Glycopyrrolate

Description

Glycopyrrolate is an antagonist of muscarinic acetylcholine receptors (mAChRs; K_is = 0.42, 1.77, 0.52, 0.78, and 1.29 nM for the M₁-M₅ receptors, respectively). It induces relaxation of precontracted isolated human bronchi when used at concentrations of 0.01, 0.1, or 1 μM. Glycopyrrolate reduces post-prandial gastric antral motility in dogs when administered at a dose of 0.01 mg/kg. It inhibits salivation in a rat model of sialorrhea induced by pilocarpine with an ED₅₀ value of 0.74 μg/kg. Formulations containing glycopyrrolate have been used in the treatment of sialorrhea, peptic ulcers, and chronic obstructive pulmonary disease (COPD).

Chemical properties

White Solid

Originator

Robinul,Robins,US,1961

The Uses of Glycopyrrolate

Inhaled glycopyrrolate treats air flow blockage and prevents the worsening chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. COPD is a long-term lung disease that causes bronchospasm (difficulty with breathing). It is a synthetic, quaternary ammonium anticholinergic. Antispasmodic; preanesthetic medicant. For use as a preoperative antimuscarinic to reduce salivary, tracheobronchial, and pharyngeal secretions, to reduce the volume and free acidity of gastric secretions and to block cardiac vagal inhibitory reflexes during induction of anaesthesia and intubation. Glycopyrrolate inhibits the secretion of digestive juices and restores normal stomach function. It is used for treating stomach ulcers and inflamed intestines and as a pre-operational drug for inhibiting excess stomach secretion.

Definition

ChEBI: A quaternary ammonium salt composed of 3-{[cyclopentyl(hydroxy)phenylacetyl]oxy}-1,1-dimethylpyrrolidin-1-ium and bromide ions in a 1:1 ratio.

Manufacturing Process

A mixture of 42.5 grams (0.17 mol) of methyl α-cyclopentyl mandelate and 18 grams (0.175 mol) of 1-methyl-3-pyrrolidinol in 500 ml of heptane was refluxed under a Dean and Stark moisture trap, with the addition of four 0.1 gram pieces of sodium at 1-hour intervals. After 5 hours' refluxing the solution was concentrated to one-half volume, and extracted with cold 3N HCl. The acid extract was made alkaline with aqueous sodium hydroxide and extracted with ether which was washed, dried over sodium sulfate, filtered and concentrated. The residue was fractionated at reduced pressure. Yield 33 grams (64%); BP 151° to 154°C/0.2 mm, nD23= 1.5265.
The hydrochloride salt was precipitated as an oil from an ethereal solution of the base with ethereal hydrogen chloride. It was crystallized from butanone; MP 170° to 171.5°C.
The methyl bromide quaternary was prepared by saturating a solution of the base in dry ethyl acetate with methyl bromide. After standing for 9 days the resulting crystalline solid was filtered and recrystallized from butanone and from ethyl acetate; MP 193° to 194.5°C.

brand name

Robinul (Baxter Healthcare); Robinul (Sciele).

Therapeutic Function

Spasmolytic

General Description

Glycopyrrolate, 3-hydroxy-1,1-dimethylpyrrolidinium bromide -cyclopentyl mandelate (Robinul), occurs as a white, crystalline powder that is soluble in water or alcohol but is practically insoluble in chloroform or ether.
Glycopyrrolate is a typical anticholinergic and possesses, at adequate dosage levels, the atropine-like effects characteristic of this class of drugs. It has a spasmolytic effect on the musculature of the GI tract as well as the genitourinary tract. It diminishes gastric and pancreatic secretions and the quantity of perspiration and saliva. Its side effects are also typically atropine-like (i.e., dryness of the mouth, urinary retention, blurred vision, constipation). Glycopyrrolate is a more potent antagonist on M1 than on M2 and M3 receptors. The low affinity of M2 receptors may partly explain the low incidence of tachycardia during the use of this drug as an antispasmodic. Because of its quaternary ammonium character, glycopyrrolate rarely causes CNS disturbances, although, in sufficiently high dosage, it can bring about ganglionic and myoneural junction block.

Biochem/physiol Actions

Glycopyrrolate is long-acting muscarinic antagonist (LAMA). It is kinetically selective muscarinic M3 receptor antagonist.

Mechanism of action

Glycopyrrolate exhibits onset of action within 1 minute when given intravenously and an elimination half-life of approximately 50 minutes. Glycopyrrolate undergoes urinary excretion and elimination.

Clinical Use

Glycopyrrolate is used as an adjunct in the management of pepticulcer and other GI ailments associated with hyperacidity,hypermotility, and spasm. In common with other anticholinergics,its use does not preclude dietary restrictions or use ofantacids and sedatives if these are indicated.

Side Effects

• dry mouth
• blurred vision
• vision problems
• loss of taste
• headache
• nervousness
• confusion
• drowsiness

Safety Profile

Poison by intravenous and intraperitoneal routes. Moderately toxic by ingestion and subcutaneous routes. Experimental reproductive effects. When heated to decomposition it emits very toxic fumes of NOx and Br-. See also BROMIDES.

Synthesis

Glycopyrrolate, 3-[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl-pyrrolidinium bromide, is synthesized from the methyl ester of α-cyclopentylmandelic acid by transesterification using 3-hydroxy-1-methylpyrrolidine as an alcohol component, which forms the ester, which is further transformed into a quaternary salt upon reaction with methylbromide, giving glycopyrrolate. The starting methyl ester of α-cyclopentyl mandelic acid is synthesized by reacting cyclopentyl magnesium bromide with the methyl ester of phenyl glyoxylic acid.

Veterinary Drugs and Treatments

Glycopyrrolate injection is approved for use in dogs and cats. The FDA approved indication for these species is as a preanesthetic anticholinergic agent. The drug is also used to treat sinus bradycardia, sinoatrial arrest, and incomplete AV block, where anticholinergic therapy may be beneficial. When cholinergic agents such as neostigmine or pyridostigmine are used to reverse neuromuscular blockade due to non-depolarizing muscle relaxants, glycopyrrolate may be administered simultaneously to prevent the peripheral muscarinic effects of the cholinergic agent.