Caffeine and The Effects of Physiology on Half Life

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Image retrieved from on October 3rd, 2014.

Regardless of your fondness for a steaming mug of joe, a fragrant cup of tea, or an ice-cold Coke, your body responds to the caffeine in these beverages as though you had just swallowed poison. As with alcohol, liver enzymes are marshaled to attack the molecules and disable them as quickly as possible. The human liver disposes of caffeine by undoing the steps that led to its formation in plants: methyl groups are plucked off one at a time. This is an important point: depending on which methyl group is removed, caffeine is transformed into theophylline, theobromine, or another dimethylxanthine called paraxanthine.
As we just saw, theophylline is roughly as potent as caffeine, so when theophylline results from the first stage of caffeine metabolism the arousing effects of the original caffeine remain unchanged. Theobromine is only one-seventh as potent as caffeine, so the conversion of caffeine to this dimethylxanthine does represent progress. But 70 percent of a given dose of caffeine is converted to paraxanthine, which is actually slightly more potent than caffeine. This means that the “buzz” you get from a cup of coffee has as much to do with the breakdown products of caffeine as with the caffeine itself. Exactly how paraxanthine affects the brain is not clear, though it seems to mimic the actions of caffeine due to the similarity of its methyl-group configuration. (We'll delve into these actions in the next chapter.)
In the second step of caffeine metabolism in humans, another methyl group is removed, producing a methylxanthine, which has no stimulating effects. From there, the last methyl group is removed, yielding plain-old xanthine, which either is eliminated in urine or is reused. The pharmacological activity of theophylline, theobromine, and paraxanthine is part of the reason it takes a relatively long time for a coffee buzz to wear off. Not only must the caffeine be eliminated, but the breakdown products have to be eliminated as well. The time it takes for a dose of a drug to wear off is measured by value called a half-life. That's the time it takes for half of a dose to be eliminated. The half-life of caffeine averages between five and six hours, which is far slower than the rate at which we eliminate alcohol. As leisurely as caffeine’s half-life is, however, it can be even longer for certain people.
Women taking oral contraceptives require about twice the normal time to eliminate caffeine (Yesair 1984). For such women, the stimulation from a single cup of coffee might last all day,. A similar, though less dramatic increase in caffeine's half-life has been reported for women during the luteal phase of the menstrual cycle—the time between ovulation and the beginning of menstruation. In one study, caffeine elimination took about 25 percent longer during this time, resulting in an average half-life of 6.8 hours (Arnaud 1993). And in infants, the half-life of caffeine is radically extended because their livers have not yet developed the enzymes needed to break down caffeine. A full-term newborn requires eighty hours to metabolize half a dose of caffeine (Snel 1993). As infants grow, their ability to process caffeine also grows. By the time a baby is between three and five months old, a dose of caffeine will have an average half-life of 14.4 hours. And by about six moths, infants have essentially the same ability to process caffeine as adults. Although studies have failed to find any adverse consequences on infants from the caffeine consumption of nursing mothers, the extremely long half-lives in young babies is one reason that many doctors advise breast-feeding mothers to avoid caffeine altogether. (This applies to expectant mothers as well, as we'll see later.)
But another segment of the population experiences exactly the opposite effect as women on oral contraceptives. By a still imperfectly understood mechanism, cigarette smoking “revs up” the liver's caffeine-destroying enzymatic machinery (Benowitz et al. 1989). As a result, the half-life of caffeine among smokers is reduced to anaverage of three hours (Parsons and Neims 1978). This double-speed elimination of caffeine may explain the long-standing observation that smokers drink more coffee than nonsmokers. Smokers may simply be adjusting their caffeine intake to maintain the same degree of stimulation achieved by nonsmokers.
Interestingly, it is apparently not the nicotine in cigarette smoke that induces liver enzymes to wrok more efficiently. Cigarette smoke contains hundreds of other volatile, reactive compounds, and it is apparently a family of such compounds called polycylic aromatic hydrocarbons that triggers the increased enzymatic activity.
The impact of smoking on caffeine clearance is important for those who quiet smoking. In one study, blood-caffeine levels jumped an average of 250 percent a few days after the subjects had quit smoking—even though they didn't change their coffee- or tea-drinking habits. This added caffeine jolt could easily exacerbate the anxiety, insomnia, irritability, and other unpleasant symptoms of nicotine withdrawal experienced by quitters.
Smokers who drink coffee and other caffeine-containing drinks are juggling the pharmacological effects of two fairly powerful alkaloids: nicotine and caffeine. This juggling is mostly unconscious: they automatically adjust their consumption of both drugs to maintain a desired physical or mental state. But as many people know from experience, this juggling is tricky. Not only do variables such as food intake and sleep alter the body's response to both substances, but interactions such as the one just mentioned between cigarette smoke and caffeine metabolism can produce effects that can leave a user grappling with physical reactions that seem out of proportion to the amount of a drug consumed. Understanding the nature of caffeine and how it behaves in the body can inform the self regulation efforts of smokers and nonsmokers alike.
Now that we know something about caffeine as a molecule, we're ready to take a look at what happens when those molecules hit an unsuspecting brain.

pp. 119-122 of Buzz The Science and lore of Alcohol and Caffeine by Stephen Braun (1996)

The caffeine cup