Pilocarpine

Origin and systemic effects

Historically, this alkaloid was extracted from the leaves of the South American shrub Pilocarpus pinnatifolius Jaborandi. In modern medical practice, a synthetic analogue is used.

Chemically, pilocarpine is a tertiary amine, which is a non-polar lipophilic compound. The main feature of this structure is that the drug easily crosses the blood-brain barrier (BBB). Upon entering the CNS, it triggers generalized excitation of the parasympathetic system, up to convulsive seizures. In experimental pharmacology, this property is even used to model epilepsy in animals. It is precisely due to its high toxicity that systemic use of the drug is severely limited.

The only indication for oral administration is the treatment of xerostomia (severe dry mouth) resulting from head and neck radiation therapy or Sjögren's syndrome. For this purpose, Salagen is used in low doses (5–10 mg), as pilocarpine powerfully stimulates the secretion of salivary, lacrimal, and sweat glands.

Effects on the eye and vision

The main field of application for pilocarpine is ophthalmology, where it is used topically (into the conjunctival sac) to avoid the resorptive effect in the systemic circulation. The drug stimulates M-cholinergic receptors of two smooth muscles of the eye:

1. Sphincter muscle of the iris (m. sphincter pupillae). Its contraction, regulated by parasympathetic fibers of the oculomotor nerve (n. oculomotorius), leads to pupil constriction — miosis.
2. Ciliary muscle. Its contraction causes relaxation of the zonule of Zinn. As a result, the lens assumes a more convex shape, and its refractive power increases.

The change in the shape of the lens leads to accommodation spasm: the eye adjusts to the near point of vision (artificial myopia develops). The patient sees distant objects blurredly and may also encounter macropsia, a condition where objects appear enlarged.

Mechanism of intraocular pressure reduction

Intraocular pressure (IOP) is normally 16–26 mm Hg and depends on the balance between fluid production by the ciliary body and its outflow. Aqueous humor drains through the drainage system of the anterior chamber angle: the trabecular meshwork, Schlemm's canal, collector channels, and scleral veins. Pilocarpine is prescribed for glaucoma, a condition with periodic or constant elevation of IOP. The mechanism of action depends on the form of the pathology:

• Angle-closure glaucoma (acute attack, pressure up to 60–80 mm Hg). Pilocarpine is the drug of choice. By causing miosis, it thins the root of the iris and pulls it away from the anterior chamber angle. The mechanical block is relieved, access to the spaces of Fontana and Schlemm's canal is opened, which dramatically improves fluid outflow.
• Open-angle glaucoma. Contraction of the ciliary muscle tensions the trabeculae of the pectinate ligament. This leads to mechanical expansion of the spaces of Fontana and facilitates the filtration of aqueous humor, despite the initially open access to the angle.

Dosage forms and complications

To control the duration of the therapeutic effect, pilocarpine is available in various forms. Aqueous solutions (1–2%) last for 4–8 hours, while solutions with polymers have a prolonged effect of up to 8–12 hours. Eye ointments and polymer inserts placed in the lower conjunctival sac 1–2 times a day are also used. The drug is often combined with other antiglaucoma agents: epinephrine (Pilaren inserts) or the beta-blocker timolol (Fotil drops).

Long-term therapy can cause serious morphological changes:

• Fibrosis of intraocular muscles;
• Irreversible (persistent) miosis;
• Increased capillary permeability with a risk of edema and hemorrhages.

To prevent these complications, it is necessary to take a break from treatment once a year for a few months, temporarily replacing pilocarpine with timolol.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Anatomy of the aqueous humor outflow pathways (trabecular meshwork, Schlemm's canal)
• Differences in the pathogenesis of angle-closure and open-angle glaucoma
• Comparison of the effects of M-cholinomimetics and M-cholinergic blockers on the eye
• Combined drugs for the treatment of glaucoma (Fotil, Pilaren)
• The role of the radial and circular muscles in regulating pupil diameter

Other topics in the section «Drugs acting on cholinergic synapses»

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