Antabuse

Caffeine consumption and its effect on the human body is a topic of ongoing debate among health care professionals and consumers. Rarely do consumers recognize caffeine as a drug with inherent adverse side effects and interactions. In fact, the rising inclusion of caffeine in food and beverages lead consumers to believe it is safe. Although most consumers know that caffeine is present in coffee, tea and assorted soft drinks, they may not know the actual amount. Also, hidden sources of dietary caffeine include some bottled water, juice, frozen desserts, yogurt, chocolate, candies, and some over-the-counter and prescription medications (see Table: "Caffeine-Associated Food, Beverages and OTC Medications"). The average consumption of caffeine by intake of coffee, tea, and cocoa, in the United States, is approximately 139 mg/person/day.1 This projection does not include soft drinks and hidden sources that may contribute an additional 210-238 mg/day.1

Advocates of caffeine intake voice therapeutic benefits such as central nervous system (CNS) stimulation. They point out that caffeine may contribute to increased alertness, decreased fatigue, increased work capacity, and improved mood. Opponents of the use of caffeine cite the deleterious effects on the neurological, cardiovascular, gastrointestinal, renal, and musculoskeletal systems. Adverse effects include: agitation, cardiac arrhythmia, insulin resistance, and increased diuresis.1'3 Individuals may present with symptoms related to caffeine over-consumption. The astute clinician must be able to correlate signs and symptoms with social and dietary histories, in order to institute the most appropriate therapy.

case Study

A 56-year-old male presented to his primary care provider for a complete physical exam and review of his medical concerns after not being seen in several years. His past medical history included, gastroesophageal reflux disease, hypercholesterolemia, mild depression with decreased libido, and colitis. Previous surgical history included a tonsillectomy, vasectomy, laparoscopic repair of an inguinal hernia, and left testicular varicocele repair. Medications taken include laiisoprazole (Prevacid) and simvastatin (Zocor). The patient was allergic to sulfa medications. Social history revealed that he works in building maintenance, smokes one-half pack of cigarettes a day, consumes eight to nine, 12-ounce cups of coffee daily, and alcohol occasionally.

Upon review of systems, the patient denied headaches, agitation, irritability, or sleep disturbances. he denied shortness of breath, palpitations, chest pain or pressure. he described one episode of epigastric pain that radiated down the right arm. It was evaluated and determined that it was not cardiac in origin. The patient also verbalized increased stress at home over the last 3 months related to his wife's illness and possible impending bone marrow transplant.

The pertinent physical examination findings included an irregularly irregular heart rate of 54. An electrocardiogram was performed, which showed atrial flutter/fibrillation with slow ventricular response. Laboratory studies included a complete metabolic panel, thyroid function tests, cholesterol panel, and prostate specific antigen. These were subsequently found to be normal with the exception of elevated total cholesterol, of 237mg/dl.

These findings were reviewed with the patient. Because the cause of the atrial fibrillation was not diagnosed with this initial screening, an echocardiogram was ordered and a referral was made to a cardiologist. The patient was instructed to reduce his caffeine intake by 50% and warfarin therapy was initiated to prevent thromboembolism and stroke. Stress echocardiography revealed normal left ventricular function and exercise tolerance, as well as adequate response to, and recovery from exercise. There was no evidence of ischemia or significant valvular disease. The patient had converted to normal sinus rhythm prior to cardiology assessment. This spontaneous conversion was attributed to his significantly reduced caffeine intake. While evidence does not exist to identify the exact etiology of the patient's arrhythmia, the history lends a high index of suspicion to caffeine intake. Based on the dietary history, his caffeine ingestion had been approximately 1,600 mg/day, over 1,400 mg more than the average.

Given society's hectic lifestyles, many people rely on caffeine for an energy boost to get their day started, get through the afternoon, or stay alert in the evening. A common societal phenomenon is to begin the day with a cup or two of coffee. As the day progresses, coffee is often replaced by soft drinks, or bottled waters. Rarely do consumers recognize excessive intake of caffeine throughout the day, not to mention the addition of added sugars and fats that may be included.

Pharmacokinetics

As clinicians, it is important to understand caffeine's mechanism of action and its effect on various body systems. Following consumption of caffeine, absorption from the gastrointestinal tract is rapid and complete within 45-60 minutes.1,2

Caffeine readily passes through all biological membranes, and can be detected in all body fluids.1,2 The CYP1A2 system in the liver accounts for more than 95% of metabolism, explaining the wide variability in individuals.2 The major route of elimination is the kidney, with several metabolites produced, but only 1% to 2% of caffeine is excreted unchanged. Elimination half-life may be twice as long in caffeine-naive individuals as in those accustomed to caffeine, a fact that may be important when investigating toxic effects.2

Specific conditions that delay excretion include: pregnancy, alcohol use, and liver disease. Medications such as oral contraceptives, cimetidine (Tagamet), and disulfiram (Antabuse) can also affect excretion of caffeine.5 Conversely, exercise and smoking enhance renal clearance of caffeine.

Pharmacodynamics

Since caffeine can be considered a drug, it is prudent to examine its pharmacodynamics. Many believe the underlying action of the pharmacological effects of caffeine, are related to adenosine antagonism.1,24-6 Adenosine is a purine nucleoside important in many cellular reactions, the transfer of chemical energy, and as a ligand for receptors.7 secondary mechanisms of action include phosphodiesterase inhibition and mobilization of intracellular calcium from skeletal, cardiac, and neuronal tissue.2

Central Nervous System

The effects of caffeine on the body may be examined from a systems approach. The most sought after effect is produced in the central nervous system. Experts agree that caffeine causes increased arousal and work capacity, decreased fatigue and motor reaction time, and elevated mood.2,5 Lower doses (20 mg to 200 nag) of caffeine produce feelings of energy, efficiency, self-confidence, and alertness.1 However, persons with caffeine toxicity may experience symptoms ranging from headache and irritability to delirium and seizures.2 Fredholm et al postulate adenosine is needed to inhibit neurotransmitter release, as well as decrease the rate of firing of central neurons.1 When the latter is blocked by caffeine, electroencephalogram arousal and in vivo seizures may occur.1 The negative impact of caffeine on sleep is well documented. Generally, more than 200 mg is required to cause decreased sleep time, increased sleep latency, and increased number of shifts between sleep stages.1 However, it is not known whether the time of ingestion, or chronic versus light intake of caffeine, impact the degree of sleep disturbance.1 Cerebral vasoconstriction that follows caffeine consumption is well known to relieve migraines. However, excess intake may have just the opposite effect. Manzoni investigated the relationship between cluster headache (CH) and lifestyle factors. The percent of patients with episodic CH compared to chronic CH patients that consumed more than six cups per day were 7% and 33%, respectively.8

Scientists are investigating other benefits of caffeine on the central nervous system. The exact mechanism of caffeine on mood is unknown, but is believed to be related to enhanced excitatory transmission, which influences gamma-aminobutyric acid transmission via adenosine blockade.1 In fact, a distinct decline in mood has been observed following caffeine deprivation over night.1 Also, a recent study indicates that caffeine may be cerebral protective and significantly reduce the incidence of Parkinson's disease.5,6 Ross et al demonstrated a decline in age-adjusted incidence of Parkinson's with increased intake of caffeine.6 The researchers postulate exposure to caffeine may counteract neurodegenerative effects that lead to loss of dopaminergic neurons.6

Cardiovascular

The effect on the cardiovascular system is related to sympathomimetic activation causing the release of plasma epinephrine, norepinephrine, and renin.1,2 Consequently, persons may experience tachycardia, palpitations, and transient elevation of blood pressure. Donnerstein et al conducted an examination of the effect of caffeine ingestion on electrocardiograms, which demonstrated a small, but statistically significant prolongation of ventricular conduction.9 The authors suggest that the effect may be more pronounced in individuals with pre-existing arrhythmia and with greater amounts of caffeine. A study of hypertensive patients demonstrated increased vascular resistance that was not attenuated by pharmacologic tolerance to caffeine. This would indicate that blood pressure might not be reduced with time.10 Mahmud and Feely investigated the effect on large artery properties, and found arterial stiffness increased substantially following caffeine intake.11

While experts agree on the physiologic changes induced by caffeine, the relationship to coronary heart disease is controversial. Reportedly, prior to 1975, the incidence of coronary artery disease (CAD) in men who drank more than five cups of coffee daily, was 2 1/2 times more than caffeine-free men.12 However, since the advent of filtered coffee in 1975, studies have been unable to link caffeine ingestion to CAD.12 It is believed that two oils, cafestol and kahweol, found in ground coffee and removed during filtration, contributed to elevated low-density lipoproteins (LDL) and triglycerides.12

Renal

According to Carrillo and Benitez, renal effects influenced by caffeine are similar to those produced by thiazide diuretics.2 The renal tubule is directly affected allowing increased sodium and chloride excretion. Women lose about 5 mg of calcium via the renal tubules for every 6 ounces of coffee or 24 ounces of cola consumed.12 While research does not show a cause-effect relationship, calciuria from caffeine may be an important factor to consider, in the development of osteoporosis. Finally, there is an increased release of renin and subsequent elevation of blood pressure with caffeine ingestion, the effects of which have been discussed above.

Musculoskeletal

The effect of caffeine on muscle is twofold. First, smooth muscle of the bronchial tree is relaxed, yielding an increase in vital capacity.2 Secondly, skeletal muscle is stimulated.2 Several studies have shown enhanced anaerobic exercise performance following the ingestion of caffeine.13-15 Specifically, increased blood epinephrine levels led to greater skeletal muscle metabolism, and thereby prolonged exercise capacity.

Gastrointestinal

The endocrine and gastrointestinal systems are influenced by caffeine as well. Skeletal muscle is important in glucose metabolism, and is the primary tissue responsible for insulin mediated glucose uptake. Adenosine is thought to be a metabolite that influences insulin binding, as well as glucose transporters. A study was designed to investigate the effect of caffeine on whole-body glucose uptake.3 Following caffeine ingestion, a significant decrease in glucose disposal and carbohydrate storage was demonstrated.3 The release of epinephrine also inhibits peripheral glucose uptake.4 Consequently, caffeine consumption may be influential in the development of insulin resistance. Alteration of acid and pepsin secretion by caffeine within the gastrointestinal tract may cause diarrhea, nausea and heartburn.2

Implications for Practice

The key to successful patient assessment includes thorough history taking. Too often, a thorough nutritional history is omitted when practitioner time is limited. Nutritional information should not be seen as optional. A thorough health history should include questions about caffeine consumption during an average day. The amount of caffeine, in milligrams, should be calculated, and when in excess of 250 mg per day, patients counseled to reduce intake. The skilled practitioner utilizes the history taking process to identify additional factors that contribute to the patient's chief complaint. When patient's present for episodic care, symptoms should be carefully evaluated for association to caffeine excess. The knowledge of caffeine pharmacodynamics should serve as a "wake-up" call to include this in the differential diagnosis. In this case example, the careful history led to the presumptive diagnosis.

Questions regarding consumption of caffeine containing products and recent changes in dietary habits should be addressed. Patients may partake in various "fad" diets that deviate from their usual patterns of eating or have other reasons for atypical habits. Alternatively, they may have recently decided to eliminate caffeine ingestion "cold turkey", which may result in withdrawal symptoms such as headache, irritabilty, mood changes, anxiety, depression, tiredness, lack of energy, and poor concentration.16 When patient's complaints have a possible dietary relationship, the practitioner should investigate contributing factors.

One helpful method of nutritional assesment is asking the patient to maintain a food diary. Having the patient also record their symptoms in the diary facilitates the correlation of symptoms to dietary intake. the diary should be maintained over at least 1 to 2 weeks to fully capture typical dietary patterns. Over-the-counter medications, herbal remedies, and prescription medications taken during the recorded period should be included.

Health and wellness education is pertinent to all patient visits. It provides an opportunity to support positive health habits and address adverse ones. Education about caffeine consumption should be included with lifestyle modification teaching, such as low cholesterol and low sodium diets, routine exercise, moderation in alcohol consumption, and smoking cessation. The impact of caffeine on various disease processes can be addressed and signs and symptoms of toxicity can be taught. Patients should be educated that there is no specific dose of caffeine that will cause toxicity since response is highly individualized. Individuals with a history of headaches or insomnia should be counseled regarding the impact of caffeine excess as a contributory factor.

When managing patients with hypertension, evaluation of caffeine intake may play a significant role in drug therapy because caffeine elevates blood pressure. Although not supported by controlled studies, it seems logical that reducing caffeine intake may allow a reduction in dosages of drug therapy. Persons at risk for osteoporosis, such as postmenopausal women, the elderly, or individuals with low calcium and vitamin D intake, should be instructed to reduce caffeine intake. Patients attempting to quit smoking should be informed that excretion of caffeine might decline with smoking cessation so their usual caffeine will have a more potent effect. Further, individuals at risk for development of type II diabetes, or those newly diagnosed, should be educated regarding the impact of caffeine on blood glucose. Insulin sensitivity decreases with caffeine use and patients should be counseled to restrict caffeine intake, as they " are taught to eliminate refined sugars and limit carbohydrates.

Conclusion

Increasing demands in society require us to be as energetic as possible. As a result, we often seek a burst of energy from a variety of substances that contain caffeine. Many of these products are consumed without full knowledge of the amount of caffeine they contain or that it is possible to take in too much. While moderate intake may not be detrimental, excess may lead to significant health problems. A practitioner should become knowledgeable about the wide variety of products that contain caffeine and the risks and benefits of caffeine consumption. Reduction of caffeine consumption could be routinely incorporated when teaching about healthy lifestyle. It is also important to understand the side effects and presentation of toxicity. A well-informed practitioner can teach patients about caffeine and offer improved quality of life.

REFERENCES

1. Fredholm BB, Battig K, Holmen J, et al: Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacological Reviews 1999;51(1): 83-133.

2. Carrillo JA, Benitez J: Clinically significant pharmacokinetic interactions between dietary caffeine and medications. Clinical Phannacokinetics 2000;39(2):127-53.

3. Greer F, Hudson R, Ross R, et al: Caffeine ingestion decreases glucose disposai during a hyperinsulinemic-euglycemic clamp in sedentary humans. Diabetes 2001; 50:2349-54.

4. Keijzers GB, DeGalan BE, Tack CJ, et al: Caffeine can decrease insulin sensitivity in humans. Diabetes Care 2002:25:364-9.

5. Debunking myths.

6. Ross GW, Abbott RD, Petrovitch H, et al: Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA 2000; 283(20): 2674-9.

7. Lingappa VR, Farey K: Physiological medicine: a clinical approach to basic medical physiology. New York: McGraw-Hill, 2000.

8. Manzoni GC: Cluster headache and lifestyle: remarks on a population of 374 male patients. Cephalagia 1999; 19(2): 88-94.

9. Dormerstein RL, Zhu D, Samson R, et al: Acute effects of caffeine ingestion on signal-averaged electrocardiograms. American Heart Journal 1998; 136: 643-6.

10. Hartley TR, Lovallo WR, Whitsett TL, et al: Caffeine and stress: implications for risk, assessment, and management of hypertension. Journal of Clinical Hypertension 2001; 3(6): 369-75.

11. Mahmud A, Feely J: Acute effect of caffeine on arterial stiffness and aortic pressure waveform. Hypertension 2001;38(2): 227-31.

12. Nutrition action health newsletter: found@www.cspinet.org

13. Bell DG, Jacobs I, Ellerington K: Effect of caffeine and ephcdrine ingestion on anaerobic exercise performance. Medicine & Science in Sports & Exercise 2001:1399-403.

14. DohertyM: The effect of caffeine on the maximal accumulated oxygen deficit and short-term running performance. International Journal of Sports Nutrition 1998;8:95-104.

15. Kalmar JM, Cafarelli E: Effects of caffeine on neuromuscular function. Journal of Applied Physiology 1999;87:801-8.

16. Evans SM, Griffiths RR: Caffeine, withdrawal: a parametric analysis of caffeine dosing conditions. Journal of Pharmacology and Experimental Therapeutics 1999;289(l):285-94.

ACKNOWLEDGMENTS

The authors thank Gwen Emery, MD1 University Hospitals Health System, Primary Care Physician Practices for sharing her practice with us and in particular the case presented herein.

Leisa Bridle, RN

June Remick, BSN, RN

Evelyn Duffy, MS, RN, CS

ABOUT THE AUTHORS

At Frances Payne Bolton School of Nursing, case Western Reserve University, Cleveland, Ohio, june Remick and Leisa Bridel are Adult Nurse Practitioner students, and Evelyn Duffy is an Instructor of Nursing.

Copyright Springhouse Corporation Apr 2004
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