Cholinergic Drugs

Cholinergic Stimulating Agents:

Acetylcholine is the chemical transmitter for nerves of the parasympathetic, somatic, preganglionic sympathetic, and parts of the central nervous system. Acetylcholine is synthesized by the transfer of an acetyl group from acetyl CoA to choline, a normal constituent of the diet.

Acetylcholine is concentrated in large amounts in presynaptic vesicles, which release their contents into the synapse when voltage-gated calcium channels open in response to membrane depolarization.

Upon interaction with the receptor, acetylcholine produces an influx of sodium through a ligand-gated ion channel which sends the impulse.

After acetylcholine interacts with the cholinergic receptor it is very rapidly hydrolyzed by the enzyme acetylcholinesterase. The hydrolysis reaction is the reverse of the synthesis reaction except that choline and acetic acid are products. The choline is retaken up by the nerve ending where it is reused for synthesis of new molecules of acetylcholine.

Acetylcholine acts on two vastly different classes of receptors - nicotinic receptors (with two subtypes, one at the neuromuscular junction of skeletal muscle, the other within ganglia and the CNS), and muscarinic receptors (widely distributed within both peripheral and central nervous systems). Muscarinic receptors originally were distinguished from nicotinic receptors by the selectivity of the agonists muscarine and nicotine respectively. Notice the similarities in structure for all three of these compounds.

Although there appears to be at least two cholinergic receptor sites, they are similar enough to be considered as one. The acetylcholine interacts with the receptor site through ionic attraction of the positive nitrogen, polar attraction of the ester group, and through hydrophobic interactions with the methyl groups. 

Stimulation:

Stimulation of cholinergic nerves is achieved either directly or indirectly. Direct acting agents (agonists) activate the receptor site by mimicking the effects of acetylcholine. Cholinesterase inhibitors act indirectly by preventing the enzyme from hydrolyzing (inactivating) acetylcholine at the receptor site. This inhibition permits the buildup of acetylcholine and results in more intensive and prolonged activation of the receptor site. The effects of cholinergic stimulation include: vasodilation of blood vessels; slower heart rate; constriction of bronchioles and increased secretion of mucus in the respiratory tract; intestinal cramps; secretion of salvia; sweat and tears; and constriction of eye pupils.

Direct Acting Cholinergic Agents - Agonists:

Direct acting cholinergic agents act as agonists and initiate stimulant type responses at the receptor site. Direct stimulation of acetylcholine receptors is achieved by: Arecholine, Pilocarpine, Urecholine(Betanechol), Carbachol, Choline, Metacholine, Mushrooms (Boletus sp., Clitocybe sp. , Inocybe sp.)

Drugs: Urecholine and philocarpine are direct acting drugs. Urecholine is used to restore parasympathetic tone to smooth muscles of the intestinal tract and bladder following abdominal surgery. Pilocarpine is used to constrict pupils and reduce pressure caused by glaucoma. Pilocarpine contracts the ciliary muscle with causes the iris to be withdrawn. This action permits drainage of the aqueous humor and thus relieves the pressure due to a glaucoma condition.

Cholinergic Poison agents which mimic the structure of acetylcholine include two poisons: muscarine - an alkaloid present in poisonous mushrooms and nicotine from cigarettes. Muscarinic effects are those of parasympathetic overactivity and include bradycardia, pinpoint pupils, sweating, blurred vision, excessive lacrimation, excessive bronchial secretions, wheezing, dyspnoea, coughing, vomiting, abdominal cramping, diarrhea, and urinary and fecal incontinence.

Nicotine: Nicotinic effects are those of sympathetic overactivity and neuromuscular dysfunction and include tachycardia, hypertension, dilated pupils, muscle fasciculation and muscle weakness.

Accidental ingestion of these poisons may produce death from heart failure unless treated with a suitable antidote. Atropine blocks the receptor site to decrease the stimulant effects produced by the muscarine type poisons, but has no effect on nicotine receptors. 

Cholinergic Drugs II

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Indirect Acting Cholinergic Stimulating Agents:

Acetylcholine Esterase Inhibitors:

Indirect stimulation of cholinergic nerves occurs by inhibiting the cholinesterase enzyme, thus permitting a build up of acetylcholine on the nerve receptor sites. As a result, acetylcholine increases in quantity with successive nerve impulses so that large amounts of acetylcholine can accumulate and repetitively stimulate receptors.

The active site in the enzyme probably has similar characteristics to the nerve receptor sites. However, the two sites are sufficiently different since chemicals which inhibit the enzyme do not effect the nerve receptor site. The active center of acetylcholinesterase consists of a negative subsite, which attracts the quaternary group of choline through both coulombic and hydrophobic forces, and an esteratic subsite, where nucleophilic attack occurs on the acyl carbon of the substrate.

A few drugs are of therapeutic use: neostigmine, physostigmine, and diisopropyl fluorophosphate, all inactivate acetylcholinesterase. These drugs have only a few clinical uses, mainly in augmenting gastric and intestinal contractions (in treatment of obstructions of the digestive tract), in generally augmenting muscular contractions (in the treatment of myasthenia gravis), and in constricting the eye pupils (in the treatment of glaucoma).

Acetylcholine Stimulation:

Cholinesterase inhibitors act indirectly by preventing the enzyme from hydrolyzing (inactivating) acetylcholine at the receptor site. This inhibition permits the buildup of acetylcholine and results in more intensive and prolonged activation of the receptor site. The effects of cholinergic stimulation include: vasodilattion of blood vessels; slower heart rate; constriction of bronchioles and reduced secretion of mucus in the respiratory tract; intestinal cramps; secretion of salvia; sweat and tears; and constriction of eye pupils.

Acetylcholine Inhibitors - Toxic Poisons

The main agents in this class are poisons such as organophosphate insecticides and nerve gases. 

Organophosphorus pesticides and Carbamate pesticides 

Organophosphorus warfare nerve agents: Sarin, Soman, Tabun

Organophosphates:

Organophosphates account for about half (by amount sold) of

all insecticides used in the U.S. In addition to major crops such as cotton, corn, and wheat, they are used on many important minor crops. Some also are used for mosquito control to protect public health against diseases such as malaria, dengue fever, and encephalitis. These insecticides are developed to be highly toxic to the target species, while being much less toxic to non-target species, such as domestic animals and humans.

These compounds, as irreversible cholinesterase inhibitors, are effective in very low concentrations and are capable of causing death within minutes of exposure. The toxicity of organophosphates and carbamates in humans is characterized by a variety of symptoms, including tension, anxiety, headaches, slurred speech, tremor, convulsions, and even death. If death occurs, it is caused by asphyxia resulting from respiratory failure.

The structural similarities to acetylcholine should be examined in the graphic on the left. Well known organophosphates include, malathion and parathion. A carbamate, carbaryl - Sevin, is also shown.

Although organophosphates are relatively toxic to both insects and man, they do not persist in the environment since the phosphate ester is relatively easily hydrolyzed by water. 

Organophosphorus Warfare Nerve Agents:

On March 20, 1995 sarin nerve gas was released in the Tokyo subway system, killing eleven and injuring over 5500 innocent Japanese citizens. Fortunately, the authorities responded quickly and treatment was administered effectively or else many more may have died. This incident was a follow up to the release of sarin in Matsumoto, Japan that killed seven and injured another 200 people.

A organophosphate such as Sarin interacts with cholinesterase, thus preventing it from doing what it is suppose to: breaking down acetylcholine. Now, since acetylcholine is being built up, the receptors nerves get fired off repeatedly thereby causing the muscles, organs and, glands to be overstimulated. If death occurs, it is caused by asphyxia resulting from respiratory failure.

Other nerve gases are Tabun, Soman, and VX. VX is the most toxic and long lasting of the nerve gases.

The molecule pralidoxime (lower graphic) is a useful antidote for intoxication with cholinesterase inhibitors such as the organophosphates. Pralidoxime, has been shown to regenerate functional AChE from the phosphorylated form, thereby reversing the effects of the organophosphates. The pralidoxime oxygen attacks the phosphorous atom of the nerve agent, freeing it from the AChE active site. The molecule removes the inhibitor from the active site in the form of an oxime phosphonate. Atropine (next panel down graphic) also is used to block responses due to excess acetylcholine. In addition, valium often is given as an antidote in conjunction with atropine to counteract seizures which may develop due to elevated levels of acetylcholine.

In moderate-to-severe cases of cholinergic syndrome due to organophosphorus pesticide or warfare agent poisoning, an acetylcholinesterase reactivator should be administered (if available) following atropine. Either pralidoxime or obidoxime are suitable.

The most effective treatment for sarin poisoning is a combination of atropine and oxime given intravenously as soon after exposure as is possible 

Cholinergic Blocking Agents - Antagonists:

Cholinergic blocking agents are compounds which prevent acetylcholine from stimulating the receptor site and thus act as antagonists. These compounds compete with acetylcholine for receptor sites. They do not themselves produce an excitant effect but rather limit the excitant effects of acetylcholine.

The cholinergic nerve depressant effects are as follows: secretions from exocrine glands such as salvia, sweat, and gastric acid in the stomach are decreased; tone and movements of smooth muscles in the gastrointestinal tract and respiratory bronchioles are reduced at high doses; death may result from respiratory failure; pupils are dilated; and paralysis of eye muscles changes the shape of the lens. Since acetylcholine is a neurotransmitter in the central nervous system, it is not surprising that behavioral changes may occur. Although normal doses of atropine produce no behavioral effects, toxic doses produce euphoria and delirium.

Scopolamine, a compound closely resembling atropine, produces drowsiness and amnesia. This drug is used in non-prescription sleeping pills such as Compoz and Sominex. Toxic doses have the same effect as atropine.

Therapeutic use of atropine and related compounds produce the afore mentioned pharmocological effects. It is used as a preoperative medication to prevent salivary and bronchial secretions stimulated by general anesthetics. It is used in gastrointestinal disorders for antisecretory effects in ulcers and antispasmodic effects in diarrhea. Atropine may also be used prior to eye examinations.

Atropine can be used as an antidote for organophosphate poisoning caused by inhibition of cholinesterase. The atropine serves as an effective blocking agent for the excess acetylcholine but does nothing to reverse the inhibition of the cholinesterase.

There are several ways in which to treat patients who have been exposed to organophosphates. One way is to inhibit the action of acetylcholine. This inhibition is accomplished by administering a cholinergic antagonist. These antagonists bind to the post-synaptic acetylcholine receptors, thereby preventing the opening of ion channels. These ion channels, when opened, cause the post-synaptic cells to become depolarized, generating action potentials. The most common antagonist used to treat organophosphorus exposure is atropine. Atropine is naturally found in the deadly nightshade plant, and it is ordinarily a potent neurotoxin. However, when administered in response to organophosphate exposure, it prevents the acetylcholine that has built up in the neuromuscular junction from binding to its receptor. This inhibition effectively suppresses the excess acetylcholine.

Botulinum toxin resulting from bacteria in improperly preserved foods acts by preventing release of stored acetylcholine from all cholinergic nerve endings. Nerve impulses are prevented from reaching the muscles causing respiratory paralysis and death.

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