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TOLERANCE TO
CAFFEINE IN HUMANS
Tolerance refers to an acquired change in responsiveness of an individual as a result of exposure to drug such that an increased dose of drug is necessary to produce the same degree of response, or that less effect is produced by the same dose of drug. The development of tolerance is most unambiguously concluded from studies that compare full dose-response curves in the presence and absence of the tolerance-inducing manipulation (73). As reviewed elsewhere (62), preclinical research has clearly demonstrated tolerance to response-rate-decreasing, behavioral stimulant, and discriminative stimulus effects of caffeine, with the extent and rate of tolerance development differing across the different measures.
Information about the development of caffeine tolerance in humans is relatively easily obtained by measuring any pharmacological response before and after caffeine exposure. As described below, "complete" tolerance development (i.e., caffeine effects no longer different from placebo) has been demonstrated after repeated administration of relatively high caffeine doses spread across the day for a number of consecutive days. Beyond these demonstrations, however, detailed quantitative knowledge of caffeine tolerance in humans is quite fragmentary.
Tolerance to Caffeine Subjective Effects
Tolerance to the subjective effects of caffeine has been demonstrated only in one recent study (32), in which two groups of subjects received either caffeine (300 mg t.i.d.) or placebo (t.i.d.) for 18 consecutive days. During the last 14 days of chronic dosing, the caffeine and placebo groups did not differ meaningfully on ratings of mood and subjective effects. Furthermore, after chronic dosing, compared to placebo, caffeine (300 mg b.i.d.) produced significant subjective effects (including increases in tension-anxiety, jittery/nervous shaky, active/stimulated/energetic and strength of drug effect) in the chronic placebo group but not in the chronic caffeine group, suggesting the development of complete tolerance at these doses. Fig. 3 shows these effects for ratings of tension-anxiety and strength of drug effect.
Tolerance to Caffeine Sleep Disruption
Unambiguous evidence for the development of tolerance to caffeine sleep-disrupting effects is also quite recent. Although Colton et al. (21) showed that heavy coffee drinkers were less sensitive to the sleep-disturbing effects of caffeine than light coffee drinkers, the study design did not allow differentiation of tolerance from other preexisting differences between these self-selected subject populations. Two recent studies provided direct experimental evidence for caffeine tolerance to sleep disruption by demonstrating decreases in caffeine-induced disruption of objective measures of sleep after caffeine dosing of 250 mg b.i.d. for 2 days (111) or 400 mg t.i.d. for 7 days (8). By day 7 in the latter study, a number of sleep measures (e.g., total sleep time, sleep efficiency, number of awakenings) were no longer different from baseline, suggesting the development of complete tolerance at these doses.
Tolerance to Caffeine Physiological Effects
There is good evidence for decreased responsiveness to physiological effects of caffeine with repeated daily caffeine administration. Such tolerance development has been demonstrated to various physiological effects of caffeine, including diuresis (29), parotid gland salivation (108), increased metabolic rate (oxygen consumption) (8), increased blood pressure (2, 93), increased plasma norepinephrine and epinephrine, and increased plasma renin activity (93). Compared to a group that received placebo, complete tolerance to caffeine (250 mg t.i.d.) was demonstrated in 1-4 days on blood pressure, plasma norepinephrine and epinephrine, and plasma renin activity (93). Results consistent with these have been reported on other cardiovascular and physiological responses (2, 24), although whether complete tolerance development occurs has been questioned (24). The only human study to quantitatively assess the extent of caffeine tolerance by constructing dose-effect curves (as has been done frequently in infrahuman research) was a study that showed a two- to threefold decrease in the minimally effective dose required to produce diuresis after a period of abstinence from caffeine (estimated 170-340 mg/day) (29).
Parametric Determinants of Tolerance
Beyond the several demonstrations of complete tolerance development at high caffeine doses described above, there is little quantitative knowledge about the parameters that determine caffeine tolerance. As with the development of tolerance to most drugs, the degree of tolerance development to caffeine can be expected to depend on the caffeine dose, the dose frequency, the number of doses, and the individual's elimination rate (97). There is some indication that the rate and/or extent of tolerance development differ across different measures (8, 24). The rate of tolerance development has been estimated to be quite rapid for blood pressure [t1/2 = 1 hr (97)], with complete tolerance to various cardiovascular effects occurring in 2-5 days (2, 24, 93). Little is known about the rate of loss of tolerance except that it was shown to be rapid for blood pressure (t1/2 = 1 hr) in one study (97), but in another study (29) was suggested to be quite slow for caffeine-induced diuresis.
Relationship Between Caffeine Tolerance and Withdrawal
Tolerance and physical dependence are sometimes thought to be functionally interrelated, reflecting common neuroadaptive changes in response to repeated drug administration. The only relevant study to address this issue is the one described above that demonstrated tolerance to caffeine subjective effects in a group of subjects that received caffeine (300 mg t.i.d.) compared to a group that received only placebo (32). In that study, the group of tolerant subjects showed withdrawal (a time-limited elevation in headache) when switched to placebo compared to the nontolerant placebo group. Overall, this study provides only limited information suggesting the covariation of tolerance and withdrawal.
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Zmieniony przez - Grasik w dniu 2004-04-09 10:08:08