Recent Advances In Therapeutic Application Of Caffeine

Description

ABSTRACT

This study is recent advances in therapeutic application of caffeine. Caffeine is widely consumed in beverages to obtain mild CNS stimulant effects. 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. Caffeine is used therapeutically in combination with ergotamine for migraine headaches and in combination with nonsteroidal anti-inflammatory drugs in analgesic formulations. 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. In some headache and in pain paradigms, caffeine may produce direct adjuvant analgesic properties, while in other headache conditions (perioperative, postdural puncture) caffeine may be effective by alleviating a manifestation of caffeine withdrawal. Other uses, such as to promote wakefulness, for respiratory stimulation and seizure prolongation, rely on central stimulant properties of caffeine. 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.

TABLE OF CONTENTS

COVER PAGE

TITLE PAGE

APPROVAL PAGE

DEDICATION

ACKNOWELDGEMENT

ABSTRACT

CHAPTER ONE

• INTRODUCTION
• BACKGROUND OF THE STUDY
• OBJECTIVE OF THE STUDY
• SIGNIFICANCE OF THE STUDY
• LIMITATION OF THE STUDY
• PHYSICAL AND CHEMICAL PROPERTIES OF CAFFEINE

CHAPTER TWO

LITERATURE REVIEW

• HISTORICAL BACKGROUND OF THE STUDY
• REVIEW OF COFFE

CHAPTER THREE

METHODOLOGY

• RECENT THERAPEUTIC APPLICATION OF THE STUDY

CHAPTER FOUR

4.1    SIDE EFFECTS OF CAFFEINE

4.2    PREGNANCY RISK

4.3     REINFORCEMENT DISORDERS

4.4     RISK OF OTHER DISEASES

4.5     OVERDOSE OF CAFFEINE

4.6     CAFFEINE FACTS

CHAPTER FIVE

5.1     CONCLUSIONS

   5.2     SUMMARY

 5.3     REFERENCES

CHAPTER ONE

1.0                                                        INTRODUCTION

Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class of psychoactive drugs. It is the world’s most widely consumed psychoactive drug, but unlike many other psychoactive substances, it is legal and unregulated in nearly all parts of the world. It is a bitter, white crystalline purine, a methylxanthine alkaloid, and thus closely related chemically to the adenine and guanine contained in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). It is found in the seeds, nuts, or leaves of a number of plants native to South America and East Asia. The most well known source of caffeine is the seed (commonly incorrectly referred to as the “bean”) of Coffea plants. Beverages containing caffeine are ingested to relieve or prevent drowsiness and to increase one’s energy level. Caffeine is extracted from the plant part containing it for making beverages by steeping it in water, a process called infusion. These beverages are very popular; in North America, 90% of adults consume caffeine daily.

Caffeine is classified by the Food and Drug Administration as “generally recognized as safe” (GRAS). Toxic doses, over 10 grams per day for an adult, are much higher than typical dose of under 500 milligrams per day. A cup of coffee contains 80–175 mg of caffeine, depending on what “bean” (seed) is used and how it is prepared (e.g. drip, percolation, or espresso). Thus it requires roughly 50–100 ordinary cups of coffee to reach a lethal dose. However pure powdered caffeine, which is widely available as a dietary supplement, can be lethal in tablespoon-sized amounts. There are several known mechanisms of action to explain the effects of caffeine. The most prominent is to reversibly block the action of adenosine on its receptor, which blocks the onset of drowsiness induced by adenosine. Caffeine also stimulates selected portions of the autonomic nervous system.

Caffeine can have both positive and negative health effects. It can be used to treat bronchopulmonary dysplasia of prematurity, and to prevent apnea of prematurity: caffeine citrate was placed on the WHO Model List of Essential Medicines in 2007. It may confer a modest protective effect against some diseases, including Parkinson’s disease and certain types of cancer. One meta-analysis concluded that cardiovascular disease such as coronary artery disease and stroke is less likely with 3–5 cups of non-decaffeinated coffee per day but more likely with over 5 cups per day. Some people experience insomnia or sleep disruption if they consume caffeine, especially during the evening hours, but others show little disturbance. Evidence of a risk during pregnancy is equivocal; some authorities recommend that pregnant women limit consumption to the equivalent of two cups of coffee per day or less. Whether or not caffeine is an addictive drug depends on how an addiction is defined. It can produce a mild form of drug dependence – associated with withdrawal symptoms such as sleepiness, headache, and irritability – when an individual stops using caffeine after repeated daily intake. Tolerance to the autonomic effects of increased blood pressure and heart rate, and increased urine output, develops with chronic use (i.e., these symptoms become less pronounced or do not occur following consistent use).

Caffeine confers a survival advantage on the plant containing it in three ways. First, if it is ingested by an insect feeding on and potentially damaging or killing the plant, caffeine functions as a natural pesticide which can paralyze and kill the insect. Second, droppings from the plant infuse the surrounding soil with caffeine, which can inhibit the growth of and kill competing seedlings (and potentially its own progeny and itself). Third, caffeine can enhance the reward memory of pollinators such as honey bees, thus increasing the numbers of its progeny.

1.2                                           BACKGROUND OF THE STUDY

Despite improvements in survival for very low birth weight infants over the past two decades, bronchopulmonary dysplasia (BPD) and patent ductus arteriosus (PDA) remain common morbidities affecting this vulnerable population. Over 40% of very low birth weight infants develop BPD based on recent estimates and BPD remains the most common chronic lung disease of infancy. Neonates with BPD are at high risk of long-term lung disease, adverse neurodevelopmental outcomes and readmission to the hospital in the first year of life. Despite the significant morbidities associated with BPD, few safe and effective therapies are available to prevent the disease. In addition to BPD, a persistent PDA is a common problem affecting approximately half of neonates <29 weeks gestation with over two-thirds receiving drug therapy for closure and approximately one-fourth requiring surgical closure. The presence of a persistent PDA is associated with increased neonatal morbidity such as prolonged ventilation and, although controversial, may also increase the risk of developing BPD.

Given the adverse outcomes associated with BPD and PDA, therapies targeted at reducing or preventing these morbidities are of significant value. In the Caffeine for Apnea of Prematurity (CAP) trial, caffeine therapy or placebo was initiated during the first 10 days of life (DOL) in infants weighing 500 to 1250 g at birth. Infants treated with caffeine had a decreased incidence of both BPD and PDA when compared with placebo. In addition, caffeine therapy reduced the duration of mechanical ventilation by approximately 1 week. Importantly, caffeine therapy also resulted in improved long-term neurodevelopmental outcomes. A post-hoc analysis of the CAP trial suggested that the efficacy of caffeine may be dependent on the timing of initiation of study drug. However, the trial only included infants who met inclusion criteria by DOL 10, potentially excluding a significant group of infants who did not meet clinical criteria for treatment.

Early caffeine (EC) therapy may carry additional benefit during a critical period of susceptibility to both lung and brain injury in the first few days of a premature infant’s life. We compared infants 1250 g at birth who received caffeine early in their hospital course with those who were treated later to determine if the timing of caffeine therapy would impact common morbidities of prematurity. Our primary hypothesis was that extremely preterm infants who receive EC therapy (initiation before DOL 3) would have a decreased incidence of BPD or death, when compared with infants who were treated with caffeine later in their hospital course (initiation at or after DOL 3). As secondary outcomes, we evaluated if EC initiation would be associated with a reduction in the treatment of PDA and a decreased duration of endotracheal ventilation.

1.3                                               OBJECTIVE OF THE STUDY

There are few people who are not aware of the stimulating effect that caffeine provides. We have a choice and choose caffeinated beverages for a reason. Caffeine is considered the most commonly used psychoactive drug in the world. A majority of adults consume it on a daily basis, and research is being done on its health benefits and consequences. Objective of this work is to analyze how caffeine is recently used as therapy.

1.4                                           SIGNIFICANCE OF THE STUDY

Caffeine is a chemical found in coffee, tea, cola, guarana, mate, and other products. Caffeine is most commonly used to improve mental alertness, but it has many other uses. Caffeine is used by mouth or rectally in combination with painkillers (such as aspirin and acetaminophen) and a chemical called ergotamine for treating migraineheadaches. It is also used with painkillers for simple headaches and preventing and treating headaches after epidural anesthesia.

1.6                                             LIMITATION OF THE STUDY

Limitations of this study include its design as a single-center, retrospective cohort study with a predominately African-American population. In addition, we were unable to ascertain the indication for caffeine therapy in each patient and no institutional protocol directed caffeine use. Although we did not evaluate long-term effects in our study, caffeine treatment has been shown to reduce the incidence of long-term neurologic impairment and cerebral palsy. The role of caffeine in protection against neurodevelopmental impairment may be explained, in part, by its effect on improving respiratory morbidity. However, a recent investigation demonstrating improved white matter microstructural development in caffeine-treated infants suggests that other unidentified mechanisms of action are likely to play a role. Although the retrospective study design prohibits the establishment of causality and differences in patient characteristics may have influenced the timing of caffeine initiation, we attempted to account for these differences in baseline characteristics through both adjustments in our statistical models and the use of subgroup analyses. However, we acknowledge our inability to control for all factors that are reflective of early severity of illness or that potentially influenced the clinical outcomes. Our findings of decreased BPD in infants receiving EC, although indicative of a substantial benefit for at-risk preterm infants, remain hypothesis-generating and necessitate additional investigation including validation in a large, multicenter cohort of patients.

People with voice disorders, singers, and other voice professionals are often advised against using caffeine. However, until recently, this recommendation was based only on hearsay. Now developing research seems to indicate that caffeine may actually harm voice quality. But further study is necessary to confirm these early findings.

1.6                     PHYSICAL AND CHEMICAL PROPERTIES OF CAFFEINE

Pure anhydrous caffeine is a white odorless powder with a melting point of 235–238 °C. Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but very soluble in boiling water (66 g/100 mL). It is also moderately soluble in ethanol (1.5 g/100 mL). It is weakly basic (pK_a = ~0.6) requiring strong acid to protonate it. Caffeine does not contain any stereogenic centersand hence is classified as an achiral molecule.

The xanthine core of caffeine contains two fused rings, a pyrimidinedione and imidazole. The pyrimidinedione in turn contains two amide functional groups that exist predominately in a zwitterionic resonance the location from which the nitrogen atoms are double bonded to their adjacent amide carbons atoms. Hence all six of the atoms within the pyrimidinedione ring system are sp² hybridized and planar. Therefore, the fused 5,6 ring core of caffeine contains a total of ten pi electrons and hence according to Hückel’s rule is aromatic.

Detection in body fluids

Caffeine can be quantified in blood, plasma, or serum to monitor therapy in neonates, confirm a diagnosis of poisoning, or facilitate a medicolegal death investigation. Plasma caffeine levels are usually in the range of 2–10 mg/L in coffee drinkers, 12–36 mg/L in neonates receiving treatment for apnea, and 40–400 mg/L in victims of acute overdosage. Urinary caffeine concentration is frequently measured in competitive sports programs, for which a level in excess of 15 mg/L is usually considered to represent abuse.

Natural occurrence

Around sixty plant species are known to contain caffeine. Common sources are the “bean” (seed) of the coffee plant (the quantity varies, but 1.3% is a typical value); in the leaves of the tea bush; and in kola nuts. Other sources include yaupon holly leaves, South American holly yerba mate leaves, seeds from Amazonian maple guarana berries, and Amazonian holly guayusa leaves. Temperate climates around the world have produced unrelated caffeine containing plants.

Caffeine in plants acts as a natural pesticide: it can paralyze and kill predator insects feeding on the plant: high caffeine levels are found in coffee seedlings when they are developing foliage and lack mechanical protection. In addition, high caffeine levels are found in the surrounding soil of coffee seedlings, which inhibits seed germination of nearby coffee seedlings, thus giving seedlings with the highest caffeine levels fewer competitors for existing resources for survival.

The differing perceptions in the effects of ingesting beverages made from various plants containing caffeine could be explained by the fact that these beverages also contain varying mixtures of other methylxanthine alkaloids, including the cardiac stimulants theophylline and theobromine, and polyphenols that can form insoluble complexes with caffeine.