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Pharmacology of Caffeine
As stated in Chapter 1, caffeine is the most widely used central nervous
system (CNS) stimulant in the world. It has numerous pharmacological and
physiological effects, including cardiovascular, respiratory, renal, and smooth
muscle effects, as well as effects on mood, memory, alertness, and physical and
cognitive performance. This chapter provides a brief summary of the metabo-
lism and physiological effects of caffeine
Caffeine (1,3,7-trimethylxanthine) is a plant alkaloid with a chemical
structure of C~H~oN402 (see Figure 2-1) and a molecular weight of 194.19. In
pure form, it is a bitter white powder. Structurally, caffeine (and the other meth-
ylxanthines) resembles the purines. The mean half-life of caffeine in plasma of
healthy individuals is about 5 hours. However, caffeine's elimination half-life
may range between 1.5 and 9.5 hours, while the total plasma clearance rate for
caffeine is estimated to be 0.078 L/h/kg (Brachtel and Richter, 1992; Busto et
al., 1989~. This wide range in the plasma mean half-life of caffeine is due to
both innate individual variation, and a variety of physiological and environ-
mental characteristics that influence caffeine metabolism (e.g., pregnancy, obe-
sity, use of oral contraceptives, smoking, altitude). The pharmacological effects
of caffeine are similar to those of other methylxanthines (including those found
in various teas and chocolates). These effects include mild CNS stimulation and
wakefulness, ability to sustain intellectual activity, and decreased reaction times.
The fatal acute oral dose of caffeine in humans is estimated to be 10-14 g
(150-200 mg/kg body weight [BW]) (Hodgman, 1998~. Ingestion of caffeine in
25
OCR for page 26
26
O
Hi_
H
-
XANTHINE
H3C~
cH3
TH EC)PHYLLINE
FIGURE 2-1 Chemical structure of methylxanthines.
O CH3
H3C: Jim ha
~ 1~ ,
0~N
CHIN
CAFFEINE
cH3
1
ON
1`J N
CH3
TH~OBROMINE
CAFFEINE FOR MENTAL TASK PE~O~ANCE
doses up to 10 g has caused convulsions and vomiting with complete recovery in 6
hours (Dreisbach, 1974~. Extreme side effects were observed in humans at caffeine
intakes of 1 g (15 mg/kg) (Gilman et al., 1990), including restlessness, nervousness,
and irritability, and progressing to delirium, emesis, neuromuscular tremors, and
convulsions. Other symptoms included tachycardia and increased respiration.
ABSORPTION, DISTRIBUTION, AND METABOLISM
Caffeine is rapidly and completely absorbed in humans, with 99 percent
being absorbed within 45 minutes of ingestion (Bonati et al., 1982; Liguori et
al., 1997~. When it is consumed in beverages (most commonly coffee, tea, or
soft drinks) caffeine is absorbed rapidly from the gastrointestinal tract and dis-
tributed throughout body water. More rapid absorption can be achieved by
chewing caffeine-containing gum or other preparations that allow absorption
through the oral mucosa.
Peak plasma concentrations occur between 15 and 120 minutes after oral
ingestion. This wide variation in time may be due to variation in gastric empty-
ing time and the presence of other dietary constituents, such as fiber (Arnaud,
1987~. Once caffeine is absorbed, there appears to be no hepatic first-pass effect
OCR for page 27
PHARMACOLOGY OF CAFFEINE
27
(i.e., the liver does not appear to remove caffeine as it passes from the gut to the
general circulation), as evidenced by the similarity in plasma concentration
curves that follow its administration by either the oral or the intravenous route
(Arnaud, 1993~. Caffeine binds reversibly to plasma proteins, and protein-bound
caffeine accounts for about 10 to 30 percent of the total plasma pool. The distri-
bution volume within the body is 0.7 L/kg, a value suggesting that it is hydro-
philic and distributes freely into the intracellular tissue water (Arnaud, 1987,
1993~. However, caffeine is also sufficiently lipophilic to pass through all bio-
logical membranes and readily crosses the blood-brain barrier. Its elimination is
by first-order kinetics and is adequately described by a one-compartment open
model system (Bonati et al., 1982~. In a study of adult men, a dose of 4 mg/kg
(280 mg/70 kg human, or about 2-3 cups of coffee) had a caffeine half-life of
2.5~.5 hours, and was not affected by age (Arnaud, 1988~.
Because caffeine is readily reabsorbed by the renal tubules, once it is filtered
by the glomeruli only a small percentage is excreted unchanged in the urine. Its
limited appearance in urine indicates that caffeine metabolism is the rate-limiting
factor in its plasma clearance (Arnaud, 1993~. Caffeine metabolism occurs pri-
marily in the liver, catalyzed by hepatic microsomal enzyme systems (Grant et
al., 1987~. In healthy humans, repeated caffeine ingestion does not alter its ab-
sorption or metabolism (George et al., 1986~. It is metabolized in the liver to
dimethylxanthines, uric acids, di- and trimethylallantoin, and uracil derivatives.
In humans 3-ethyl demethylation to paraxanthine is the primary route of metabo-
lism (Arnaud, 1987~. This first metabolic step accounts for approximately 75-80
percent of caffeine metabolism and involves cytochrome P4501A2 (Arnaud,
1993~. Paraxanthine is the dominant metabolite in humans, rising in plasma to
concentrations 10 times those of theophylline or theobromine. Caffeine is cleared
more quickly than paraxanthine, so 8 to 10 hours after caffeine ingestion, para-
xanthine levels exceed caffeine levels in plasma (Arnaud, 1993~.
The fact that the human body converts 70-80 percent of caffeine into para-
xanthine with no apparent toxic effects following caffeine doses of 300-500
mg/day suggests that paraxanthine's toxicological potency is low. Formation of
paraxanthine and its excretion in the urine appears to be the major pathway for
caffeine metabolism (Stavric, 1988~.
Hetzler et al. (1990) demonstrated that lipolytic effects of caffeine may be
due to the action of paraxanthine rather than caffeine itself. Increasing concen-
tration of plasma-free fatty acids following intravenous administration of caf-
feine was negatively correlated to plasma caffeine concentrations, and highly
positively correlated to plasma paraxanthine concentrations. Paraxanthine has
been found to be an equipotent adenosine antagonist to caffeine in vitro. Be-
nowitz et al. (1995) demonstrated that both caffeine and paraxanthine signifi-
cantly increased diastolic blood pressure, plasma concentrations of epinephrine,
and free fatty acids. Plasma levels of caffeine peaked 75 minutes after oral dos-
ing of caffeine, while plasma levels of paraxanthine peaked at 300 minutes after
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28
CAFFEINE FOR MENTAL TASK PERFORMANCE
an oral dose of paraxanthine. At doses of 4 mg/kg BW, caffeine and paraxan-
thine were equipotent. At doses of 2 mg/kg BW, however, caffeine was more
potent. Benowitz and colleagues (1995) concluded that after a single dose of
caffeine, paraxanthine concentrations are relatively low and probably do not
contribute much to the effect of caffeine. However, with long-term exposure to
caffeine there is a substantial accumulation of paraxanthine, and thus paraxan-
thine almost certainly contributes to the pharmacologic activity of caffeine. It
would be reasonable to expect then, that with long-term caffeine exposure, para-
xanthine would also contribute to development of tolerance to caffeine and
withdrawal symptoms.
There is likely to be considerable individual variation in the extent of con-
version of caffeine to paraxanthine, and because paraxanthine has pharmaco-
logic activity, the extent of conversion would be a factor in determining individ-
ual differences in response to caffeine.
FACTORS AFFECTING CAFFEINE METABOLISM
Caffeine metabolism is increased by smoking, an effect mediated by an ac-
celeration in its demethylation (it also increases xanthine oxidase activity) (Par-
sons and Neims, 1978~. Smoking cessation returns caffeine clearance rates to
nonsmoking values (Murphy et al., 1988~. A number of studies with rodents have
demonstrated an additive effect of caffeine and nicotine on both schedule-
controlled behavior and locomotor activity (Lee et al., 1987; Sansone et al., 1994;
White, 1988~. However, data in humans are scarce. Kerr et al. (1991) found both
caffeine and nicotine facilitated memory and motor function in a variety of psy-
chomotor tasks. Though there were differences across tasks, combining caffeine
and nicotine did not appear to produce a greater effect than either drug alone.
Conversely, nicotine did not decrease the effectiveness of caffeine.
The effects of caffeine on women have been examined in the context of its
effects on menstrual function, interactions with oral contraceptives, pregnancy
and fetal health, and postmenopausal health. Earlier studies suggested that
elimination of caffeine may vary across the menstrual cycle, with elimination
being about 25 percent longer in the luteal phase (Balogh et al., 1987~. More
recent studies, however, indicate no significant effects on caffeine pharmacoki-
netics across phases of the menstrual cycle in healthy, nonsmoking women who
are not using oral contraceptives (Kamimori et al., 1999~. Decreased paraxan-
thine or caffeine metabolic rates in healthy postmenopausal women on estrogen
replacement therapy suggest that exogenous estrogen in older women may in-
hibit caffeine metabolism through the P450 isozyme CYP1A2, an isozyme
common to both estrogen and caffeine metabolism (Pollock et al., 1999~. Addi-
tionally, it is known that oral contraceptive use can double caffeine half-life
(Abernathy and Todd, 1985; Patwar&an et al., 1980~. The effects of newer oral
contraceptives on caffeine half-life have not been studied.
OCR for page 29
PHARMACOLOGY OF CAFFEINE
29
PHYSIOLOGICAL EFFECTS
Caffeine administration affects the functioning of the cardiovascular, respi-
ratory, renal, and nervous systems. Proposed mechanisms of action differ for
different physiological effects. Caffeine action is thought to be mediated via
several mechanisms: the antagonism of adenosine receptors, the inhibition of
phosphodiesterase, the release of calcium from intracellular stores, and antago-
nism of benzodiazepine receptors (Myers et al., 1999~.
Caffeine and Adenosine Receptors
The ability of caffeine to inhibit adenosine receptors appears to be highly
important in its effects on behavior and cognitive function. This ability results
from the competitive binding of caffeine and paraxanthir e to adenosine receptors
and is of importance in contributing to CNS effects, especially those involving
the neuromodulatory effects of adenosine. Due to the blocking of adenosine in-
hibitory effects through its receptors, caffeine indirectly affects the release of
norepinephrine, dop amine, acetylcholine, serotonin, glutamate, gamma-
aminobutyric acid (GABA), and perhaps neuropeptides (Daly et al., 1999~.
There are two main classes of adenosine receptor: Al and A2; caffeine and
paraxanthine are nonselective antagonists at both, although they are not espe-
cially potent antagonists. The caffeine concentrations attained in viva that cause
mild CNS stimulation (5-10 EM) and that are associated with antiasthmatic
effects (50 EM), are in the range associated with adenosine receptor blockade
(as quantitated by in vitro receptor binding assays) (Daly, 1993~.
Caffeine and Phosphodiesterase
Caffeine increases intracellular concentrations of cyclic adenosine mono-
phosphate (cAMP) by inhibiting phosphodiesterase enzymes in skeletal muscle
and adipose tissues. These actions promote lipolysis via the activation of hor-
mone-sensitive lipases with the release of free fatty acids and glycerol. The
increased availability of these fuels in skeletal muscle acts to spare the con-
sumption of muscle glycogen. Increased cAMP could also lead to an increase in
blood catecholamines. However, caffeine is a fairly weak inhibitor of phos-
phodiesterase enzymes, and the in viva concentrations at which behavioral ef-
fects occur are probably too low to be associated with meaningful phosphodi-
esterase inhibition (Burg and Werner, 1975; Daly, 1993~.
In contrast, phosphodiesterase inhibition may account for caffeine's (and
theophylline's) cardiostimulatory and antias~rnatic actions, since nonxanthine
phosphodiesterases are cardiac stimulants (Schmitz et al., 1989) and are also
effective as bronchiolar and tracheal relaxants. Indeed, in the latter case, the po-
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30
CAFFE - EFORMENTAL TASKPE~O~ANCE
tency correlates with phosphodiesterase inhibition, not with affinity for adenosine
receptors (Brackett et al., 1990; Persson et al., 1982; Polson et al., 1985~.
Caffeine and Calcium Mobilization
The earliest proposed mechanism of action for caffeine involved the mobi-
lization of intracellular calcium. Certain actions of caffeine in skeletal muscle
appear to involve ionic calcium (Cam. Caffeine in high concentrations (1-10
mM) was found to interfere with the uptake and storage of calcium in the sarco-
plasmic reticulum of striated muscle and to increase the translocation of Cam
through the plasma membrane (Nehlig et al., 1992~. Caffeine may also increase
myofilamental sensitivity to Ca++ through its binding to ryanodine receptors in
calcium channels of muscle and brain (McPherson et al., 1991~.
Although caffeine has been shown to release calcium from intracellular
storage pools (sarcoplasmic reticulum) in skeletal and cardiac muscle, the
threshold concentration required in vitro to observe this effect (250 ~M) is sub-
stantially higher than the concentrations required in viva for cardiac stimulation
(50 ~M). Hence, this subcellular action of caffeine is probably physiologically
irrelevant (though it conceivably could be relevant at toxic concentrations of
caffeine) (Daly, 1993~.
Caffeine and Benzodiazepine Receptors
Caffeine modifies or antagonizes the effects of benzodiazepines on behavior
in both animals and humans (de Angelis et al., 1982; ME Mattila et al., 1992;
MJ Mattila et al., 1992~. The mechanism for this antagonism was proposed to be
the blocking of benzodiazepine receptors by caffeine. Caffeine does have weak
antagonistic properties at these receptors. However, this mechanism requires
very high concentrations of caffeine (Nehlig et al., 1987; Weir and Hruska,
1983~. More recent evidence (Lopez et al., 1989; Nehlig et al., 1992) suggests
that the interaction between caffeine and benzodiazepines is mediated through
caffeine's effects on adenosine receptors. There is some evidence that caffeine
may also be a histamine receptor antagonist (Acquaviva et al., 1986~.
General Effects of Caffeine on Physiological Functions
The effects of caffeine on sodium-potassium adenosine triphosphate pump
activity lead to a decrease in plasma potassium concentrations, and affect the
depolarization-repolarization process during exercise with potential effects on
fine motor coordination.
The effects of caffeine on the heart are primarily stimulatory and are ac-
companied by increased coronary blood flow. These effects are thought to be
mediated not by an action on adenosine receptors (Collie et al., 1984), but in-
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PHARMA COLOGY OF CAFFEINE
31
stead via phosphodiesterase inhibition. In the lungs caffeine can cause smooth
muscle relaxation and bronchial dilatation, possibly accounting for its antiasth-
matic effects. However, the relative roles of adenosine receptors and phosphodi-
esterase as mechanisms of caffeine's antiasthmatic actions remain unresolved
(Brackett and Daly, 1991; Ghai et al., 1987; Persson et al., 1982~.
The effects of caffeine on the kidney diuresis, increased blood flow, and
rennin secretion appear to be due to an action of caffeine at adenosine recep-
tors (Spielman and Arend, 1991~. Caffeine's behavioral effects appear to be
mediated both through adenosine receptors and phosphodiesterase effects and
can readily be seen on neurochemically specific neurons. Caffeine's stimulatory
action on dopamine, norepinephrine, serotonin, acetylcholine, glutamate, and
GABA neurons is hypothesized to result from its ability to block the action of
adenosine, which typically inhibits neuronal function. Phosphodiesterase inhibi-
tion by xanthines may also account for some stimulatory effects.
Interactions with other nutrients and drugs also characterize certain effects
attributed to caffeine. Such interactions include those associated with aspirin,
alcohol, nicotine, cocaine, certain other botanicals, and other narcotics (Callahan
et al., 1982; Falk and Lau, 1991; Kuribara end Tadokoro, 1992; Parsons and
Neims, 1978; White, 1999~.
The repeated administration of caffeine does not change its pharmacokinet-
ics, but in many cases development of tolerance does occur. Tolerance is not
observed for all effects of the drug, such as fat cell lipolysis (Holtzman et al.,
1991), but is seen for certain behavioral actions, such as some of its stimulant
properties (increase in locomotor activity in rats) (Finn and Holtzman, 1986~.
Following the cessation of caffeine use, withdrawal-like symptoms are some-
times seen in humans, such as headache, irritability, nervousness, and a reduc-
tion in energy (Griffiths et al., 1986, 1990~. The physiological bases for these
symptoms are not known. Although the development of withdrawal symptoms
might indicate an addictive property, caffeine does not have a convincing profile
as an addictive drug.
SUMMARY
Caffeine is rapidly and completely absorbed within an hour following inges-
tion. It is distributed throughout body water and readily crosses cell membranes
including the brain. Its primary mechanisms for stimulatory activity appear to be
the blocking of adenosine receptors and inhibition of phosphodiesterases. Caf-
feine is metabolized and excreted in humans primarily as paraxanthine, which
also has pharmacologic activity. With repeated caffeine dosing, paraxanthine may
contribute to development of tolerance and withdrawal symptoms. Caffeine
clearance rates are affected by both environmental and physiological factors, such
as use of oral contraceptives, smoking, and pregnancy. Tolerance to some of
caffeine's physiological affects develops with continued use.
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32
CAFFEINE FOR MENTAL TASK PERFORMANCE
A number of studies have reported on the effect of age on physiological and cognitive
responses to caffeine. Arciero et al. (1995) reported that caffeine ingestion (Sing/kg fat-free
mass) increased free fatty acids and tended to increase rate of appearance of fatty acids in
younger men (19-26 yr), but not in older men (65-80 yr); while norepinephrine kinetics and fat
oxidation were not affected by caffeine in either age group. Arciero et al. (1998) reported on
effects of caffeine ingestion (5 mg/kg fat-free mass) on blood pressure, heart rate, norepinephrine
kinetics, and behavioral mood in younger and older men. Resting baseline blood pressure was
significantly lower for younger men than for older men. Following caffeine ingestion, blood
pressure increased significantly above baseline for older men whereas it remained statistically
unchanged in younger men. Heart rates in both groups were unaffected by caffeine ingestion.
Norepinephrine kinetics (appearance and clearance rates) were not affected by caffeine in either
group, although older men had higher norepinephrine concentrations with caffeine. Older men
reported declines in feelings of tension and anger following caffeine ingestion, while younger
men reported increased feelings of anger.
Rees et al. (1999) examined the interaction of caffeine and age and found that 250 mg of
caffeine significantly decreased reaction times in both 20- to 25-year-olds and 50- to 65-year-
olds with no effect on word recall. In contrast, Hogervorst et al. (1998) evaluated the effects of
225 mg of caffeine on memory and memory-related processes in three age groups: young (20-34
y), middle-aged (4~54 y), and older (6~74 y). Short-term memory was negatively affected by
caffeine in the young group, positively affected in the middle-age group, and had no effect in the
older group. Jarvis (1993), in a large survey study on coffee and tea consumption, found that
when results for reaction time tests were categorized by age group (~34 y, 35-54 y; 55+ y),
caffeine intake had a greater performance-enhancing effect for older people (35-54 y, and 55+ y)
than younger people (] 6-34 y). The author hypothesized, that this greater sensitivity to caffeine
in older adults might be due to the fact that older people tend to operate further below their
ceiling than do the young. Alternatively, since the survey only measured coffee and tea
consumption the caffeine intake in the young group was more likely to be underestimated due to
much heavier cola and soft drink use in this age group (Jarvis, 1993~. Amendola et al. (1998),
using subjects in two age groups (l 8-30 y, and > 60 y), tested oral caffeine doses of 0, 64, 128,
and 256 mg and found a dose-dependent improvement in mood and performance on the modified
Wilkinson Auditory Vigilance Task that was not affected by age.
Thus, it would appear that caffeine effects on performance of vigilance types of tasks is
independent of age, while caffeine effects on memory-related tasks may be age-dependent.
COMPENSATION OF SLEEP DEPRIVATION IMPAIRMENTS
Effects of Sleep Deprivation on Cognitive Behavior
Military personnel face many situations in which extended wakefulness may be required,
including sentry duty, deployment-related activities, air transportation during emergencies,
submarine duty, and combat. As part of their duties in these situations, individuals may have to
perform complex cognitive tasks. The performance of these tasks is compromised during periods
of extended wakefulness. Sleep deprivation leads to a sequence of impairments in cognitive
functioning including decreases in alertness, decrements in mental performance and increases in
response reaction time (Kautz, 1999; Newhouse et al., 1989; Penetar et al., 1993, 1994; Wyatt,
~ 999~. These impairments include decreases in alertness, decrements in mental performance,
reductions in self-reports of vigor, and increases in sleepiness and fatigue.
Representative terms from entire chapter:
caffeine metabolism
