Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Parasympathominetic, ATC code: N07A X01.
Mechanism of action
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.
Pharmacodynamic effects
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.
Clinical efficacy and safety
In a study in healthy male volunteers an increase in salivary flow following single 5 and 10 mg doses of Salagen was noted 20 minutes after administration, and lasted for 3 to 5 hours with a peak at 1 hour.
• For head and neck cancer patients: In two 12-week randomised, double-blind placebo-controlled clinical studies in patients with xerostomia resulting from irradiation to the head and neck for cancer, Salagen treatment reduced dryness of the mouth; in one of these studies this did not occur until after 12 weeks of treatment. Also, Salagen treatment increased salivary flow. The greatest improvement in dryness was noted in patients with no measurable salivary flow at baseline.
In both studies, some patients noted improvement in the overall condition of xerostomia, speaking without drinking liquids, and mouth comfort, and there was reduced use of concomitant therapy (i.e.
artificial saliva) for dry mouth.
• For Sjögren's syndrome patients: Two separate 12-week randomised, double-blind placebo-controlled clinical studies were conducted in patients diagnosed with primary or secondary Sjögren's syndrome. In both studies, the majority of patients best fit the European criteria for having primary Sjögren's syndrome. The ability of Salagen to stimulate saliva production was assessed. Relative to placebo, an increase in the amount of saliva being produced was observed following the first dose and was maintained throughout the duration of the trials in an approximate dose response fashion.
Compared to placebo a statistically significant global improvement for both dry mouth and dry eyes was observed.
Efficacy of Salagen has not been established in patients with the Sjögren's syndrome during long term treatment (>12 weeks).

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
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 Salagen 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.
Distribution
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.
Metabolism
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.
Elimination
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.
Elderly
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.
Renal impairment
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.