Caffeine

Cardiovascular

There is debate over the association between caffeine intake and cardiovascular disease. Increases in mean blood pressure, blood glucose and free fatty acid concentrations, and urinary catecholamine excretion have been found after acute ingestion of 150 mg of caffeine [ ]. While not particularly potent, caffeine appears to produce cardiac dysrhythmias, including ventricular tachycardia. Furthermore, in non-smokers, daily consumption of five cups of percolated coffee per day (about 680 mg of caffeine) was associated with a modestly increased risk of having a cardiac arrest without a prior history of cardiovascular disease [ ]. In patients with preexisting heart disease, caffeine lowers the effective and functional refractory period of the atrioventricular node [ ]. A twofold increased risk of myocardial infarction has been suggested for women who drink six or more cups of coffee a day [ ], and in two studies, men who drank five or more cups of coffee a day had an approximately twofold increase in the risk of myocardial infarction [ ] or coronary artery disease [ ]. However, prospective studies of the relation between caffeine consumption and an increased risk of coronary artery disease (or stroke) have been negative [ ] or inconclusive [ , ], as has been the association between the consumption of coffee and serum cholesterol concentration assessed in 24 cross-sectional epidemiological studies [ ]. However, a Finnish study did show a positive-dose relation with serum cholesterol after adjustment for confounding variables, in men but not in women. It has also been suggested that the relation is seen only with boiled and not instant or filter coffee.

Guaraná is produced from the guaraná plant ( Paullina cupana ), the seeds of which contain 3.6–5.8% caffeine.

• A 25-year-old woman, who had pre-existing mitral valve prolapse and a history of having had bouts of palpitation with caffeine, developed intractable ventricular fibrillation after consuming a “natural energy” guaraná health drink containing a high concentration of caffeine [ ]. At autopsy, she was found to have sclerosis and myxoid changes in the mitral valve leaflets. The caffeine concentration in her aortic blood was 19 μg/ml.

This case highlights the need for more careful regulation of “natural” products, including warning patients with underlying health problems, and clear labeling to document the presence of any constituents with potentially adverse effects. It also shows the need for medical practitioners to be familiar with the more widely used “natural remedies” and their toxicological profiles. Following the death of this patient, the Western Australian Coroner recommended that Race 2005 Energy Blast should be removed from the local market, and the product was recalled nationally in August 1999.

Nervous system

Insomnia, anxiety, tachycardia, and tremor are among the symptoms most commonly reported with caffeine [ ]. Tenseness and irritability also occur and, with high intake, symptoms resembling those of anxiety neurosis [ ]. A case of “caffeine psychosis” has also been reported [ ]. Dose–response associations have not been particularly well studied, but some are known [ ]. Paradoxically, six cases have been reported of pathological sleepiness induced by caffeine [ ]. Tonic-clonic seizures occurred postpartum in a woman who had received 500 mg of caffeine sodium benzoate for headache after lumbar puncture; a prolonged half-life was implicated [ ].

Consumption of methylxanthine-containing products can aggravate the neurological symptoms associated with the glucose transporter type 1 (Glut 1 deficiency syndrome). The human erythrocyte and the brain glucose transporters are identical, and the erythrocyte transporter has been used in four patients with individual mutations in the Glut 1 gene to demonstrate that caffeine and theophylline inhibit glucose transport [ ]. The Glut 1 deficiency syndrome represents impaired glucose transport across the blood–brain barrier caused by partial Glut 1 deficiency, which results in hypoglycorrhachia, seizures, and developmental delay. Identifying potential inhibitors of Glut 1 is essential in preventing further impairment of glucose transport in these patients. In addition to phosphodiesterase inhibition and adenosine A1 receptor antagonism by methylxanthines, it is likely that inhibition of glucose transport also contributes to the convulsive effects of methylxanthines in high doses.

Psychological

Red Bull, a mixture of caffeine, taurine, and inositol, a widely consumed “power drink,” affects mental performance and mood.

• A 36-year-old man with bipolar-I disorder had a second manic episode, after having been in remission for 5 years while taking lithium to maintain a serum lithium concentration of 0.8–1.1 mmol/l [ ]. One week before this episode, he drank three cans of Red Bull at night, as he needed less sleep; 3 days later he drank three more cans. After 4 days he was feeling euphoric, hyperactive, and insomniac. He gradually became more hyperactive and had increased libido and irritability. He took no more Red Bull and improved within 7 days.

Based on this report, the authors suggested that stimulant beverages that contain caffeine might cause cognitive and behavioral changes, especially in vulnerable patients with bipolar illness.

Metabolism

The major metabolic effects of caffeine are increase in free fatty acids and blood glucose concentration [ , ].

Electrolyte balance

Hypokalemia and myopathy are known effects of caffeine toxicity, and severe hypokalemia and fatigue and hypokalemia with myopathy have been described before [ ].

Gastrointestinal

Large doses of caffeine can cause nausea and vomiting. Caffeine is a potent stimulant of hydrochloric acid secretion [ ] and has been incriminated in exacerbating duodenal ulcers. However, decaffeinated coffee has also been reported to be as potent as instant coffee in stimulating gastric acid secretion [ ].

Pancreas

A relation between coffee consumption and pancreatic cancer was originally reported in a case-control study [ ], with an unexpected increase in pancreatic cancer in coffee drinkers (relative risk in men 2.6). The same group studied differences in mortality from pancreatic cancer in different countries in relation to differences in coffee consumption and found a significant relation between increases in coffee consumption and increases in mortality from pancreatic cancer. However, the data on which the findings were based were crude.

Although the results of published epidemiological studies are compatible with a small effect of coffee consumption on pancreatic carcinogenesis, the interpretation of these findings is not clear, because of the possibility of residual confounding and other sources of bias [ ]. In two large cohort studies of 1 907 222 person-years of follow-up, there were 288 cases of pancreatic cancer with no evidence of an association between coffee and pancreatic cancer [ ]. Furthermore, there is no association between folate intake, caffeine consumption, and the risk of pancreatic cancer [ ].

The relation between coffee drinking and the presence of the K- ras mutation in patients with exocrine pancreas cancer has been investigated in Spain in 121 cases in which tissue specimens were available [ ]. In exocrine pancreatic cancer, the K- ras gene may be activated less often among regular coffee drinkers, suggesting that caffeine, or other compounds present in coffee, or other factors with which coffee drinking is associated, may modulate K- ras activation. While the results of this study may have mechanistic and pathogenic relevance, they have no clinical or health policy implications.

Urinary tract

Large doses of caffeine cause diuresis. Daily consumption of caffeine citrate increased the mean urinary excretion rate of tubular cells and erythrocytes in volunteers [ ]. The nephrotoxicity of analgesic antipyretic drug combinations may result from a combined effect, in which aspirin, phenacetin, and caffeine all play a role [ , ]. In 10 asymptomatic women and 20 women with confirmed detrusor instability, caffeine caused a significant increase in detrusor pressure on bladder filling in the latter, but no difference in volume at first contraction, height of contraction, or bladder capacity [ ].

As up to 10% of about 42 000 dialysis patients have suffered from renal insufficiency due to analgesic nephropathy (in the postphenacetin era), German nephrologists have demanded that medications that contain fixed combinations of analgesics (paracetamol, aspirin, or propyphenazone plus caffeine) be withdrawn from the market, following the example of their US colleagues in the National Kidney Foundation [ ].

Skin

Urticaria as an allergic response to caffeine has been reported [ ].

Musculoskeletal

Caffeine toxicity is an uncommon cause of myopathy, but a history of excessive dietary and pharmaceutical consumption of caffeine should be sought in any patient with unexplained myopathy, particularly if there is concomitant hypokalemia [ ].

• A 21-year-old woman with a 12-month history of progressive muscle weakness, nausea, vomiting, diarrhea, and weight loss had significant worsening of muscle weakness over 2 weeks, associated with exercise-induced muscle stiffness and pain. She had severe hypokalemia and metabolic acidosis. For the past 1–2 years she had been consuming about 8 liters of cola every day. She stopped drinking cola and took potassium supplements, after which her hypokalemia and muscle weakness resolved and the serum creatine kinase activity fell. Based on the concentration of caffeine in the cola, it was estimated that she had been consuming at least 1 g/day of caffeine for more than 12 months.

Drug abuse

Abuse of analgesic combinations has been thought to be especially facilitated if they contain caffeine or codeine, reinforcing abuse. However, this has not been confirmed in an expert review, in which it was concluded that the available evidence does not support the claim that analgesics co-formulated with caffeine, in the absence of phenacetin, stimulate or sustain overuse [ ]. Caffeine has a synergistic effectiveness with analgesics, but although it can cause dependence, the risk is low. Withdrawal is not likely to cause increased need of analgesics. However, there is strong dependence behavior in patients using formulations containing phenacetin, antipyretics/analgesics, and caffeine. This finding may have led to the impression that caffeine stimulates overuse of analgesics.

Drug withdrawal

Restlessness, irritability, and headache are withdrawal effects attributable to caffeine. These and other symptoms can occur with lower doses of caffeine than generally supposed [ ]. The caffeine withdrawal headache may be responsible for the widespread practice of taking caffeine-containing analgesics habitually, since a withdrawal headache could create a vicious cycle of drug use [ ].

Tumorigenicity

A possible association between the use of methylxanthine consumption and the occurrence of fibrocystic breast disease has been suggested [ , ]. It was concluded that in women who are predisposed to fibrocystic disease, methylxanthines are factors in its development. The mechanism of this effect might be an inhibitory action on the activity of cyclic AMP and cyclic GMP phosphodiesterases.