Caffeine is bioavailable by oral (PO), intravenous (IV), subcutaneous, intramuscular, and rectal routes of administration. PO administration, which is by far the most common route of exposure, results in nearly 100% bioavailability. The presence of food in the gut does little to affect peak concentration. However, food in the gut delays the time until the peak serum concentration is reached, which is typically 30 to 60 minutes in the absence of food. Caffeine rapidly diffuses into the total body water and all tissues and readily crosses the blood–brain barrier and into the placenta. The volume of distribution (Vd) is 0.6 L/kg, and 36% is protein bound. Caffeine is secreted in breast milk with concentrations of 2 to 4 μg/mL in breast milk after 100 mg PO dosing in a breastfeeding mother.190 Consumption of caffeine does not result in clinically relevant breast milk caffeine concentrations in lactating women or toxicity in their breastfeeding children. Breast milk caffeine concentrations are lower than maternal serum caffeine concentrations, with breast milk having 0.006% to 1.5% of the quantity of maternal serum.23
When taken in amounts that produce serum caffeine concentrations exceeding a therapeutic range, or approximately 20 mg/kg, caffeine exhibits Michaelis-Menten kinetics and is metabolized, primarily by CYP1A2. The major pathway involves demethylation to 1,7-dimethylxanthine (paraxanthine) followed by hydroxylation or repeated demethylation followed by hydroxylation. To a lesser extent, caffeine is also metabolized to theobromine and theophylline. Neonates demethylate caffeine, producing theophylline, and possess the unique ability to convert theophylline to caffeine by methylation.1,76 By 4 to 7 months of age, infants metabolize and eliminate caffeine in a manner similar to adults.10 All patients demethylate some quantity of caffeine to active metabolites, including theophylline and theobromine. The degree to which this occurs depends on the patient’s age, CYP1A2 induction status, and other factors.
Less than 5% of caffeine is excreted in the urine unchanged. The half-life of caffeine is highly variable and dependent on several factors. Generally speaking, younger patients, particularly infants as well as patients with CYP1A2 inhibition, such as pregnant patients and patients with cirrhosis, have longer caffeine half-lives than the 4.5-hour half-life in healthy, adult, nonsmoking patients.34,52,57,89
Caffeine toxicity is a dose dependent phenomenon. The range of toxic concentrations reported in different references varies greatly, and no definite conclusions can be drawn regarding the relationship between serum concentrations and symptomatology in overdose. Therapeutic dosing in neonates is typically a loading dose of 20 mg/kg, with daily maintenance dosing of 5 mg/kg. Based on case reports and series, lethal dosing in adults is estimated at 150 to 200 mg/kg, and death may occur with serum concentrations above 80 μg/mL. Numerous fatalities are reported with serum concentrations under 200 μg/mL; and survival is reported of a patient with an acute caffeine overdose and a serum concentration over 400 μg/mL.194 Infants tolerate greater serum concentrations of caffeine than do children and adults.
Theophylline is approximately 100% bioavailable by the PO and IV routes. Many of the available PO preparations are sustained release designed to provide stable serum concentrations over a prolonged period of time with less frequent dosing. Peak absorption for immediate-release preparations is 60 to 90 minutes; peak absorption of sustained-release preparations generally occurs 6 to 10 hours after ingestion.
Similar to caffeine, theophylline rapidly diffuses into the total body water and all tissues, readily crosses the blood–brain barrier, and crosses into the placenta and breast milk.14 The Vd of theophylline is 0.5 L/kg, and 56% of it is protein bound at therapeutic concentrations.
Theophylline is metabolized primarily by CYP1A2. The major pathway is demethylation to 3-methylxanthine in addition to being demethylated or oxidized to other metabolites. Less than 10% of theophylline is excreted in the urine unchanged.
Similar to caffeine, the half-life of theophylline is highly variable and depends on several factors. In healthy, adult, nonsmoking patients, the half-life is 4.5 hours. Infants and elderly adults as well as patients with CYP1A2 inhibition, pregnant patients, and those with cirrhosis may have theophylline half-lives twice as long as healthy children and nonsmoking adults.100,132,188 Factors that induce CYP1A2, such as cigarette smoking, or others that inhibit CYP1A2, such as exposure to cimetidine, macrolides, and oral contraceptives, can significantly alter theophylline clearance.84,130,146,147,162,199 Cessation of smoking, such as when a patient with chronic obstructive pulmonary disease develops bronchitis, leads to a reversal of CYP1A2 induction and predisposes to the development of chronic toxicity.
As in the case of caffeine, theophylline exhibits Michaelis-Menten kinetics, presumably when greater than a single therapeutic dose is taken.152 At higher doses and in overdose, it undergoes zero-order elimination, and only a fixed amount of the drug can be eliminated in a given time because of saturation of metabolic enzymes.159
Therapeutic serum concentrations of theophylline are 5 to 15 μg/mL. Although morbidity and mortality are not always predictable based on serum concentrations, life-threatening toxicity is associated with serum concentrations of 80 to 100 μg/mL in acute overdoses and of 40 to 60 μg/mL in chronic overdoses.
Theobromine Toxicokinetics and Pharmacokinetics
Similar to the other methylxanthines, theobromine is well absorbed from the gastrointestinal (GI) tract and is 80% bioavailable when administered in solution. It is completely bioavailable orally and rectally. Theobromine has 21% protein binding, a Vd of 0.62 L/kg, and a serum half-life of 6 to 10 hours.62,156 Theobromine undergoes hepatic metabolism by CYP1A2 and CYP2E1.31 Theobromine is excreted in breast milk. Toxic concentrations of theobromine in animals are known, but comparable human data are lacking.
Selective β2-Adrenergic Agonist Pharmacokinetics
The β2-adrenergic agonists are bioavailable by both inhalation and ingestion, and much of “inhaled” β2-adrenergic agonists may actually be swallowed and absorbed from the GI tract. Absorption, distribution, and elimination are quite variable. The half-life of albuterol is approximately 4 hours, less than 5% crosses the blood–brain barrier, it is metabolized extensively in the liver, and it is excreted in urine and feces as albuterol and metabolites.3
Terbutaline is partially metabolized in the liver, mainly to inactive conjugates. With parenteral administration, 60% of a given dose is excreted in the urine unchanged.2
Clenbuterol has a terminal half-life of approximately 22 hours and a prolonged duration of action. It is more potent than other β2-adrenergic agonist, with a typical therapeutic dose of 20 to 40 μg, as opposed to milligram doses for other β2-adrenergic agonists.
Selective β2-Adrenergic Agonist Toxicokinetics.
Overdose of albuterol, which happens predominantly in young children treated with oral albuterol preparations, may cause significant effects.115 For oral albuterol poisoning 1 mg/kg appears to be the dose threshold for developing clinically significant toxicity.205
Clenbuterol toxicity occurs following illicit drug use by ingestion, intranasal, and IV use of clenbuterol or clenbuterol-tainted street drugs.96
Methylxanthine and β2-Adrenergic Agonist Toxicity
Caffeine, theobromine, and theophylline affect the same organ systems and cause qualitatively similar effects. There are distinct differences in the activity and effects of the various methylxanthines, particularly in therapeutic dose. Toxicity affects the GI, cardiovascular, central nervous, and musculoskeletal systems in addition to causing a constellation of metabolic derangements. A putative cause for toxicity involves the increase in metabolism that occurs with methylxanthine toxicity, particularly in the setting of a decreased tissue perfusion.
Concomitant poisoning with other xenobiotics that result in adrenergic stimulation, such as pseudoephedrine, ephedrine, amphetamines, or cocaine, may be particularly severe.58,203
In overdose, methylxanthines cause nausea, and most significant acute overdoses result in severe and protracted emesis. Whereas emesis occurs in 75% of cases of acute theophylline poisoning, only 30% of cases of chronically poisoned patients have emesis.181 When it occurs, the emesis may be difficult to control despite the use of potent antiemetics. This is especially evident with sustained-release theophylline preparations.4 Emesis is less common with β2-adrenergic agonists, than with methylxanthine overdose.
Methylxanthines cause an increase in gastric acid secretion and smooth muscle relaxation. These factors contribute to the gastritis and esophagitis reported in chronic methylxanthine users.46 Gastritis is noted in drinkers of decaffeinated coffee, indicating that some adverse gastric effects associated with coffee drinking may be caused by ingredients other than caffeine or even the pH of the beverage.
Methylxanthines are cardiac stimulants and result in positive inotropy and chronotropy even with therapeutic dosing. Dysrhythmias, particularly tachydysrhythmias, are common in patients with methylxanthine overdose. Tachydysrhythmias, particularly ventricular extrasystoles, are more common after overdose of methylxanthines.42,139,174 Cardiac dysrhythmias, although described with β2-adrenergic agonist poisoning, are most frequently supraventricular in origin and clinically inconsequential. Dysrhythmias other than sinus tachycardia associated with β2-adrenergic agonist toxicity are not routinely noted with toxicity from other β2-adrenergic agonists, but clenbuterol may result in atrial fibrillation.55 Palpitations, tachycardia, and chest pain are common presenting complaints for patients with clenbuterol toxicity.
In the setting of acute poisoning, generally benign sinus tachycardia is nearly universal in patients without antecedent cardiac disease. In any patient, particularly those with underlying cardiac disease, sinus tachycardia may degenerate to a more severe rhythm disturbance, and these represent the most common causes of fatality associated with methylxanthine poisoning. Both atrial and ventricular dysrhythmias, including supraventricular tachycardia (SVT), multifocal atrial tachycardia, atrial fibrillation, premature ventricular contractions, and ventricular tachycardia, may all result from methylxanthine toxicity.21,178 Electrolyte disturbances, particularly hypokalemia, may be a contributing factor in the development of dysrhythmias. Dysrhythmias occur more commonly and at lower serum concentrations in cases of chronic poisoning with methyxanthines. Consequential dysrhythmias occur in 35% of patients with chronic theophylline poisoning but in only 10% of acute poisoning.178 Ventricular dysrhythmias occur at serum concentrations of 40 to 80 μg/mL in patients with chronic theophylline overdoses and most commonly at serum concentrations greater than 80 μg/mL in patients with acute overdoses. Neonates born to mothers who consumed more than 500 mg/day of caffeine are more likely to have dysrhythmias compared with cohorts born to mothers consuming less than 250 mg/day of caffeine.86 See Table 66–1 for the caffeine content of other popular products.
Myocardial ischemia and myocardial infarction (MI) may result from acute caffeine or theophylline poisoning.69,91,134 MI is associated with albuterol66 and more recently clenbuterol.114 Isoproterenol, once a common asthma therapy before widespread use of selective β2-adrenergic agonists, has both β1- and β2-adrenergic agonist activity and is a well-reported cause of MI. Given the frequency of use of selective β2-adrenergic agonists as well as toxicity and adverse effects reported from them, MI should be considered unlikely to occur. The same cannot be presumed about clenbuterol because the toxicity profile for this drug is still emerging. Clenbuterol is clearly documented to cause myocardial ischemia and MI in young otherwise healthy patients without coronary artery disease.114
Elevation of troponin, muscle creatine phosphokinase (CK-MM) and cardiac (CK-MB) fractions after large doses of β2-adrenergic agonist, particularly terbutaline infusions and continuous albuterol nebulization, is described.49,50,109,193 In the absence of electrocardiographic (ECG) changes suggestive of ischemia, the clinical significance of increased CPK-MB and cardiac troponins in patients receiving terbutaline infusions, particularly children, is unclear and has not been demonstrated to correlate with clinically adverse effects.44
In therapeutic doses, methylxanthines cause cerebral vasoconstriction, which is a desirable effect when caffeine is used to treat a migraine headache. However, in overdose, this effect likely exacerbates CNS toxicity by diminishing cerebral perfusion.134 Tolerance to the vasopressor effects of methylxanthines develops after several days of use and rapidly disappears after relatively brief periods of abstinence.
Dietary caffeine use is associated with a significant increase in blood pressure that may contribute to population levels of morbidity and mortality.103 At elevated serum concentrations, patients with methylxanthine or β2-adrenergic agonist poisoning often develop a characteristic widened pulse pressure. This is caused by enhanced inotropy (β1) and may result in increases in systolic blood pressure combined with peripheral vasodilation (β2), which may result in diastolic hypotension. In cases of acute theophylline overdose, serum concentrations greater than 100 μg/mL are usually associated with significant hypotension.
Methylxanthines cause renal vasodilation that, in addition to the increased cardiac output, results in a mild diuresis.148
Methylxanthines stimulate the CNS respiratory center, causing an increase in respiratory rate. For this reason, caffeine and theophylline are used to treat neonatal apnea syndromes. Caffeine and theophylline overdose may cause hyperventilation, respiratory alkalosis, respiratory failure, respiratory arrest, and acute respiratory distress syndrome.
The stimulant and psychoactive properties of methylxanthines, particularly caffeine, elevate mood and improve performance of manual tasks.26,36,102 These stimulant effects are some of the reasons caffeine is so widely used. CNS stimulation is an effect sought by users of coffee, tea, cocoa, and chocolate, but CNS stimulation resulting from therapeutic use of theophylline is generally considered to be an undesirable side effect. Although at low doses methylxanthines have beneficial effects, with increasing doses, they result in adverse effects. Headache, anxiety, agitation, insomnia, tremor, irritability, hallucinations, and seizures may result from caffeine or theophylline poisoning. In adults, caffeine doses of 50 to 200 mg result in increased alertness, decreased drowsiness, and lessened fatigue, and caffeine doses of 200 to 500 mg produce adverse effects such as tremor, anxiety, diaphoresis, and palpitations. Children tend to develop CNS symptoms at lower serum theophylline concentrations than adults, and such excitation is a significant clinical disadvantage of theophylline use.
Seizures are a major complication of methylxanthine poisoning. The ability of caffeine to both promote and prolong seizures is well recognized. Caffeine has been used to prolong therapeutically induced seizures in electroconvulsive therapy.54,112 Seizures resulting from methylxanthine overdose tend to be severe and recurrent and may be refractory to conventional treatment. Antagonism of adenosine, the endogenous neurotransmitter responsible for halting seizures, contributes to the profound seizures associated with methylxanthine overdose.64,70,179,209 When studied prospectively, chronic theophylline toxicity results in seizures in 14% of patients, but 5% of acutely poisoned patients experience seizures. In cases of chronic and acute-on-chronic toxicity, seizures are more likely to occur, and they occur at lower serum concentrations.150 Patients at extremes of age—those younger than age 3 years and older than age 60 years—are more likely to experience seizures with overdose.
Methylxanthines increase striated muscle contractility, secondarily decreasing muscle fatigue. They also increase muscle oxygen consumption and increase the basal metabolic rate. These effects are sought by users to enhance or improve athletic performance or weight loss.9,19,46,65,79,80 All methylxanthines cause smooth muscle relaxation.
Tremor is the most common adverse effect of methylxanthines. Skeletal muscle excitation, which may include fasciculation, hypertonicity, myoclonus, or even rhabdomyolysis, may occur with methylxanthine overdose.119,129,164,208 Mechanisms by which rhabdomyolysis may result include increased muscle activity, particularly from seizures, and direct cytotoxicity from excessive sequestered intracytoplasmic calcium. Interestingly, multiple case reports associate atraumatic compartment syndrome with rhabdomyolysis with theophylline overdose.128,195
Numerous metabolic derangements result from acute methylxanthine toxicity and are similar to those in other hyperadrenergic situations.84,88,168,180
Severe hypokalemia may result from β2-adrenergic stimulation.196 This results from influx of extracellular potassium into the intracellular compartment despite normal total body potassium content. Both ECG and neuromuscular complications of hypokalemia may develop. Other metabolic effects of methylxanthine and β2-adrenergic agonist poisoning include hypomagnesemia and hypophosphatemia.30,115,202
Transient hypokalemia resulting from β-adrenergic agonism occurs in 85% of patients with acute theophylline overdose, and typically the serum potassium decreases to approximately 3 mEq/L.5,183 Stimulation of Na-+ K+- ATPase results in a shift of serum potassium to the intracellular compartment of skeletal muscle. Total body potassium stores are unchanged. The significance of hypokalemia in patients with methylxanthine overdose is unclear. Vomiting and renal losses do not contribute significantly to hypokalemia, but these may result in fluid loss. Hyperkalemia may result from rhabdomyolysis and overly aggressive repletion of potassium.
Metabolic acidosis with increased serum lactate concentration is commonly noted as a complication of theophylline overdose.25,124 Tachypnea and respiratory alkalosis secondary to stimulation of the respiratory center are also common. Clenbuterol excess demonstrates significant β2-adrenergic agonists toxicity associated with an anion gap metabolic acidosis in some cases.96
Hyperglycemia with serum glucose of approximately 200 mg/dL in those without diabetes is common and occurs in 75% of patients with acute theophylline overdose. Hyperthermia caused by increased metabolic activity and increased muscle activity may result from caffeine and theophylline overdose. Leukocytosis, probably secondary to the high concentrations of circulating catecholamines, results from acute methylxanthine overdose. This phenomenon apparently lacks clinical significance. In the absence of seizures or protracted emesis, chronic methylxanthine poisoning does not typically lead to metabolic derangements because such toxicity is an ongoing, compensated process.
Chronic Methylxanthine Toxicity
The distinction between acute and chronic toxicity is based on the duration of exposure to the xenobiotic. Patients with chronic toxicity may manifest subtle signs such as anorexia, nausea, palpitations, or emesis, although they may also present with seizures or dysrhythmias.
Patients chronically receiving theophylline or caffeine have higher total body stores and often underlying medical disorders, and they may develop toxicity with a smaller amount of additional theophylline or caffeine. Chronic methylxanthine poisoning typically occurs in the setting of therapeutic use of theophylline and may occur with iatrogenic administration of caffeine or from frequent, chronic consumption of caffeinated products. Patients often manifest subtle signs of illness, such as anorexia, nausea, palpitations, or emesis. However, the initial presentation in these patients, even with serum concentrations in the 40 to 60 μg/mL range, may be a seizure. In children chronically overdosed with theophylline, the peak serum theophylline concentration may fail to identify those who will progress to life-threatening toxicity. In the absence of protracted emesis or seizures, the initial electrolytes and blood gases are expected to be normal in patients with chronic methylxanthine toxicity.
Chronic Methylxanthine Use
Data on the effect of caffeine on many chronic health issues are mixed and highly contradictory. Studies show inconclusive links to cancer, heart disease, osteoporosis, hyperlipidemia, and hypercholesterolemia associated with caffeine use.68,71,83,160,206 Excessive consumption of caffeine-containing beverages may cause hypokalemia.163
Caffeine induces tolerance, and a withdrawal syndrome, including headache, yawning, nausea, drowsiness, rhinorrhea, lethargy, irritability, nervousness, a disinclination to work, and depression, may result upon abstinence.192 Caffeine withdrawal symptoms are described in neonates born to mothers with consequential caffeine use.136 The onset of caffeine withdrawal symptoms begins 12 to 24 hours after cessation and lasts up to one week.82 In a double-blind trial, 52% of adults with low to moderate caffeine intake, defined as 2.5 cups of coffee daily, developed a withdrawal syndrome upon caffeine abstinence.186
Massive doses of methylxanthines are teratogenic, but the doses of typicaluse are not associated with birth defects. Decreased fecundity and adverse fetal outcome are noted in animals with chronic exposure to methylxanthines.72,77,135 Human studies of fertility, fetal loss, and fetal outcome produce divergent results, and the effects of methylxanthines use during gestation are unclear.99,106,141,144
An ECG, serum electrolytes, and serum caffeine or theophylline concentrations are indicated as appropriate in cases of suspected methylxanthine toxicity. Because toxicity is dose related in acute overdose, serum concentrations of caffeine and theophylline may be loosely applied as a correlate with toxicity.
Hospitals in which caffeine is used therapeutically typically have the capability to assay serum caffeine concentration within the institution, and likewise hospitals in which theophylline is used therapeutically typically are able to assay serum theophylline concentrations. Overdose of caffeine may result in a spuriously elevated serum theophylline concentration.67,107
Theophylline concentrations, and to a lesser extent, caffeine concentrations, may be used prognostically to guide management of poisoning. Proper interpretation requires knowledge of whether the poisoning is acute, chronic, or acute on chronic. In the setting of toxicity, serum methylxanthine concentrations should be obtained immediately and then serially every 1 to 2 hours until a downward trend is evident.
Likewise, serum electrolytes, particularly potassium, should be monitored serially as long as the poisoned patient remains symptomatic and such values are in a range that may warrant treatment. Cardiac monitoring should continue until the patient is free of dysrhythmias other than sinus tachycardia, has a falling serum methylxanthine concentration, and is clinically stable. In patients with systemic illness, hyperthermia, or increased muscle tone, assessing serum CK and urinalysis to detect rhabdomyolysis is also indicated.