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Caffeine Pharmacology

Description: Caffeine is a naturally occurring xanthine derivative used as a CNS and respiratory stimulant, or as a mild diuretic. Other xanthine derivatives include the bronchodilator theophylline and theobromine, a compound found in cocoa and chocolate. Caffeine is found in many beverages and soft drinks. Caffeine is often combined with analgesics or with ergot alkaloids for the treatment of migraine and other types of headache. Caffeine is also sold without a prescription in products marketed to treat drowsiness, or in products for mild water-weight gain. Caffeine was first approved by the FDA for use in a drug product in 1938. Clinically, it is used both orally and parenterally as a respiratory stimulant in neonates with apnea of prematurity. Caffeine reduces the frequency of apneic episodes by 30-50% within 24 hours of administration.[2070] Caffeine is preferred over theophylline in neonates due to the ease of once per day administration, reliable oral absorption, and a wide therapeutic window. A commercial preparation of parenteral caffeine, Cafcit®, was FDA approved for the treatment of apnea of prematurity in October 1999, after years of availability only under orphan drug status (e.g., Neocaf®). The FDA has continued the orphan drug status of the approved prescription formulation.

Mechanism of Action: Caffeine is a mild, direct stimulant at all levels of the CNS and also stimulates the heart and cardiovascular system. The related xanthine, theophylline, shares these properties and is widely used in the treatment of pulmonary disease. Both caffeine and theophylline are CNS stimulants, with theophylline exerting more dramatic effects than caffeine at higher concentrations. Caffeine also stimulates the medullary respiratory center and relaxes bronchial smooth muscle. Caffeine stimulates voluntary muscle and gastric acid secretion, increases renal blood flow, and is a mild diuretic.

While the clinical responses to caffeine are well known, the cellular mechanism of action is uncertain. Several theories have been proposed. At high concentrations, caffeine interferes with the uptake and storage of calcium by sarcoplasmic reticulum of striated muscle. While this action would explain the effects of caffeine on cardiac and skeletal muscle, it does not appear to occur at clinically achievable concentrations. Inhibition of phosphodiesterases (and subsequent accumulation of cyclic nucleotides) also does not appear to occur at clinically achievable concentrations.

Currently, it is believed that xanthines act as adenosine-receptor antagonists. Adenosine acts as an autocoid, and virtually every cell contains adenosine receptors within the plasma membrane. Adenosine exerts complex actions. It inhibits the release of neurotransmitters from presynaptic sites but works in concert with norepinephrine or angiotensin to augment their actions. Antagonism of adenosine receptors by caffeine would appear to promote neurotransmitter release, thus explaining the stimulatory effects of caffeine. Recently, a distinct syndrome has been associated with caffeine withdrawal. It is possible that the manifestations of caffeine withdrawal may be secondary to catecholamine or neurotransmitter depletion.

The following mechanisms of action are hypothesized for caffeine's action in apnea of prematurity:

  1. Stimulation of the respiratory center,

  2. Increased minute ventilation,

  3. Decreased threshold to hypercapnia,

  4. Increased response to hypercapnia,

  5. Increased skeletal muscle tone,

  6. Decreased diaphragmatic fatigue,

  7. Increased metabolic rate, and

  8. Increased oxygen consumption.

All of these actions are thought to be related to adenosine receptor antagonism.

Pharmacokinetics: Caffeine is administered orally and intravenously. Caffeine and citrated caffeine are well absorbed from the GI tract. Absorption from suppositories may be slow and erratic. Following oral administration, peak plasma concentrations in adults are reached within 50-75 minutes. Therapeutic caffeine concentrations are reported to be 5-25 mg/L in adults. Caffeine is distributed rapidly to all body tissues and readily crosses the blood-brain and placental barriers. It is distributed into breast milk. Caffeine is roughly 36% bound to plasma proteins.

In adults, caffeine is partially metabolized in the liver via demethylation reactions dependent on the CYP-450 1A2 isoenzyme; major metabolites include paraxanthine (80%), theobromine (10%) and theophylline (4%). The plasma half-life of caffeine is 3-7 hours in adults.

*Special populations: Caffeine is administered orally and intravenously. Caffeine and citrated caffeine are well absorbed from the GI tract in neonates. In neonates, the oral administration of caffeine results in peak concentrations in 0.5-2 hours. Formula feedings do not affect the time to maximum concentrations after oral dosing. Therapeutic plasma concentrations of caffeine for the treatment of neonatal apnea of prematurity are roughly 13-25 mg/L, however, concentrations of 26-40 mg/L may be needed for some infants to obtain a reduction in apneic episodes.[2070]

Caffeine metabolism in neonates is limited due to their immature hepatic enzyme systems. In neonates, it is interesting to note that interconversion from theophylline to caffeine has been noted. Unchanged caffeine and its metabolites are excreted in the urine. Plasma half-life for neonates may vary widely, from 65-100 hours, and the fraction of caffeine excreted unchanged in the urine is roughly 86% within 6 days. Young infants have a plasma half-life of caffeine of 3-4 days. By 9 months of age post-term, the plasma half-life and urinary excretion of unchanged caffeine in infants approximates that of adults (1%). Cytochrome P450 metabolism of caffeine is inhibited in infants who are breast-fed; formula feeding does not appear to affect the pharmacokinetics of caffeine in infants. The pharmacokinetics of caffeine have not been studied in neonates with impaired renal or hepatic function; however, caffeine elimination is more dependent on renal clearance in premature neonates and neonates than in older infants or adults, due to the underdeveloped hepatic metabolism and renal elimination. If renal or hepatic impairment is present, caffeine elimination may be reduced, and serum concentrations should be carefully monitored and dosages adjusted to avoid toxicity. Serious toxicity has been reported in infants with serum caffeine concentrations > 50 mg/L.

Adverse Reactions

Caffeine is a CNS stimulant. Many adverse reactions to caffeine are an extension of caffeine's pharmacologic actions. At therapeutic or nontoxic doses, caffeine can cause tremor, sinus tachycardia, and heightened attentiveness. Other adverse reactions include diarrhea, excitement, irritability, insomnia, headache, muscle twitches and palpitations. Alterations in blood glucose, such as hyperglycemia or hypoglycemia, have been reported. After excessive doses, caffeine can cause considerable nausea/vomiting and anxiety. Cardiac arrhythmias, seizures, and delirium are possible after deliberate overdoses. In humans, a caffeine level of > 50 mg/L may produce toxic symptoms.

Caffeine is a mild diuretic. Polyuria can occur. Increased creatinine clearance and increased urinary calcium (hypercalciuria) and sodium excretion are reported in the literature.

In controlled clinical trials of caffeine citrate injection in premature neonates, the following adverse events occurred more commonly in caffeine-treatment groups than with placebo: accidental injury, bleeding, cerebral hemorrhage, disseminated intravascular coagulation, dyspnea, pulmonary edema, metabolic acidosis, xerosis, rash (unspecified), renal failure (unspecified), retinopathy of prematurity, and skin breakdown. In neonates, intolerance or overdose of caffeine may manifest as tachypnea, hyperglycemia, azotemia, fever, or seizures. No deaths have been reported in relation to overdose of caffeine in neonates. During controlled clinical trials of caffeine citrate in premature infants, necrotizing enterocolitis was reported in 6 patients, 5 of whom were administered caffeine. Three of the infants died. The incidence was 4.3% in caffeine-treatment groups vs. 2.6% of placebo-treated infants. Feeding intolerance (3.5%), gastritis (2.2%) and gastrointestinal bleeding (2.2%) also occurred in the caffeine treatment groups. Clinicians should be alert for signs and symptoms of gastric distress, abdominal bloating, nausea, vomiting, bloody stools and lethargy in treated infants.

High caffeine intake has been reported to cause spermatogenesis inhibition in male animals, as noted by spermatogenic cell degeneration within the testes. Although controversial, infertility, as manifested by increased difficulty in getting pregnant, has been reported in females. Couples who are pursuing pregnancy should probably limit excessive intake of caffeine.

In 1992, a distinct caffeine withdrawal syndrome was described. Patients who consume or receive caffeine daily for several weeks experience notable physical and psychiatric responses including lethargy, anxiety, dizziness, or headache upon caffeine withdrawal.


The OTC use of caffeine products is not recommended in children under the age of 12 years.

Caffeine with sodium benzoate injection (see Separate monograph) is not recommended for use in premature neonates because the benzoate may displace bilirubin and induce kernicterus. In addition, elevated serum concentrations of benzoate, similar to benzyl alcohol, have been associated with neurological disturbances, hypotension, gasping respiration, and metabolic acidosis (i.e., 'gasping syndrome') in neonates. Make sure to use Cafcit??, which does not contain sodium benzoate, or to use an extemporaneously compounded caffeine citrate injection in newborns and premature infants. The safety and efficacy of the prescription used of caffeine in infants for longer than 12 days has not been established. Caffeine has not been established for the prophylaxis of sudden infant death syndrome (SIDS) or for use prior to extubation in mechanically ventilated infants.

Caffeine is a central nervous system stimulant. Caffeine should be used cautiously in patients with anxiety disorders and/or panic disorder because it can aggravate these conditions. Patients suffering from insomnia should not consume caffeine, nor should caffeine be consumed prior to retiring because it can cause insomnia. In overdoses, caffeine has been associated with seizures and it should be prescribed cautiously to those patients with a seizure disorder.

Caffeine should be used cautiously in those patients, including neonates, with cardiac disease. Caffeine can stimulate the force of contraction and can increase heart rate. It may increase left ventricular output and stroke volume. Patients who have angina or a history of cardiac arrhythmias should not receive or should minimize their intake of caffeine. Caffeine should not be taken in the first few days-weeks after a myocardial infarction. Patients with hypertension should minimize their intake of caffeine.

Caffeine should be used cautiously in those with hepatic disease or hepatic impairment. Caffeine clearance may be delayed, leading to toxicity. Also, renal impairment or renal failure may delay caffeine clearance. It should be noted that caffeine elimination is more dependent on renal clearance in neonatal prematurity and term neonates than in older infants or adults, due to the underdeveloped hepatic metabolism and renal elimination of drugs in general. Thus monitoring of serum caffeine levels is recommended in neonates or neonatal prematurity, especially those with renal or hepatic impairment.

Patients with diabetes mellitus should not receive or should minimize their intake of caffeine. Although the effects are mild, caffeine can either raise or decrease blood sugar. In neonates, both hypoglycemia and hyperglycemia have been observed.

Patients with thyroid disease, especially hyperthyroidism, should not receive or should minimize their intake of caffeine. The stimulatory effects of caffeine can be augmented in hyperthyroidism.

Caffeine can stimulate gastric secretions. Patients with peptic ulcer disease should minimize their intake of caffeine because the condition can be aggravated. In neonates, there are reports in the literature suggesting a possible association between the use of methylxanthines like caffeine and the development of necrotizing entero-colitis. Six cases of this disease were reported during clinical trials of caffeine injection. All preterm neonates treated with caffeine should be monitored for the development of gastric side-effects (i.e., abdominal distension, vomiting, bloody stools, and lethargy).

Caffeine is generally classified in FDA pregnancy risk category B; however, Cafcit?? (injectable and oral solution) prescription products are classified in FDA pregnancy risk category C but concern for teratogenicity of caffeine is not relevant when such products are administered for neonatal apnea.

Caffeine easily crosses the placenta; fetal blood and tissue concentrations approximate maternal concentrations. There are no large, well-controlled studies of caffeine administration in pregnant women; it is generally recommended that the intake of caffeine-containing beverages, like coffee, teas, and sodas, be limited in pregnancy (usually no more than 1-2 caffeine-containing beverages/day) or avoided if possible. Likewise, caffeine-containing medications should be limited to use only when absolutely necessary. Low to moderate caffeine intake does not appear to increase the risk of congenital malformation, spontaneous abortion, pre-term birth or low birth weight. The association between high daily intake (> 500 mg/day) of caffeine and increased rates of low birth weight, spontaneous abortion, difficulty in getting pregnant or infertility is still controversial, as some studies have not controlled for concomitant cigarette smoking. There are no adequate and well-controlled studies of caffeine administration in pregnant women. Neonatal arrhythmias (e.g., tachycardia, premature atrial contractions) and tachypnea have been reported when caffeine was consumed during pregnancy in amounts > 500 mg/day; caffeine withdrawal after birth may account for these symptoms.

Cytochrome P450 metabolism of caffeine is inhibited in infants who are breast-fed; formula feeding does not appear to affect the pharmacokinetics of caffeine in infants. Peak caffeine milk levels usually occur within 1 hour after the maternal ingestion of a caffeinated beverage; with milk:plasma ratios of 0.5-0.7 reported. Although only small amounts are secreted in breast-milk, caffeine can accumulate in the neonate if maternal ingestion is moderate to high. Higher caffeine intake (> 500 mg/day) by a nursing mother may cause irritability or poor sleeping patterns in the infant who is breast-feeding. Although the American Academy of Pediatrics generally considers the usual use of caffeinated beverages to be compatible with lactation, nursing mothers should limit their intake of beverages containing caffeine if possible. Caffeine containing drug-products should be used cautiously during lactation due to their high caffeine contents.

Mothers who are breast-feeding infants who are prescribed caffeine for apnea should avoid additional caffeine.

Tobacco smoking (cigarettes) has been shown to increase the clearance of caffeine. Also, passive smoke exposure may cause an increase in caffeine clearance. This may help to explain why tobacco smokers often have concommitantly high caffeine intakes. Tobacco smoke contains hydrocarbons that induce hepatic CYP450 microsomal enzymes. Because the effect on hepatic microsomal enzymes is not related to the nicotine component of tobacco, sudden smoking cessation may result in a reduced clearance of caffeine, despite the initiation of nicotine replacement. Caffeine dosage may need to be reduced at the cessation of smoking.

Clinical Pharmacology Copyright © 2005 - Gold Standard Multimedia

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Last updated 2005/09/05

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