Indications
Pilocarpine is a therapeutic agent with specific indications based on its formulation. Oral tablets of pilocarpine are primarily indicated for the treatment of xerostomia (dry mouth) associated with Sjogren's Syndrome or following radiotherapy for head and neck cancer. In ophthalmic formulations, pilocarpine is utilized to alleviate presbyopia in adults, lower elevated intraocular pressure (IOP) in individuals with open-angle glaucoma or ocular hypertension, manage acute angle-closure glaucoma, prevent postoperative IOP increases related to laser surgery, and induce miosis.
Pharmacodynamics
Pilocarpine functions as a muscarinic receptor agonist, impacting several physiological systems. Its pharmacodynamic profile includes diaphoretic, miotic, and central nervous system effects. It stimulates exocrine gland secretion, notably increasing salivary, sweat, lacrimal, and gastrointestinal secretions. Orally administered pilocarpine significantly enhances salivary flow rates, showing an increase of two to ten times compared to placebo, with peak effects lasting for one to two hours. Additionally, pilocarpine enhances smooth muscle tone, contracts pupillary and iris sphincter muscles, and induces pupil constriction. By affecting all five muscarinic receptor subtypes, pilocarpine may result in parasympathetic-related side effects.
Absorption
The absorption of pilocarpine varies based on its administration route. When administered orally, pilocarpine reaches peak plasma concentrations of 15 μg/L within 1.25 hours at a dose of 5 mg taken three times daily. A higher dose of 10 mg administered thrice daily results in peak plasma levels of 41 μg/L within 0.85 hours, with accelerated absorption when consumed with food. In ophthalmic administration to healthy subjects, the median time to maximum concentration (Tmax) is approximately 2.2 hours, with mean peak concentrations (Cmax) and area under the curve (AUC) values of 897.2 pg/mL and 2699 hr x pg/mL, respectively. In presbyopic patients, the mean Cmax and AUC0-t,ss are 1.95 ng/mL and 4.14 ng x hr/mL, with a median Tmax of 0.3 hours post-dose, ranging from 0.2 to 0.5 hours.
Metabolism
The metabolic pathway of pilocarpine in humans is not extensively characterized. It is known that pilocarpine can be inactivated at neuronal synapses and potentially in the plasma. Pilocarpine is metabolized via CYP2A6-mediated 3-hydroxylation, resulting in stereoisomers of 3-hydroxypilocarpine. Additionally, hydrolysis catalyzed by paraoxonase 1, a calcium-dependent esterase present in plasma and the liver, is another metabolic route. Pilocarpic acid may emerge as a metabolic product from this hydrolysis. The pharmacological activity of pilocarpine's metabolites is reported to be negligible or nonexistent.
Mechanism of Action
Pilocarpine functions primarily through its interaction with the muscarinic M3 receptor, which is prominently expressed in various endocrine and exocrine glands, such as the gastric and salivary glands. It is also found in smooth muscle tissues, including the pupillary sphincter and ciliary bodies. The M3 receptor, a Gq-protein-coupled receptor, facilitates the activation of phospholipase C, leading to an increase in inositol trisphosphate and intracellular calcium levels. Activation of these pathways is crucial for inducing smooth muscle contraction and stimulating the salivary glands. Notably, pilocarpine acts as an agonist for both the M1 and M2 receptors and serves as a full or partial agonist at the M3 receptor, thereby enhancing its efficacy in these physiological processes.
