Caffeine and the Methylxanthines

1
Caffeine and the Methylxanthines
xanthine stimulants (methylxanthines) caffeine,
theophylline and theobromine. Main natural
sources tea, coffee, chocolate Caffeine first
isolated in 1820
2
Dietary sources of xanthines
Also Energy drinks like Red Bull
Caffeine content link
3
Coffee Coffee is made from the fruit of a bush
or small tree of the genus Coffea. The two most
common species are the arabica and the canephora
(also called robusta), Native of Ethiopia. But
now grown primarily in South America. The coffee
bean is the seed of the cherry which is dried and
roasted.
The roasted beans are ground and mixed with
boiling water. A cup of coffee may contain
between 40 and 176mg of caffeine, but average is
normally taken to be about 100 mg/ 5 oz cup.
4
Tea leaves of Camellia sinensis,
median of 27 mg per 5-ounce cup with a range of 8
to 91 mg. Also contains theophylline and
theobromine
5
Cocoa Cocoa is made from seeds found in the
seedpods of the cacao tree, Theobroma cacao,
which is native to the dense, tropical Amazon
rain forest.
Made from seeds found in the seed pods that grow
from the trunk and limbs
Cocao refers to the tree and the seeds cocoa
refers to the processed products of the bean Do
not confuse with coca the plant that is the
source of cocaine
Ground beans are pressed to remove cocoa butter
and alkalized. Then mixed with sugar, cocoa
butter and milk solids to make chocolate. One oz
sweet chocolate may contain between 75 and 150 mg
of combined theobromine and caffeine.
First used by Incas, Mayans and Aztecs of South
America
6
Other natural sources Ilex plant of the Amazon
region of South America. ilex plant, Ilex
paraguayensis, is a holly that contains between 1
and 2 percent caffeine. It is made into a
tea-like drink called maté
Ilex vomitoria, of North America from which a
beverage known as youpon, cassinatea, or black
drink is made.
Maté gourd
Gurana Guarana is a paste made from the seeds
of Paullaina cupana, from South America, which,
at 2 to 6 percent caffeine, is the most potent of
the natural sources of caffeine. The paste is
molded into sticks or bars or even sculptures and
dried in the sun. For use, it is powdered and
mixed with water. Because it has an acrid taste,
like chocolate, it is usually sweetened with
sugar. Now made into energy drinks
7
HISTORY Coffee A traditional drink in Ethiopia
and eventually found its way to Europe in the
1600s where it was consumed in coffee houses and
developed a tradition of intellectual
stimulation. Tea became more popular in England,
but coffee remained the drink of choice in Europe.
Tea Originated in China and discovered by
Europeans in the early 1600s. Became fashionable
in England and its North American Colonies . A
tea tax in the 1700s was one if the sparks for
the American Revolution
8
Cocoa Used by South American civilizations where
it was a drink of the gods (theobroma). Believed
to be an aphrodisiac. Introduces to the Spanish
court by Cortés in 1520. It enjoyed a brief
popularity before coffee took over. Chocolate was
expensive and used by wealthy and nobility.
Became cheaper but never was popular as a
beverage. Widely used as a confection. Most
chocolate now grown in West Arica.
9
Route of Administration is almost always oral
Absorption Absorbed through stomach and
intestine. Bases with pKa 0.5. so no
ionization, therefore can be absorbed from
intestines. Food slows absorption rate Peak
levels between 30-60 min although variable
Distribution. Crosses brain and placental
barriers and is found in all body fluids.
Excretion almost all is concerted to
metabolites. Different pathways for different
animals and humans of different ages. Half-life
3.5 hrs although variable between
individuals. Slowed by alcohol Sensitive to
female hormone levels, slower after ovulation
during pregnancy and while taking oral
contraceptives.
10
Neurophysiology. Adenosine receptor blockers.
Blocks A1 and A2a adenosine receptors.
Adenosine is an inhibitory neuromodulator Blocks
benzodiazepine receptors at higher doses. Causes
the release of catecholamines
Chocolate also contains substances that are
similar to anandamide, the naturally occurring
substance that works at the cannabinoid receptor.
11
Effects on Body Sympathetic arousal caused by
release of catecholamines Smooth muscles
(involuntary) relax and striated muscles
(voluntary) are strengthened. Dilation of bronchi
and peripheral blood vessels. Theophylline used
to treat asthma. Striated muscle strength due to
increased fatty acid metabolism. Constriction of
blood vessels in the brain used to treat
headache caused by high blood pressure..
Stimulates respiration centres in the medulla
12
Effects on Performance and Behavior Traditionally
believed to be an intellectual stimulant and
clarify and speed thought, but there is little
evidence of this. Mostly a result of improved
mood and inaccurate assessment of abilities.
Can improve performance on a range of activities,
but main effect id to reduce the effect of
fatigue and boredom. Improves mood and attitude
toward the task. Seems coffee breaks are
useful. These findings may be a result of relief
from caffeine withdrawal.
13
Athletic performance Caffeine can improve
performance in events that require sum maximal
effort for an extended period of time such as
cycling and cross-country skiing. Due to
increased fatty acid metabolism.
High blood levels of caffeine ( 12 mg/litre)
were banned by IOC and one athlete was banned in
the 1988 summer Olympics in Seoul (a member of
the Australian Pentathlon team) The World
Anti-Doping agency lifted this ban in 2004.
14
Sleep Increases the stability of wakefulness.
Increases the time to sleep and decreases
sleeping time. Lowers acoustic arousal
threshold. Individual variability due to
tolerance levels Can counteract the effects of
sedative-hypnotic drugs (sleeping pills)
15
Behavior of Nonhumans Increases Spontaneous Motor
Activity, but decreases SMA after long term
exposure. LD50 250mg/Kg i.p. due to
convulsions Death may also be due to
automutilation
Operant and respondent behavior Pavlov found that
caffeine disrupted discriminations dogs
responded to S- (negative) stimulus as though it
were an S. Effects on operant behavior similar
to psychomotor stimulants like amphetamine.
Probably a result of catecholamine
release. Increases avoidance responding like
amphetamine, but may also increase punishment
suppressed responding (unlike amphetamine).
16
Discriminative Stimulus Properties Caffeine s an
effective discriminative stimulus. Generalizes to
lower doses of caffeine and higher doses of
theophylline, but not nicotine.
Low doses, but not high doses, generalize to
cocaine and amphetamine. DA receptor blockers
block discrimination of caffeine. Turkey Drugs
drugs that are legal, but sold as a controlled
substance, sometimes even advertised. They
contain caffeine, ephedrine, phenylpropanolamine
in various combinations. This combination of
drugs can mimic the effect of 10 mg/kg
cocaine. Some humans can discriminate the effects
of caffeine at very low doses, 1.8 mg, but others
are less sensitive 178 mg. Theophylline is less
detectable.
17
Subjective Effects Causes positive effects,
alertness, well-being, energy, motivation and
self-confidence.
These effects are seen in users who had abstained
as well as nonusers. More likely at low doses
(20-200 mg) higher doses are unpleasant. Rated
more pleasant in those for whom caffeine is a
positive reinforcer. With a 178 mg dose, effects
start within 30 min and last fore 8
hrs Theophylline same effect, but less intense
and followed by headache and lethargy. IV
infusions rated as cocaine by experienced street
drug users
18
Tolerance Some tolerance seems to be due to an
upegulation to adenosine receptors. With operant
responding in rats, the DRC was shifted to the
right by a factor of 6 after chronic
treatment. Heavy coffee drinkers are less
sensitive to the adverse effects of 300 mg dose
than nondrinkers This could be due to selection
rather than tolerance. In humans cardiovascular
effects go 2-5 days Increased urination may never
show tolerance. Sleep disrupting effects fade
after 7 days Most effects are gone within a week.
19
Withdrawal Drowsiness, decreased energy fatigue
and most frequently, headache
People also report decreased motivation for work
and impaired concentration, decreased feelings of
well-being and self-confidence, increased
irritability, and flu-like feelings such as aches
and muscle stiffness, hot and cold spells, heavy
feelings in the limbs, and nausea.
600mg.day dependence within 6-14 days. It takes
longer with 100g/day Start 12-28n hrs, peak
29-51hrs last 2-9 days
20
Griffiths, et al, 1990
Changes in frequency of reported headaches and
scores on an energy/active scale of subjects
for 24 days while they consumed 100-mg caffeine
capsules, then a placebo, and then switched back
to caffeine. Caffeine withdrawal caused increases
in reported headaches and a decrease in energy
and activity that lasted as long as a week.
(From Griffiths et al., 1990)
21
27-52 of coffee drinkers experience caffeine
withdrawal if they go without coffee for 24
hrs. Coffee withdrawal may be responsible for
headaches and fatigue seen when normal diet is
disrupted, eg holidays, hospital diets and
fasting. Caffeine withdrawal is an official
diagnosis in the DSMIV-TR (2000) and the ICD-10.
Is caffeine withdrawal real? Some say it is a
placebo effect and an expectation.
(International Life Sciences Institute vs. Roland
Griffiths et al.
Caffeine is put in many analgesics
22
Caffeine Self-Administration in nonhumans Not a
robust reinforcer in nonhumans. Usually requires
a period of forced consumption. Responding
erratic
Baboon with experience administering stimulants
on an FR2 for caffeine (Griffiths and Mumford,
1995)
Caffeine will potentate the reinforcing effects
of cocaine and serve as a primer for cocaine
self-administration.
23
Caffeine Self-Administration in Humans Regular
caffeine consumers permitted to use coffee for a
week will prefer caffeinated coffee. If denied
coffee consumption for one week (not dependent)
results are variable. Preference for caffeine
pills and caffeinated coffee greatly facilitated
by caffeine dependence. People seeking coffee and
avoiding withdrawal symptoms. Individual
variation people who report positive subjective
effects prefer caffeine and those who report
negative effects avoid it. 100 mg doses are
preferred, but 400-600 mg doses are
avoided. Caffeine preference enhanced when
followed by a vigilance task and diminished when
followed by a relaxation task. Demand inelastic,
slope between -0.23 and -0.51. Related to
Cigarette consumption.
24
Caffeine Dependence Syndrome Is it possible to be
diagnosed Caffeine Dependent according to the
DSM? Yes. One study interviewed 16 people who
believed they were dependent on caffeine. Of
these 16, 94 percent reported withdrawal 94
percent reported use continuing despite knowledge
of persistent or recurrent physical or
psychological problems likely to have been caused
or exacerbated by caffeine use 81 percent
reported persistent desire or unsuccessful attempt
s to cut down or control use 75 percent
reported tolerance. Daily dose ranged from
129-2548 mg caffeine/day. 7 drank soft drinks, 1
drank tea and the rest drank coffee.
25
Average world consumption of caffeine is
70mg/person/day. 90 consumed as coffee and
tea. North American consumption is 200
mg/person/day and 230 mg/day total methyxanthines
26
Harmful Effects Reproduction
caffeine consumption lowers birth weight in
humans if exceeds 300 mg per day. caffeine will
potentate the effect that smoking has on reducing
birth weight. More than four cups of coffee per
day during pregnancy increases the risk of SIDS
(sudden infant death syndrome) Caffeine
metabolism slowed during pregnancy. This
increases caffeine exposure of mother Found in
breast milk. Women who are pregnant and nursing
should not consume caffeine.
27
Cardiac Disease Conflicting results in large
scale studies. Epidemiology difficult with
caffeine studies. It is difficult to accurately
measure consumption.
Cancer Conflicting epidemiological findings.
Duration of consumption may be an important
variable (more than 40 years). Coffee (both
caffeinated and decaf) may enhance the risk of
pancreatic cancer only in smokers. Bone
Density daily consumption of two to three cups of
coffee accelerates bone loss in the spine and
body of postmenopausal women who consumed less
than the recommended daily dietary source of
calcium.
28
Abnormal behavior Caffeinism 5 to 10 cups per
day, caffeine can cause sensory disturbances such
as ringing in the ears and flashes of light, as
well as mild delirium and excitement.
Similar to anxiety neurosis Symptoms include
flushing, chilliness, insomnia, irritability,
irregular heartbeat, and loss of appetite.
Unlike anxiety neurosis, does not respond to
treatment with tranquilizers. Caused by blocking
of benzodiazepine receptors Worsens symptoms of
both neurotic and psychotic disorders and
interferes with the effectiveness of
psychotherapeutic medicines.
NASA Technical report, 1995, David Noever
29
What do we really know about Caffeine?
Under the guise of public interest, the industry
actively supports continuing research on
noncaffeine constituents of coffee, knowing fully
that nothing untoward (and nothing of particular
interest to the public) is likely to be revealed
(J. J. James, 1994, p. 1579).