Glycopyrronium tosylate

Uses

Maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD).

Glycopyrronium tosylate is also used to associated treatment for these conditions: Airway Obstruction, Chronic Obstructive Pulmonary Disease (COPD), Increased upper airway secretion, Peptic Ulcer, Primary Axillary Hyperhidrosis, Sialorrhea (Excessive Drooling), Cardiac vagal inhibitory reflexes, Cardiac vagal inhibitory reflexes caused by General Surgery, Cardiac vagal inhibitory reflexes caused by Medication, Gastric secretions, Peripheral muscarinic effects

How Glycopyrronium tosylate works

Glycopyrronium tosylate is a muscarinic antagonist with the highest affinity for M1 receptors, followed by M3, M2/M4, and M5.

Muscarinic receptors M1 to M4 are found in the lung, although M3 is predominantly responsible for bronchoconstriction and airway secretions. Secretions from salivary and sweat glands, as well as gastric acid secretions, are also predominantly mediated by the M3 receptor. Salivary and gastric acid secretions are also partially mediated by the M1 receptor. Antagonism of these receptors decreases the volume of their respective secretions, and in the case of the gastrointestinal system, reduces the acidity of the stomach.

In the cardiovascular system, muscarinic receptors M1 to M5 are all present, however the function of M5 has not been described in literature. Under normal circumstances, stimulation of the vagal nerve lowers the heart rate, potentially leading to intraoperative bradycardia. Studies in mice suggest that this stimulation is predominantly mediated by the M3 receptor, and mutant knockout mice are not susceptible to these effects.

Dosage

Glycopyrronium tosylate dosage

The recommended dosage of Glycopyrronium tosylate is the inhalation of the contents of one capsule once daily with the ConviHaler device at the same time of day.

Side Effects

Inhaled medicines may cause inhalation-induced bronchospasm, dehydration, dry mouth, constipation, dizziness, insomnia, skin and subcutaneous tissue disorders, immune system disorders.

Toxicity

Patients presenting with an overdose typically present with flushing, hyperthermia, tachycardia, ileus, urinary retention, loss of ocular accommodation, light sensitivity, mydriasis, nausea, vomiting, dizziness, light headedness, and obstipation. Patients should be treated with symptomatic and supportive therapy, which may include the use of catheters for urinary retention, cardiovascular support, airway maintenance, ventilation, or neostigmine.

The oral LD₅₀ in mice is 570 mg/kg, and in rats is 709 mg/kg. The intraperitoneal LD₅₀ in mice is 90 mg/kg, and in rats is 196 mg/kg.

Precaution

Glycopyrronium tosylate, as a once-daily maintenance bronchodilator, should not be used for the initial treatment of acute episodes of bronchospasm, i.e. rescue therapy. Immediate hypersensitivity reactions may occur after administration of Glycopyrronium tosylate inhalation powder. As with other anticholinergic drugs, Glycopyrronium tosylate should be used with caution in patients with narrow-angle glaucoma, prostatic hyperplasia or bladder-neck obstruction.

Interaction

Although no formal drug interaction studies have been performed, Glycopyrronium tosylate inhalation powder has been used concomitantly with other drugs, commonly used in the treatment of COPD, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids without clinical evidence of drug interactions.

Food Interaction

• Take with or without food. The absorption is unaffected by food.

Volume of Distribution

The mean volume of distribution in patients aged 1-14 years old is 1.3-1.8 L/kg, with a range of 0.7-3.9 L/kg. The volume of distribution in adults aged 60-75 years is 0.42 ± 0.22 L/kg.

Elimination Route

In adults, a 66 mg topical dose of glycopyrronium reaches a C_max of 0.08 ± 0.04 ng/mL, with a T_max of 1 hour, and an AUC_0-24 of 0.88 ± 0.57 h*ng/mL.

Inhaled glycopyrronium is approximately 40% bioavailable. A 25 µg inhaled solution reaches a C_max of 34.5 pg/mL, with a T_max of 0-inf of 255 h*pg/mL.

An 8 µg/kg intramuscular dose reaches a C_max of 3.47 ± 1.48 µg/L, with a T_max of 27.48 ± 6.12 minutes, and an AUC of 6.64 ± 2.33 h*g/L.

Oral glycopyrronium has highly variable pharmacokinetics, reaching a mean C_max of 0.318 ng/mL, a T_max of 3.1 hours, and an AUC_0-24 of 1.74 h*ng/mL.

Half Life

The half life after inhalation is approximately 33-53 hours. The mean half life of a 6 µg/kg intravenous dose is 0.83 ± 0.27 hours. The mean half life of oral glycopyrronium is 3.0 hours.

Clearance

A 6 µg/kg intravenous dose has a clearance of 0.54 ± 0.14 L/kg/h. An oral solution has a clearance of 5.28-38.95 L/h/kg in healthy adults and 8.07-25.65 L/h/kg in patients with cerebral palsy.

Elimination Route

85% of an intravenous dose was recovered in the urine, with 12 >80% of the recovered dose is the unchanged parent drug. The remainder is recovered as the inactive M9 metabolite.

Pregnancy & Breastfeeding use

There is a limited amount of data from the use of Glycopyrronium tosylate in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity at clinically relevant doses. Glycopyrronium tosylate should not be used in pregnant or nursing women unless the expected benefit outweighs any possible risk to the unborn child or the infant.

Contraindication

Hypersensitivity to the active substance or to any of the excipients.

Acute Overdose

High doses of Glycopyrronium tosylate may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 150 micrograms Glycopyrronium tosylate in healthy volunteers.

Storage Condition

Should be stored at temperature not exceeding 25ºC but do not freeze. Should be stored in cool and dry place, protected from light.

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