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Caffeine
Caffeine
2D structure of caffeine
Caffeine based on CIF
3D structure of caffeine
Names
Synonyms Guaranine
Brand names Cafnea, Cafcit, No Doz and others

IUPAC name
IUPAC name
1,3,7-trimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione
Clinical information
Preg. cat.
AU: A
US: C
Legal status
AU: Unscheduled
CA: OTC
UK: GSL
US: OTC
Routes Oral and various others


Identifiers
ATC code N06BC01
ChemSpider 2424
DrugBank DB00201
PubChem 2519
MedlinePlus 002445
MeSH ID D002110
External links
DailyMed Caffeine search
Drugs.com international, monograph
Jmol
Licensing data US FDA: link.
MSR monograph
emc Caffeine search
TGA-eBS Caffeine search
Chemical properties
Formula C8H10N4O2
SMILES
SMILES
CN1C=NC2=C1C(=O)N(C)C(=O)N2C
InChI
InChI
1S/C8H10N4O2/c1-10-4-9-6-5(10)7(13)12(3)8(14)11(6)2/h4H,1-3H3
InChIKey
InChIKey
RYYVLZVUVIJVGH-UHFFFAOYSA-N


Caffeine is probably the single most popularly used stimulant or for that matter recreational drug in our society, it is a xanthine alkaloid that exerts its effects via two mechanisms – firstly, it blocks the adenosine receptors (A1-A3) and inhibits the phosphodiesterase family of enzymes (PDE1-11). The adenosine receptors are inhibitory metabotropic receptors that regulate neurotransmitter release (including dopamine,[1] acetylcholine, noradrenaline and glutamate), indirectly potentiate the CB1 receptor[2] and regulate the activity of dopamine receptors in the CNS.[3][4] It also acts on the adrenal medulla to increase the release of the fight or flight hormones noradrenaline and adrenaline.[3] Its action at the PDE family of enzymes is likely responsible for its modulatory effects on the immune system.[3] It can be found in a number of different natural sources, including the coffee bean (Coffea), tea plant (Camellia sinensis), cocoa tree (Theobroma cacao), guarana (Paullinia cupana), etc. It is produced by these plants as a defence against herbivorous insects as caffeine is a powerful insecticide. As you probably know it is usually administered orally (that is, ingested in beverages or capsules/tablets).[1][3][5][6]



Short-term effectsEdit

It is primarily used to treat fatigue, although it is also used medically to treat apnoea (lack of oxygen) in premature infants, orthostatic hypotension (drops in blood pressure that occur upon standing up), migraine (as an adjuvant), psoriasis and asthma in children/adults and as an adjuvant (i.e., a drug taken alongside others, never by itself when used for this purpose) for the management of acute pain. It has also been used to promote weight loss in the obese, due to its appetite-suppressing and body energy utilization-promoting effects. It also, similarly to other stimulants, improves various aspects of cognition and athletic performance.[4][5][7]

Adverse effects of its use include:

  • Sweating, polyuria (urinating excessively) – tolerance to these effects does build up rather quickly over time.
  • Headache
  • Insomnia
  • High heart rate
  • Hypertension
  • Anxiety
  • Irritability
  • Restlessness
  • Seizures (usually only with high doses/in epileptics)

Many of these effects are subject to tolerance over time. When caffeine is abruptly stopped a withdrawal syndrome appears that includes: fatigue, sedation and, with higher doses, nausea and headaches. It is generally not considered addictive per say, as addiction, as I previously mentioned, usually implies additional features of drug craving and seeking. Although, of course, as with all scientific views there are some that disagree. The DSM-5 classifies caffeine as without abuse potential, whereas the ICD-10 classifies caffeine as a drug of abuse.[8]

Long-term effectsEdit

Long-term use of caffeine has been associated with a reduced risk of Parkinson’s disease, Alzheimer’s disease, cardiovascular disease (heart attacks, strokes, etc.), cancer, depression, anxiety disorders and even type II diabetes mellitus.[9][10][11] Why, it may even slow down age-related cognitive decline.[12]

Special populationsEdit

PregnancyEdit

There has been significant debate over whether or not caffeine consumption during pregnancy is associated with poorer pregnancy outcomes, such as low birth weight, miscarriage, or even birth defects. The evidence for this notion is contradictory at best. So the general consensus of opinion is that women that are trying to become pregnant or are already pregnant should avoid caffeine where practical and/or possible.[13]

LactationEdit

Caffeine is secreted in breast milk, hence there is some potential for adverse effects in the infant (the most notable ones would probably be them being grumpy or unable to settle) and hence it is advisable to avoid caffeine whilst breastfeeding.[14][15]

ChildhoodEdit

Caffeine consumption during childhood may cause some lasting changes on brain functions, although nothing negative has been able to stick from clinical research. In fact, there is some evidence that caffeine exposure during childhood might prevent future seizures. The evidence, however, does not support the view that caffeine causes growth stunting in children. The major concern when it comes to children is that caffeine has the ability to enhance the rewarding effects of other substances, such as sugary foods or other drugs of abuse. That and the fact it is often found in less healthy of beverages such as soft drinks. Another important factor to consider is that children do not have the same body weight as adults, consequently, a low dose to an adult, may be an overdose for a child. If you want to know a rough guide as to what is safe for a kid, here’s one: take a dose of caffeine, in mg, that you would consider fair for yourself (if you are an adult), then divide it by 75 kg (the average adult weight, additional weight you might have due to obesity/being overweight should not count unless your weight is really high) and multiply by your child’s body weight in kg.[16][17]

Diabetes mellitusEdit

The evidence is not quite complete enough for one to make any real conclusion regarding the safety of caffeine in this population. There is one clinical trial that showed impaired glucose control and impaired insulin sensitivity and hence there is reason for caution to be exercised.[18]

Cardiovascular diseaseEdit

As with diabetes mellitus, the evidence is not complete enough for one to make any real conclusion regarding the safety of caffeine in this population. Those with cardiac arrhythmias (irregular heart rate) can safely consume caffeine in moderation, however, as can those with atrial fibrillation (AF), as consumption in moderation may even possess a protective effect against AF.[19][20] Those with hypertension are advised to avoid caffeine as it can raise one’s blood pressure in a dose-dependent manner.[21][22]

EpilepsyEdit

While caffeine exposure during childhood might produce lasting changes in brain function that prevent seizures, in people with established epilepsy it may invoke seizures and it may reverse some of the protective effects of anti-seizure medicines against epilepsy.[23]

CancerEdit

Caffeine is likely to interact with various anti-cancer agents, potentially reducing their efficacy or increasing their side effects.[24]

PropertiesEdit

Caffeine is, in its most pure form, a white or almost white crystalline powder, that degrades upon contact with air and is sparingly soluble in cool water and freely soluble in boiling water. It can be absorbed via the skin, digestive tract, injection sites or even rectally as a suppository. Its half-life is in the range 3-7 hours for adults and children over the age of 9 months, whereas in neonates the half-life is about 3-4 days. This half-life in adults is unaffected by old age (which is unusual for a drug) or obesity. It is primarily excreted in the urine (in the form of metabolites), but also in saliva and breast milk. It is metabolised by the enzyme CYP1A2, hence those with increased CYP1A2 activity (such as smokers) may eliminate caffeine more rapidly and hence experience less of an effect. Metabolites include (with the % of caffeine digested that is metabolised into these compounds): theobromine (12%), paraxanthine (84%) and theophylline (4%).[3] Theobromine is better known for its toxic properties in dogs as many people know if you feed a dog chocolate it can make them really sick or even kill them and this is due the presence of theobromine in the chocolate. Theophylline is used medically in the short-term management of asthma (as it widens the airways) and emphysema, due to its prominent PDE inhibitory activity. It is seldom used in these indications nowadays, however, due to its problematic side effects (mostly digestive in nature and can include diarrhoea, nausea, vomiting, etc.). Paraxanthine is less biologically active than the other metabolites.[6]

Caffeine content of selected beveragesEdit

Note: These values are all taken from an American source hence may not accurately depict Australian values, except for the Mother value as Mother is solely marketed in Australia and New Zealand.

Beverage Caffeine Content (mg) per 8 oz (237 mL)[6]
Coffee – decaffeinated 3-12 (mean: 5)
Coffee – instant 27-173 (mean: 93)
Coffee – plain, brewed 102-200 (mean: 133)
Coffee – expresso 240-720 (mean: 320)
Tea – plain, brewed 40-120 (mean: 53)
Tea – green 30-50 (mean: 45)
Tea – black 25-110 (mean: 47)
Tea – yerba mate 65-130 (mean: 78)
Coca-Cola 23
Pepsi-Cola 25
Sunkist 28
Diet Coke 31
Mountain Dew 37
Amp 72
Full Throttle 72
Red Bull 76
Monster 80
Rockstar 80
Mother 76
Water Joe 28
Cranergy 70

External linksEdit


Reference listEdit

  1. 1.0 1.1 Cauli, O; Morelli, M (March 2005). "Caffeine and the dopaminergic system.". Behavioural Pharmacology 16 (2): 63–77. PMID 15767841.
  2. Rossi, S; De Chiara, V; Musella, A; Mataluni, G; Sacchetti, L; Siracusano, A; Bernardi, G; Usiello, A et al. (April 2010). "Effects of caffeine on striatal neurotransmission: focus on cannabinoid CB1 receptors.". Molecular Nutrition & Food Research 54 (4): 525–31. doi:10.1002/mnfr.200900237. PMID 20087854.
  3. 3.0 3.1 3.2 3.3 3.4 Ferré, S (2010). "Role of the central ascending neurotransmitter systems in the psychostimulant effects of caffeine.". Journal of Alzheimer's Disease. 20 Suppl 1: S35–49. doi:10.3233/JAD-2010-1400. PMID 20182056.
  4. 4.0 4.1 Ribeiro, JA; Sebastião, AM (2010). "Caffeine and adenosine.". Journal of Alzheimer's Disease. 20 Suppl 1: S3–15. doi:10.3233/JAD-2010-1379. PMID 20164566.
  5. 5.0 5.1 Einöther, SJ; Giesbrecht, T (January 2013). "Caffeine as an attention enhancer: reviewing existing assumptions.". Psychopharmacology 225 (2): 251–74. doi:10.1007/s00213-012-2917-4. PMID 23241646.
  6. 6.0 6.1 6.2 Glade, MJ (October 2010). "Caffeine-Not just a stimulant.". Nutrition 26 (10): 932–8. doi:10.1016/j.nut.2010.08.004. PMID 20888549.
  7. Snel, J; Lorist, MM (2011). "Effects of caffeine on sleep and cognition." (PDF). Progress in Brain Research 190: 105–17. doi:10.1016/B978-0-444-53817-8.00006-2. PMID 21531247.
  8. Meredith, SE; Juliano, LM; Hughes, JR; Griffiths, RR (September 2013). "Caffeine Use Disorder: A Comprehensive Review and Research Agenda.". Journal of Caffeine Research 3 (3): 114–130. doi:10.1089/jcr.2013.0016. PMID 24761279.
  9. Arendash, GW; Cao, C (2010). "Caffeine and coffee as therapeutics against Alzheimer's disease.". Journal of Alzheimer's Disease. 20 Suppl 1: S117–26. doi:10.3233/JAD-2010-091249. PMID 20182037.
  10. Ding, M; Bhupathiraju, SN; Chen, M; van Dam, RM; Hu, FB (February 2014). "Caffeinated and decaffeinated coffee consumption and risk of type 2 diabetes: a systematic review and a dose-response meta-analysis.". Diabetes Care 37 (2): 569–86. doi:10.3233/JAD-2010-1378. PMID 24459154.
  11. van Dam, RM (December 2008). "Coffee consumption and risk of type 2 diabetes, cardiovascular diseases, and cancer.". Applied Physiology, Nutrition, and Metabolism 33 (6): 1269–83. doi:10.1139/H08-120. PMID 19088789.
  12. Arab, L; Khan, F; Lam, H (January 2013). "Epidemiologic evidence of a relationship between tea, coffee, or caffeine consumption and cognitive decline.". Advances in Nutrition 4 (1): 115–22. doi:10.3945/an.112.002717. PMC 3648732. PMID 23319129.
  13. American College of Obstetricians and Gynecologists (August 2010). "ACOG Committee Opinion No. 462: Moderate caffeine consumption during pregnancy.". Obstetrics and Gynecology 116 (2 Pt 1): 467–8. doi:10.1097/AOG.0b013e3181eeb2a1. PMID 20664420.
  14. Liston, J (August 1998). "Breastfeeding and the use of recreational drugs--alcohol, caffeine, nicotine and marijuana.". Breastfeeding Review 6 (2): 27–30. PMID 9849117.
  15. Stavchansky, S; Combs, A; Sagraves, R; Delgado, M; Joshi, A (May-June 1988). "Pharmacokinetics of caffeine in breast milk and plasma after single oral administration of caffeine to lactating mothers.". Biopharmaceutics & Drug Disposition 9 (3): 285–99. doi:10.1002/bod.2510090307. PMID 3395670.
  16. Tchekalarova, JD; Kubová, H; Mareš, P (May 2014). "Early caffeine exposure: Transient and long-term consequences on brain excitability.". Brain Research Bulletin 104C: 27–35. doi:10.1016/j.brainresbull.2014.04.001. PMID 24727007.
  17. Temple, JL (June 2009). "Caffeine use in children: what we know, what we have left to learn, and why we should worry.". Neuroscience and Biobehavioral Reviews 33 (6): 793–806. doi:10.1016/j.neubiorev.2009.01.001. PMC 2699625. PMID 19428492.
  18. Whitehead, N; White, H (April 2013). "Systematic review of randomised controlled trials of the effects of caffeine or caffeinated drinks on blood glucose concentrations and insulin sensitivity in people with diabetes mellitus.". Journal of Human Nutrition and Dietetics 26 (2): 111–25. doi:10.1111/jhn.12033. PMID 23331476.
  19. Caldeira, D; Martins, C; Alves, LB; Pereira, H; Ferreira, JJ; Costa, J (October 2013). "Caffeine does not increase the risk of atrial fibrillation: a systematic review and meta-analysis of observational studies.". Heart 99 (19): 1383–9. doi:10.1136/heartjnl-2013-303950. PMID 24009307.
  20. Cheng, M; Hu, Z; Lu, X; Huang, J; Gu, D (April 2014). "Caffeine intake and atrial fibrillation incidence: dose response meta-analysis of prospective cohort studies.". The Canadian Journal of Cardiology 30 (4): 448–54. doi:10.1016/j.cjca.2013.12.026. PMID 24680173.
  21. Mesas, AE; Leon-Muñoz, LM; Rodriguez-Artalejo, F; Lopez-Garcia, E (October 2011). "The effect of coffee on blood pressure and cardiovascular disease in hypertensive individuals: a systematic review and meta-analysis.". The American Journal of Clinical Nutrition 94 (4): 1113–26. doi:10.3945/ajcn.111.016667. PMID 21880846.
  22. Ding, M; Bhupathiraju, SN; Satija, A; van Dam, RM; Hu, FB (February 2014). "Long-term coffee consumption and risk of cardiovascular disease: a systematic review and a dose-response meta-analysis of prospective cohort studies.". Circulation 129 (6): 643–59. doi:10.1161/circulationaha.113.005925. PMID 24201300.
  23. Chrościńska-Krawczyk, M; Jargiełło-Baszak, M; Wałek, M; Tylus, B; Czuczwar, SJ (2011). "Caffeine and the anticonvulsant potency of antiepileptic drugs: experimental and clinical data." (PDF). Pharmacological Reports 63 (1): 12–8. PMID 21441607.
  24. Sabisz, M; Skladanowski, A (August 2008). "Modulation of cellular response to anticancer treatment by caffeine: inhibition of cell cycle checkpoints, DNA repair and more.". Current Pharmaceutical Biotechnology 9 (4): 325–36. doi:10.2174/138920108785161497. PMID 18691092.

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