197185471 mk

Sagar Institute Of Pharmaceutical Sciences,Sagar(M.P.)
1
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INTRODUCTION:-
Caffeine is a bitter, white crystalline xanthine alkaloid and a stimulant drug.
Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants,
where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the
plants, as well as enhancing the reward memory of pollinators. It is most commonly
consumed by humans in infusions extracted from the seed of the coffee plant and the
leaves of the tea bush, as well as from various foods and drinks containing products
derived from the kola nut. Other sources include yerba maté, guarana berries, guayusa,
and the yaupon holly.
In humans, caffeine acts as a central nervous system stimulant, temporarily
warding off drowsiness and restoring alertness. It is the world's most widely consumed

2
psychoactive drug, but unlike many other psychoactive substances, it is legal and
unregulated in nearly all parts of the world. Beverages containing caffeine, such as
coffee, tea, soft drinks, and energy drinks, enjoy great popularity. In North America, 90%
of adults consume caffeine daily.
Caffeine is the most widely consumed central-nervous-system stimulant. Three
main mechanisms of action of caffeine on the central nervous system have been
described. Mobilization of intracellular calcium and inhibition of specific
phosphodiesterases only occur at high non-physiological concentrations of caffeine. The
only likely mechanism of action of the methylxanthine is the antagonism at the level of
adenosine receptors. Caffeine increases energy metabolism throughout the brain but
decreases at the same time cerebral blood flow, inducing a relative brain hypoperfusion.
Caffeine activates noradrenaline neurons and seems to affect the local release of
dopamine. Many of the alerting effects of caffeine may be related to the action of the
methylxanthine on serotonin neurons. The methylxanthine induces dose-response
increases in locomotor activity in animals. Its psychostimulant action on man is, however,
often subtle and not very easy to detect. The effects of caffeine on learning, memory,
performance and coordination are rather related to the methylxanthine action on arousal,
vigilance and fatigue. Caffeine exerts obvious effects on anxiety and sleep which vary
according to individual sensitivity to the methylxanthine. However, children in general do
not appear more sensitive to methylxanthine effects than adults. The central nervous
system does not seem to develop a great tolerance to the effects of caffeine although
dependence and withdrawal symptoms are reported.
Caffeine Vs Neurotransmitter:-
Caffeine is the most widely consumed central-nervous-system stimulant. Three
main mechanisms of action of caffeine on the central nervous system have been
described. Mobilization of intracellular calcium and inhibition of specific
phosphodiesterases only occur at high non-physiological concentrations of caffeine. The
only likely mechanism of action of the methylxanthine is the antagonism at the level of
adenosine receptors. Caffeine increases energy metabolism throughout the brain but
decreases at the same time cerebral blood flow, inducing a relative brain hypoperfusion.
Caffeine activates noradrenaline neurons and seems to affect the local release of
dopamine. Many of the alerting effects of caffeine may be related to the action of the

3
methylxanthine on serotonin neurons. The methylxanthine induces dose-response
increases in locomotor activity in animals. Its psychostimulant action on man is, however,
often subtle and not very easy to detect. The effects of caffeine on learning, memory,
performance and coordination are rather related to the methylxanthine action on arousal,
vigilance and fatigue. Caffeine exerts obvious effects on anxiety and sleep which vary
according to individual sensitivity to the methylxanthine. However, children in general do
not appear more sensitive to methylxanthine effects than adults. The central nervous
system does not seem to develop a great tolerance to the effects of caffeine although
dependence and withdrawal symptoms are reported.
Drug Profile:-
Sources: Caffeine is found in many plant species, where it acts as a natural pesticide,
with high caffeine levels being observed in seedlings still developing foliage but lacking
mechanical protection; caffeine paralyzes and kills certain insects feeding on the plant.
High caffeine levels have also been found in the surrounding soil of coffee bean
seedlings. Therefore, caffeine is understood to have a natural function as both a natural
pesticide and an inhibitor of seed germination of other nearby coffee seedlings, thus
giving it a better chance of survival. Caffeine has also been found to enhance the reward
memory of honeybees, improving the reproductive success of the plant.
Common sources of caffeine are coffee, tea, soft drinks and energy drinks, caffeine
supplements, and (to a lesser extent) chocolate derived from cocoa beans. Less
commonly used sources of caffeine include the yerba maté, guarana and ilex guayusa
plants, which are sometimes used in the preparation of teas and energy drinks. Two of
caffeine's alternative names, mateine and guaranine, are derived from the names of
these plants.
MOLECULAR MASS: - 194.19 g/mol
STRUCTURE:-

4
Systematic (IUPAC) name:1,3,7-Trimethyl-1H-purine-2,6(3H,7H)-dione
3,7-Dihydro-1,3,7-trimethyl-1H-purine-2,6-dione
MECHANISM OF ACTION:-
Caffeine's primary mechanism of action is as an antagonist of adenosine
receptors in the brain
Adenosine acts as an inhibitory neurotransmitter that suppresses activity in the
central nervous system. "Largely as a consequence of its blockade of adenosine
receptors, caffeine also has profound effects on most of the other major
neurotransmitters, including dopamine, acetylcholine, serotonin, and, in high doses, on
norepinephrine", and to a small extent epinephrine, glutamate, and cortisol. At high
doses, exceeding 500 milligrams, caffeine inhibits GABA neurotransmission. GABA
reduction explains why caffeine increases anxiety, insomnia, rapid heart and respiration
rate.

5
Because caffeine is both water- and lipid-soluble, it readily crosses the blood–
brain barrier that separates the bloodstream from the interior of the brain. Once in the
brain, the principal mode of action is as a nonselective antagonist of adenosine receptors
(in other words, an agent that reduces the effects of adenosine). The caffeine molecule is
structurally similar to adenosine, and is capable of binding to adenosine receptors on the
surface of cells without activating them, thereby acting as a competitive inhibitor.
Adenosine is found in every part of the body, because it plays a role in the
fundamental adenosine triphosphate (ATP) related energy producing mechanism and is
also needed for RNA synthesis, but it has additional functions in the brain. The evidence
indicates that brain adenosine acts to protect the brain by suppressing neural activity and
by increasing blood flow via receptors located on vascular smooth muscle. Brain
adenosine levels are increased by various types of metabolic stress, including lack of
oxygen and interruption of blood flow. There is evidence that adenosine functions as a
synaptically released neurotransmitter in some parts of the brain; however, stress-related
adenosine increases appear to be produced mainly by extracellular metabolism of ATP.
Unlike most neurotransmitters, adenosine does not seem to be packaged into vesicles
that are released in a voltage-controlled manner, but the possibility of such a mechanism
has not been fully ruled out.
Several classes of adenosine receptors have been described, with different
anatomical distributions. A1 receptors are widely distributed, and act to inhibit calcium
uptake. A2A receptors are heavily concentrated in the basal ganglia, an area that plays a
critical role in behavior control, but can be found in other parts of the brain as well, in
lower densities. There is evidence that A 2A receptors interact with the dopamine system,
which is involved in reward and arousal. (A2A receptors can also be found on arterial
walls and blood cell membranes.)
Beyond its general neuroprotective effects, there are reasons to believe that
adenosine may be more specifically involved in control of the sleep–wake cycle. Robert
McCarley and his colleagues have argued that accumulation of adenosine may be a
primary cause of the sensation of sleepiness that follows prolonged mental activity, and
that the effects may be mediated both by inhibition of wake-promoting neurons via A1

6
receptors, and activation of sleep-promoting neurons via indirect effects on A2A
receptors. More recent studies have provided additional evidence for the importance of
A2A, but not A1, receptors.
Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor. As a
competitive nonselective phosphodiesterase inhibitor, caffeine raises intracellular cAMP,
activates protein kinase A, inhibits TNF-alpha and leukotriene synthesis, and reduces
inflammation and innate immunity.
A number of potential mechanisms have been proposed for the athletic
performance-enhancing effects of caffeine. In the classic or metabolic theory, caffeine
may increase fat utilization and decrease glycogen utilization. Caffeine mobilizes free
fatty acids from fat and/or intramuscular triglycerides by increasing circulating
epinephrine levels. The increased availability of free fatty acids increases fat oxidation
and spares muscle glycogen, thereby enhancing endurance performance. In the nervous
system, caffeine may reduce the perception of effort by lowering the neuron activation
threshold, making it easier to recruit the muscles for exercise.
SOLUBILITY: - Caffeine Is Both Water- And Lipid-Soluble
Solubility of caffeine in organic solvents.
1.1octanol
2.PEG400
3.PEG400/water(25:75)vol
6.acetone
7.benzene

7
8.carbon tetrachloride
9.chloroform
10.dichloromethane
11.ethanol
12.ethanol/water(10:90)vol
21.ethyl acetate
MELTING POINT: - 235-237°C
UV/VISIBLE SPECTRUM:-

8
CAFFEINE THERAPEUTIC USE:-
1. Caffeine is widely consumed in beverages to obtain mild CNS stimulant effects.
2. Long term use produces tolerance to some of the pharmacological effects.
Withdrawal of caffeine, even from moderate intake levels, can produce symptoms such
as headache, fatigue and anxiety.
3. Caffeine is used therapeutically in combination with ergotamine for migraine
headaches and in combination with nonsteroidal anti-inflammatory drugs in analgesic
formulations.
4. Caffeine alone is used as a somnolytic, to treat various headache conditions,
respiratory depression in neonates, postprandial hypotension and obesity, and to
enhance seizure duration in electroconvulsive therapy.
5. In some headache and in pain paradigms, caffeine may produce direct adjuvant
analgesic properties, while in other headache conditions (perioperative, postdural
puncture)
6. caffeine may be effective by alleviating a manifestation of caffeine withdrawal.
7. Other uses, such as to promote wakefulness, for respiratory stimulation and
seizure prolongation, rely on central stimulant properties of caffeine.

9
8. Effects of caffeine on the vasculature may contribute to the relief of some
headaches and in postprandial hypotension. Blockade of methylxanthine-sensitive
adenosine receptors is the currently accepted mechanism of action of caffeine.
LITERATURE REVIEW OF CAFFEINE:-
Lenore Arab, (2013) A systematic literature review of human studies relating caffeine or
caffeine-rich beverages to cognitive decline reveals only 6 studies that have collected
and analyzed cognition data in a prospective fashion that enables study of decline across
the spectrum of cognition. These 6 studies, in general, evaluate cognitive function using
the Mini Mental State Exam and base their beverage data on FFQs. Studies included in
our review differed in their source populations, duration of study, and most dramatically
in how their analyses were done, disallowing direct quantitative comparisons of their
effect estimates. Only one of the studies reported on all 3 exposures, coffee, tea, and
caffeine, making comparisons of findings across studies more difficult. However, in
general, it can be stated that for all studies of tea and most studies of coffee and
caffeine, the estimates of cognitive decline were lower among consumers, although there
is a lack of a distinct dose response. Only a few measures showed a quantitative
significance and, interestingly, studies indicate a stronger effect among women than
men.
Innov Clin Neurosci., (2012) Caffeine is one of the most commonly consumed alkaloids
worldwide in the form of coffee, tea, or soft drinks, and in high doses may cause
abnormal stimulation of the nervous system as well as adverse effects in the
cardiovascular, hematologic, and gastrointestinal systems. With energy drinks becoming
a worldwide phenomenon, the short- and long-term effects of these beverages must be
evaluated more closely in order to fully comprehend the psychological impact of these
products.
S. Picone, (2012) The efficacy of caffeine in an episode of Apnoea of Prematurity (AOP)
has been known for over thirty years. Its use over long periods of time has not only found
it to be manageable within the field of neonatology, but it has also been found to have
other favourable actions, such as reducing the incidence of extubation failure, preventing
Bronchopulmonary Dysplasia (BPD), reducing the need for Patent DuctusArteriosus
treatment and the beneficial effect it has on Retinopathy of Prematurity. Recent in vitro

10
trials have highlighted the neuroprotective role that caffeine plays, which has already
partly been observed from in vivo trials. Just recently, caffeine citrate has become a
“label” drug and it would be beneficial if more studies could confirm the more significant
effects it has on the more severe conditions of prematurity.
Marina Machado Vilarim, (2011) This systematic review aimed to examine the results of
studies that have investigated the induction of panic attacks and/or the anxiogenic effect
of the caffeine challenge test in patients with panic disorder. The literature search was
performed in PubMed, Biblioteca Virtual em Saúde and the ISI Web of Knowledge. The
words used for the search were caffeine, caffeine challenge test, panic disorder, panic
attacks and anxiety disorder. In total, we selected eight randomized, double-blind studies
where caffeine was administered orally, and none of them controlled for confounding
factors in the analysis. The percentage of loss during follow-up ranged between 14.3%
and 73.1%. The eight studies all showed a positive association between caffeine and
anxiogenic effects and/or panic disorder.
SHINJI MIWA, (2010) Desmoplastic small round cell tumour (DSRCT) is a rare tumour,
usually arising in the abdominal cavity. DSRCT remains an aggressive malignancy, with
a poor prognosis despite multi-modality treatments. In the published literature, there has
been no patient who lived for three years or more without surgical excision. This report
describes a case of DSRCT arising from the brachial plexus and successfully treated
with caffeine-assisted chemotherapy. A 29-year-old male presented with pain and
numbness in his left forearm. Radiological findings were suggestive of malignant tumour.
Histology, immunohistochemical stain and fluorescence in situ hybridisation (FISH)
results confirmed the diagnosis of DSRCT. He underwent caffeine-potentiated
chemotherapy and the tumour disappeared. The tumour was not removed surgically as it
was intertwined in the brachial plexus. Four years after the initial diagnosis, no local
relapse and no distant metastases have been observed. Therefore, it is concluded that
caffeine-assisted chemotherapy should be one of the treatment options for DSRCT.
Melanie A. Heckman, (2010) Caffeine ranks as one of the top most commonly
consumed dietary ingredients throughout the world. It is naturally found in coffee beans,
cacao beans, kola nuts, guarana berries, and tea leaves including yerba mate. The total
daily intake, as well as the major source of caffeine varies globally; however, coffee and

11
tea are the 2 most prominent sources. Soft drinks are also a common source of caffeine
as well as energy drinks, a category of functional beverages. Moderate caffeine
consumption is considered safe and its use as a food ingredient has been approved,
within certain limits, by numerous regulatory agencies around the world. Performance
benefits attributed to caffeine include physical endurance, reduction of fatigue, and
enhancing mental alertness and concentration. Caffeine has also been recently linked to
weight loss and consequent reduction of the overall risks for developing the metabolic
syndrome. However, the caloric contribution of caffeine-sweetened beverages needs to
be considered in the overall energy balance. Despite all these benefits the potential
negative effects of excessive caffeine intake should also be considered, particularly in
children and pregnant women.
E. J. Waugh, (2009) There was good evidence that low body weight and post-
menopausal status are risk factors for low BMD. There was good or fair evidence that
alcohol and caffeine intake, and reproductive history are not risk factors. There was
inconsistent or insufficient evidence for the effect of calcium intake, physical activity,
smoking, age at menarche, history of amenorrhea, family history of OP, race and current
age on BMD.
C. H. S. Ruxton, (2008) The reputed benefits of moderate caffeine consumption include
improvements in physical endurance, cognitive function, particularly alertness and
vigilance, mood and perception of fatigue. In contrast, there are concerns that excessive
intakes increase the risks of dehydration, anxiety, headache and sleep disturbances.
This paper is a review of double-blind, placebo-controlled trials published over the past
15 years to establish what range of caffeine consumption would maximise benefits and
minimise risks for cognitive function, mood, physical performance and hydration. Of the
41 human studies meeting the inclusion criteria, the majority reported benefits associated
with low to moderate caffeine intakes (37.5 to 450 mg per day). The available studies on
hydration found that caffeine intakes up to 400 mg per day did not produce dehydration,
even in subjects undergoing exercise testing. It was concluded that the range of caffeine
intake that appeared to maximise benefit and minimise risk is 38 to 400 mg per day,
equating to 1 to 8 cups of tea per day, or 0.3 to 4 cups of brewed coffee per day. The
limitations of the current evidence base are discussed.

12
Katrina A. Bramstedt,(2007) Fair play, both in academics and sports, is a concept that is
challenged by the notion of performance enhancement. Both cognitive and physical
performance can be viewed as potentially enhanceable, and arguments can be made
that enhancement can serve two purposes: gaining an edge or keeping up with others
(who may or may not have used performance-enhancing substances). Caffeine, a central
nervous system and cardiac stimulant, is frequently used by children for both academic
and athletic performance enhancement. In fact, the marketplace contains a plethora of
caffeinated products marketed directly to children. This article examines safety and
ethical issues associated with the use of caffeine by children and explore the question:
Can cognitive performance enhancement be ethically permissible if sports performance
enhancement.
Sally Satel, (2006) The common-sense use of the term addiction is that regular
consumption is irresistible and that it creates problems. Caffeine use does not fit this
profile. Its intake does no harm to the individual or to society and its users is not
compelled to consume it. Though cessation of regular use may result in symptoms such
as headache and lethargy, these are easily and reliably reversed by ingestion of caffeine.
Some have argued that continued caffeine use is an attempt to suppress low grade
withdrawal symptoms such as sleepiness and lethargy. In some moderate users, this is
possible; however, in experimental contexts, the phenomenon is too inconsistent to
constitute a reliably valid syndrome.
RESEARCH ENVISAGED: -
Drug dependence has been defined as “a pattern of behavior focused on the
repetitive and compulsive seeking and taking a psychoactive drug” (Heishman and
Henningfield, 1992). However, it is necessary to demonstrate psychoactive effects to
differentiate drug dependence from other habitual or controlled behaviors, such as the

13
daily ingestion of medications. Moreover, it is necessary to demonstrate that the drug is
positively reinforcing its own ingestion. Caffeine is present in a number of dietary sources
consumed worldwide: tea, coffee, cocoa beverages. Recent studies reported that
caffeine injection increases the amount of self-administered cocaine while caffeine
drinking reduces it (Kuzmin et al., 1999, 2000). Thus, caffeine does not appear to be a
very robust reinforcer in animals. Also the development of tolerance to caffeine in
animals is rapid, usually insurmountable, and shows cross-tolerance. The content of
caffeine in these food items ranges from 71 to 220 mg/150 ml for coffee to 32 to 42
mg/150 ml for tea etc. Caffeine also has modest role against parkinsons disease and
some of the cancers. The purpose of the present work is to establish the central nervous
system activity of caffeine in combination with rutin to nullify the aforementioned
drawbacks.
PLAN OF WORK:-
1. Exhaustive literature survey.
2. Pharmacological screening.
 2.1. Assessment of locomotor activity in mice.
 2.2 Assessment of pentobarbital sleeping time in rats.
 2.3 Hole board test for exploratory behavior in mice.
 2.4 Test for motor coordination (Rotarod test in mice).
 2.5 Apomorphine induces stereotyping studies in mice.
3. Interpretation of data and statistical analysis.
4. Submission of thesis.
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Signature …………………………
Candidate Name: Mithun Khatik
Enrollment No. 0602PY12MP34

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