Indirect cholinomimetic drugs

See also: direct cholinomimetic drugs

Indirect choline-mimetic drugs have a different mechanism of action, which involves the reversible (therapeutic effect) or irreversible (toxic effect) block of the enzyme responsible for the degradation of acetylcholine, so as to increase its concentration at the synaptic level; therefore we can define them as cholinergic receptor agonists.

To understand the mechanism of action of this class of drugs, it is first of all necessary to clarify the functioning of the enzyme Acetylcholineesterase: it has two sites, a negatively charged one with which the cationic portion of acetylcholine interacts, and an esterase site responsible for de -acetylation of acetylcholine. Indirect choline mimetics therefore have a cationic portion, which interacts with the anionic site of the enziama, and a functional group similar to the esterase site; depending on which functional group they present, the cholinesterase inhibitors are divided into:

simple alcohols equipped with a quaternary ammonium group that binds to the active site of the enzyme by weak bonds (ionic or hydrogen), such as edrophonium; the enzyme-inhibitor complex does not involve covalent bonds, therefore it resists for a short time;
esters of carbamic acid endowed with alcohols bearing quaternary ammonium groups or tertiary amine groups, such as neostigimin. The latter undergoes a hydrolysis similar to that of acetylcholine, although the covalent bond of the carbamylated enzyme is very resistant (up to 6 hours); it is however a reversible process;
organic derivatives of phosphoric acid (organ phosphates), initially bind to the enzyme and are hydrolyzed; the result is a phosphorylated enzyme at the active site. The phosphorus-enzyme bond is extremely stable and hydrolysis takes very long times (hundreds of hours); moreover, the phosphorylated enzyme can undergo the “aging” process, this implies the breaking of one of the two oxygen-phosphorus bonds of the inhibitor and a further strengthening of the phosphorus-enzyme bond. The aging rate varies according to the chemical nature of the phosphate organ, for example the nerve gases, constituents of the most dangerous chemical weapons, have an extremely reduced aging time. Strongly nucleophilic substances, such as pralidoxime, are able to split the phosphorus-enzyme bond, as long as they are administered before aging has taken place. Many organ phosphates are highly fat-soluble liquids, therefore well absorbed by the skin, lungs, gastrointestinal tract and conjunctiva; which makes them highly dangerous for humans, but just as effective as insecticides and pesticides. Due to the considerable duration of action, which degenerates into a toxic effect, organ phosphoric inhibitors are sometimes defined as irreversible cholinesterase inhibitors, while edrophonium and carbamates would fall into the category of reversible inhibitors. A phosphoric organ intoxication has central and peripheral effects: mental confusion, coma, increased secretions, diarrhea, vomiting, slowing of cardiac activity, broncho-constriction, initial vascular fasciculations and muscle paralysis; usually death occurs due to blockage of the respiratory muscles.

The main therapeutic uses of direct and indirect cholinergic agonists concern:

the therapy of glaucoma, where they reduce intraocular pressure through the contraction of the ciliary muscle, facilitating the outflow of aqueous humor;
intestinal and postoperative bladder atony, in this case the doctor must first make sure that there are no mechanical obstructions, because an increase in pressure in the tract preceding the obstruction could lead to perforation;
as antidotes in the case of atropine poisoning.

Cholinesterase inhibitors are also widely used in very serious diseases, such as myasthenia and Alzheimer's disease; in the latter case, they slow down the onset of dementia in the patient by increasing the concentration of acetylcholine in the brain areas responsible for cognitive functions. Myasthenia is a disease of the neuromuscular junctions of the skeletal muscles, in which an autoimmune process leads to the malfunction or destruction of nicotinic receptors; in other words, the muscles lose the ability to contract, therefore the administration of sieve-mimetics that indirectly increase the concentration of Ach is valid.
The most common side effects related to the use of colino-mimetic drugs are due to the excessive stimulation of muscarinic receptors, therefore they are characterized by: diarrhea, profuse sweating, miosis, nausea and urinary urgencies.