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.
• 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

• in excessive amounts may also cause:
  • extreme restlessness
  • cardiac arrhythmias such as SVT and even potentially lethal ventricular arrhythmias
  • 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 sleepiness¹⁾
  • 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