Colino-mimetic drugs

The choline-mimetic drugs act on the functioning of the cholinergic system by mimicking the action of acetylcholine (Ach). These medicines are divided into:

direct colino-mimetics, which interact with the same Ach receptors
indirect strainer mimetics, which prevent Ach degradation by increasing its concentration at the synaptic level.

In both cases the cholinergic signal is enhanced.

The indirect choline-mimetic drugs or anti-cholinesterases have the task of inhibiting the acetylcholinesterase enzyme, responsible for the degradation of the same neurotransmitter; they can bind to the enzyme in a reversible way (therapeutic-temporary effect) or irreversibly (toxic-permanent effect).
Acetylcholine, in addition to being the main neurotransmitter of the afferent and above all efferent nervous pathways of the parasympathetic system, is also localized at the level of the brain and the cerebral cortex, specialized in cognitive and learning functions: the death of cholinergic neurons at the level of the CNS is the cause of a neurodegenerative disease with a fatal outcome, not pharmacologically curable, known as Alzheimer's disease.

Direct choline-mimetic drugs are classified pharmacologically on the basis of the way they act and their spectrum of action, which depends on the type of cholinergic receptor - muscarinic or nicotinic - with which they interact.

The nicotinic receptor it is a channel (ionotropic) receptor permeable to sodium ions; so called because the nicotine alkaloid is the molecule closest to this type of receptor.

the muscle-type nicotinic receptor, which induces the contraction of skeletal muscles;
the nicotinic receptor of the neuronal ganglionic type (also located in the adrenal medulla), responsible for post-ganglionic depolarization, consequently for the continuation of impulse transmission to the effector organ.

The muscarinic receptor it is a receptor with seven trans-membrane domains, linked to the G protein (metabotropic receptor), which regulate the second messengers (adenin-mono-phosphate-cyclic, inositol-tri-phosphate and di-acyl-glycerol); this type of receptor is so called because the muscarine alkaloid is the molecule closest to it.

Among the muscarinic receptors there are three categories, structurally similar, but different for the amino acid sequence and for the localization;

the M1 receptors are mainly located at the nervous level (ganglia, cerebral cortex, hippocampus, parietal cells of the gastric mucosa), with an excitatory action due to an increase in AMPc, IP3 and DAG;
M2 receptors are mainly located in the heart, where, as we have seen, they induce a reduction in heart rate due to the inhibition of adenylate cyclase;
the M3 receptors are also of the excitatory type and are located in the exocrine glands (salivary, lacrimal, bronchial ...) and in smooth muscles.

Ach acts indifferently on each of these receptors, but the synthetic compounds with pharmacological action can be formulated so as to have a selective action.

Direct cholinergic agonists

Among the direct cholinergic agonists we find:

Acetylcholine: endogenous neurotransmitter, which cannot be administered as a drug because it would be hydrolyzed too quickly without having any effect. Therefore, slower acting ester derivatives have been synthesized in the laboratory, such as: la methacholine, little susceptible to cholinesterases and active on muscarinic receptors; the carbachol not susceptible to cholinesterases and active on both cholinergic receptors; the bethanechol not susceptible to cholinesterases and active on muscarinic receptors.

Pilocarpine: natural alkaloid contained in the leaves of a tree belonging to the Rutaceae family, widespread in South America. In the past the drug (dried leaves) was used as a diuretic / diaphoretic, since pilocarpine causes: contraction of the smooth muscles of the bladder, relaxation of sphincters and increase in exocrine secretions. Pilocarpine is used: for external use to prevent hair loss; for internal use for the treatment of glaucoma, an eye disease caused by an increase in aqueous humor, which exerts greater pressure on the cornea increases intraocular pressure. High intraocular pressure values for a long time can cause damage to the retina, the optic nerve and, in the case of chronic pathology, it can even lead to blindness. Pharmacological therapy consists in the reduction of aqueous humor by inhibition of secretion or by removal from the anterior chamber of the eye by contraction of the ciliary muscle. Pilocarpine, like all colino-mimetics, favors the outflow of aqueous humor, reducing endo-ocular pressure, because it causes the contraction of the ciliary muscle. It is administered through the eye, in the slow-release form "ocusert".
The dried leaves are marketed for infusions or decoctions with an antirheumatic action, an adjuvant to gastro-intestinal transit and as an antidote for poisoning by belladonna berries (rich in atropine, blocker of cholinergic receptors).

Muscarina: see dedicated article

Nicotine: see dedicated article.