Caffeine - Other routes

1. CONTEXT
Caffeine is a central stimulant whose therapeutic activity has been well documented and does not need to be discussed in detail.
As a summary, caffeine belongs to the methylxanthine family, a group of alkaloids that stimulate the CNS (Central Nervous System). In addition to caffeine, theophylline (tea) and theobromine (cocoa) are part of this group. Among its positive effects, in addition to being CNS stimulants, they act by increasing motor activity, intellectual performance, pain perception, reducing fatigue and sleep . Therefore, its use as an ergogenic aid is quite (re)known.

2. MECHANISM OF ACTION.
The main mechanism of action of caffeine is to act as a non-selective antagonist of adenosine A 1 and A 2 receptors (Fig. 2). During periods of wakefulness, brain levels of the neurotransmitter adenosine constantly increase, triggering fatigue and drowsiness. The caffeine molecule is structurally similar to adenosine (Fig. 1), which allows it to bind to adenosine receptors on the surface of cells without activating them, thus acting as a competitive inhibitor.

Figure 1: Caffeine and adenosine molecules

Along with this, caffeine also has effects on most other important neurotransmitters, including dopamine, acetylcholine, serotonin, in high doses it also acts on norepinephrine, and to a small extent on epinephrine, glutamate, and cortisol. At high doses, greater than 500 milligrams, caffeine inhibits GABA neurotransmission, this reduction of GABA results in increased anxiety, insomnia, heart rate and respiratory rate.

Figure 2: Caffeine binds to adenosine receptors to block them, thus preventing adenosine from binding.

However, caffeine intake also has its disadvantages, since there are factors such as genetics (CYP1A2), age, pregnancy, obesity, smoking, intake of certain medications... influencing its metabolization. In addition to the tolerance that is generated by its continued (ab)use, needing an increasing amount to obtain the same effect.

Caffeine is usually administered in oral formulations in tablets, capsules, oral/nasal suspensions, drinks, chewing gum... These oral formulations are not rapidly absorbed from the intestinal tract and often do not produce significantly high blood levels in a short time. .

Some of the desired product may be wasted by excretion before being absorbed. In addition, it is known that caffeine irritates the stomach mucosa, causing tachycardia, tremors, insomnia, headaches, etc.

For this, new routes of administration have been proposed where the % of caffeine can be lower, generating fewer side effects. This is due to its better bioavailability and absorption as we will explain below.

3. PHARMACOKINETICS AND PHARMACODYNAMICS BY OTHER WAYS.
Drug absorption through the mucosa (oral or nasal) is an alternative to standard oral administration because it can avoid first-pass metabolism in the liver and degradation in the digestive tract. The mucous membranes receive an abundant blood supply and have a relatively high permeability, allowing drugs to enter and act quickly.

An example of this is revealed in a study published by a landmark study by Kamimori et al., 2002, where the rate of caffeine absorption was examined by measuring plasma caffeine concentrations at various time points after ingestion of capsules or chewing gum. that contained 50, 100 or 200 mg of caffeine. Both forms were separated into groups of 12 healthy male subjects who consumed less than 300 mg of caffeine/day and had abstained from caffeine intake for 20 hours, and fasted for 3 hours.

Subsequently, blood samples were taken every so often after ingestion/chewing. The time to reach maximum caffeine concentration was faster in the gum tests (44.2 to 80.4 min) than in the capsule tests (84 to 120 min). However, the maximum concentrations of caffeine in both capsule and chewing gum formats and the area under the curve were not different in each of the three doses, but they were different in the rate of absorption, which was markedly faster with the chewing gum format, since a dose of 200 mg, as a large increase in plasma caffeine concentration occurred between 5 and 15 min. (Fig. 2) This study demonstrated the effectiveness of administering caffeine more rapidly with gum than with capsules, in part by absorption in the oral cavity along with absorption by swallowing while chewing gum.

Figure 2: Mean plasma caffeine concentration after a 200 mg dose of caffeine in capsule or gum form for healthy male volunteers (12 subjects in each of the two treatment groups). Inset shows plasma concentration profiles of the 200 mg dose administered in capsule or gum formulation up to 90 minutes after caffeine administration

There are also mouthwashes with caffeine, but we will not go into detail as more evidence is needed on this. As a matter of fact, the proposed mechanism by which caffeine mouthwash acts has to do with bitter taste receptor cells located specifically in the oropharyngeal epithelium, which have been shown to be activated when exposed to caffeine. These bitter taste receptors can activate gustatory neural pathways and ultimately stimulate brain regions associated with information and reward processing.

Another route of administration, not only of caffeine, but of drugs, is the administration of nasal sprays, where the proposed mechanisms are several.

The first of them suggests that part of the substance enters directly into the systemic circulation, eventually reaching the brain, easily crossing the blood-brain barrier.

To understand this, we have to take into account the nasal epithelium. The nasal epithelium is an extremely permeable membrane that allows molecules with a molecular weight less than 1000 Dalton to quickly access the brain through the bloodstream. Caffeine molecules could easily cross the epithelium and ultimately affect the CNS through aerosol administration since they have a low molecular weight.

Another mechanism studied is that nasal administration can be transported directly from the nasal cavity to the cerebrospinal fluid and brain tissue through intracellular axonal transport through the olfactory and trigeminal neural pathways (Fig. 4).

It has also been shown that there are bitter taste receptors in the nasal cavity, similar to those found in the mouth, so nasal caffeine sprays can also activate the bitter taste receptors located in said cavity, thus forming connections with the trigeminal nerve and, ultimately, stimulating brain regions associated with reward and information processing, just as it would through the oral route.

As a final proposed mechanism, it is suggested that aerosols could deliver caffeine directly to the lungs where it would be absorbed into the blood, thereby taking it directly to the heart.

Figure 4: Proposed mechanism of nasal drug administration

4. CONCLUSIONS.
As we have seen, administration through the mucosal route is an effective alternative with fewer side effects than the conventional one, since, due to its pharmacokinetics, the ingestion of caffeine through these routes does not cause irritation, tachycardia, nervousness, insomnia, etc. This is achieved by an increase in bioavailability after administration, therefore requiring less concentration of substance to achieve the desired effects.

Regarding dosage, the level of tolerance between individuals must be taken into account; although as a general rule, the recommendations provided by the manufacturer must be followed.

REFERENCES

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