Investigations of the actions of neurotoxins have provided insight into how the nervous system works.
Some metabolic poisons are known to limit their action to the nervous system. These include poisons such as strychnine and curare (a South American Indian dart poison), as well as the dreaded nerve gases developed for chemical warfare. The exact modes of action of most neurotoxins are not known for certain, but investigations have discovered the action of a few.
A nerve impulse or stimulus is transmitted along a nerve fiber by electric impulses. The nerve fiber connects either with another nerve fiber or with some other cell (such as a gland or cardiac, smooth, or skeletal muscle) capable of being stimulated by the nerve impulse (Fig. 10-9). Neurotoxins often act at the point where two nerve fibers come together, called a synapse. When the impulse reaches the end of certain nerves, a small quantity of acetylcholine is liberated. This activates a receptor on an adjacent nerve or organ. The acetylcholine is thought to activate a nerve ending by changing the permeability of the nerve cell membrane. (Permeability: The ability of a membrane to let chemicals pass through it.) The method of increasing membrane permeability is not clear, but it may be related to an ability to dissociate fat-protein complexes or to penetrate the surface films of fats. Such effects can be brought about by as little as 10-6 mole of acetylcholine (10-6 of a mole of acetylcholine is 6 X 1017 molecules.), which could alter the permeability of a cell so that ions can cross the cell membrane more freely.
To enable the receptor to receive further electrical impulses, the enzyme cholinesterase breaks down acetylcholine into acetic acid and choline (Fig. 10-10).
CH3 O CH3
+| Cholinesterase " +|
CH3COCH2CH2N-CH3,OH- + H2O ----------------> CH3COH + HOCH2CH2N-CH3,OH-
" | |
O CH3 CH3
Acetylcholine Water Acetic Acid Choline
In the presence of potassium and magnesium ions, other enzymes such as acetylase resynthesize new acetylcholine from the acetic acid and the choline within the incoming nerve ending:
Acetylase Acetic acid + Choline -------------> Acetylcholine + H2OThe new acetylcholine is available for transmitting another impulse across the gap (see Fig. 10-10a).
Neurotoxins can affect the transmission of nerve impulses at nerve endings in a variety of ways. The anticholinesterase poisons prevent the breakdown of acetylcholine by deactivating cholinesterase. These poisons are usually structurally analogous to acetylcholine, so they bond to the enzyme cholinesterase and deactivate it (Fig. 10-10b). The cholinesterase molecules bound by the poison are held so effectively that the restoration of proper nerve function must await the manufacture of new cholinesterase. In the meantime, the excess acetylcholine overstimulates nerves, glands, and muscles, producing irregular heart rhythms, convulsions, and death. Many of the organic phosphates widely used as insecticides are metabolized in the body to produce anticholinesterase poisons. For this reason, they should be treated with extreme care. Some poisonous mushrooms also contain an anticholinesterase poison. Figure 10-11 contains the structures of some anticholinesterase poisons.
Neurotoxins such as atropine and curare (Table 10-6) are able to occupy the receptor sites on nerve endings of organs that are normally occupied by the impulse-carrying acetylcholine. When atropine or curare occupies the receptor site, no stimulus is transmitted to the organ (Fig. 10-10b). Acetylcholine in excess causes a slowing of the heartbeat, a decrease in blood pressure, and excessive saliva, whereas atropine and curare produce excessive thirst and dryness of the mouth and throat, a rapid heartbeat, and an increase in blood pressure. The normal responses to acetylcholine activation are absent, and the opposite responses occur when there is sufficient atropine present to block the receptor sites.
Neurotoxins of this kind can be extremely useful in medicine. For example, atropine is used to dilate the pupil of the eye to facilitate examination of its interior. Applied to the skin, atropine sulfate and other atropine salts relieve pain by deactivating sensory nerve endings on the skin. Atropine is also used as an antidote for anticholinesterase poisons. Curare has long been used as a muscle relaxant.
A well-known alkaloid (alkaloids are discussed in Chapter 7) that blocks receptor sites in a manner similar to that of curare and atropine is nicotine. This powerful poison causes stimulation and then depression of the central nervous system. The probable lethal dose for a 70-kg person is less than 0.3 g. It is interesting to note that pure nicotine was first extracted from tobacco and its toxic action observed after tobacco use was established as a habit.
Natural or synthetic morphine is the most effective pain reliever known. It is widely used to relieve short-term acute pain resulting from surgery, fractures, burns, and so on, as well as to reduce suffering in the latter stages of terminal illnesses such as cancer.
The manufacture and distribution of narcotic drugs are stringently controlled by the Federal government through laws designed to keep these products available for legitimate medical use. Under Federal law, some preparations containing small amounts of narcotic drugs may be sold without a prescription (for example, cough mixtures containing codeine), but not many.
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Name Normal Contact Lethal Dose
(for 70-kg human)
_______________________________________________________________________________
Atropine Dilation of the pupil of the eye 100 mg
Curare Muscle relaxant 20 mg
Nicotine Tobacco, insecticides 75 mg
Caffeine Coffee, tea, cola drinks 13.4 g (one cup of
coffee contains
about 40 mg caffeine)
Morphine Opium--pain killer 100 mg
Codeine Opium --pain killer 300 mg
Cocaine Leaves of Erythroxylon coca 1 g
plant in South America
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Chemical warfare is the use of toxic chemicals to kill and incapacitate the enemy. The Creeks used choking clouds of sulfur dioxide (SO3) gas caused by burning sulfur and pitch during the Peloponnesian War between Sparta and Athens (413-404 B.C.) Modern chemical warfare began in 1915 when the Germans released chlorine gas on Allied troops at Ypres, Belgium, during World War I. After the initial use of chlorine, various other gases were developed and used (Table 10-7).
In general, the World War I war gases caused death if the victim was exposed to high enough doses, but their most significant contribution to warfare was their effect on dispersing unprotected troops as they ran from the areas of highest concentration. Because most of the early war gases were strongly irritating, their use always caused confusion and disorder among troop concentrations. The actual number of deaths due to chemical warfare agents during World War I was fairly small. This was probably due to technical problems of delivering the toxic chemical so as to produce consistently a lethal concentration exactly where the enemy troops were located. In addition, gas masks were quickly issued to troops of all belligerent nations. These gas masks offered sufficient protection to prevent death from exposures except in cases where wounded troops could not put on their masks as the toxic cloud approached.
After World War I, most nations agreed to never use toxic chemicals in warfare -- yet development of these agents continued. In its war with Ethiopia in 1938, Italy used both nerve gases and mustard gas. During World War II, the Germans developed Tabun and Sarin (Table 10-7), two nerve gases that are anticholinesterase poisons. Their discovery led to our present-day phosphate ester insecticides such as Parathion and Malathion. Throughout World War II, war gases were available but were never used.
Recently, in the 1980s, chemical agents were used in the Iran-Iraq war against both troops and civilians. Against civilians, chemical warfare agents are especially devastating because civilians are not only untrained and uninformed about the effects of these chemicals, but are unprepared to protect themselves. Modern concern regarding chemical warfare agents centers on protecting civilians, especially against terrorist attacks using weapons of this sort.
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Type Example Action History
_______________________________________________________________________________
Mustard gas Bis(2-chloroethyl)sulfide Strong blisters, strong WW I
(CICH2CH2)2S irritant
Choking gas Phosgene Cl2CO Lung damage WW I
Chlorine Cl2
Blood gas Hydrogen cyanide HCN Cell death WW I
Nerve gas Tabun (see text) Anticholinesterase poisons WW II
Sarin (see text) WW II
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Figure 10-9. "Cholinergic" nerves, which transmit impulses by means of acetylcholine, include nerves controlling both voluntary and involuntary activities. Exceptions are parts of the "sympathetic" nervous system that utilize norepinephrine instead of acetylcholine. Sites of acetylcholine secretion are circled in color, poisons that disrupt the acetylcholine cycle can interrupt the body's communications at any of these points. The role of acetylcholine in the brain is uncertain, as is indicated by the broken circles.
Figure 10-10. The acetylcholine cycle, a fundamental mechanism in nerve impulse transmission, is affected by many poisons. An impulse reaching a nerve ending in the normal cycle (a) liberates acetylcholine, which then stimulates a receptor. To enable the receptor to receive further impulses, the enzyme cholinesterase breaks down acetylcholine into acetic acid and choline; other enzymes resynthesize these into more acetylcholine. (b) Botulinus and dinoflagellate toxins inhibit the synthesis, or the release, of acetylcholine(1). The "anticholinesterase" poisons inactivate cholinesterase and therefore prevent the breakdown of acetylcholine(2). Curare and atropine desensitize the receptor to the chemical stimulus.(3).
Figure 10-11. Some anticholinesterase poisons. In animals, parathion is converted into paraoxon in the liver. Carbaryl and malathion do not bind to cholinesterase as strongly. Malathion was the insecticide used in California in July 1981 to eradicate Medflies.