Podcast 1007: Caffeine Pharmacology

Contributor: Travis Barlock, MD Educational Pearls:   Caffeine Geography and Types: Caffeine is found throughout the world and has evolved independently in various plants that are not evolutionarily related through direct lineage, but rather demonstrate convergent evolution (i.e. different species evolve the same traits).  These plants use caffeine as an insecticide.  Examples of caffeine sources include coffee, tea, yerba-mate, guaraná, cacao, and yaupon holly. Roughly 85% of Americans are estimated to consume caffeine daily.   Caffeine Pharmacology in Humans:  In humans, caffeine is a nonselective competitive antagonist (blocker) of adenosine receptors (A1 and A2A).  During waking hours, neuronal metabolic activity consumes ATP, and a byproduct of ATP hydrolysis is created: adenosine.  Adenosine proceeds to build a "sleep pressure".  Acting on A1 and A2A adenosine receptors to induce sleep (on A1, it suppresses neuronal "wakefulness" and on A2A it is believed to be an inducer of sleep).  Caffeine, by blocking those receptors, blunts sleep induction and feelings of being tired.  Caffeine has a half-life of around 6 hours, and a quarter life of approximately 12 hours, which is when the caffeine will off-load and adenosine can once again occupy those receptors, potentially causing a "crash".  Thus, for shift-workers, it is important to time caffeine intake roughly 10 hours before target bed time.  Caffeine exerts other effects on the body.  It is methylxanthine similar to theophylline, which works as a bronchodilator (via phosphodiesterase and adenosine pathways). Caffeine has clinical use to promote bronchodilation in pre-term infants.  Caffeine exerts diuretic effects as well (blocking proximal renal tubule reabsorption).  Recent ingestion of caffeine may blunt therapeutic use of adenosine in patients with SVT.  Key Takeaway? Caffeine exerts a wide variety of effects beyond making us feel more awake. It has cardiovascular, pulmonary, and renal implications in its pharmacodynamics.   References    Benarroch EE. Adenosine and its receptors: multiple modulatory functions and potential therapeutic targets for neurologic disease. Neurology. 2008;70(3):231-236. doi:10.1212/01.wnl.0000297939.18236.ec Mitchell DC, Knight CA, Hockenberry J, Teplansky R, Hartman TJ. Beverage caffeine intakes in the U.S. Food Chem Toxicol. 2014;63:136-142. doi:10.1016/j.fct.2013.10.042 Bruschettini M, Brattström P, Russo C, Onland W, Davis PG, Soll R. Caffeine dosing regimens in preterm infants with or at risk for apnea of prematurity - Bruschettini, M - 2023 | Cochrane Library. Accessed May 23, 2026. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD013873.pub2/full?cookiesEnabled Huang R, O'Donnell AJ, Barboline JJ, Barkman TJ. Convergent evolution of caffeine in plants by co-option of exapted ancestral enzymes. Proc Natl Acad Sci U S A. 2016;113(38):10613-10618. doi:10.1073/pnas.1602575113 Cabalag MS, Taylor DM, Knott