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caffeine (NoDoz, Vivarin)

Tradenames: NoDoz, Vivarin. Indications: 1) drowsiness, fatigue - associated with lower crash risk in commercial drivers [19] 2) treatment of apnea in infants 3) obesity, weight loss ? [7,9] 4) neuroprotection in women ? [6] 5) may diminish risk of non melanoma skin cancer [9] 6) may reduce risk of diabetes mellitus type 2 [15,16] 7) may reduce risk of stroke in women [17] 8) may reduce risk of depression in women [14] 9) nasal congestion, sinusitis [20] 10) urinary incontinence [20] 11) higher caffeine intake associated with reduced cardiovascular risk [25] - 200-300 mg of caffeine/day may confer 40% reduced cardiometabolic risk [32] 12) diminished risk of Parkinson's disease (PD) [26,29] - caffeine intake does not alter this risk after a diagnosis of PD is made - caffeine &/or coffee does not provide a symptomatic benefit for tremor or motor symptoms of PD [26] Dosage: - 100-200 mg PO every 3-4 hours PRN - maximum: 400 mg/day [12] - < 500 mg/day considered to be safe [18] - lethal dose: >= 3 grams within a few hours [18] Tabs: 100 & 200 mg. Pharmacokinetics: 1) metabolized in liver to paraxanthine 2) caffeine is a minor metabolite of theophylline 3) metabolized by cyt P450 1A2 [3] 4) maternal metabolism reduced during early pregnancy, clearance is prolonged [8] 5) fetal metabolism is low [8] 6) high-dose 800 mg in 6 hours increases renal calcium clearance 77% [30] Drug interactions: 1) any drug which inhibits cyt P450 1A2 can increase caffeine levels a) barbiturates c) phenytoin 2) any drug which induces cyt P450 1A2 can diminish caffeine levels a) cimetidine b) erythromycin Laboratory: 1) specimen: serum, plasma (heparin, EDTA) 2) methods: HPLC, GLC, color, RIA, EIA Adverse effects: - hypertension in adults, adolescents [5] - moderate use does not increase risk of miscarriage [10] - high caffeine intake in combination with high stress may be associated with auditory hallucinations [13] - no association between caffeine intake & cardiovascular events [23] - no association with arrhythmia (500 mg over 5 hours) in patients with heart failure, even during exercise [24] - caffeine (>=200 mg/day) during pregnancy associated with overweight offspring up to 5 years of age [27] - genetic variant in CYP1A2 resulting in slow metabolism of caffeine increases risk of albuminuria, hyperfiltration, & hypertension in heavy coffee consumers (> 3 cups/day) [31] - toxic effects of caffeine occur with intake > 1.2 grams/day - 10-14 grams is considered fatal [33] Mechanism of action: - blocks adenosine A-2A receptors - relaxes smooth muscle of bronchial airways & pulmonary blood vessels - in mice, inhibits PP-2A dephosphorylation of threonine 75 on DARPP-32 - may have neuroprotective properties in women [6] - may have anti-tumor properties [7] - enhances alertness [19] - activates arousal [19] - suppresses the urge to sleep [19] - may enhance memory consolidation [21] Notes: - energy drinks may contain significant amounts of caffeine [12] - FDA recommends avoiding powdered pure caffeine being marketed directly to consumers [23]

Interactions

drug interactions drug adverse effects (more general classes)

Related

coffee

General

analeptic (CNS stimulant) methylxanthine smooth muscle relaxant

Properties

MISC-INFO: elimination route LIVER 1/2life 3.5 HOURS therapeutic-range 3-15 UG/ML toxic-range >50 UG/ML protein-binding 35% pregnancy-category C safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Clinical Guide to Laboratory Tests, 3rd ed. Teitz ed., W.B. Saunders, 1995
  3. Prescriber's Letter 13(3): 2006 Cytochrome P450 drug interactions Detail-Document#: 220233 (subscription needed) http://www.prescribersletter.com
  4. Lindskog et al. Nature 418:774-8, 2002
  5. Journal Watch 24(11):88, 2004 Savoca MR, Evans CD, Wilson ME, Harshfield GA, Ludwig DA. The association of caffeinated beverages with blood pressure in adolescents. Arch Pediatr Adolesc Med. 2004 May;158(5):473-7. PMID: 15123481
  6. Ritchie K, Carriere I, de Mendonca A, Portet F, Dartigues JF, Rouaud O, Barberger-Gateau P, Ancelin ML. The neuroprotective effects of caffeine: a prospective population study (the Three City Study). Neurology. 2007 Aug 7;69(6):536-45. PMID: 17679672
  7. Lu YP, Nolan B, Lou YR, Peng QY, Wagner GC, Conney AH. Voluntary exercise together with oral caffeine markedly stimulates UVB light-induced apoptosis and decreases tissue fat in SKH-1 mice. Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12936-41. Epub 2007 Jul 30. PMID: 17664435
  8. Prescriber's Letter 15(3): 2008 Caffeine and the Risk of Miscarriage Detail-Document#: 240309 (subscription needed) http://www.prescribersletter.com
  9. Heffernan TP et al. ATR-Chk1 pathway inhibition promotes apoptosis after UV treatment in primary human keratinocytes: Potential basis for the UV protective effects of caffeine. J Invest Dermatol 2009 Feb 26 PMID: 19242509 http://dx.doi.org/10.1038/jid.2008.435
  10. Committee Opinion No. 462: Moderate Caffeine Consumption During Pregnancy Obstetrics & Gynecology, 2010 116:467-468 PMID: 20664420 http://journals.lww.com/greenjournal/Citation/2010/08000/Committee_Opinion_No__462__Moderate_Caffeine.42.aspx
  11. Mayo Clinic Staff Caffeine content for coffee, tea, soda and more Mayo clinic Health Information http://www.mayoclinic.com/health/caffeine/AN01211
  12. Prescriber's Letter 18(1): 2011 Energy Drinks Detail-Document#: 270107 (subscription needed) http://www.prescribersletter.com
  13. Crowe SF et al The effect of caffeine and stress on auditory hallucinations in a non-clinical sample. Pers Individ Dif 2011 Apr; 50:626 Not indexed in PubMed http://www.sciencedirect.com/science/article/pii/S019188691000591X - Journal Watch Psychiatry July 11, 2011 Massachusetts Medical Society (Subscription required) http://psychiatry.jwatch.org/cgi/content/full/2011/711/1?q=pfw-featured
  14. Lucas M et al Coffee, Caffeine, and Risk of Depression Among Women Arch Intern Med. 2011;171(17):1571-1578. PMID: 21949167 http://archinte.ama-assn.org/cgi/content/abstract/171/17/1571 - Berkowitz SA Coffee Consumption and Depression Risk Arch Intern Med. 2011;171(17):1578 PMID: 21949168 http://archinte.ama-assn.org/cgi/content/extract/171/17/1578
  15. Salazar-Martinez E et al Ann Intern Med 140:1, 2004 PMID: 14706966
  16. van Dam RM, Hu FB. Coffee consumption and risk of type 2 diabetes: a systematic review. JAMA. 2005 Jul 6;294(1):97-104. Review. PMID: 15998896
  17. Larsson SC et al. Coffee consumption and risk of stroke in women. Stroke 2011 Mar 10 PMID: 21393590 http://stroke.ahajournals.org/cgi/content/abstract/STROKEAHA.110.603787v
  18. Journal Watch: Massachusetts Medical Society http://www.jwatch.org Sepkowitz KA Energy Drinks and Caffeine-Related Adverse Effects JAMA. 2012, Dec 19 PMID: 23330171 http://jama.jamanetwork.com/article.aspx?articleid=1487123
  19. Journal Watch. April 10, 2013 Massachusetts Medical Society http://www.jwatch.org - Sharwood LN et al. Use of caffeinated substances and risk of crashes in long distance drivers of commercial vehicles: Case-control study. BMJ 2013 Mar 19; 346:f1140. PMID: 23511947
  20. Deprecated Reference
  21. Borota D et al Post-study caffeine administration enhances memory consolidation in humans. Nature Neuroscience. Jan 12, 2014 PMID: 24413697 http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.3623.html
  22. FDA Safety Alert. July 20, 2014 FDA Consumer Advice on Powdered Pure Caffeine. http://www.fda.gov/Food/RecallsOutbreaksEmergencies/SafetyAlertsAdvisories/ucm405787.htm
  23. Hand L Moderate Tea Drinking Tea May Slow CAC Progression, Cut CV Event Risk: MESA. Medscape. Sep 23, 2016 http://www.medscape.com/viewarticle/869038
  24. Zuchinali P et al. Short-term effects of high-dose caffeine on cardiac arrhythmias in patients with heart failure: A randomized clinical trial. JAMA Intern Med 2016 Oct 17; [e-pub] PMID: 27749954 http://jamanetwork.com/journals/jamainternalmedicine/article-abstract/2569283
  25. Miller PE, Zhao D, Frazier-Wood AC et al. Associations of coffee, tea, and caffeine intake with coronary artery calcification and cardiovascular events. Am J Med 2017 Feb; 130:188 PMID: 27640739 http://www.amjmed.com/article/S0002-9343(16)30925-1/abstract
  26. Postuma RB, Anang J, Pelletier A et al. Caffeine as symptomatic treatment for Parkinson disease (Cafe-PD): A randomized trial. Neurology 2017 Sep 27 PMID: 28954882
  27. Papadopoulou E, Botton J, Brantsaeter AL. Maternal caffeine intake during pregnancy and childhood growth and overweight: results from a large Norwegian prospective observational cohort study. BMJ Open, Volume 8, Issue 3. April 2018 http://bmjopen.bmj.com/content/8/3/e018895
  28. Rothaus C Coffee, Caffeine, and Health NEJM Resident 360. July 22, 2020 https://resident360.nejm.org/clinical-pearls/coffee-caffeine-and-health
  29. George J Does Caffeine Protect Against Parkinson's? - Benefit seen even for people with Parkinson's genetic risk MedPage Today September 30, 2020 https://www.medpagetoday.com/neurology/parkinsonsdisease/88893 - Crotty GF, Maciuca R, Macklin EA et al Association of caffeine and related analytes with resistance to Parkinson's disease among LRRK2 mutation carriers: A metabolomic study. Neurology 2020. Sept 30. PMID: 32999056 https://n.neurology.org/content/early/2020/09/30/WNL.0000000000010863
  30. Reuter SE, Schultz HB, Ward MB et al The effect of high-dose, short-term caffeine intake on the renal clearance of calcium, sodium and creatinine in healthy adults. Br J Clin Pharmacol 2021. April 14 PMID: 33852164 https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bcp.14856
  31. Mahdavi S, Palatini P, El-Sohem A. CYP1A2 Genetic Variation, Coffee Intake, and Kidney Dysfunction JAMA Netw Open. 2023;6(1):e2247868 PMID: 36701157 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2800839
  32. Lu X, Zhu X, Li G, Wu L, Shao L, Fan Y, Pan CW, Wu Y, Borne Y, Ke C. Habitual Coffee, Tea, and Caffeine Consumption, Circulating Metabolites, and the Risk of Cardiometabolic Multimorbidity. J Clin Endocrinol Metab. 2024 Sep 17:dgae552. PMID: 39287934
  33. Spriano P Ready for a Jolt? Caffeine Brings Benefits and Risks Medscape. Oct 11, 2024 https://www.medscape.com/viewarticle/ready-jolt-caffeine-brings-benefits-and-risks-2024a1000ilx

Component-of

acetaminophen/aspirin/caffeine (Excedrin Extra, Excedrin migraine) acetaminophen/aspirin/caffeine/codeine/salicylamide acetaminophen/aspirin/caffeine/salicylamide acetaminophen/butalbital/caffeine (Fioricet, Esgic) acetaminophen/butalbital/caffeine/codeine (Fioricet with Codeine) acetaminophen/caffeine acetaminophen/caffeine/chlorpheniramine acetaminophen/caffeine/chlorpheniramine/guaifenesin acetaminophen/caffeine/chlorpheniramine/guaifenesin/n methylephedrine acetaminophen/caffeine/chlorpheniramine/hydrocodone/phenylephrine acetaminophen/caffeine/chlorpheniramine/phenylephrine acetaminophen/caffeine/citrate acetaminophen/caffeine/citrate/phenyltoloxamine/salicylamide acetaminophen/caffeine/citrate/salicylamide acetaminophen/caffeine/dihydrocodeine acetaminophen/caffeine/guaifenesin/phenylephrine acetaminophen/caffeine/isometheptene acetaminophen/caffeine/magnesium salicylate acetaminophen/caffeine/magnesium salicylate/phenyltoloxamine acetaminophen/caffeine/phenyltoloxamine acetaminophen/caffeine/phenyltoloxamine/salicylamide acetaminophen/caffeine/pyrilamine acetaminophen/caffeine/salicylate aspirin/butalbital/caffeine (Fiorinal) aspirin/butalbital/caffeine/codeine (Fiorinal with Codeine) aspirin/caffeine aspirin/caffeine/citrate/orphenadrine aspirin/caffeine/dihydrocodeine aspirin/caffeine/orphenadrine (Norgesic) aspirin/caffeine/propoxyphene (Darvon Compound) aspirin/caffeine/salicylamide belladonna alkaloid/caffeine/ergotamine/pentobarbital belladonna alkaloid/caffeine/ergotamine/phenobarbital benzoate/caffeine caffeine/choline salicylate caffeine/cobalamin/ibuprofen/pyridoxine/riboflavin/thiamine caffeine/codeine/pheniramine/phenylephrine/salicylate caffeine/ergotamine (Cafergot, Ercaf, Wigraine) caffeine/ergotamine/pentobarbital (Cafergot PB) caffeine/magnesium salicylate caffeine/pheniramine/phenylephrine/salicylate caffeine/salicylate Camellia sinensis (green & black tea) coffee guarana sodium benzoate/caffeine