Question 3

Compare and contrast the pharmacology of intravenously administered atropine and glycopyrrolate

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College Answer

Most candidates exhibited a structural approach with reasonable understanding of
the pharmacology of atropine although there was a lack of precision (anticholinergic
is correct, competitive muscarinic antagonist is more precise). Some answers did not
contrast glycopyrrolate adequately. The phrase ‘hepatic metabolism, renal excretion’
needed to be accompanied with detail if marks were to be awarded.
Syllabus: G3b
Recommended sources: Goodman and Gillman, The Pharmacological Basis of
Therapeutics, Chp 7

Discussion

Name Atropine Glycopyrrolate
Class Anticholinergic Anticholinergic
Chemistry Tropane alkaloid Tropane alkaloid
Routes of administration Oral, IV, subcutaneous, inhaled, intraocular, and topical on the mucosa Oral, IV, IM, inhaled
Absorption Well absorbed - 90% bioavailability Poorly absorbed; oral bioavailability is only about 3.3%
Solubility pKa 9.7; the sulfate salt is reasonably water-soluble, 1g in 455ml of water pKa 11.53, good water solubility.
Distribution VOD=1-6L/kg; 50% protein bound VOD = 1.3-1.8 L/kg, 38-44% protein bound
Target receptor Both agents have similar affinities for muscarinic receptors (M1-M5), which are mainly Gq-coupled receptors. Glycopyrrolate does not have a chance to bind the M1 receptors because these are mainly found in the CNS.
Metabolism 50% metabolised, mainly by hepatic enzymatic hydrolysis, into a variety of metabolities, including tropane, tropic acid, and noratropine Minimal hepatic metabolism
Elimination 50% is eliminated unchanged About 85% is excreted unchange din the urine
Time course of action Half life is 2-5 hours, but the duration of tissue-specific efects could be longer, eg. mydriasis could last as long as 96 hours Half-life is 2-4 hours
Mechanism of action By compettively blocking the effets of acetylcholine on Gq-coupled muscrinic receptors, both agents decrease the intracellular concentration of ioniased calcium and cAMP. This results in numerous downstream clinical effects.
Clinical effects

- Decreased airway secretions
- Bronchodilation
- Tachycardia
- Urinary retention
- Decreased gastric acid secretion
- Decreased intestinal motility
- Constipation

CNS effects:

- Delirium, hallucinations
- Mydriasis

- Antiemetic effect

- Decreased airway secretions
- Bronchodilation
- Tachycardia
- Urinary retention
- Decreased gastric acid secretion
- Decreased intestinal motility
- Constipation


- No CNS effects!

Single best reference for further information Shutt, 1979 Chabicovsky et al, 2019

References

Chabicovsky, Monika, et al. "Pharmacology, toxicology and clinical safety of glycopyrrolate." Toxicology and Applied Pharmacology 370 (2019): 154-169.

Lounasmaa, Mauri, and Tarja Tamminen. "The tropane alkaloids." The alkaloids: chemistry and pharmacology 44 (1993): 1-114.

Kohnen-Johannsen, Kathrin Laura, and Oliver Kayser. "Tropane alkaloids: chemistry, pharmacology, biosynthesis and production." Molecules 24.4 (2019): 796.

Proakis, Anthony G., and Gladys B. Harris. "Comparative penetration of glycopyrrolate and atropine across the blood—brain and placental barriers in anesthetized dogs." The Journal of the American Society of Anesthesiologists. Vol. 48. No. 5. The American Society of Anesthesiologists, 1978.