Effects of Caffeine in the Human Body

Caffeine has a number of different methods of action on the body, but its primary mechanism concerns reducing levels of adenosine. Adenosine occurs naturally in the body, particularly the central nervous system, and has important roles in several biochemical processes such as energy transfer. Adenosine is also classed as a neurotransmitter and it can aid in protecting neurons by reducing levels of activity in the brain. To give an example, some evidence suggests animals that go into hibernation use adenosine to induce torpor.

Mechanisms of Caffeine

Caffeine works primarily as adenosine receptor antagonist; by blocking adenosine receptors, adenosine is prevented from binding with them, and cannot suppress neural activity. As a secondary consequence of lowered adenosine activity, the action of most other neurotransmitters is also altered. This includes acetylcholine, serotonin, dopamine, and where concerning particularly high doses, norepinephrine. To a lesser extent, cortisol, glutamate and epinephrine are also affected. At doses of 500mg and over, caffeine is known to inhibit signal transmission in GABA pathways. This is the mechanism responsible for some of caffeine’s negative side effects which can include Insomnia and anxiety, as well as increased heart and respiratory rates.

Unlike some other supplements, caffeine can easily pass across the blood brain barrier, a structure regulates materials passing between the bloodstream and brain interior. This is due to the fact that it is both lipid and water-soluble. Once it reaches the brain, caffeine functions primarily as a non-selective adenosine receptor antagonist, which can dramatically reduce the effectiveness of adenosine. This is achieved through competitive inhibition wherein caffeine molecules bind to receptor sites without stimulating them. Consequently, adenosine molecules will no longer be able to bind to these caffeine occupied receptors.

Adenosine is present in practically every cell in the body. As the primary component of adenosine triphosphate (ATP), adenosine plays a vital role in energy production and transfer processes. Additionally, it is also important for the synthesis of ribonucleic acid (RNA), a molecule involved in the transcription and expression of genes. Increases in adenosine concentration in the brain may be a response to various kinds of stress, such as insufficient oxygen or bloodflow. These higher concentrations of adenosine can compensate for such deficiencies by affecting smooth muscle receptors in vascular tissues, thus increasing blood flow. Some evidence suggests that in the brain, adenosine is released by synapses, though adenosine release as a result of stress is more likely a result of dephosphorylation of ATP into its constituents. Adenosine differs from a majority of other neurotransmitters as it is not contained within voltage-operated vesicles (a cell organelle composed of a lipid bilayer) although this theory has not been entirely disproven.

There are several known types of adenosine receptor, each of which has different distributions throughout the body. Namely these are A1 and A2A receptors, the former of which has a wide distribution and functions by inhibiting the uptake of calcium. Meanwhile, high densities of A2A receptors can be found in the basal ganglia where they are linked to behavioural control, although they are also found to a lesser extent in other brain regions. Some research suggests A2A receptors are linked to dopamine pathways which are responsible for arousal and reward.

Although adenosine possesses neuroprotectant properties, it has a more important role in modulating sleep-wake cycles. The prominent psychologist and neuroscientist Robert McCarley hypothesises that, feelings of sleepiness following a mentally demanding or prolonged activity, may be caused in part by the build-up of adenosine. These effects are further mediated by the activation of neurons that promote sleep, an indirect result of A2A type receptors. Additionally, neurons that keep us awake are also inhibited through the action of A1 receptors. Other contemporary studies also advocate the importance of A2A receptors in this context, though comparatively little evidence that supports such claims for A1 receptors.

Caffeine is classed as a xanthine, and like other substances in this group, it is able to inhibit the action of phosphodiesterase. Caffeine inhibits phosphodiesterase in a competitive, non-selective manner and can increase levels of intracellular cyclic adenosine monophosphate (cAMP), Inhibit the synthesis of leukotriene and TNF-alpha, activate protein kinase A (PKA), as well as reduce innate immunity and inflammation.
There are several hypothesised mechanisms for caffeine in regard to its physical performance enhancing properties. Considering classic metabolic theory, is has been suggested that caffeine is able to decrease utilisation of glycogen, while simultaneously increasing fat utilisation. The increased concentration of epinephrine caused by caffeine ingestion is thought to aid in mobilising free fatty acids present in adipose tissue and intramuscular triglycerides. As a result, a higher degree of fat oxidation takes place, allowing the body to conserve muscular glycogen which enhances overall physical stamina and endurance. Caffeine can also reduce the amount of effort perceived by the user in regard to physical activities. This is achieved by reducing the threshold at which neurons are activated, meaning muscles can be more easily recruited for physical activity.

Metabolites of Caffeine

The liver metabolises caffeine into three main metabolites; paraxanthine, theobromine and theophylline in proportions of approximately 84%, 12% and 4% respectively. Following ingestion, caffeine is normally absorbed within 45 minutes by the small intestine, after which it is transported to all parts of the body. Concentrations of caffeine in the blood normally peak within an hour and it can be eliminated with first order kinetics (elimination is proportional to plasma concentration and half-life of the substance). Caffeine can be absorbed by the rectum and several types of suppository exist, including those for migraines, which use caffeine and ergotamine tartrate, as well as caffeine with chlorobutanol, used to treat hyperemesis.

The time that it takes to eliminate half of the caffeine molecules in the body, also known as half-life, can vary considerably between individuals as a result of factors that include age, use of medication, liver function, pregnancy and the concentration of enzymes that metabolise caffeine. Half-life is also subject to significant changes due to the presence of certain hormones, but in healthy adults it ranges from around 4.9 to 6 hours. Tobacco also appears to have some effect on the half-life of caffeine; in individuals who are heavy smokers, it was decreased by approximately 30 to 50%. At the other end of the scale, use of oral contraceptives has shown to double the half-life of caffeine. Similarly, pregnancy can increase this to an even greater degree, particularly in the last trimester where this can extended by up to 15 hours. In neonates, the half-life of caffeine can be in excess of 80 hours, although this has been observed to rapidly decrease with age; at 6 months old, an infant’s half-life for caffeine may be even less than that of an adult. Fluvoxamine, an antidepressant, is known to greatly reduce the breakdown of caffeine by over 90%, prolonging its half-life over ten times from around 4.9 to 56 hours.
Metabolism of caffeine is carried out in the liver by the CYP1A2 isozyme which is a part of the cytochrome P450 oxidase enzyme system. It is metabolised into the three aforementioned dimethylxanthines which have their own distinct physiological effects:

• Paraxanthine: A central nervous stimulant that functions by increasing lipolysis (the breakdown of lipids and hydrolysis of triglycerides), resulting in elevated levels of fatty acids and glycerol in blood plasma.
• Theobromine: Works as a vasodilator which dilates blood vessels and a diuretic that increase the volume of urine produced.
• Theophylline: Able to relax bronchial smooth muscle, increases contractility and efficiency of the heart muscle, and has anti-inflammatory effects. The concentrations obtained from metabolising caffeine however are unlikely to be sufficient for therapeutic applications.

These dimethylxanthines are further broken down, before being excreted in urine. Caffeine is known to accumulate in people with severely reduced liver function, which may increase its half-life.
A class of broad spectrum antibacterial drugs, known as quinolone antibiotics, have been observed to inhibit the action of CYP1A2 isozymes, thus reducing clearance and increasing levels of caffeine in the blood.
A meta-analysis carried out in 2011 by PLoS Genetics evaluated the findings of five studies that used over 47,000 participants with European ancestry in total. The results suggest that regular caffeine use correlated with the presence of two gene variations responsible for regulating the rate of caffeine metabolism. Individuals that possessed a high caffeine intake genotype, for either gene on both chromosomes, consumed around 40mg more caffeine a day compared to those that lacked this mutation.

Detection of Caffeine in Biological Fluids

It is possible to quantify the concentration of caffeine present in plasma, blood and serum with the purposes of monitoring neonatal therapy, to confirm a poisoning diagnosis, or aid in medico legal death investigations. Levels of caffeine in plasma normally range between 2 to 10mg/L in coffee drinkers, around 12 to 36mg/L in newborns undergoing apnea treatment, and between 40 to 400mg/L when concerning instances of acute overdose. Many competitive sports that do not allow performance enhancing drugs also measure the levels of caffeine in urine, with concentrations of 15mg/L or more representing possible abuse.

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