66: Methylxanthines and Selective β₂-Adrenergic Agonists

Methylxanthines are plant-derived alkaloids that include caffeine (1,3,7-trimethylxanthine), theobromine (3,7-dimethylxanthine), and theophylline (1,3-dimethylxanthine). They are so named because they are methylated derivatives of xanthine. Members of this group have very similar pharmacologic properties and clinical effects. Methylxanthines are used ubiquitously throughout the world, most commonly in beverages imbibed for their stimulant, mood-elevating, and fatigue-abating effects. Coffea arabica and related species are used to make coffee, a beverage rich in caffeine. Cocoa and chocolate are derived from the seeds of Theobroma cacao, which contains theobromine and to a lesser extent caffeine. Thea sinensis, a bush native to China but now cultivated worldwide, produces leaves from which various teas, rich in caffeine and containing small amounts of theophylline and theobromine, are brewed. Paullinia spp, commonly known as guarana, is a South American plant that produces berries with caffeine content much greater than that of coffee beans.

Selective β₂-adrenergic agonists have been developed for the treatment of bronchoconstriction. Their selectivity has improved therapy for bronchoconstriction, allowing avoidance of the adverse effects of the previously used therapies: epinephrine, an α- and β-adrenergic agonist, as well as isoproterenol, a β₁- and β₂-adrenergic agonist. All β₂-adrenergic agonists have nearly identical clinical effects; the principal differences are their pharmacokinetics. This chapter does not examine each β₂-adrenergic agonist individually but instead discusses them as a class. The β₂-adrenergic agonists include albuterol, clenbuterol, bitolterol, formoterol, pirbuterol, salmeterol, terbutaline, and ritodrine.

The American Association of Poison Control Centers (AAPCC) reported the following trends in methylxanthine exposures. Theophylline exposures, which previously caused thousands of poisonings and dozens of deaths annually, have remained rare. From 2007 to 2011, there were 300 to 400 exposures annually, representing how infrequently theophylline is now used therapeutically. Caffeine exposures continue to decrease at a slow and steady rate. In 1998, there were 7390 reported caffeine exposures. This number has steadily declined: from 2007, with 5448 caffeine exposures, to 2011, with 3667 exposures. Caffeine, as a component of energy drinks, has only recently been added to the National Poisoning Data System (NPDS) of the AAPCC. Included as subcategory of poisoning in 2010, there were 308 reported exposures. The following year, the number of reported exposures to caffeine-containing energy drinks increased to 1610 and exposures to caffeine-containing alcoholic beverages was 131.

It is impossible to know the precise reasons, which may be related to underlying patient health as well as differences in toxicity, but the disparity between theophylline deaths and caffeine deaths is notable. The number of deaths resulting from theophylline remains at approximately one or two per year, and even though caffeine poisoning occurred much more frequently, during this same 5-year time period, there was only a single death attributed to caffeine toxicity in the United States.

The number of β₂-adrenergic agonist exposures has remained stable during the past 5 years, with approximately 8000 to 9000 reports annually and no reported deaths from these substances (Chap. 136).

The overwhelming preponderance of caffeine consumed is in beverages, and a lesser portion is consumed in foods and tablets or capsules. Users typically seek the stimulant effects of caffeine. Caffeine, particularly in herbal forms such as guarana or cola nut, is also increasingly advocated for various health effects.^15,81 The use of guarana, a plant with very high caffeine content, for weight loss and athletic performance enhancement has become common in recent years. With some scientific evidence demonstrating benefit in athletic performance, caffeine is advocated as a concentration^110,172 and “energy” booster and as an athletic performance enhancer.^35,108 High caffeine content products are widely available as dietary supplements, which are not regulated by the Food and Drug Administration (FDA). These include tablets as well as liquid energy “shots.” Energy drinks, which are FDA regulated, typically containing caffeine and other stimulant ingredients are increasingly popular, particularly with adolescents and athletes (Table 66–1).¹³¹

These drinks have only recently been recognized as having significant adverse side effects.⁸⁵ Although these adverse effects do not routinely result in severe toxicity, major morbidity and mortality have resulted from their use and misuse.⁴ Between 30% and 50% of adolescents and young adults in the United States regularly consume energy drinks.¹⁷³ Surveys of parents in the United States reveal that children as young as 5 years commonly drink caffeinated beverages daily.²⁰¹

Beverages that combine alcohol with relatively large doses of caffeine have rapidly gained popularity, particularly among young adults and underage drinkers. Toxicity from use of such drinks became apparent very soon after these were introduced to the United States.⁴⁵ In some instances, the incidence of toxicity and adverse events associated with such drinks was so significant that some have been legally banned because they are considered exceptionally dangerous. Caffeine has also been recently discovered as a very common adulterant in drug products sold by Internet vendors.⁵⁶ The quantity of caffeine in such products places users at risk for toxicity, although reports of such have not yet surfaced.

Caffeine, theophylline and aminophylline are used in neonates to treat the apnea and bradycardia syndrome of prematurity. The result of such treatment is an increased respiratory rate, decreased apnea, increased ­cardiac chronotropy and inotropy, and increased cardiac output.³³

Caffeine is used as an analgesic adjuvant, particularly when combined with analgesics such as acetaminophen, aspirin, and ibuprofen.⁵⁹

Theophylline or its water-soluble salt, aminophylline, is used to treat varied respiratory conditions but is most well studied for its use in reversible bronchospastic airway disease, particularly asthma. Theophylline was once the mainstay of therapy for such diseases, but albuterol and other selective β₂-adrenergic agonists with fewer adverse effects are now used.

Caffeine toxicity is generally classified as acute, acute on chronic, or chronic in nature. Neonates receiving caffeine therapy may develop acute or chronic caffeine toxicity.^7,17

Chronic toxicity from caffeine is most typically results from frequent self-administration of excessive caffeine. The Diagnostic and Statistical Manual of Mental Disorders,4th edition, text revision, notes five distinct caffeine-related disorders, acute toxicity, withdrawal, caffeine-related anxiety disorder, insomnia, and effects not otherwise specified.⁶³ Classically, a syndrome associated with chronic caffeine use consisting of headache, palpitations, tachycardia, insomnia, and delirium has been termed caffeinism.

Theophylline toxicity results from the use of theophylline as a medicinal and may develop as acute, chronic, or acute-on-chronic toxicity.

Acute-on-chronic toxicity may occur with caffeine or theophylline and is the circumstance of acute overdose in a patient already receiving chronic therapy.

Most reported cases of theobromine poisoning occur in the veterinary literature and typically result from small animals ingesting cocoa or chocolate.^61,90 Theobromine has become an ingredient of numerous “energy” drinks used for stimulation and athletic enhancement, but human toxicity has not yet been reported.

Use of β₂-adrenergic agonists is widespread. Adverse effects are associated with both therapeutic dosing and overdose. Excessive use of β₂-adrenergic agonists may result in tachyphylaxis, a phenomenon in which downregulation of receptors occurs and the effects of the drug diminish as a result of excessive use.^48,104 Consequently, patients may require higher doses to achieve the same clinical effects previously experienced at lower doses, resulting in consequential adverse effects. The most common selective β₂-adrenergic agonist toxicity results from children ingesting albuterol syrup. The toxicity associated with terbutaline and ritodrine is infrequently reported. Clenbuterol, a long-acting β₂ agonist adrenergic, used for the purpose of treating bronchoconstriction in countries outside the United States, has in recent years emerged as an abused anabolic xenobiotic as well as additive in street drugs. Epidemic clenbuterol exposures have occurred in recent years, as a result of both its admixture with illicit xenobiotics and its intentional use for bodybuilding purposes in the United States.⁵⁵ Food poisoning by consumption of animal meat from livestock treated with clenbuterol has occurred in Europe.¹⁸

Methylxanthines

Methylxanthines cause the release of endogenous catecholamines, resulting in stimulation of β₁ and β₂ receptors.¹⁹⁷ Endogenous catecholamine concentrations are extremely elevated in patients with methylxanthine poisoning.²²

Methylxanthines are structural analogs of adenosine and function pharmacologically as adenosine antagonists. Adenosine modulates histamine release and causes bronchoconstriction, which may explain the primary therapeutic efficacy of adenosine antagonists in the treatment of bronchospasm. Additionally, adenosine antagonism results in release of norepinephrine, and to a lesser extent epinephrine, through blockade of presynaptic A₂ receptors. The additional methyl group possessed by caffeine (1,3,7-trimethylxanthine) permits greater central nervous system (CNS) penetration relative to theophylline and theobromine, which are dimethylxanthines. Caffeine is an effective analgesic adjuvant, possibly because of the stimulant properties of the drug.^{138,140,170,171}

Methylxanthines also inhibit phosphodiesterase, the enzyme responsible for degradation of intracellular cyclic AMP (cAMP), which has many effects, including an increase in intracellular calcium concentrations. Phosphodiesterase inhibition was long considered to be the primary therapeutic mechanism of the methylxanthines, but clinically significant elevations in cAMP concentrations are not achieved until serum methylxanthine concentrations are well above the therapeutic range. This likely occurs as a result of the structural similarity of the adenosine moiety of cAMP and the methylxanthines. cAMP is involved in the postsynaptic second messenger system of β-adrenergic stimulation. Thus, elevated cAMP concentrations cause clinical effects similar to adrenergic stimulation, including smooth muscle relaxation, peripheral vasodilation, myocardial stimulation, skeletal muscle contractility, and CNS excitation.

Selective β₂-Adrenergic Agonists

Selective β₂-adrenergic agonists act very specifically at β₂-adrenergic receptors, resulting in an increase in intracellular cAMP. Effects of β₂ agonism include relaxation of vascular, bronchial, and uterine smooth muscle; glycogenolysis in skeletal muscle; and hepatic glycogenolysis and gluconeogenesis. Selective β₂-adrenergic agonists have been characterized as directly activating the β₂ receptor, such as albuterol; being taken up into a membrane depot, such as formoterol; or interacting with a receptor-specific auxiliary binding site, such as salmeterol. These differences do not appear to be relevant in acute toxicity.⁹⁹ However, emerging evidence suggests that prolonged overuse of long-acting β₂-adrenergic agonists may have severe or fatal adverse effects.¹⁶⁸

Caffeine Pharmacokinetics

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 Toxicokinetics.

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 Pharmacokinetics

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.

Theophylline Toxicokinetics.

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

Gastrointestinal.

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.

Cardiovascular.

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

Pulmonary.

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.

Neuropsychiatric.

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.

Musculoskeletal.

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

Metabolic.

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 Withdrawal

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

Reproduction

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}

Diagnostic Testing

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.

General Principles and Gastrointestinal Decontamination

After assuring adequacy of airway, breathing, and circulation, supportive care and maintenance of vital signs within acceptable limits are the mainstays of therapy for patients with methylxanthine and selective β₂-adrenergic agonist toxicity. Decisions regarding GI decontamination, including orogastric lavage, administration of activated charcoal (AC), or whole-bowel irrigation (WBI), depend on the dosage and type of preparation involved, the time since exposure, and the patient’s physical condition (Chap. 8). AC is the only GI decontamination that should be routinely considered for selective β₂-adrenergic agonist ingestion.

Emesis.

Induced emesis is not indicated for selective β₂-adrenergic agonist ingestion or methylxanthine ingestion. A simulated overdose controlled volunteer study with sustained-release theophylline was unable to demonstrate reduction of absorption of theophylline in patients treated with syrup of ipecac.¹⁴² Seizures are possible with any significant methylxanthine poisoning, and induced emesis in a patient with potential to experience a seizure is contraindicated. Because the benefits of emetics are undemonstrated and emesis interferes with administration of AC, induced emesis is rarely considered for those with methylxanthine poisoning.^6,175

Orogastric Lavage.

Orogastric lavage may be considered for patients with potentially toxic methylxanthine ingestions who reach medical care shortly after ingestion. Selective β₂-adrenergic agonist liquid ingestion that occurs within one hour before treatment may warrant aspiration through a small nasogastric tube.

Ingestion of sustained-release theophylline tablets is associated with the formation of bezoars that may be difficult to remove or dislodge. Treatment in such cases has included endoscopic removal.⁴⁰

Activated Charcoal.

AC is essential in the treatment of methylxanthine poisoning. AC can adsorb methylxanthines and selective β₂-adrenergic agonist present in the GI tract and limit their absorption. Multiple-dose activated charcoal (MDAC) is helpful to enhance the elimination of methylxanthine toxicity but is not indicated for selective β₂-adrenergic agonist ingestion. MDAC may be useful for any sustained-release methylxanthine preparation. Additionally, MDAC enhances elimination of theophylline by “gut dialysis” (Antidotes in Depth: A1). Such enhanced elimination by gut dialysis is not demonstrated experimentally or otherwise for caffeine or theobromine toxicity. Because caffeine is to some extent metabolized to theophylline, in cases of caffeine poisoning, MDAC would at the very least enhance elimination of theophylline metabolites. The pharmacologic similarity of the methylxanthines and the relative safety of MDAC therapy warrant the use of such treatment for patients with any methylxanthine toxicity. MDAC is used for enhanced elimination.

Whole-Bowel Irrigation.

Treatment of patients with significant ingestions of sustained-release pills may include WBI with a balanced electrolyte solution to enhance GI elimination (Antidotes in Depth: A2). Polyethylene glycol electrolyte lavage solution used for WBI may displace theophylline already bound to activated charcoal.⁹⁵ This may be a particular problem in patients who have taken several doses of AC before WBI, in which desorption of methylxanthines from AC may result in a bolus of methylxanthines available for GI absorption. Also, WBI is experimentally demonstrated to provide no additional benefit to AC in treatment of sustained-released theophylline ingestion.³⁸ Despite these data, WBI with MDAC remains the preferred and recommended treatment of a patient with ingestion of sustained-release theophylline.

Selecting a Method of Decontamination.

The use of decontamination methods that involve more than minimal risk, specifically orogastric lavage, should only occur after careful consideration of the indications. Patients with potentially life-threatening acute ingestions occurring approximately one hour previously may be treated with orogastric lavage (Chap. 8).

Treatment

Gastrointestinal Toxicity.

Phenothiazine antiemetics are contraindicated in those with methylxanthine poisoning because they are typically ineffective and may lower the seizure threshold. The preferred antiemetic is ondansetron, although metoclopramide may be used also.^53,157,167 Ondansetron dosing in the upper end of the therapeutic dosing range, or even chemotherapeutic doses may be used if necessary. Histamine (H₂) blockers or proton pump inhibitors may be administered to any patient with hematemesis. Cimetidine is contraindicated because it inhibits mutiple CYP enzymes, delaying clearance of methylxanthines.

Cardiovascular Toxicity.

Patients with hypotension should initially be treated by administration of isotonic IV fluid, such as 0.9% sodium chloride or lactated Ringer solution, in bolus volumes of 20 mL/kg. If acceptable blood pressure cannot be maintained despite several fluid boluses or if there are contraindications to fluid bolus, vasopressor therapy should be considered.

Methylxanthine and selective β₂-adrenergic agonist toxicity may cause hypotension via β-adrenergic agonism; therefore, administration of vasopressors with β-adrenergic agonist effects, such as epinephrine, dobutamine, or isoproterenol, is suboptimal. An α-adrenergic agonist such as phenylephrine is the first-line pressor of choice in such a situation, although norepinephrine is also acceptable (Table 66–2).

In rare cases of refractory hypotension, the administration of an adrenergic antagonist may be warranted.⁶⁰ Administration of an adrenergic antagonist to a hypotensive patient may seem counterintuitive, but it may reverse β₂-adrenergic–mediated vasodilation. In addition, β₁-adrenergic blockade treats tachycardia and any associated decreased cardiac output. In dogs with aminophylline-induced tachycardia and hypotension, administration of esmolol results in a return to normal heart rate and blood pressure, and it does not exacerbate ­hypotension.⁷³ Propranolol, esmolol, and metoprolol have been used successfully to treat methylxanthine-induced hypotension.^27,154 It is most appropriate to use a β-adrenergic antagonist with a brief duration of action, such as esmolol, at least initially, in such circumstances. In the event of an adverse reaction or side effect such as hypotension or bronchospasm were to occur, the duration of such will be relatively brief. Any β-adrenergic antagonist therapy should ideally be preceded and accompanied by assessment of cardiac output and central venous pressure, either directly or noninvasively.¹¹³

Because of its long half-life and possibly potency, toxicity from clenbuterol exposure appears more likely to require treatment with β-adrenergic antagonist medications.⁹⁴

When drug toxicity is not in question, adenosine or electrical cardioversion are the preferred treatment for SVT, but this is not so for SVT resulting from methylxanthine toxicity. Because of the antagonist effects at the adenosine receptor, administration of adenosine should not be expected to convert a methylxanthine-induced SVT. However, even if adenosine is successfully used to convert an SVT, the effect is likely to be transient. Because methylxanthine toxicity has a global effect on the myocardium and methylxanthine concentrations do not change rapidly, cardioversion, which is effective in electrically “reorganizing” depolarization, is unlikely to result is a sustained normal rhythm.

The primary treatment for methylxanthine-induced SVT includes administration of benzodiazepines, which work to abate CNS stimulation and concomitant release of catecholamines. More focused pharmacologic therapy to treat SVT would be through cautious administration of a conduction-­attenuating calcium channel blocker such as diltiazem or verapamil.

In animal models, treatment of acute theophylline toxicity with the calcium channel blockers diltiazem, verapamil, and nifedipine each results in decreased cardiac-related deaths and prevention of dysrhythmias, hypotension, myocardial necrosis, and seizures.²⁰⁴ In addition to the cardiovascular benefit of calcium channel blockers, they may also afford neurologic protection and prevention of seizure. In patients without asthma, ­methylxanthine-induced SVT and other tachydysrhythmias may be treated by administration of an adrenergic antagonist.

Central Nervous System Toxicity.

Administration of a benzodiazepine, such as diazepam, lorazepam, or midazolam, is appropriate treatment for anxiety, agitation, or seizure. Seizures associated with methylxanthine toxicity are severe and often refractory to treatment. Seizures not controlled with one or two therapeutic doses of a benzodiazepine should be treated with a barbiturate such as phenobarbital or pentobarbital or another suitable sedative–hypnotic such as propofol. No delay should occur before administering such medications. Unsuccessful treatment of methylxanthine-induced seizures with any particular antiepileptic should quickly be abandoned in favor of treatment with an additional or more potent and efficacious anticonvulsant. The administration of barbiturates may result in or exacerbate hypotension. Treatment of agitation or seizure with benzodiazepines, barbiturates, or other sedative–hypnotic may require repeated dosing until clinical effect is achieved.

Administration of phenobarbital to prevent seizures in theophylline-poisoned rabbits and mice increases survival by decreasing the incidence of seizures.^51,78 Although historically, phenobarbital was the recommended drug for such prophylaxis, use of a benzodiazepine such as lorazepam seems preferable based on pharmacokinetic and practical considerations. Patients at risk for seizure include those identified earlier in this chapter—patients older than age 60 years or younger than age 3 years, those with chronic overdose and a serum concentration above 40 μg/mL, and acutely overdosed patients with serum concentrations greater than 100 μg/mL.

Phenytoin and fosphenytoin are of no benefit in controlling methylxanthine-induced seizures, and they have no role in such treatment.^93,133 Retrospective review of human cases demonstrated phenytoin to be ineffective in treating seizures in 21 of 22 cases.¹⁰¹ Phenytoin results in the occurrence of seizures at an earlier time after overdose and results in higher mortality when administered to theophylline-poisoned mice.²⁸

Metabolic Derangements.

Patients with symptomatic hypocalcemia should be treated with electrolyte repletion. Most cases of mild hypokalemia are well tolerated, but any patient with symptomatic hypokalemia, particularly those associated with ECG changes of T waves or QT interval prolongation, should be treated. The frequency of ventricular dysrhythmias in methylxanthine poisoning is exacerbated by hypokalemia coupled with increased intrinsic catecholamine release. Correction of hypokalemia may be crucial in methylxanthine poisoning associated with ventricular dysrhythmias.

There is no specific degree of hypokalemia that absolutely necessitates treatment. In the absence of associated dysrhythmia, the clinical significance of such hypokalemia is unclear. Although correction is generally performed with the administration of IV or PO potassium, hypokalemia experimentally responds to treatment with β-adrenergic antagonists.

Cautious administration of potassium to treat symptomatic hypokalemia may be indicated, but this is distinct from higher doses of potassium used in total body potassium repletion. In cases of hypokalemia secondary to β-adrenergic agonism, after the β-adrenergic agonism returns to baseline level, an efflux of potassium from the intracellular compartment occurs. A concomitant increase in the serum potassium concentration occurs at that time. Overly aggressive attempts to correct hypokalemia may result in hyperkalemia after the β-adrenergic agonist effects abate. Acute methylxanthine-induced hypokalemia may be treated with potassium supplementation, but because of the nature of the problem with excess β-adrenergic agonism, potassium supplementation is typically unnecessary and poorly effective.

Experimentally, administration of propranolol to theophylline-poisoned dogs prevented or partially reversed hypokalemia, hypophosphatemia, hyperglycemia, and metabolic acidosis as well as hypotension.¹¹¹ Prevention or correction of the metabolic derangements associated with theophylline toxicity by administration of β-adrenergic antagonists is congruent with the fact that these derangements, particularly hypokalemia, are the consequence of β-adrenergic agonism. The efficacy of β-adrenergic antagonists as therapy for hypokalemia resulting from acute methylxanthine poisoning in humans is unstudied.

Hypomagnesemia, hypophosphatemia, and hypocalcemia should be treated as they would for other patients. As with hypokalemia, QT interval prolongation is an absolute indication to treat these derangements.

Hyperglycemia, likely resulting from increased circulating catecholamines, is common. This hyperglycemia does not necessitate treatment, both because it is a transient effect and because in other situations of hyperglycemia resulting from adrenergic agonism, rebound hypoglycemia may occur.

Musculoskeletal Toxicity.

The use of benzodiazepines is appropriate treatment for fasciculations, hypertonicity, myoclonus, and rhabdomyolysis. Rhabdomyolysis necessitates aggressive IV fluid therapy, possibly with sodium bicarbonate (Antidotes in Depth: A5).

Enhanced Elimination.

Fortunately, methylxanthine toxicity lends itself well to several methods of enhanced elimination, including GI dialysis with MDAC, charcoal hemoperfusion, and hemodialysis, as well as lesser used methods such as continuous arteriovenous hemoperfusion, continuous venovenous hemoperfusion, and plasmapheresis.^16,120,126

Infants with methylxanthine poisoning may be too ill, unstable, or small to be treated with hemodialysis or hemoperfusion. Both MDAC and exchange blood transfusion are effective methods of enhanced elimination in infants and may be the preferred method of treatment in these patients if hemodialysis is unavailable.^{151,153,182,184}

The therapeutic effects of AC in such cases are much greater than simply limiting absorption of ingested methylxanthines. AC, particularly MDAC, allows elimination of theophylline through GI dialysis.¹³ MDAC is extremely effective at enhancing elimination of theophylline.^{24,74,125,149} Experimentally in dogs, rabbits, and human volunteers, AC administered after IV aminophylline administration results in increased systemic clearance and decreased half-life of theophylline.^{98,117,137,155} The pharmacologic similarity of the methylxanthines suggests that MDAC may be effective in caffeine or theobromine poisoning, and MDAC certainly is effective in eliminating theophylline generated from metabolism of caffeine or theobromine. The efficacy of MDAC combined with the safety and ease with which this therapy can be administered makes MDAC the mainstay of enhanced elimination in methylxanthine toxicity. Severe emesis associated with methylxanthine poisoning may result in intolerance of MDAC¹⁷⁶ (Antidotes in Depth: A1).

Charcoal hemoperfusion was once considered the most effective method of enhanced elimination of methylxanthines, decreasing theophylline’s half-life to 2 hours and increasing its clearance up to sixfold.^{37,144,165,207} Variations of charcoal hemoperfusion, including albumin colloid hemoperfusion, resin hemoperfusion, and charcoal hemoperfusion in series with hemodialysis, are reported.^{41,97,121,158,191} If hemoperfusion is available, it is preferable, but when charcoal hemoperfusion is unavailable,¹⁷⁷ hemodialysis is excellent and has become routine therapy.

Hemodialysis is slightly less efficient than hemoperfusion in the extracorporeal removal of methylxanthines.^{8,122,124,187} The ability of hemodialysis to correct fluid and electrolyte imbalances, the greater availability of hemodialysis in many regions, greater technical ease, and lower complication rates have resulted in a paradigm shift from considering charcoal hemoperfusion to be the definitive treatment for significant methylxanthine toxicity to one in which charcoal hemoperfusion and hemodialysis are considered equivalent treatment options.¹⁸⁵

The specific indications for hemodialysis are not agreed upon. In the treatment of patients with methylxanthine poisoning. Several studies and clinical experience are the basis for the following suggested indications for extracorporeal elimination by charcoal hemoperfusion, hemodialysis, combined charcoal hemoperfusion and hemodialysis, or combined hemodialysis and MDAC.

Many recommendations regarding hemoperfusion and hemodialysis for theophylline toxicity use serum theophylline concentration as a guideline. Serum concentrations may not be available in instances of caffeine poisoning and do not exist for theobromine poisoning. Thus, the clinical aspects of theophylline management guidelines can be generalized to all methylxanthine toxicities.

When indicated, hemodialysis preferably should be initiated while the patient is still hemodynamically stable. Hemodialysis therapy should be used for patients with clinically significant chronic theophylline poisoning associated with a serum theophylline concentration above 40 to 60 μg/mL or with a deteriorating clinical status.

Hemodialysis should be strongly considered any time a methylxanthine exposure results in a serum theophylline or caffeine concentration of greater than 90 μg/mL and symptoms regardless of clinical stability (Table 66–3). Any patient with a symptomatic methylxanthine poisoning that is associated with ventricular dysrhythmias, seizures, hypotension unresponsive to fluids, or emesis unresponsive to antiemetics should also be treated with charcoal hemoperfusion, hemodialysis, or both.

The fact that a patient experiences seizure or dysrhythmias or becomes extremely ill is not a contraindication for extracorporeal drug removal. To the contrary, these events make administration of such therapy more critical to ensure survival of the patient.

Treatment of Chronic Methylxanthine Toxicity

Treatment of chronic methylxanthine toxicity is determined by the patient’s clinical status and by the efficacy of MDAC. The precise serum theophylline or caffeine concentration at which patients with chronic theophylline or caffeine toxicity should receive hemodialysis is controversial. For a hemodynamically stable patient without signs of life-threatening methylxanthine toxicity such as ventricular dysrhythmias or seizures, therapy with MDAC may be sufficient. If the serum theophylline or caffeine concentration does not decline after the administration of AC or if the patient’s clinical status deteriorates, hemodialysis is indicated.

Treatment of Acute-on-Chronic Methylxanthine Toxicity

Patients chronically receiving theophylline or caffeine who acutely overdose should be initially managed in the same manner as patients with acute overdose, although action concentrations for dialysis are the same for chronic toxicity. Total body stores of the methylxanthines are higher in patients who are chronically exposed, and the threshold for toxicity may be reached at lower serum concentrations.

• Caffeine is the most widely used methylxanthine, and as a result of novel products such as energy drinks and caffeinated alcoholic beverages, there are increasing numbers of poisoning from these ­products.

• Methylxanthine toxicity results from both the use of medicinals and therapeutics as well as foods and beverages.

• There are significant differences in the clinical presentation and management of patients with acute and chronic methylxanthine poisoning. Supportive care and treatment of GI, cardiovascular, CNS, metabolic, and musculoskeletal effects are the mainstay of therapy. The unique properties of methylxanthines necessitate specific therapies for the GI, cardiovascular, and CNS toxicities of methylxanthines.

• Methods of enhanced elimination, particularly extracorporeal elimination by charcoal hemoperfusion, hemodialysis, or combined charcoal hemoperfusion and hemodialysis in series, as well as gut dialysis with MDAC, are effective treatments for patients with methylxanthine toxicity.

• Selective β₂-adrenergic agonists are widely used for the treatment of bronchospasm. Selective β₂-adrenergic agonist toxicity typically results from excessive therapeutic use of these agents, but illicit use of clenbuterol or the admixture of clenbuterol with drugs of abuse has increased.

References