Drug Receptors N. S.

Drug Action

Drugs of C.N.S
 Elmhurst College
Nervous System Cholinergic Drugs II Adrenergic Drugs II  Chemistry Department
Cholinergic Drugs I Adrenergic Drugs I Adrenergic Drugs III  Virtual ChemBook

Cholinergic Drugs II

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).

Link to Chime Tutorial of Acetylcholinesterase


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 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.

Botox is currently an approved treatment to remove facial wrinkles, but must be repeated every several months.