VA Class:CN809

AHFS Class:

• Respiratory and CNS Stimulants 28:20.32

Generic Name(s):

• Caffeine

• Sodium Benzoate

• Caffeine Citrate

Caffeine is a xanthine-derivative CNS stimulant that occurs naturally in tea and coffee, but is prepared synthetically for commercial drug use.

CNS Stimulation

Caffeine is used orally as a mild CNS stimulant to aid in staying awake and to restore mental alertness in fatigued patients.

Caffeine also is used orally in combination with antihistamines to overcome the sedative properties of the latter drugs, but the efficacy of caffeine and the dosage required have not been adequately established.

Caffeine and sodium benzoate injection has been used in conjunction with supportive measures to treat respiratory depression associated with overdosage of CNS depressant drugs (e.g., opiate analgesics, alcohol) and with electric shock. However, because of the questionable benefit and transient action, most authorities believe caffeine and other analeptics should not be used in these conditions and recommend other supportive therapy.

Apnea of Prematurity

Caffeine citrate is used IV or orally in the short-term (10-12 days) treatment of apnea of prematurity in neonates who are between 28 and less than 33 weeks of gestational age.115 Caffeine is designated an orphan drug by the US Food and Drug Administration (FDA) for use in apnea in premature neonates.

The use of caffeine citrate in apnea of prematurity was established in a randomized, placebo-controlled clinical trial of the drug in premature neonates (gestational age 28 to less than 33 weeks) with apnea of prematurity (defined as having at least 6 episodes of apnea of greater than 20 seconds' duration in a 24-hour period with no other identifiable causes of apnea).115 A 20-mg/kg loading dose of caffeine citrate (10 mg/kg of caffeine) was administered IV, followed by a daily maintenance dose of 5 mg/kg of caffeine citrate (2.5 mg/kg of caffeine) IV or orally (generally via a feeding tube).115 Patients randomized to placebo were allowed to cross over to caffeine treatment if their apnea became uncontrolled during the double-blind phase of the trial; the study period lasted 10-12 days.115 The percentage of patients without apnea on the second day of treatment (i.e., 24-48 hours after the loading dose) was greater in the caffeine-treated patients compared with placebo-treated patients (26.7 versus 8.1%, respectively).115 The mean number of days with zero apnea events was 3 in the caffeine-treated group and 1.2 in the placebo group, while the mean number of days with a 50% reduction from baseline in apnea events was 6.8 in the caffeine-treated group and 4.6 in the placebo group.115 Serum caffeine concentrations ranged from 8-40 mcg/mL in treated patients; however, a therapeutic plasma concentration could not be determined from this clinical trial.115 In low-birthweight neonates, the drug has decreased the frequency of apneic episodes without any substantial effect on heart rate. Some clinicians recommend that when conservative measures (e.g., tactile stimulation, flotation on a waterbed) are ineffective in preventing severe, recurrent apnea in neonates, caffeine may be used as an alternative to mechanical ventilation†. The manufacturer states that the safety and efficacy of treatment with caffeine citrate in neonates with apnea of prematurity for longer than 10-12 days† have not been established.115 The manufacturer also states that use of caffeine citrate in the prevention of sudden infant death syndrome† (SIDS) or prior to extubation in mechanically ventilated neonates† also has not been established.115 Use of the combination preparation containing caffeine and sodium benzoate† in neonates is generally avoided because of the potential for sodium benzoate to produce kernicterus.(See Cautions: Pediatric Precautions.)

Headache

Caffeine is used orally or rectally in combination with ergotamine tartrate to abort vascular headaches such as migraine and cluster headaches (histamine cephalalgia). There is conflicting evidence regarding the efficacy of this combination in the treatment of acute migraine attacks.116 Caffeine's cerebral vasoconstrictor effect is reportedly additive with that of ergotamine, but the results of one study suggest that the principal value of caffeine in this combination is related to its ability to increase GI absorption of ergotamine tartrate. Some clinicians question the value of the combination because caffeine may keep patients awake and sleep can contribute to the relief of migraine. (For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.)

Caffeine is used orally alone and in combination with analgesics (e.g., acetaminophen, aspirin) for the treatment of headache. Some experts state that the combination of acetaminophen, aspirin, and caffeine is a reasonable first-line therapy for mild to moderate migraine attacks or for severe migraine attacks that have responded in the past to similar nonsteroidal anti-inflammatory agents (NSAIAs) or non-opiate analgesics.116 Caffeine exerts no intrinsic analgesic activity. Although analgesic-caffeine combinations have been reported to produce slightly more analgesia than analgesic agents alone and to have a beneficial effect on mood, which may be clinically important in some patients with headache, these results have not always been reproducible in well-controlled studies and additional studies are needed to determine the role, if any, of caffeine as an analgesic adjuvant.

Caffeine and sodium benzoate injection has been used for the symptomatic relief of headache following spinal puncture.

Other Uses

Caffeine is used orally alone and in combination with other drugs (e.g., analgesics, diuretics) to relieve tension, fatigue, and fluid retention associated with menstruation. However, because caffeine's diuretic activity in patients with fluid retention is minimal, its usefulness in this condition is questionable.

Caffeine (30% in a topical hydrophilic base) has been used effectively alone or in combination with topical hydrocortisone in the topical treatment of atopic dermatitis†.

Caffeine also has been used in combination with ephedrine to promote weight loss in patients with exogenous obesity†.112,113 (See Uses: Misuse and Abuse, in Ephedrine 12:12.12.) It has been suggested that weight loss may be associated with increased energy expenditure (thermogenesis) and appetite suppression.112,113 However, the US Food and Drug Administration (FDA), which did not evaluate the efficacy of ephedrine dietary supplements in obesity therapy, has stated that such use of ephedrine may be associated with an unacceptable incidence of adverse effects.114 (See Misuse and Abuse: Dietary Supplements under Uses, in Ephedrine 12:12.12.)

Administration

Caffeine may be administered orally. Caffeine citrate is administered orally or by slow IV infusion using a syringe infusion pump.115 Caffeine and sodium benzoate injection may be administered by IM or slow IV injection; the drug has also been administered subcutaneously.

The preservative-free commercially available injection is for single use only, and any unused portion should be discarded. It is important that such oral solution be measured accurately (e.g., using a 1-mL or other appropriate syringe).

Dosage

Some clinicians suggest that when used as a mild CNS stimulant to overcome fatigue, oral doses of 100-200 mg of anhydrous caffeine are required. The manufacturers state that adults and children 12 years of age or older may receive a dosage of 100-200 mg no more frequently than every 3-4 hours.117,118

For the treatment of apnea of prematurity, commercially available caffeine citrate injection in a loading dose of 20 mg/kg (10 mg/kg when expressed in terms of anhydrous caffeine) is administered by slow IV infusion (i.e., over 30 minutes) using a syringe infusion pump.115 Beginning 24 hours after the loading dose, maintenance doses of caffeine citrate of 5 mg/kg (2.5 mg/kg when expressed as anhydrous caffeine) may be administered every 24 hours, either orally or via slow IV infusion (i.e., over 10 minutes) using a syringe infusion pump.115 The manufacturer states that the safety and efficacy of dosing periods exceeding 10-12 days have not been established.115 Other dosing regimens† for the treatment of apnea of prematurity have used caffeine doses (in terms of anhydrous caffeine) of 5-10 mg/kg, given IV, IM, or orally as a loading dose, and followed by 2.5-5 mg/kg, given IV, IM, or orally once daily.105,106,107,108,109,110 Maintenance dosage has been adjusted according to the patient's response and tolerance and plasma caffeine concentrations.105,106,107,108,109,110

When caffeine citrate is used for the treatment of apnea of prematurity in infants with hepatic or renal impairment, serum concentrations of caffeine should be monitored and dosage adjusted to avoid toxicity.115

Analeptic use of caffeine is strongly discouraged by most clinicians. However, the manufacturers of caffeine and sodium benzoate injection recommend IM, or in emergency respiratory failure, IV injection of 500 mg of the drug (about 250 mg of anhydrous caffeine) or a maximum single dose of 1 g (about 500 mg of anhydrous caffeine) for the treatment of respiratory depression associated with overdosage of CNS depressants, including opiate analgesics and alcohol, and with electric shock.

Some clinicians recommend that when caffeine and sodium benzoate injection is used in children for CNS stimulation†, an IM, IV, or subcutaneous dose of 8 mg/kg (about 4 mg of anhydrous caffeine per kg) (not to exceed 500 mg) or 250 mg/m² (about 125 mg of anhydrous caffeine per m²) be given up to every 4 hours if necessary.

Adverse Effects

CNS stimulation and GI irritation usually occur with therapeutic dosages of caffeine. Adverse CNS effects, which are usually more severe in children than in adults, include insomnia, restlessness, nervousness, and mild delirium. Adverse GI effects include nausea, vomiting, and gastric irritation. Although chronic administration of caffeine in animals has been associated with gastric ulceration, such a causal relationship in humans has not been adequately established to date. Suppositories containing caffeine may produce rectal irritation. Large doses of caffeine may produce headache, excitement, agitation, a condition resembling anxiety neurosis, scintillating scotoma, hyperesthesia, tinnitus, muscle tremors or twitches, diuresis, tachycardia, extrasystoles, and possibly other cardiac arrhythmias.

Further CNS depression may occur when already depressed patients are too vigorously treated with caffeine and sodium benzoate.

In a placebo-controlled study, the most common adverse effects occurring more frequently in patients receiving caffeine citrate than in those receiving placebo included rash and feeding intolerance, each of which occurred in 8.7% of patients, and sepsis and necrotizing enterocolitis, each of which occurred in 4.3% of patients.115 In this same trial, accidental injury,115 hemorrhage,115 gastritis,115 GI hemorrhage,115 disseminated intravascular coagulation,115 acidosis,115 abnormal healing,115 cerebral hemorrhage,115 pulmonary edema,115 dyspnea,115 dry skin,115 skin breakdown,115 retinopathy of prematurity,115 and kidney failure115 each occurred in 2.2% of caffeine-treated patients.115 In addition, during the trial of caffeine citrate for the apnea of prematurity, 6 cases of necrotizing enterocolitis developed among the 85 neonates studied, 3 cases of which were fatal.115 Five of the 6 neonates had been randomized to treatment with or had been exposed to caffeine citrate.115 Adverse effects reported in the literature include CNS stimulation (i.e., irritability, restlessness, jitteriness), cardiovascular effects (i.e., tachycardia, increased left ventricular output, increased stroke volume), GI effects (i.e., increased gastric aspirate, GI intolerance), alterations in serum glucose (i.e., hyperglycemia or hypoglycemia), and renal effects (i.e., increased urine flow rate, increased creatinine clearance, increased sodium and calcium excretion).115

Ingestion of large amounts of combinations containing aspirin, phenacetin, and caffeine (combinations containing phenacetin no longer are commercially available in the US) has been associated with analgesic nephropathy which is characterized by sterile pyuria, asymptomatic bacteriuria, pyelonephritis, papillary necrosis, interstitial fibrosis and nephritis, and increased excretion of renal tubular cells and erythrocytes. Caffeine's role in the etiology of this condition has not been conclusively established.

Precautions and Contraindications

Because it has been suggested that caffeine may promote gastric ulceration, the drug should be used cautiously in patients with a history of peptic ulcer. Because of its suspected arrhythmogenic potential, it is generally recommended that caffeine be avoided in patients with symptomatic cardiac arrhythmias and/or palpitations and during the first several days to weeks after an acute myocardial infarction.100

When self-administered as a mild CNS stimulant to overcome fatigue or drowsiness, caffeine is intended for occasional use only and should not be used as a substitute for sleep.117,118

When preparations containing caffeine in combination with other drugs (see Preparations) are used, the cautions, precautions, and contraindications applicable to each ingredient should be considered.121

Caffeine is contraindicated in patients with a history of hypersensitivity to the drug.

Pediatric Precautions

Use of caffeine tablets for self-medication in children younger than 12 years of age is not recommended.117,118

Adverse CNS effects of caffeine are usually more severe in children than in adults. (See Cautions: Adverse Effects.) The sodium benzoate component in caffeine and sodium benzoate injection reportedly produces kernicterus in neonates by uncoupling albumin-bilirubin binding. Long-term follow-up studies have not shown caffeine administration in premature neonates to affect adversely either neurologic development or growth parameters.115

In neonates receiving caffeine citrate therapy, periodic monitoring of serum caffeine concentrations may be necessary to avoid toxicity.115 Prior to initiation of caffeine citrate therapy, baseline serum concentrations of caffeine should be measured in neonates previously treated with theophylline, since preterm neonates metabolize theophylline to caffeine.115 Similarly, baseline serum concentrations of caffeine should be measured in infants born to mothers who consumed caffeine prior to delivery since caffeine readily crosses the placenta.115 Serious toxicity has been reported when serum caffeine concentrations exceed 50 mcg/mL.115

Because studies examining the pharmacokinetics of caffeine in neonates with renal or hepatic insufficiency have not been conducted, caffeine citrate should be administered with caution in premature neonates with impaired renal or hepatic function.115 Serum concentrations of caffeine should be monitored in these neonates, and dosage adjusted to avoid toxicity.115

Few data exist on drug interactions with caffeine in premature neonates.115 Based on data in adults, lower doses of caffeine may be needed following concomitant use of drugs that are reported to decrease caffeine elimination (e.g., ketoconazole, cimetidine) and higher caffeine doses may be required following concomitant use of drugs that increase caffeine elimination (e.g., phenobarbital, phenytoin).115 Interconversion between caffeine and theophylline has been reported in premature neonates.115 The concurrent use of these drugs is not recommended.115 In healthy adults, concomitant administration of caffeine with ketoprofen resulted in decreased urinary volume; the clinical significance of this interaction in premature neonates is not known.

In clinical trials reported in the literature, cases of hypoglycemia and hyperglycemia have been reported in patients receiving caffeine; therefore, blood glucose concentration may need to be monitored periodically in neonates receiving caffeine citrate.115

Although no cases of cardiac toxicity were reported in the placebo-controlled trial of caffeine citrate for the treatment of apnea of prematurity, caffeine has been shown to increase heart rate, left ventricular output, and stroke volume.115 Therefore, caffeine citrate should be used with caution in neonates with cardiovascular disease.115

If signs of GI intolerance (e.g., abdominal distention, vomiting, bloody stools) or lethargy develops in premature neonates receiving caffeine citrate oral solution, a clinician should be consulted.

Because seizures have been reported in cases of caffeine overdose, caffeine citrate should be used with caution in neonates with seizure disorders.115

The duration of treatment with caffeine citrate in neonates with apnea of prematurity was limited to 10-12 days in the placebo-controlled trial.115 The safety and efficacy of caffeine citrate for longer periods in this condition have not been established.115 If premature neonates receiving caffeine citrate oral solution continue to experience apnea events, dosage of the drug should not be increased without advice of a clinician. Safety and efficacy of caffeine citrate in the prevention of sudden infant death syndrome (SIDS) or prior to extubation in mechanically ventilated patients also have not been established.115

Apnea of prematurity is a diagnosis of exclusion.115 Other causes of apnea (e.g., CNS disorders, primary lung disease, anemia, sepsis, metabolic disturbances, cardiovascular abnormalities, obstructive apnea) should be ruled out or treated appropriately prior to initiation of treatment with caffeine citrate.115

During the placebo-controlled trial of caffeine citrate establishing efficacy in the US for apnea of prematurity, 6 cases of necrotizing enterocolitis developed among the 85 neonates studied, 3 cases of which were fatal.115 Five of the 6 neonates had been randomized to treatment with or had been exposed to caffeine citrate.115 Reports in the literature have raised the possibility of an association between the use of methylxanthines and the development of necrotizing enterocolitis, although a causal relationship between methylxanthine use and the development of necrotizing enterocolitis has not been established.115 Therefore, as with all premature neonates, patients being treated with caffeine citrate should be monitored carefully for the development of necrotizing enterocolitis.115

Mutagenicity and Carcinogenicity

Although clastogenicity and mutagenicity have been demonstrated in some in vitro and animal studies, most clinicians believe that these effects are not important in relation to the amounts of caffeine consumed by humans.

In a 2-year study in Sprague-Dawley rats, caffeine (as caffeine base) administered in drinking water was not carcinogenic in male rats at doses up to 102 mg/kg or in female rats at doses up to 170 mg/kg (approximately 2 and 4 times, respectively, the maximum IV loading dose for neonates on a mg/m² basis). In an 18-month study in C57BL/6 mice, no evidence of tumorigenicity was seen at dietary doses of up to 55 mg/kg (less than the maximum IV loading dose for neonates on a mg/m² basis).

Caffeine (as caffeine base) increased the sister chromatid exchange (SCE) SCE/cell metaphase (exposure time dependent) in an in vivo mouse metaphase analysis. Caffeine also potentiated the genotoxicity of known mutagens and enhanced the micronuclei formation fivefold in folate-deficient mice. However, caffeine did not increase chromosomal aberrations in in vitro Chinese hamster ovary (CHO) and human lymphocyte assays and was not mutagenic in an in vitro CHO/HGPRT gene mutation assay, except at cytotoxic concentrations. In addition, caffeine was not clastogenic in an in vivo mouse micronucleus assay.

Although it has been suggested that coffee consumption is associated with an increased risk of lower urinary tract, renal, and pancreatic cancers, most studies conducted to date have had methodologic flaws and there is currently no clear evidence that coffee consumption is causally related to an increased risk of these cancers.

Pregnancy, Fertility, and Lactation

Pregnancy

There are no adequate and well-controlled studies in pregnant women. In studies performed in adult animals, caffeine (as caffeine base) administered to pregnant mice as sustained-release pellets at 50 mg/kg (less than the maximum IV loading dose for neonates on a mg/m² basis) during the period of organogenesis caused a low incidence of cleft palate and exencephaly in fetuses. Based on data from a large retrospective epidemiologic study and from a large retrospective case-control study in humans, it appears that use of caffeine during pregnancy has little, if any, effect on the outcome of pregnancy. Although caffeine use during pregnancy does not appear to be associated with substantial risk, most clinicians recommend that pregnant women avoid or limit their consumption of foods, beverages, and drugs containing caffeine, since caffeine crosses the placenta.

Fertility

Caffeine (as caffeine base) administered subcutaneously to male rats at 50 mg/kg daily (approximately equal to the maximum IV loading dose for neonates on a mg/m² basis) for 4 days prior to mating with untreated females caused decreased male reproductive performance in addition to causing embryotoxicity. In addition, long-term exposure to high oral doses of caffeine (3 g over 7 weeks) was toxic to rat testes as manifested by spermatogenic cell degeneration.

Lactation

Caffeine is distributed into the milk of nursing women. Milk-to-plasma ratios of 0.5-0.76 have been reported.119 The amount of caffeine ingested from usual quantities of caffeinated beverages is considered compatible with breast-feeding; however, caffeine may accumulate in nursing infants following moderate to heavy maternal consumption of caffeine, resulting in irritability and poor sleeping patterns.119

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Caffeine is metabolized by the cytochrome P-450 (CYP) enzyme system, principally by isoenzyme 1A2.115 Therefore, caffeine has the potential to interact with drugs that are metabolized by CYP1A2 or with drugs that induce or inhibit this isoenzyme.115 (See Cautions: Pediatric Precautions.) Caffeine has been reported to increase its own metabolism.

-Adrenergic Agonists

Caffeine and other xanthines may enhance the cardiac inotropic effects of β-adrenergic stimulating agents.

Disulfiram

When caffeine and disulfiram are administered concomitantly in healthy individuals or recovering alcohol-dependent patients, the total blood clearance of caffeine is substantially decreased and its elimination half-life is increased.103 The exact mechanism of the interaction is not known, but disulfiram may inhibit hepatic metabolism of caffeine.103 The clinical importance of the interaction has not been established, but the possibility that exaggerated or prolonged effects of caffeine might occur in patients receiving disulfiram who also ingest substantial quantities of coffee, tea, or other caffeine-containing beverages should be considered.103,104 Further studies are needed.103,104

Laboratory Test Interferences

Caffeine produces false-positive elevations of serum urate as measured by the Bittner method. The drug also produces slight increases in urine levels of vanillylmandelic acid (VMA), catecholamines, and 5-hydroxyindoleacetic acid. Because high urine concentrations of VMA or catecholamines may result in false-positive diagnosis of pheochromocytoma or neuroblastoma, caffeine intake should be avoided during tests for these disorders.

Acute Toxicity

Manifestations

Acute toxicity involving caffeine has been reported rarely. GI pain, mild delirium, insomnia, diuresis, dehydration, and fever commonly occur with overdosage. More serious symptoms of overdosage include cardiac arrhythmias and tonic-clonic seizures. In adults, IV doses of 57 mg/kg and oral doses of 18-50 g have been fatal. In one 5-year-old patient, death occurred following oral ingestion of approximately 3 g of caffeine.

Following overdose of caffeine citrate in preterm neonates, serum caffeine concentrations have ranged from approximately 24-350 mcg/mL.115 Signs and symptoms of caffeine overdose in premature neonates reported in the literature include fever, tachypnea, jitteriness, insomnia, fine tremor of the extremities, hypertonia, opisthotonos, tonic-clonic movements, nonpurposeful jaw and lip movements, vomiting, hyperglycemia, elevated BUN, and elevated total leukocyte concentration.115 Seizures also have been reported in cases of overdose.115 One case of caffeine overdose complicated by development of intraventricular hemorrhage and long-term neurologic sequelae has been reported.115 In another case of caffeine citrate overdosage, administration of caffeine citrate 600 mg (approximately 322 mg/kg) over 40 minutes was associated with tachycardia, ST-segment depression, respiratory distress, heart failure, gastric distension, acidosis, and severe extravasation burn with tissue necrosis at the peripheral infusion site.115 No deaths associated with caffeine overdose have been reported in premature neonates.115

Treatment

Treatment of caffeine overdose in premature neonates is mainly symptomatic and supportive.115 In acute oral caffeine overdosage, the stomach should be emptied immediately by inducing emesis or by lava activated charcoal may be administered; and supportive measures should be initiated. Serum caffeine concentrations have been shown to decrease following exchange transfusions.115 Administration of demulcents such as aluminum hydroxide gel may diminish GI irritation. Seizures may be treated with IV administration of diazepam or a barbiturate such as pentobarbital sodium.

Chronic Toxicity

Prolonged, high intake of caffeine may produce tolerance, habituation, and psychological dependence. Physical signs of withdrawal such as headaches, irritation, nervousness, anxiety, and dizziness may occur upon abrupt discontinuation of the stimulant.

Pharmacology

Caffeine is pharmacologically similar to the other xanthine drugs, theobromine and theophylline; however, these three agents differ in the intensity of their actions on various structures. Caffeine's CNS and skeletal muscle effects are greater than those of the other xanthines. In all other areas, theophylline has greater activity than caffeine, although some studies report that caffeine has a greater diuretic effect than theobromine. Caffeine competitively inhibits phosphodiesterase, the enzyme that degrades cyclic 3',5'-adenosine monophosphate (AMP). Increased levels of intracellular cyclic AMP mediate most of caffeine's pharmacologic actions.

CNS Effects

Caffeine stimulates all levels of the CNS. In oral doses of 100-200 mg, the drug stimulates the cerebral cortex producing a more rapid and clearer thought flow, wakefulness or arousal in fatigued patients, and improved psychomotor coordination. Caffeine's cortical effects are milder and of shorter duration than those of the amphetamines. In slightly larger doses, caffeine stimulates medullary vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate. Tolerance to the CNS effects of caffeine may develop.

Cardiovascular Effects

Caffeine produces a positive inotropic effect on the myocardium and a positive chronotropic effect at the sinoatrial node, causing transient increases in heart rate, force of contraction, cardiac output, and heart work. In doses of greater than 250 mg, the centrally mediated vagal effects of caffeine may be masked by increased sinus rates; tachycardia, extrasystoles, or possibly other major ventricular arrhythmias may result. The arrhythmogenic potential of caffeine remains to be fully evaluated.100

Caffeine constricts cerebral vasculature. In contrast, the drug directly dilates peripheral blood vessels, decreasing peripheral vascular resistance. The effect of this decrease in peripheral vascular resistance (and possibly that of vagal cardiac stimulation) on blood pressure is offset by increased cardiac output (and possibly stimulation of the medullary vasomotor area). The overall effect of caffeine on heart rate and blood pressure depends on whether CNS or peripheral effects predominate. Generally, therapeutic doses of caffeine increase blood pressure only slightly, but in healthy individuals, chronic ingestion of caffeine has little or no effect on blood pressure, heart rate, plasma catecholamine concentrations, or plasma renin activity.101 Individuals with borderline hypertension do not appear to have an increased susceptibility to the pressor effects of caffeine or increased resistance to the tolerance to the cardiovascular effects that develops with prolonged administration.102

Other Effects

Caffeine stimulates voluntary skeletal muscle, increasing the force of contraction and decreasing muscular fatigue. The drug also stimulates gastric acid secretion from parietal cells. Caffeine increases renal blood flow and glomerular filtration rate and decreases proximal tubular reabsorption of sodium and water, resulting in mild diuresis; tolerance may develop to the diuretic effect.

Caffeine stimulates glycogenolysis and lipolysis, but increases in blood glucose and in plasma lipids are usually insignificant in normal patients.

Pharmacokinetics

Absorption

Caffeine and citrated caffeine are well absorbed following oral administration. Absorption of caffeine following oral administration may be more rapid than that following IM injection of caffeine and sodium benzoate. Absorption following rectal administration of caffeine in suppositories may be slow and erratic. Absolute bioavailability of caffeine in preterm neonates has not been fully determined.115 Following oral administration of 100 mg of caffeine (as coffee), peak plasma concentrations of about 1.5-1.8 mcg/mL are reached after 50-75 minutes. After oral administration of 10 mg/kg caffeine to preterm neonates, the peak plasma concentration for caffeine ranged from 6-10 mg/L and the mean time to reach peak concentration ranged from 30 minutes to 2 hours.115 The time to reach peak plasma concentration was not affected by formula feeding.115

Distribution

Caffeine is rapidly distributed into body tissues, readily crossing the placenta and blood-brain barrier. Caffeine concentration in the CSF fluid of preterm neonates approximates the plasma concentration.115 The mean volume of distribution of caffeine in infants (0.8-0.9 L/kg) is slightly higher than that in adults (0.6 L/kg).115 Approximately 17-36% of the drug is bound to plasma proteins in adults. Plasma protein binding data are not available for neonates or infants.115 Caffeine has been shown to distribute into milk in a milk-to-plasma concentration ratio of 0.5-0.76.119

Elimination

Caffeine has a plasma half-life of 3-5 hours in adults. In one study, when administered to pregnant women prior to delivery, caffeine had a prolonged mean half-life of 80 hours in the neonates after delivery. In young infants, the elimination of caffeine is much slower than that in adults because of immature hepatic and/or renal function.115 Mean half-life and fraction excreted unchanged in urine of caffeine in infants have been shown to be related inversely to gestational/postconceptional age.115 In neonates, the half-life of caffeine is approximately 3-4 days, and the mean fraction excreted unchanged in urine is approximately 86% (within 6 days).115 By 9 months of age, the metabolism of caffeine approximates that seen in adults.115 Hepatic cytochrome P-450 (CYP) isoenzyme 1A2 is involved in caffeine enzymatic metabolism.115 In adults, the drug is rapidly metabolized in the liver to 1-methyluric acid, 1-methylxanthine, and 7-methylxanthine. Interconversion between caffeine and theophylline has been reported in preterm neonates;115 caffeine concentrations are approximately 25% of theophylline concentration following theophylline administration and approximately 3-8% of an administered dose of caffeine would be expected to convert to theophylline.115 Caffeine and its metabolites are excreted mainly by the kidneys; approximately 1% of a dose of caffeine is excreted unchanged in urine in adults.

Studies examining the pharmacokinetics of caffeine in neonates with renal or hepatic insufficiency have not been conducted.115

Chemistry and Stability

Chemistry

Caffeine, like theobromine and theophylline, is a xanthine derivative. Caffeine occurs naturally in tea and coffee, but is prepared synthetically for commercial drug use. Caffeine is present in amounts of about 100-150 mg/180 mL of brewed coffee; 60-80 mg/180 mL of instant coffee; 40-100 mg/180 mL of tea; and 17-55 mg/180 mL of cola beverage.

Caffeine occurs as a white powder or white, glistening needles that are usually matted together. The drug is odorless and has a bitter taste. Caffeine, which may contain one molecule of water or be anhydrous, is sparingly soluble in water and in alcohol. The hydrate effloresces in air.

Various synthetic mixtures of caffeine have been prepared to increase its solubility. The mixture of caffeine and sodium benzoate contains 45-52% anhydrous caffeine and occurs as a white powder with a slightly bitter taste. The mixture is freely soluble in water and soluble in alcohol. Caffeine and sodium benzoate injection has a pH of 6.5-8.5. Citrated caffeine is a white powder with a bitter taste, obtained by combining caffeine with citric acid. Citrated caffeine is freely soluble in water and soluble in alcohol and contains approximately 50% anhydrous caffeine. Commercially available caffeine citrate injection and oral solution have a pH of 4.7.

Stability

Commercially available caffeine and sodium benzoate injection and caffeine citrate injection and oral solution should be stored at 15-30°C.115,120 The commercially available injections and oral solution should be inspected visually for particulate matter and discoloration prior to administration.115,120 Vials containing discolored solution or visible particulate matter should be discarded.115

Based on compatibility studies, the commercially available caffeine citrate injection is chemically stable for 24 hours at room temperature when mixed with any of the following solutions: 5% dextrose injection; 50% dextrose injection; Intralipid^® 20% emulsion; Aminosyn^® 20% solution; dopamine hydrochloride injection (diluted to 0.6 mg/mL with 5% dextrose injection); calcium gluconate 10% injection; heparin sodium injection (diluted to 1 unit/mL with 5% dextrose injection); fentanyl citrate injection (diluted to 10 mcg/mL with 5% dextrose injection).115

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115. Mead Johnson. Cafcit^® (caffeine citrate) injection and oral solution prescribing information. Evansville, IN; 2003 May.

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