Caffeine is a stimulant and the most widely consumed psychoactive substance in the world from its presence in coffee, tea, cola beverages, energy drinks and chocolate.

Chemistry

Chemically, caffeine is 1,3,7-trimethylxanthine, i.e. a methylated form of xanthine. The normal catabolism of cellular purines, e.g. adenine and guanine, results in formation of xanthine, another purine, which itself is converted into uric acid by the action of xanthine oxidase ^2,3,6,7.

Other medically-important xanthines include theophylline (1,3-dimethylxanthine) and theobromine (3,7-dimethylxanthine). All these molecules are phytochemicals, that is of plant origin, and are thought to have originally arose as part of plants’ defences against predators, principally insects ^3,6.

Pharmacodynamics

Mechanism of action

Caffeine seems to act as an antagonist at adenosine receptors leading to inhibition of intracellular adenylate cyclase and a cascade of signalling molecules. It is its action at the A2A adenosine receptor that is believed to be the primary mechanism by which caffeine acts as a stimulant and dopaminergic substance ^3,7.

Physiological effects

In view of the abundance of four distinct adenosine receptor subtypes throughout the body caffeine has wide ranging physiological effects. Adenosine is normally sedating and tends to decrease the heart rate, hence the effects that caffeine has when it antagonises adenosine action ⁷.

Caffeine’s effects are dose-dependent. Its stimulant effects which include better concentration, wakefulness and contentedness tend to occur with <400 mg doses ⁷.

Toxicity

Undesirable effects of caffeine become apparent in most individuals with >500 mg doses and this includes edginess, anxiety, restlessness, irritability, nausea, diaphoresis, tremors, paraesthesia, and palpitations ⁷.

At higher doses, that is sub-gram and gram levels, caffeine becomes toxic with a broad range of clinical effects including arrhythmias, cardiac ischaemia, abdominal pain, diarrhoea, vomiting, seizures, loss of consciousness, electrolyte disturbances, and even death ⁷.

Treatment is mainly supportive ⁷.

Clinical importance

Caffeine as a drug has several uses, most commonly caffeine is added to over the counter painkillers e.g. paracetamol, as it appears to augment their analgesic action ⁸. In a more niche role, caffeine citrate may be used to treat neonatal apnoea ⁸.

However since many healthcare workers rely on the stimulant effects of caffeine to get them through the day, one could posit that it is one of the most clinically important substances in the medical world!

Radiological importance

In view of caffeine's cardiovascular effects it is contraindicated prior to some forms of cardiac imaging e.g. coronary CT angiography and myocardial perfusion scintigraphy.

History and etymology

Caffeine was first obtained in an impure form in 1819 by the German chemist, Friedlieb Ferdinand Runge (1794-1867) from the Coffea arabica plant. A French pharmacologist, Joseph Caventou (1795-1878) was the first to isolate it in a pure form in 1822. Interestingly, a substance called theine purified from the Chinese tea plant in 1838 by Carl Jobst, was later shown to be the one and same molecule as caffeine ^4,7. The first chemical synthesis of caffeine was achieved in 1895 by the Nobel Prize winning German chemist Emil Fischer (1852-1919) ^7,9,10.

The word caffeine was first recorded in print in 1830, a direct borrowing from the French coinage caféine, itself derived from café, the French for coffee, in turn borrowed from the Italian caffè, meaning the same thing. The suffix “-ine” is a common usage for chemicals – think of fluorine or cocaine – and is ultimately from the Latin suffix “-ina” used for abstract nouns ⁵.