Introduction

Caffeine is a methylxanthine whose primary biologic effect is

antagonism of the adenosine receptor.That can also acts as a mild central nervous

system stimulant. Caffeine is the most widely consumed drug in Western society. It belongs to a class of organic compounds called alkaloids, which also include morphine, codeine, LSD, cocaine and nicotine.{1}
.
1. Carbon.
2. Hydrogen.
3. Nitrogen.
4. Oxygen.

Structure of caffeine,(1,3,7-trimethylxanthine ,C8H10N4O2)
Coffee was first discovered around 850 A.D. Caffeine sensitivity varies

from person to person. Several factors may be involved in increased sensitivity to

caffeine.They are Body mass , age, smoking habits, medication or hormone use, and

health conditions such as anxiety disorders. . Although age may play some role in a

person’s sensitivity to caffeine, most studies have shown that caffeine affects children

and adults in a similar manner.The intake of caffeine-containing beverages in many

Derivation of caffein

Its presence in coffee, tea, soda beverages, chocolate, and many

prescription and over-the-counter drugs makes it the most commonly consumed stimulant

drug.Below table shows other foods which containing caffeine.

Caffeine
Dark (semi-sweet) chocolate, 1 oz. 5 to 35
Unsweetened chocolate, 1 oz. 26
Milk chocolate, 1 oz. 1 to 15
Coffee flavored yogurt, 6 oz. 35
Coffee ice cream, 1/2 cup 20 to 30
Chocolate ice cream, 1/2 cup 2
Beverage Caffeine
Brewed coffee, 8 oz. 60 to 160
Instant coffee, 8 oz. 30 to 120
Espresso, 2 oz. 100
Brewed imported tea, 8 oz. 25 to 110
Brewed American tea, 8 oz. 20 to 90
Energy drinks, 8 oz. 35 to 90
Functional waters, 8 oz. 20
Iced tea, 8 oz. 6 to 60
Caffeinated water, 8 oz. 30 to 60
Soft drinks or soda, 8 oz. 15 to 50
Instant tea, 8 oz. 24 to 31
Chocolate milk, 8 oz. 2 to 7
Decaffeinated coffee, 8 oz. 2 to 4
Medication Caffeine
Aspirin, 1 tablet 0
Appetite suppressant, 1 tablet
200
Medication to help people stay alert,
1 tablet 100 to 200
Phenylpraponolanine Hcl 30
acetominophen 32
Propoxyphene Hcl 32.4

The medical literature dealing with developmental and reproductive risks of caffeine was

reviewed, and the biological plausibility of the epidemiological and animal findings, as

well as the methods and conclusions of previous investigators, were evaluated.Also The

the effect of caffeine level in tea and coffee on acute physiological responses and mood

In addition to that Coffee is often perceived as producing greater pharmacological effects

than cola. The present study compared the magnitude and rapidity of peak caffeine levels

and subjective effects between coffee and cola.

Epidemiologic risk of caffeine .
Coffee and/or caffeine consumption has been linked to {8}many human diseases in

epidemiologic studies. Causal relationships have been difficult to substantiate. Initial

investigations, showing an association between coffee and{2}coronary heart disease,

suffer from confounding variables and have been difficult to replicate. Recent studies,

showing a significant effect over long follow-up periods and with high coffee intake,

have again raised the question of a role for coffee and/or caffeine consumption in the

pathogenesis of atherosclerotic heart disease. Contrary to common belief, the published

literature provides little evidence that coffee and/or caffeine in typical dosages

increases the risk of infarction, sudden death or arrhythmia.

Also; The epidemiological studies describe exposures of women to caffeine during
pregnancy, as well as the occurrence of congenital malformations, fetal growth
retardation, small-for-date babies, miscarriages (spontaneous abortions), behavioral
effects, and maternal fertility problems that presumably resulted from the caffeine
consumption. A few epidemiological studies were concerned with the genetic effects of
preconception exposures to caffeine. Animal studies, conducted mostly in pregnant rats
and mice, were designed to produce malformations. The objectives of the present review
are to summarize the findings from the various clinical and animals studies, objectively
discuss the merits and/or faults inherent in the studies and establish a global
reproductive risk assessment for caffeine consumption in humans during pregnancy. It
should be noted that evaluation of the developmental risks of caffeine based solely on
epidemiological studies is difficult because the findings are inconsistent. Even more
important, is the fact that caffeine users are subject to multiple confounding factors that
make analyses difficult and prevent investigators from reaching definitive conclusions.
For example, the caffeine content of foods and beverages can vary considerably, which
can interfere with obtaining valid interpretations from many human studies. Isolated
epidemiological studies dealing with the risk of abortion, without evaluating other
developmental and reproductive effects, are the most difficult to interpret, because they
present special problems that are sometimes ignored in epidemiological studies. The
results of animal studies are probably most helpful in solving some of the dilemmas
created by the epidemiological studies. An animal study reported in 1960 first focused
our attention on the potential developmental effects of caffeine. However, the exposure
reported by Nishimura and Nakai (’60) was an intraperitoneal dosage of 250 mg/kg in

the mouse, an extremely high dosage that would result in a blood plasma level that
could never be obtained from consuming caffeine containing products. More recent
animal studies have demonstrated, that depending on the method of administration and
species, the developmental NOEL in rodents is approximately 30 mg/kg per day, the
teratogenic NOEL is 8,100 mg/kg per day, and the reproductive NOEL approximately
80-120 mg/kg per day. Lack of biological plausibility to support the concept that
caffeine has been responsible for human malformations is another important part of this
analysis. For example, no one has described the Caffeine “teratogenic syndrome,” a
cluster of malformations associated with caffeine ingestion. Proven human teratogens
have an identifiable syndrome. The malformations described in the animal studies at
very high doses fit the description of vascular disruptive types of malformations.
.Advers effect of the caffein

Ninety-nine percent of ingested caffeine is absorbed and distributed to all tissues and

organs. The effects of caffeine intake differ greatly according to acute or chronic intake,

level of intake, and the development of tolerance. Caffeine administered acutely to non-

users or recent abstainers can induce hypertension, arrhythmias, altered myocardial{5}

function, increased plasma catecholamine levels, plasma renin activity, serum cholesterol

levels, increased production of urine, gastric acid secretion, and alterations in mood and

sleep patterns.Tolerance to chronic caffeine intake develops in most individuals,with the {4}
cessation of its effects on the renal system, the cardiovascular system, the gastrointestinal

system and, to some extent, the central nervous system. Moderate caffeine consumers

probably need to have little concern for the effect of caffeine intake on their health if their

other life-style habits are also moderate.

Caffeine is probably the most frequently ingested pharmacologically active substance in
the world.. Because of its wide consumption at different levels by most segments of the
population, the public and the scientific community have expressed interest in the
potential for caffeine to produce adverse effects on human health. The possibility that
caffeine ingestion adversely affects human health was investigated based on reviews of
(primarily) published human studies obtained through a comprehensive literature search.
Based on the data reviewed, it is concluded that for the healthy adult population,{3}
moderate daily caffeine intake at a dose level up to 400 mg day(-1) (equivalent to 6 mg
kg(-1) body weight day(-1) in a 65-kg person) is not associated with adverse effects such
as general toxicity, cardiovascular effects, effects on bone status and calcium balance
(with consumption of adequate calcium), changes in adult behaviour, increased incidence
of cancer and effects on male fertility. The data also show that reproductive-aged women
and children are ‘at risk’ subgroups who may require specific advice on moderating their
caffeine intake. Based on available evidence, it is suggested that reproductive-aged
women should consume day(-1) for a 65-kg person) while children should consume Coffee is consumed in large quantities worldwide and any adverse effects would likely
have important public health consequences. Because of the widespread exposure to
coffee and other caffeine-containing beverages and because teratogenic effects of
caffeine have been recorded in several species since 1960, women are concerned that
there may be reason to limit their intake of coffee when pregnant. Several human studies
on birth defects have been conducted and the overall results do not implicate coffee as a
likely human teratogen. However, there is some evidence that consumption of three or

more cups of coffee per day may have a modest effect on lowering infant birth weight.
Studies of coffee consumption and increased rates of spontaneous abortion and delayed
time to conception are inconsistent and conclusions cannot yet be drawn.

The health effects of caffeine have been examined in a review of its toxicological and

pharmacological properties together with its effect on children. Caffeine commonly

causes symptoms of an acute overdose and withdrawal symptoms. These may be

identified as anxiety in moderate consumers and can lead to severe central nervous

system effects in heavy consumers. Pharmacological effects occur even at low doses but

their severity is influenced by wide individual variation and the development of

tolerance. Nevertheless, chronic consumption of caffeine is implicated in various minor

symptoms of ill health and is associated with elevated serum cholesterol levels. At the

doses that are consumed by humans, there is little evidence at present to suggest effects

on reproduction, teratogenesis, tumour formation or the incidence of myocardial

infarction. A reduced consumption of caffeine is advocated for all age groups.{7}

In addition to that ;Initially caffeine increases blood pressure, plasma catecholamine

levels, plasma renin activity, serum free fatty acid levels, urine production, and gastric

acid secretion. Its long-term effects have been more difficult to substantiate. Most of the

caffeine consumed is in coffee, which contains many other chemicals that may have other

biologic actions. The consumption of coffee is a self-reinforcing behavior, and caffeine

dependence and addiction are common. Coffee and caffeine intake have been linked to

many illnesses, but definitive correlations have been difficult to substantiate. Initial trials

showing coffee’s association with coronary disease and myocardial infarction have been

difficult to reproduce and have many confounding variables. Recent studies showing a

larger effect over long follow-up periods and with heavy coffee consumption have again

brought the question of the role of coffee in disease states to the fore. Caffeine in average

dosages does not seem to increase the risk of arrhythmia{6}. At present there is no

convincing evidence that caffeine or coffee consumption increases the risk for any solid

tumor. The intake of coffee and caffeine has clearly been decreasing in this country over

the past two decades, largely brought about by the increasing health consciousness of

Americans. Although there have been many studies that hint that the fears of increased

disease with coffee drinking may be warranted, many questions have yet to be answered

about the health effects of coffee and caffeine use.
coffee or caffeine dose, despite a fourfold variation in the Increasing beverage strength
was associated with greater increases. in DBP and energetic arousal. In study 2,
caffeinated beverages increased SBP, DBP, and skin conductance and lowered heart rate
and skin temperature compared to water. Significant dose-response relationships to
caffeine were seen only for SBP, heart rate, and skin temperature. There were
significant effects of caffeine on energetic arousal but no consistent dose-response
effects. Caffeinated beverages acutely stimulate the autonomic nervous system and
increase alertness. Although caffeine can exert dose-dependent effects on a number of
acute autonomic responses, caffeine level is not an important factor. Factors besides
caffeine may contribute to these acute effects,
It alters the electroencephalographic spectrum, mood, and sleep patterns of normal
volunteers. Chronic caffeine consumption has no effect on blood pressure, plasma
catecholamine levels, plasma renin activity, serum cholesterol concentration, blood
glucose levels, or urine production. Caffeine does not appear to be useful for increasing
the motility of hypomotile sperm in artificial insemination or in the therapy of minimal

brain dysfunction, cancer, or Parkinson’s syndrome, but it may be effective as a topical
treatment of atopic dermatitis and as systemic therapy for neonatal apnea. Caffeine does
not seem to be associated with myocardial infarction; lower urinary tract, renal, or
pancreatic cancer; teratogenicity; or fibrocystic breast disease. The role of caffeine in
the production of cardiac arrhythmias or gastric or duodenal ulcers remains uncertain.
Sprint and power performance

Research evidence on the effects of caffeine ingestion on sprint and power performance

is limited and inconclusive by comparison with the large volume supporting its use with

endurance athletes. And any beneficial effects on power performance are likely to be

most marked in trained athletes.{8}

A precise explanation for the ergogenic effects of caffeine remains elusive. It is likely

that the enhancement in endurance capacity results from caffeine’s ability to facilitate the

use of fat as an exercise fuel, thus sparing the body’s limited carbohydrate reserve.{9}

Caffeine’s facilitating effect on neuromuscular activity is thought to be responsible for

any improvement in short duration, high intensity exercise.{11}

Irrespective of the mode of exercise, many research subjects have reported lower levels

of perceived exertion and localised muscular fatigue following caffeine ingestion, which

will undoubtedly have boosted their performance capacity.{10}

It would be remiss not to mention at this stage that athletes who normally avoid

caffeine may experience adverse effects if they start using it as an ergogenic aid. Many

of these side effects are well known and include anxiety, gastrointestinal disturbances,

restlessness, insomnia, tremors and heart arrhythmias. The scientific literature suggests

that the risk of such side effects is increased if caffeine is taken in doses higher than 9mg

per kg of body mass.{12}

In addition, caffeine can act as a diuretic, which could lead to an unnecessary pre

exercise loss of fluid, with negative knock-on effects on thermal balance and exercise

performance, particularly in hot environments. However, this diuretic effect is reduced

when caffeine is consumed during exercise, which helps to explain why some athletes

rely on defizzed cola during events.The ergogenic effects of caffeine vary greatly, but

are most predictable in trainedathletes.{12}

Athletes should also be aware that beneficial effects do not occur consistently in habitual

caffeine users, suggesting a level of ‘caffeine tolerance’. One way round this may be for

caffeine users to shun all caffeinated foods and drinks for a period of 4-6 days prior to

pre-event supplementation in order to optimise its benefits.{10}
Physiological and Pharmacological effects

The largest sources of caffeine are from the plants used to make coffee, tea, cocoa and

kola (the basis of cola beverages), although it is also found in Latin America as mate’ and

guarana. Caffeine particularly has a profound effect on the central nervous system, but it

also affects, to a lesser degree the heart muscle, gastric secretion and diuresis.

Interestingly, caffeine is ingested daily by a vast number of people and is unique in that

it is a potent drug, considered to be part of our normal diet.

Caffeine stimulates the central nervous system first at the higher levels, the cortex and

medulla, and finally the spinal cord at higher doses. Mild cortex stimulation appears to be

beneficial resulting in more clear thinking and less fatigue. Caffeine has been shown to

improve attention in a study which simulated night driving {19} The onset of

the effect of caffeine occurs within one hour and lasts for three to four hours {17}

The equivalent of one or two cups of coffee (150 to 250 mg of caffeine) is sufficient to

induce adverse effects. The occurrence of hyperesthesia, an unpleasant sensory sensation,

can be stimulated by large doses of caffeine.

The medullary, respiratory, vasomotor and vagal centers are stimulated by caffeine. This

effect is due to an increased sensitization to carbon dioxide but needs large doses to elicit

this effect, 150 to 250 mg, parenterally. The spinal cord is stimulated at higher doses and

convulsions and death may result. More than 10 g are needed for such toxicity to occur in

man {20}

Stimulation of the CNS is followed by depression{25}, although the effect is small at low

doses e.g. a single cup of coffee. After two hours, Klein reported that males (but not

females) showed a lower CNS stimulation compared to placebo. The post stimulation “let

down” with caffeine results in fatigue and lethargy and the constant stimulation caused by

chronic caffeine dosing could be disastrous{13};

Children, because of their smaller size, are more susceptible to caffeine. One report noted

that hyperactivity and ir~somnia observed in children could be attributed to excess

caffeine intake from cola drinks.

“There is no doubt that children should be kept from using coffee and the popular

caffeine containing soft drinks.” {13}

Caffeine’s effect on the cardiovascular system is less profound than its central nervous

system action. Its direct stimulatory effect on the heart may be neutralized by its central

vagus stimulation. The direct effect predominates at very large doses with tachycardia

and, eventually, arrythmias resulting. Caffeine’s ability to potentiate cyclic AMP can

explain its ability to potentiate ionotropic responses to B-adrenergic agonists and

glucogon {20}Although caffeine dilates blood vessels by a direct action, its central effect

is one of constriction. At higher doses, the dilating effect is apparent {26}

Similarly, because its direct and central effects are antagonistic, the resultant effect of

caffeine on blood pressure is unpredictable. The net effect is usually of less than 10 mm

of Hg in blood pressure {20} Caffeine’s purported efficacy in hypertensive headaches

may be due to a decrease in blood flow as a result of the increased cerebral resistance {20}
Caffeine also stimulates releases of catecholamines from the adrenal medulla and

norepinephrine is released from nerve endings in the isolatA heart {18}

It has been shown that prolonged augmentation of gastric ‘secretion results from caffeine

administration and that ulcer patients have sustained elevation of acid as opposed to

normals {20}Although a dose of approximately 10 g or more taken orally can be fatal, an

oral (3.2 g IV) one gram dose will cause adverse effects The toxic effects are

due to CNS and circulatory system stimulation and include some well recognized

prominent symptoms in addition to those which can result at high doses or in

hypersensitive persons: insomnia, restlessness, excitement, tinnitus, flashes of light,

quivering muscles, tachycardia, extrasystoles, and even low grade fever and mild

delirium have been observed.

Although caffeine is well absorbed when taken orally, its absorption may be erratic

because of its low solubility and because it may cause gastric irritation. Caffeine is

principally metabolized with only 10 percent excreted in the urine unchanged{20}

Caffeine has a physiological half-life of three and a half hours to six hours {16} Its

physiological effects are observed in less than one hour{24}. Infants do not metabolize

caffeine as well as adults and thus have a half-life of about four days {16}Certainly,

continuous ingestion of caffeine by infants can be dangerous. If a cup of coffee is

consumed by an adult six or seven times a day it would result in a high steady

concentration of caffeine in the blood. As little as four cups a day can result in

appreciable omnipresent amounts of caffeine in the body.

Caffeine can accumulate in severe liver disease {23}when its half-life can

increase to 96 hours. If these patients drink coffe(~ they should be closely monitored.

Caffeine is known to interact with other drugs resulting in a modified effect. For

example, caffeine administered with nardil (an MAO inhibitor) caused headaches and

high blood pressure{22}. This potentially dangerous interaction was first noted

by Berkowitz et al., and implicated serotonin in the mechanism.

Caffeine and barbitol are antagonistic, with caffeine (in coffee) reducing the sleeping

time induced by barbitol. Decaffeinated coffee had no effect {14}

In another study, caffeine resulted in reduced sleeping time which was counteracted by

pentobarbitol in hospitalized patients {21};Recent investigations of caffeine abuse have

questioned the indiscriminant use of this commonly accepted drug. In some individuals,

chronic excessive caffeine consumption leads to the development of caffeinism, a

syndrome which includes increased anxiety, depression, frequency of

psychophysiological disorders, and possibly degraded performance. research

demonstrating the abuse potential of caffeine. Special attention
has been given those factors which mediate the wide individual differences in
consumption patterns, susceptibility to abuse, and the varied psychological and
physiological responses to this drug. While the development of caffeine abuse is
probably best viewed as an idiosyncratic process, general guidelines for the recognition
of potential abuse, and caffeinism proper, are offered.

Thank you

References
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3. Pathologic steepness induces by caffeine, Am J med 1981:87 (586-588), Regestein QR.
4. Caffeine induces changes in cerebral circulation, 1985; 16:814-817 Mathew RJ, Wilson WH.
5 Caffeine and hypertension, Am J med (1984) 77:54-60, Robertson D , Hollister AS, Kincaid S, workman R, Goldberg MR.
6 the genesis of ventricular extrasystoles under chloroform; with special reference to consecutive ventricular fibrillation, heart (1914);5:219-234.levy AGG
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15 ALDRIDGE, A. at al.: Caffeine Metabolism in the Newborn. Clin. Pharm. and Ther. 25, 4, 447, 1979.
16 ARANDA. J.V. at al.: Pharmacokinetic Profile of Caffeine in the Premature Newborn Infant with Apnea. J. Pediatr. 94, 4, 663-666,1979.
17 BAKER, W.J. et al.: Effects of Caffeine on Visual Monitoring. J. Appl. Psych. 56, 5, 422-427,1972.
18 BELLETT, S. et al.: Effect of Coffee Ingestion on Catecholamine Release. Metabolism 18, 288,1969.
19 LIENERT. G.A. and HUBER, H.P,: Differential Effects of Coffee on Speed and Power Tests. J. of Psychoi. 63, 269-274, 1966,
20 RITCHIE. M.J.. GOODMAN. L. and GILMAN, A.: The Pharmacological Basis of Therapeutics. 5th Ed.. MacMillan, N.Y., 1975.
21 FORREST. W.H. et aL: The interaction of Caffeine with Pentobarbital as a Nightime Hypnotic. Anesthesiology 36.1. 37,1972.
. 22 PAKES. G.: Phenelzine-cola Headache. Am. J. Hasp. Pharm. 36, 6, 736, June,1979.
23 STRATLAND, B.: Caffeine Accumulation Associated with Alcoholic Liver Disease New England J. Med. 295,2.110-111.1976.
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