcholine are widespread, remarkably varied, and can be contradictory. Acetylcholine is the chemical messenger in many areas of the nervous system: autonomic ganglia, the neuromuscular junction, post-ganglionic parasympathetic nerves, and the brain.
Cholinergic agents inhibit the enzyme acetylcholinesterase (AChE), which breaks down acetylcholine (ACh) and provides the physiologic “off-switch” that prevents the actions of ACh from running amok. Without that control mechanism, secretion from glands and spasm of both smooth and skeletal muscle cannot be stopped. Biological chaos ensues, and can be fatal quickly.
Fortunately, thinking about nerve agents can be simplified radically, if one breaks down their effects into three categories, and remembers that there is a separate antidote for each type of effect.
Muscarinic effects involve autonomic innervation of glands and smooth (involuntary) muscle, specifically the muscles of the respiratory and gastrointestinal tracts. Cholinergic agents cause markedly increased output from all secretory glands, as well as increased activity and constriction of smooth muscles. The mnemonic for the muscarinic manifestations of nerve agents is SLUGBAM. (See table 1.)
Another frequently used mnemonic device is SLUDGE: Salivation, Lacrimation, Urination, Diarrhea, Gastrointestinal upset, and Emesis, but this omits the most serious clinical muscarinic effects: bronchorrhea (profuse respiratory secretions) and bronchospasm. These are sometimes called the “Killer Bs” because they are the most frequent cause of death in nerve agent victims, who can't breathe because their respiratory tract is flooded with secretions and clamped down from smooth muscle spasm. These “Killer Bs” often respond readily to treatment with a specific antidote.
The antidote for the muscarinic effects of nerve agents is atropine, which should be given in a dose sufficient to dry respiratory secretions and relax bronchospasm, allowing the victim to be ventilated and oxygenated. This can be life-saving. Although nerve agents may cause a slow heart rate, the victim is often tachycardic because of hypoxia or the nicotinic effects of the toxin. It is crucial to understand that when treating exposure to nerve agents or to organophosphate insecticides, which also are cholinergic poisons, tachycardia is not a contraindication to treatment with atropine.
Because nicotinic acetylcholine receptors are found at the neuromuscular junction, nicotinic effects involve primarily striated (voluntary) skeletal muscle. Hyperstimulation from acetylcholine excess causes muscular twitching and fasciculation, followed by weakness and flaccid paralysis when the muscle fatigues. Nicotinic receptors in autonomic ganglia are responsible for the tachycardia that is frequently seen after exposure to cholinergics.
The antidote for the nicotinic effects of nerve agents is pralidoxime hydrochloride (2-PAM). This reverses toxin-induced inhibition of the enzyme acetylcholinesterase, regenerating active enzyme that can again break down excess acetylcholine. Unfortunately, after exposure to a nerve agent, enzyme inactivation will become irreversible after a period of time. This process is called aging, and occurs with a half-life that varies among agents. (See table 2.) After aging takes place, treatment with 2-PAM will not reactivate the enzyme, and recovery will be delayed until the body can produce entirely new acetylcholinesterase. The enzyme is replaced at a rate of approximately one percent of normal activity per day.
Nerve agents have a direct effect on the central nervous system through mechanisms that are not yet completely understood. Significant exposure can cause rapid loss of consciousness, generalized seizures, and central apnea. Animal studies have demonstrated that seizure activity after exposure to nerve agents increases the risk of death and the incidence of histopathological changes in brain cells (i.e., neuronal necrosis). Early treatment with antidote can prevent seizures and minimize this structural brain damage.
The antidote for the central effects of nerve agents is diazepam or another benzodiazepine. A recent article by Marrs reviewed data from animal models suggesting that atropine plus diazepam may be more effective than atropine alone in preventing fatality after exposure to the nerve agent soman. (Toxicol Rev 2004;23:145.) In some animal studies, midazolam was superior to diazepam as an antidote to nerve agents. In addition to the actions mentioned, benzodiazepines also will decrease anxiety and produce sedation. It would seem prudent to administer them early to any victim with known or suspected exposure to a nerve agent who is seizing, unconscious, exhibiting fasciculation or muscle twitching, or has other indications of significant exposure.
Conceptually, cholinergic toxins, including nerve agents, are as simple as 1–2–3. There are three different antidotes for these three different mechanisms: atropine for the muscarinic effects, 2-PAM for the nicotinic effects, and benzodiazepines for the central effects. Early treatment with the appropriate antidotes can minimize death and brain damage after significant exposure.