GLYCOPYRROLATE — glycopyrrolate injection
Caplin Steriles Limited
Glycopyrrolate Injection, USP is a synthetic anticholinergic agent. Each 1 mL contains:
Glycopyrrolate, USP 0.2 mg
Water for Injection, USP q.s.
Benzyl Alcohol, NF 0.9% (preservative)
pH adjusted, when necessary, with hydrochloric acid and/or sodium hydroxide.
For Intramuscular (IM) or Intravenous (IV) administration.
Glycopyrrolate is a quaternary ammonium salt with the following chemical name: 3[(cyclopentylhydroxyphenylacetyl)oxy]-1,1-dimethyl pyrrolidinium bromide. The molecular formula is C19 H28 BrNO3 and the molecular weight is 398.33.Its structural formula is as follows:
Glycopyrrolate occurs as a white, odorless crystalline powder. It is soluble in water and alcohol, and practically insoluble in chloroform and ether.
Unlike atropine, glycopyrrolate is completely ionized at physiological pH values. Glycopyrrolate Injection, USP is a clear, colorless, sterile liquid; pH 2.0 – 3.0. The partition coefficient of glycopyrrolate in a n-octanol/water system is 0.304 (log10 P = -1.52) at ambient room temperature (24°C).
Glycopyrrolate, like other anticholinergic (antimuscarinic) agents, inhibits the action of acetylcholine on structures innervated by postganglionic cholinergic nerves and on smooth muscles that respond to acetylcholine but lack cholinergic innervation. These peripheral cholinergic receptors are present in the autonomic effector cells of smooth muscle, cardiac muscle, the sinoatrial node, the atrioventricular node, exocrine glands and, to a limited degree, in the autonomic ganglia. Thus, it diminishes the volume and free acidity of gastric secretions and controls excessive pharyngeal, tracheal, and bronchial secretions.
Glycopyrrolate antagonizes muscarinic symptoms (e.g., bronchorrhea, bronchospasm, bradycardia, and intestinal hypermotility) induced by cholinergic drugs such as the anticholinesterases.
The highly polar quaternary ammonium group of glycopyrrolate limits its passage across lipid membranes, such as the blood-brain barrier, in contrast to atropine sulfate and scopolamine hydrobromide, which are highly non-polar tertiary amines which penetrate lipid barriers easily.
With intravenous injection, the onset of action is generally evident within one minute. Following intramuscular administration, the onset of action is noted in 15 to 30 minutes, with peak effects occurring within approximately 30 to 45 minutes. The vagal blocking effects persist for 2 to 3 hours and the antisialagogue effects persist up to 7 hours, periods longer than for atropine.
Pharmacokinetics The following pharmacokinetic information and conclusions were obtained from published studies that used nonspecific assay methods.
The mean volume of distribution of glycopyrrolate was estimated to be 0.42 ± 0.22 L/kg.
The in vivo metabolism of glycopyrrolate in humans has not been studied.
The mean clearance and mean T1/2 values were reported to be 0.54 ± 0.14 L/kg/hr and 0.83 ± 0.13 hr, respectively post IV administration. After IV administration of a 0.2 mg radiolabeled glycopyrrolate, 85% of dose recovered was recovered in urine 48 hours postdose and some of the radioactivity was also recovered in bile. After IM administration of glycopyrrolate to adults, the mean T1/2 value is reported to be between 0.55 to 1.25 hrs. Over 80% of IM dose administered was recovered in urine and the bile as unchanged drug and half the IM dose is excreted within 3 hrs. The following table summarizes the mean and standard deviation of pharmacokinetic parameters from a study.
|Group||t1/2 (hr)||Vss (L/kg)||CL (L/kg/hr)||Tmax (min)||Cmax (µg/L)||AUC (µg/L•hr)|
|(6 µg/kg IV)||0.83±0.27||0.42±0.22||0.54±0.14||–||–||8.64±1.49*|
|(8 µg/kg IM)||–||–||–||27.48±6.12||3.47±1.48||6.64±2.33*|
Gender differences in pharmacokinetics of glycopyrrolate have not been investigated.
In one study glycopyrrolate was administered IV in uremic patients undergoing renal transplantation. The mean elimination half-life was significantly longer (46.8 minutes) than in healthy patients (18.6 minutes). The mean area‑under‑the‑concentration-time curve (10.6 hr‑μg/L), mean plasma clearance (0.43 L/hr/kg), and mean 3-hour urine excretion (0.7%) for glycopyrrolate were also significantly different than those of controls (3.73 hr-μg/L, 1.14 L/hr/kg, and 50%, respectively). These results suggest that the elimination of glycopyrrolate is severely impaired in patients with renal failure.
Pharmacokinetic information in patients with hepatic impairment is unavailable.
Pediatrics: Following IV administration (5 μg/kg glycopyrrolate) to infants and children, the mean T1/2 values were reported to be between 21.6 and 130.0 minutes and between 19.2 and 99.2 minutes, respectively.
Glycopyrrolate Injection, USP is indicated 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 anesthesia and intubation. When indicated, Glycopyrrolate Injection, USP may be used intraoperatively to counteract surgically or drug‑induced or vagal reflexes associated arrhythmias. Glycopyrrolate protects against the peripheral muscarinic effects (e.g., bradycardia and excessive secretions) of cholinergic agents such as neostigmine and pyridostigmine given to reverse the neuromuscular blockade due to non-depolarizing muscle relaxants.
In Peptic Ulcer
For use in adults as adjunctive therapy for the treatment of peptic ulcer when rapid anticholinergic effect is desired or when oral medication is not tolerated.
Known hypersensitivity to glycopyrrolate or any of its inactive ingredients.
In addition, in the management of peptic ulcer patients, because of the longer duration of therapy, glycopyrrolate injection may be contraindicated in patients with the following concurrent conditions: glaucoma; obstructive uropathy (for example, bladder neck obstruction due to prostatic hypertrophy); obstructive disease of the gastrointestinal tract (as in achalasia, pyloroduodenal stenosis, etc.); paralytic ileus, intestinal atony of the elderly or debilitated patient; unstable cardiovascular status in acute hemorrhage; severe ulcerative colitis; toxic megacolon complicating ulcerative colitis; myasthenia gravis.
This drug should be used with great caution, if at all, in patients with glaucoma.
Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications containing this preservative must take into account the total amount of benzyl alcohol administered. The amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources (see PRECAUTIONS, Pediatric Use).
Glycopyrrolate injection may produce drowsiness or blurred vision. The patient should be cautioned regarding activities requiring mental alertness such as operating a motor vehicle or other machinery or performing hazardous work while taking this drug.
In addition, in the presence of fever, high environmental temperature and/or during physical exercise, heat prostration can occur with use of anticholinergic agents including glycopyrrolate (due to decreased sweating), particularly in children and the elderly.
Diarrhea may be an early symptom of incomplete intestinal obstruction, especially in patients with ileostomy or colostomy. In this instance treatment with glycopyrrolate injection would be inappropriate and possibly harmful.
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