caffeine

see also:

• methylxanthines
• tea and coffee
• Wikipedia for a good article on caffeine.

• caffeine is a natural trimethylxanthine alkaloid which acts as a pesticide and perhaps herbicide and thus protects the growth of coffee bean plant and similar plants (tea, kola, cacao plants) which produce it.
• coffee drinking became popular in Europe in mid-17th century
• chocolate was introduced to Europe by the Spaniards and became a popular beverage by 1700.
• caffeine was 1st isolated in 1819 and its structure elucidated by the end of the 19th century.
• theophylline was first extracted from tea leaves around 1888.
• 1st Coca-cola recipe invented in 1885 based on coca leaves & the kola nut.
  • initially Coca Cola also contained ~9mg cocaine per glass but this was removed in 1903 but retained coca flavoring using a cocaine-free coca leaf extract.
• Coca-Cola drink created controversy in the U.S. in 1911 over concerns of its caffeine content causing unwanted behaviour, and caffeine was soon added to the U.S. list of “habit-forming” and “deleterious” substances and foods and drinks containing it must label it accordingly.

• actions of caffeine include:
  • acting as a methylxanthine
  • crossing the blood brain barrier to have CNS effects
    • upregulates brain-derived neurotrophic factor (brain-derived neurotrophic factor (BDNF))
    • interacts with mTOR complex (relevant to all facets in learning and memory)
      • caffeine downregulates a signaling partner of the mTOR complex pathway in a dose-related manner: p70s6k
      • in 'normal' individuals, excessive levels of caffeine might be pathological in terms of learning and memory function, but these would be at extremely high doses, and in almost a steady-state system due to chronic administration
  • effects of its 3 main dimethylxanthine metabolites each with methylxanthine effects:
    • paraxanthine (84%)
    • theobromine (12%)
    • theophylline (4%)

• almost completely absorbed from GIT within 45min of oral intake.
• metabolized by the polymorphic cytochrome P450 1A2 (CYP1A2) enzyme.
  • individuals who are homozygous for the CYP1A2*1A allele are “rapid” caffeine metabolizers, whereas carriers of the variant CYP1A2*1F are “slow” caffeine metabolizers.
  • the genetic variant of CYP1A2, rs762551, alters inducibility: AA carriers are classified as fast metabolizers, AC carriers as intermediate metabolizers, and CC carriers as slow metabolizers, with slower metabolism resulting in prolonged systemic exposure to caffeine.
• half life in adults is generally 3-4hrs but increased to 5-10hrs in women on the combined oral contraceptive pill (OCP), and 9-11hrs in pregnant women.
• severe liver disease may result in half life of 96hrs.

• acute effects in those who have not developed tolerance:
  • stimulant effect
    • increased alertness, nervousness, may prevent sleep
    • increased sympathetic activity - tremor, tachycardia, etc
  • diuretic effect
  • increased gastric acid secretion

• most adults can safely consume up to 400mg caffeine per day in tea and coffee and many may see beneficial effects at these levels¹⁾
  • an expresso shot of coffee generally has about 60mg of caffeine, a cup of brewed cup may have twice this amount
• energy drinks, bars, gels and caffeine-based supplements often contain other added ingredients that may increase the absorption of caffeine, may accelerate its effects on the body, may raise blood pressure and increase the risk of cardiovascular harm even at these doses - including episodes of AF on young adults
  • one 250 ml can of Red Bull contains 80 mg of caffeine
• excessive amounts well above these levels may also cause:
  • extreme restlessness
  • cardiac arrhythmias such as AF, SVT and even potentially lethal ventricular arrhythmias at doses over 10 cups worth (>1000mg doses) ²⁾
  • high BP
  • severe hypokalaemia via high renal losses (along with sodium, calcium and magnesium renal losses)
  • intracellular shift of phosphate causing hypophosphataemia
  • hyperglycemia from hepatic stimulation
  • lactic acidosis from increased tissue metabolic needs from the excess stimulation
  • insomnia
  • confusion, seizures
  • GIT effects - nausea, vomiting, diarrhoea, abdominal pains
  • excessive diuresis and thirst

• frequent intake results in pharmacologic tolerance to caffeine:
  • heavy intakes of 750-1200mg/day may result in complete tolerance
  • in middle-aged adults who regularly drink coffee, there was little to no association between habitual caffeine intake, sleep quality, and daytime sleepiness³⁾
  • lower regular intakes result in incomplete tolerance

• nervousness, irritability, anxiety, tremulousness, muscle twitching (hyperreflexia), insomnia, headaches, respiratory alkalosis, palpitations.
• increased gastric acid secretion leading to peptic ulcers and gastro-oesophageal reflux
• increased migraine headaches
• impaired learning and long term memory

• may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at ~48 hours, and usually last from 1-5 days
• symptoms include headache, irritability, poor concentration, abdominal pains
• Rx includes analgesics, small doses of caffeine

• max. recommended daily dose in adults is 400mg
• caffeine should probably be avoided in children aged under 16yrs as they are more sensitive to its stimulant effects
• the Australia New Zealand Food Standards Code says formulated caffeinated beverages (“energy drinks”) can't contain more than 32mg of caffeine per 100mL.

Source: partly from European Food Safety Authority