Acetylcholine (AC) is the most abundant neurotransmitter. It is found in many synapses in the autonomic nervous system (related to involuntary muscle movement), in neurons that control voluntary muscle movement, and in many parts of the central nervous system. AC is stored in the neuron in subcellular vesicles and released from the axon into the synapse when a rapid influx of calcium occurs from an action-potential-induced change in membrane potential.
Botulinum toxin has the unenviable distinction of being probably the most toxic substance known to man with an LD50 in the ng/kg range. It impedes the formation of functional AC vesicles thus reducing the amount of AC that can be released during the depolarization of a motor neuron. It causes, therefore, a presynaptic problem. The toxin is a protein of 150 kD size that is cleaved into two smaller chains. One chain, of 100 kD size, is involved in neuron binding and promotes the intracellular penetration of the toxin. The other chain, 50 kD, obstructs neurotransmitter activity in other ways.
Eight serotypes of botulinum toxin have been identified. They are manufactured by Clostridium botulinum, a Gram positive bacillus. The term botulus means sausage and refers to an outbreak of the disease in Germany in the eighteenth century in which many died from contaminated sausage. The microorganism is anaerobic and grows in sealed containers. Many cases of botulinum exposure involve home-canned foods. In addition, some victims are wounded and their wounds become infected with Clostridium which then produces toxin in vivo. In infants, consumption of honey may lead to botulinum poisoning from Clostridium present in the honey. This source is thought not to be a hazard in adults because of the very small amounts of Clostridium likely to be present in honey.
One could predict the symptoms of botulinum poisoning on the basis of bodily functions that depend on AC. Neurons that use AC are immobilized and the victim experiences muscle weakness (AC involved in voluntary muscle action), paralysis
(AC acts at the neuromuscular junction), and autonomic effects such as nausea, diarrhea, and blurring of vision (AC acts in the autonomic nervous system). The earliest signs of poisoning are paralysis around the eyes and weakness of the facial muscles. Nerve conduction studies reveal low amplitude muscle action potentials. The suspicion of botulinum poisoning can be confirmed by injecting a sample of the patient's serum into a mouse. If the mouse undergoes paralysis and then dies, the diagnosis of botulism is confirmed.
As stated, poisoning with botulinum often results from contaminated food. Cases have been reported in which the victims ate smoked fish, cheese sauces, and many other food products. Since 1982 botulinum toxin has also been used as a medicinal for the treatment of a variety of musculoskeletal disorders. For example, one patient received regular injections of botulinum toxin into the lacrimal gland to reduce pathological tear secretion. Her profuse tear production had occurred as the aftermath of a viral infection of the eye. The localized paralysis of the lacrimal gland was effective in preventing excessive tears. In cases like this the medication may diffuse away from the injection site. When this happens ptosis and diplopia may result. Not surprisingly, therefore, use of a substance as potent as botulinum toxin, in a therapeutic manner, is not without danger.
Acetylcholine neurotransmitter is said to be found in cholinergic synapses, so named after the neurotransmitter itself. In actuality, AC receptors can be subdivided further into those sensitive to nicotine and those that respond to muscarine. Nicotinic receptors are located in autonomic neurons and on skeletal muscle. Muscarine-responding receptors are at neurons of the parasympathetic system where such neurons attach to smooth muscle or glands. These two compounds, nicotine and muscarine, are cholinergic agonists in the sense that they bind to their respective receptors and cause the same effect as if AC were released into the synapse. Nicotine (methylpyridylpyrrolidine) is, of course, the addictive agent of tobacco. Nicotine in the appropriate area of the CNS has psychoactive actions. Because nicotine acts directly at many synapses, one can surmise correctly that it is a potentially neurotoxic agent. Moreover, nicotine is rapidly absorbed through skin and lungs. There are deaths on record due to ingestion of nicotine as a pesticide and even by exposure through the skin. It directly stimulates the nicotine subset of CNS and peripheral AC receptors. Moderate poisoning is said to produce symptoms of cholinergic excess (described in Chapter 17, under pesticide poisoning). These include miosis, salivation, urination, defecation, emesis, and increased pulmonary secretions. The cause of these symptoms is parasympathetic stimulation. In large-dose exposure a shortlived stimulation is followed rapidly by neuromuscular blockade related to persistent membrane depolarization. If death occurs, the most common mechanism is respiratory arrest due to peripheral neuromuscular blockade and cardiovascular collapse.
Muscarine is analogous to nicotine in that it is able to mimic the actions of acetyl-choline in certain cholinergic neurons. This compound is found naturally in some mushrooms such as Amanita muscaria, Clitocybe dealbata, C. illudens, and others. Muscarinic effects on the autonomic nervous system are similar to effects produced from nicotine and are summarized by the acronym SLUD: salivation, lacrimation, urination, and defecation. Because muscarine is a quaternary ammonium compound it does not cross the blood-brain barrier and effects are more peripheral than central for this reason.
Some compounds are toxic because they antagonize the actions of acetylcholine. They behave like nicotine only in the sense that they bind to the postsynaptic receptor. Once they are bound there, however, they block the receptor and prevent the action potential in the postsynaptic neuron. Curare is a nicotinic antagonist. This compound is famous for use as an arrow poison by South American Indians. One of the major sources of curare is the South American plant Chondrodendron tomentosum. Curare is a mixture containing d-tubocurarine. By blocking the nicotinic receptor motor, weakness up to the point of paralysis is induced. Death may occur from paralysis of the diaphragm, the muscle that permits breathing. Today, poisoning by curare is as likely to occur by a medical error as from some other source. The hypotension and respiratory failure that it causes are treatable if intervention is rapid. Neostigmine acts as an antidote for curare poisoning. Blocking at the ganglia causes low blood pressure and reduced heart rate. Today, curare has been purified and is used frequently in surgery; for example, it has been employed as a muscle relaxant prior to tracheal intubation.
Atropine is a highly potent compound that acts as a muscarinic blocker. It is found in numerous plants including Jimsonweed and Atropa belladonna, deadly nightshade. Exposure to atropine blocks muscarinic receptors and prevents their normal action of innervating parasympathetic neurons of muscles and glands. The symptoms that occur from atropine overdose are tachycardia, pupillary and bronchiolar dilation, and decreases in secretions and in peristalsis. At the level of the CNS, atropine causes excitation at low doses but depression at large doses. Hallucinations often accompany atropine abuse and, for this reason, some persons deliberately have employed large amounts of it as a drug of abuse.
Scopolamine, structurally analogous to atropine (see Figure 10.11), is found in many species of plants, and has actions that are nearly identical to those of atropine. It has a notorious history of being employed by thieves to render their victims unconscious and amnesiac. At the present time, it is described as a national problem in Columbia where it is known as burundanga. Criminals sprinkle the highly potent scopolamine into the victim's food and wait for the person to achieve a zombie-like state. At that point, the victim is powerless to resist his assailant. Not only is scopolamine capable of causing profound sedation but there is often an amnesiac aftermath that only makes it more desirable as a means of perpetrating crime.
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