Caffeine


Article Author:
Justin Evans


Article Editor:
Amanda Battisti


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Jasleen Jhajj
Cliff Caudill
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James Hughes
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Phillip Hynes
Tehmina Warsi


Updated:
3/13/2019 4:10:12 PM

Indications

Caffeine is a naturally occurring, central nervous system (CNS) stimulant of the methylxanthine class and is the most widely taken psychoactive stimulant in the world. This drug is most commonly sourced from the coffee bean, but can also be found naturally occurring in certain types of tea and cacao beans. It is also an additive to soda and energy drinks. The primary goal of caffeine consumption is to combat fatigue and drowsiness, but there are many additional uses.[1]

The FDA has approved caffeine for the use in the treatment of apnea of prematurity and prevention and treatment of bronchopulmonary dysplasia of premature infants.[2][3][4] Non-FDA approved uses of caffeine include treating migraine headaches and post-dural puncture headaches and enhancing athletic performance, especially in endurance sports.[5][1] Caffeine has been linked with decreased all-cause mortality and is also being investigated for its efficacy in the treatment of depression and neurocognitive declines, such as that seen in Alzheimer and Parkinson diseases.[6][7][8][9][10]

Mechanism of Action

Caffeine’s primary mechanism of action is on the adenosine receptors in the brain. As it is both fat and water soluble, it readily crosses the blood-brain barrier, resulting in antagonism to all 4 adenosine receptor subtypes (A1, A2a, A2b, A3). Specifically, antagonism of the A2a receptor is responsible for the wakefulness effects of caffeine.[11][12]

Adenosine receptors are not limited to the CNS but found throughout the body. In cardiac muscle, direct antagonism of receptor A1 results in positive inotropic effects. Likewise, adenosine receptor antagonism stimulates the release of catecholamines, which contributes to the systemic stimulatory effects of caffeine and further stimulates cardiac inotropy and chronotropy. At the vascular level, caffeine undergoes a complex interaction to control vascular tone. This includes direct antagonism of vascular adenosine receptors to promote vasodilation, as well as stimulation of endothelial cells to release nitric oxide, which promotes further relaxation of vascular smooth muscle cells. This vasodilation is counteracted by the increase in sympathetic tone via catecholamine release and positive cardiac inotropic and chronotropic effects, which promotes vasoconstriction. As there are multiple constriction and dilatation mechanisms at work, the overall result is individualized and dependent upon caffeine dose, the frequency of use, and comorbidities such as diabetes or hypertension. Overall, caffeine seems to increase systolic blood pressure by approximately 5 to 10 mmHg in individuals with infrequent use. However, there is little to no acute effect on habitual consumers.[13][12]

Furthermore, adenosine receptor blockage stimulates respiratory drive by increasing medullary ventilator response to carbon dioxide, stimulating central respiratory drive and improving diaphragm contractility. Caffeine increases renal blood flow, glomerular filtration, and sodium excretion resulting in diuresis. It is also a potent stimulator of gastric acid secretion and gastrointestinal (GI) motility.[12][14]

Metabolism of caffeine primarily occurs in the liver via the cytochrome P450 oxidase system, specifically enzyme CYP1A2. Metabolism results in 1 of 3 dimethylxanthine, including paraxanthine, theobromine, and theophylline, each with unique effects on the body. These metabolites are then further metabolized and excreted in the urine.[13][15]

The half-life of caffeine is approximately 5 hours in the average adult. However, multiple factors can influence metabolism. Half-life is reduced by up to 50% in smokers compared to nonsmokers. Conversely, pregnant patients, especially those in the final trimester, will have prolonged half-life upwards of 15 hours. Newborns will also have a significantly prolonged half-life, up to 8 hours for full-term and 100 hours for premature infants, due to reduced activity of cytochrome P450 enzymes and immature demethylation pathways. Children older than 9 months will have similar half-life eliminations to that of adults. Additionally, patients with liver disease or those taking cytochrome inhibitors will also experience prolonged half-lives due to reduced enzyme activity. [16][17]

Administration

Caffeine has nearly 100% oral bioavailability and is the primary route of administration. Caffeine can be sourced from coffee beans, cacao beans, kola nuts, tea leaves, yerba mate, guarana berry, as an additive to sodas and energy drinks, or consumed as powder or tablets.[1] When taken orally, onset typically occurs in 45 to 60 minutes and last approximately 3 to 5 hours. Absorption is somewhat delayed when taken with food. It can be administered via the parenteral route, which is a common method when treating apnea of prematurity in newborns or post-dural puncture headaches.

Alternatively, caffeine can be absorbed rectally, insufflated or inhaled. Consumption via insufflation or inhalation is generally that of abuse with the intention of getting high. These routes lead to significantly faster absorption, usually within minutes, and bypass the first-pass metabolism. Although this route can lead to a faster onset of action, multiple studies have shown lower bioavailability from inhalation of caffeine; approximately 60% to 70%. When taken via this route, the duration of action is decreased.[15][18]

Adverse Effects

As with most drugs or medications, there comes a long list of adverse effects associated with its use, and caffeine is no different. The adverse effects of caffeine range from mild to severe to even fatal and are generally related to the dose consumed and an individual’s sensitivity to the drug. The most common side effects are listed below. Mortality is usually related to cardiac arrhythmia, hypotension, myocardial infarction, electrolyte disturbances, and aspiration.[19][7]

Mild

Anxiety, restlessness, fidgeting, insomnia, facial flushing, increased urination, muscle twitches or tremors, irritability, agitation, elevated or irregular heart rate, GI upset

Severe

Disorientation, hallucinations, psychosis, seizure, arrhythmias, ischemia, rhabdomyolysis

Caffeine can also cause withdrawal symptoms if habitual users abruptly stop.  These symptoms usually begin 12 to 24 hours from last consumption, peak in 1 to 2 days and may persist for up to 1 week.  Withdrawal can be prevented if caffeine is tapered off instead of abruptly discontinued. If symptoms do arise, they can be rapidly reversed by re-administration of caffeine.[20]

Lastly, when used for the treatment of apnea of prematurity, there is evidence of an increased risk of necrotizing enterocolitis in neonates.[21]

Contraindications

Although there are no absolute contraindications to caffeine, there are some medical conditions in which caution should be used, which includes:[7][22][14][17][7]

  • Severe anxiety
  • Cardiovascular disease or symptomatic cardiac arrhythmias
  • Peptic ulcer disease or gastroesophageal reflux disease
  • Hepatic impairment
  • Renal impairment
  • Seizures (as may lower seizure threshold)
  • Pregnancy

American College of Obstetricians and Gynecologists (ACOG) considers 200 mg daily safe during pregnancy.[23] There is no evidence to suggest caffeine increases the risk of congenital malformations, although some studies have concluded that high caffeine consumption during pregnancy (generally more than 350 mg per day) can be associated with lower birth weights and increased risk of miscarriage.[24][25][26] However, the evidence is inconclusive at this time and pending further investigation.[27] Caffeine is considered a pregnancy class C drug.[23]

Monitoring

The average dose of caffeine is 2.4 mg/kg per day for adults; however, daily doses of up to 400 mg are considered safe.[28] Consumption of 100 mg of caffeine generally increases blood levels by 5 to 6 mg/L. Severe intoxication that causes altered mentation, vomiting, hypotension has been reported at levels of 80 mg/L. The average blood level of patients who succumb to caffeine toxicity is 180 mg/L (+/- 97 mg/L).[29][30]

For the treatment of apnea of prematurity, caffeine is administered at 20 mg/kg loading dose, followed by 5 to 10 mg/kg per day of caffeine citrate via enteral or parenteral routes with therapeutic index goals of 5 to 25 mg/L.[31][32]

Toxicity

Caffeine consumption is generally recognized as safe. Most substances do not require FDA approval for additive caffeine as long as it falls within safe levels dictated by the statue. The typical dose of caffeine is roughly 70 to 100 mg per drink. Although there is no specific daily allowance for caffeine, doses of up to 400 mg a day are considered safe.[33]

The exact LD50 for humans is variable and largely dependent on sensitivity to caffeine. However, it is estimated to be 150 to 200 mg/kg. There are however case reports of doses as low as 57 mg/kg being fatal. A toxic dose of caffeine, or a dose at which significant unfavorable side effects begin to occur, for example, tachycardia, arrhythmia, altered mentation, and seizure, is estimated to be approximately 1.2 grams while a life-threatening dose is estimated in the range of 10 to 14 grams.[19][34]

Ultimately, treatment is primarily supportive for mild ingestions. For more severe ingestions, additional interventions may be necessary. Patients may require intubation for airway protection from vomiting or altered mental status. Benzodiazepines can be given to abort any seizures that develop. Patients may require vasopressors to combat persistent hypotension if intravenous (IV) fluid resuscitation alone fails. The first-line vasopressor should be either phenylephrine or norepinephrine. However, phenylephrine is the ideal choice due to its pure alpha agonism as well as reflex bradycardia. Magnesium and beta blockers can be used to combat cardiac arrhythmias secondary to the hyperadrenergic response. In the event of lethal arrhythmias, patients will require defibrillation and resuscitation per ACLS protocol.[22] Activated charcoal, intralipid infusion, and hemodialysis can assist in preventing further metabolism and subsequent effects of caffeine overdose.[34][19][35]

Enhancing Healthcare Team Outcomes

Caffeine consumption is relatively safe in limited amounts. The problem is that many people today are consuming high energy drinks that contain massive amounts of caffeine which can lead to complications. The nurse practitioner and primary care physician are in a prime position to educate the public on the dangers of high energy drinks and related foods. While there are no absolute contraindications to caffeine, the public should be educated that if they have cardiac disorders, panic disorder, anxiety, or too much stress, caffeine is best avoided.


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Caffeine - Questions

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Which of the following statements about caffeine is incorrect?



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Which is not associated with high levels of caffeine ingestion during pregnancy?



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Which of the following stimulants does not have more toxicity when combined with caffeine?



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Which of the following is not caused by taking caffeine at bedtime?



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Which of the following products contains the most caffeine?



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How does the caffeine in coffee worsen peptic ulcer disease?



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Caffeine - References

References

Apnea of prematurity: caffeine dose optimization., Francart SJ,Allen MK,Stegall-Zanation J,, The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG, 2013 Jan     [PubMed]
A comprehensive approach to the prevention of bronchopulmonary dysplasia., Kugelman A,Durand M,, Pediatric pulmonology, 2011 Dec     [PubMed]
Methylxanthine therapy for apnea of prematurity: evaluation of treatment benefits and risks at age 5 years in the international Caffeine for Apnea of Prematurity (CAP) trial., Schmidt B,, Biology of the neonate, 2005     [PubMed]
Apnea of prematurity: pathogenesis and management strategies., Mathew OP,, Journal of perinatology : official journal of the California Perinatal Association, 2011 May     [PubMed]
Caffeine, mental health, and psychiatric disorders., Lara DR,, Journal of Alzheimer's disease : JAD, 2010     [PubMed]
Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects., Nehlig A,Daval JL,Debry G,, Brain research. Brain research reviews, 1992 May-Aug     [PubMed]
Association of coffee drinking with total and cause-specific mortality., Freedman ND,Park Y,Abnet CC,Hollenbeck AR,Sinha R,, The New England journal of medicine, 2012 May 17     [PubMed]
Chronic caffeine consumption prevents memory disturbance in different animal models of memory decline., Cunha RA,Agostinho PM,, Journal of Alzheimer's disease : JAD, 2010     [PubMed]
Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production., Arendash GW,Schleif W,Rezai-Zadeh K,Jackson EK,Zacharia LC,Cracchiolo JR,Shippy D,Tan J,, Neuroscience, 2006 Nov 3     [PubMed]
Caffeine intake and dementia: systematic review and meta-analysis., Santos C,Costa J,Santos J,Vaz-Carneiro A,Lunet N,, Journal of Alzheimer's disease : JAD, 2010     [PubMed]
An update on the mechanisms of the psychostimulant effects of caffeine., Ferré S,, Journal of neurochemistry, 2008 May     [PubMed]
Coffee and gastrointestinal function: facts and fiction. A review., Boekema PJ,Samsom M,van Berge Henegouwen GP,Smout AJ,, Scandinavian journal of gastroenterology. Supplement, 1999     [PubMed]
Comparison of caffeine disposition following administration by oral solution (energy drink) and inspired powder (AeroShot) in human subjects., Laizure SC,Meibohm B,Nelson K,Chen F,Hu ZY,Parker RB,, British journal of clinical pharmacology, 2017 Dec     [PubMed]
Evaluation of caffeine and the development of necrotizing enterocolitis., Cox C,Hashem NG,Tebbs J,Bookstaver PB,Iskersky V,, Journal of neonatal-perinatal medicine, 2015     [PubMed]
ACOG CommitteeOpinion No. 462: Moderate caffeine consumption during pregnancy.,, Obstetrics and gynecology, 2010 Aug     [PubMed]
Evaluation of the reproductive and developmental risks of caffeine., Brent RL,Christian MS,Diener RM,, Birth defects research. Part B, Developmental and reproductive toxicology, 2011 Apr     [PubMed]
Maternal caffeine intake during pregnancy is associated with risk of low birth weight: a systematic review and dose-response meta-analysis., Chen LW,Wu Y,Neelakantan N,Chong MF,Pan A,van Dam RM,, BMC medicine, 2014 Sep 19     [PubMed]
Maternal caffeine intake during pregnancy and risk of pregnancy loss: a categorical and dose-response meta-analysis of prospective studies., Chen LW,Wu Y,Neelakantan N,Chong MF,Pan A,van Dam RM,, Public health nutrition, 2016 May     [PubMed]
Population pharmacokinetics of caffeine and its metabolites theobromine, paraxanthine and theophylline after inhalation in combination with diacetylmorphine., Zandvliet AS,Huitema AD,de Jonge ME,den Hoed R,Sparidans RW,Hendriks VM,van den Brink W,van Ree JM,Beijnen JH,, Basic & clinical pharmacology & toxicology, 2005 Jan     [PubMed]
Nonfatal and fatal intoxications with pure caffeine - report of three different cases., Magdalan J,Zawadzki M,Skowronek R,Czuba M,Porębska B,Sozański T,Szpot P,, Forensic science, medicine, and pathology, 2017 Sep     [PubMed]
Electrocardiogram Abnormalities of Caffeine Overdose., Fabrizio C,Desiderio M,Coyne RF,, Circulation. Arrhythmia and electrophysiology, 2016 Jul     [PubMed]
Intralipid in acute caffeine intoxication: a case report., Muraro L,Longo L,Geraldini F,Bortot A,Paoli A,Boscolo A,, Journal of anesthesia, 2016 Oct     [PubMed]
Fatal caffeine overdose: two case reports., Kerrigan S,Lindsey T,, Forensic science international, 2005 Oct 4     [PubMed]
Pesta DH,Angadi SS,Burtscher M,Roberts CK, The effects of caffeine, nicotine, ethanol, and tetrahydrocannabinol on exercise performance. Nutrition     [PubMed]
Echeverri D,Montes FR,Cabrera M,Galán A,Prieto A, Caffeine's Vascular Mechanisms of Action. International journal of vascular medicine. 2010;     [PubMed]
Fisone G,Borgkvist A,Usiello A, Caffeine as a psychomotor stimulant: mechanism of action. Cellular and molecular life sciences : CMLS. 2004 Apr;     [PubMed]
Fredholm BB,Bättig K,Holmén J,Nehlig A,Zvartau EE, Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacological reviews. 1999 Mar;     [PubMed]
Verbeeck RK, Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. European journal of clinical pharmacology. 2008 Dec;     [PubMed]
Juliano LM,Griffiths RR, A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology. 2004 Oct;     [PubMed]
Jones AW, Review of Caffeine-Related Fatalities along with Postmortem Blood Concentrations in 51 Poisoning Deaths. Journal of analytical toxicology. 2017 Apr 1;     [PubMed]
Cappelletti S,Piacentino D,Fineschi V,Frati P,Cipolloni L,Aromatario M, Caffeine-Related Deaths: Manner of Deaths and Categories at Risk. Nutrients. 2018 May 14     [PubMed]
Neves DBDJ,Caldas ED, Determination of caffeine and identification of undeclared substances in dietary supplements and caffeine dietary exposure assessment. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2017 Jul     [PubMed]
Bracken MB,Triche EW,Belanger K,Hellenbrand K,Leaderer BP, Association of maternal caffeine consumption with decrements in fetal growth. American journal of epidemiology. 2003 Mar 1     [PubMed]
Poole R,Kennedy OJ,Roderick P,Fallowfield JA,Hayes PC,Parkes J, Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes. BMJ (Clinical research ed.). 2017 Nov 22     [PubMed]
Koch G,Datta AN,Jost K,Schulzke SM,van den Anker J,Pfister M, Caffeine Citrate Dosing Adjustments to Assure Stable Caffeine Concentrations in Preterm Neonates. The Journal of pediatrics. 2017 Dec     [PubMed]

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