Chemical formula: C₁₁H₁₆N₂O₂ Molecular mass: 208.257 g/mol PubChem compound: 5910
Pilocarpine is a cholinergic parasympathomimetic agent exerting a broad spectrum of pharmacologic effects with predominant muscarinic action. Pilocarpine, in appropriate dosage, can increase secretion by exocrine glands such as the sweat, salivary, lacrimal, gastric, pancreatic and intestinal glands and the mucous cells of the respiratory tract.
The precise mechanism by which pilocarpine reduces intra-ocular pressure has not been established, though it is believed to involve direct stimulation of the longitudinal muscle of the ciliary body, which in turn affects the scleral spur, widening the trabecular spaces and allowing for increased aqueous flow. Pilocarpine may also decrease aqueous formation with long term administration. Due to its activity at the muscarinic receptor sites of the ciliary muscles and iris sphincter, pilocarpine causes varying degrees of accommodation spasm and pupillary constriction.
Dose-related smooth muscle stimulation of the intestinal tract may cause increased tone, increased motility, spasm and tenesmus. Bronchial smooth muscle tone may increase. The tone and motility of urinary tract, gallbladder and biliary duct smooth muscle may be enhanced.
Pilocarpine may have paradoxical effects on the cardiovascular system. The expected effect of a muscarinic agonist is vasodepression, but administration of pilocarpine may produce hypertension after a brief episode of hypotension. Bradycardia and tachycardia have both been reported with use of pilocarpine.
There are literature reports of the ocular use of pilocarpine in concentrations up to 2% in patients aged 1 month and older. However, information on the dose and strength used is limited. Safety data do not suggest any significant safety issues in children, or any difference between the safety profiles of pilocarpine in children and adults.
In a multiple-dose pharmacokinetic study in volunteers given 5 or 10 mg of pilocarpine hydrochloride three times daily for two days, the Tmax after the final dose was approximately 1 hour, the elimination T½ was approximately 1 hour, and the mean Cmax were 15 ng/ml and 41 ng/ml for the 5 and 10 mg doses, respectively.
When taken with a high-fat meal, there was a decrease in the rate of absorption of pilocarpine from pilocarpine tablets. Mean Tmax were 1.47 and 0.87 hours and mean Cmax were 51.8 and 59.2 ng/ml for fed and fasted male volunteers, respectively.
Pilocarpine is extensively distributed with an apparent volume of distribution of 2.1 L/kg. Data from animal studies indicates that pilocarpine is distributed into breast milk at concentrations similar to plasma. Preclinical data also suggests that pilocarpine can cross the blood brain barrier at high dose. Pilocarpine does not bind to plasma proteins.
Pilocarpine is primarily metabolized by CYP2A6 and has demonstrated a capacity to inhibit CYP2A6 in vitro. Serum esterases are also involved in the biotransformation of pilocarpine to pilocarpic acid.
Approximately 35% of dose is eliminated as 3-hydroxypilocarpine in urine and 20% of dose is excreted unchanged in the urine. Mean elimination half-lives for pilocarpine is 0.76 and 1.35 hours after repeated oral doses of 5 and 10 mg of pilocarpine hydrochloride, respectively.
Pilocarpine AUC values in elderly male volunteers were comparable to those in younger males. In a small number of healthy elderly female volunteers the mean AUC was approximately twice that of elderly and young male volunteers due to reduced volumes of distribution. However, the observed difference in pharmacokinetics was not reflected in the incidence of adverse events between young and elderly female patients. No dosage adjustment is required in elderly subjects.
A pharmacokinetic study of pilocarpine in patients with mild and moderately impaired renal function showed that there was no significant difference in clearance and exposure compared with subjects with normal renal function.
Onset of miosis after topical administration of a 1% solution of pilocarpine hydrochloride or nitrate to the conjunctival sac occurs within 10-30 minutes, with maximal effect within 30 minutes. Miosis usually persists for 4-8 hours, rarely, up to 20 hours. Reduction of intra-ocular pressure is evident within 60 minutes, peaks within 75 minutes and, depending on the concentration of pilocarpine used, persists for 4-14 hours. Spasms of accommodation commence in about 15 minutes and persist for 2-3 hours.
Pilocarpine did not indicate a genotoxic potential in a series of in vitro and in vivo genotoxicity studies. In lifetime oral carcinogenicity studies in rodents Pilocarpine did not cause an increase in tumour incidence in mice, but was associated with an increased incidence in benign pheochromocytomas in rats at >15 times the exposure at the maximum recommended human dose and therefore not considered relevant to clinical use. Preclinical data revealed no special hazard for humans based on conventional studies of genotoxicity and carcinogenic potential.
Animal studies have shown adverse effects on the male reproductive tract following chronic exposures to pilocarpine. Impaired spermatogenesis was observed in rats and dogs following 28-day and 6-month oral exposures respectively. Histopathological changes were also observed in the testes and bulbourethral glands of mice given pilocarpine for 2 years.
The safety margin for the effects in humans is unknown. However, body surface area [mg/m²] comparisons suggest that the lowest dose associated with impaired fertility, (3 mg/kg/day in the dog), is approximately 3 times the maximum recommended human dose, therefore a risk to humans cannot be ruled out. A study in rats has also indicated a possible impairment of female fertility.
Studies in pregnant rats showed treatment-related reductions in the mean fetal body weight and increases in the incidence of skeletal variations [at approximately 26 times the maximum recommended dose for a 50 kg human (based on comparisons of body surface area [mg/m²]. These effects occurred at doses that were maternally toxic. There was no evidence of a teratogenic effect in the animal studies. Treatment related increases in the incidence of stillbirths with decreased neonatal survival and reduced mean body weight of pups were observed in pre- and postnatal studies. A safety margin for these effects cannot be calculated. However, body surface area [mg/m²] comparisons suggest that the effect occurred at approximately 5 times the maximum recommended dose for a 50 kg human. The clinical relevance of these findings is unknown.
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