Glycopyrrolate

GLYCOPYRROLATE- glycopyrrolate injection, solution
Cardinal Health

For Intramuscular or Intravenous Administration

Rx Only

NOT FOR USE IN NEONATES

CONTAINS BENZYL ALCOHOL

DESCRIPTION

Glycopyrrolate Injection, USP is a clear, colorless, sterile solution of Glycopyrrolate, USP with Benzyl Alcohol, NF in Water for Injection, USP. The formulation is used for intramuscular or intravenous administration.

Each mL contains:
Glycopyrrolate, USP…………………………..0.2 mg
Benzyl Alcohol, NF (preservative)………….….0.9%
Water for Injection, USP……………………………… q.s.

When necessary, pH (2.0 to 3.0) adjusted with hydrochloric acid and/or sodium hydroxide.

Glycopyrrolate is a quaternary ammonium salt with the following chemical name:

3[(cyclopentylhydroxyphenylacetyl)oxy]-1, 1-dimethyl pyrrolidinium bromide. Glycopyrrolate is a synthetic anticholinergic agent that has the following molecular structure and molecular weight.

4d517ecd-figure-01
(click image for full-size original)

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. The partition coefficient of glycopyrrolate in a n-octanol/water system is 0.304 (log10 P= -1.52) at ambient room temperature (24°C).

CLINICAL PHARMACOLOGY

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 nonpolar 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.

Distribution: The mean volume of distribution of glycopyrrolate was estimated to be 0.42 ± 0.22 L/kg.

Metabolism: The in vivo metabolism of glycopyrrolate in humans has not been studied.

Excretion: 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 intravenous administration. After intravenous 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 intramuscular administration of glycopyrrolate to adults, the mean T1/2 value is reported to be between 0.55 to 1.25 hrs. Over 80% of intramuscular dose administered was recovered in urine and the bile as unchanged drug and half the intramuscular dose is excreted within 3 hrs. The following table summarizes the mean and standard deviation of pharmacokinetic parameters from a study.

Group T 1/2
(hr)
VSS
(L/kg)
CL
(L/kg/hr)
T max
(min)
Cmax
(mcg/L)
AUC
(mcg/L•hr)
*0-8 hr

(6 mcg/kg intravenous)

0.83 ± 0.27

0.42 ± 0.22

0.54 ± 0.14

-

-

8.64 ± 1.49*

(8 mcg/kg intramuscular)

-

-

-

27.48 ± 6.12

3.47 ± 1.48

6.64 ± 2.33*

Special Populations

Gender: Gender differences in pharmacokinetics of glycopyrrolate have not been investigated.

Renal Impairment:In one study glycopyrrolate was administered intravenously 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-mcg/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-mcg/L, 1.14 L/hr/kg, and 50%, respectively). These results suggest that elimination of glycopyrrolate is severely impaired in patients with renal failure.

Hepatic Impairment:Pharmocokinetic information in patients with hepatic impairment is unavailable.

Pediatrics: Following intravenous administration (5mcg/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.

INDICATIONS AND USAGE

In Anesthesia: Glycopyrrolate injection 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 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.

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