INTRODUCTION
Methylxanthines include caffeine, theophylline, theobromine, and nicotine. These agents are plant-derived alkaloids with ubiquitous use in beverages (caffeine in coffee and soda), foods (theobromine in chocolate), tobacco products (nicotine), and medications (theophylline and caffeine). Newer methylxanthine derivatives include pentoxifylline (improves peripheral blood flow) and doxofylline (a bronchodilator).1,2 All methylxanthines have shared pharmacologic properties and very similar pharmacodynamic effects.
METHYLXANTHINES
Caffeine (1,3,7-trimethylxanthine), a methylxanthine and structural analog of adenosine, is the most commonly used psychoactive drug in the world and the only one that can be legally purchased by children. It is found in varying amounts in beverages and “energy-enhanced” foods, such as candy bars, potato chips, and oatmeal (Table 192-1).3 Nearly 6 billion caffeinated “energy drinks” were purchased in the United States in 2012.4 Many “energy drinks” contain guarana, a plant whose seeds contain high concentrations of caffeine and other methylxanthines. Drinks with guarana may not list caffeine as an ingredient.5 Other uses for caffeine include apnea of prematurity, analgesic adjuncts, appetite suppression for weight loss, sleep prevention, and diuresis.
| Source | Caffeine Content (milligrams) |
|---|---|
| Coffee (8 oz or 240 mL, brewed) | 60–120 |
| Tea (8 oz or 240 mL, brewed) | 20–90 |
| Colas, caffeinated (8 oz or 240 mL) | 20–40 |
| Dark chocolate (1 oz or 30 mL) | 5–35 |
| “Higher caffeine energy drinks” (8–24 oz) | 70–505 |
| Acetaminophen-aspirin-caffeine tablet | 65 |
| Nonprescription antidrowsiness tablet | 200 |
Theophylline (1,3-dimethylxanthine) and its water-soluble salt, aminophylline, were used extensively in the past for the treatment of asthma and chronic obstructive pulmonary disease. However, theophylline’s use has declined due to its narrow therapeutic window and the development of safer agents. Theophylline is still used in patients with debilitating bronchospastic disease, particularly outside the United States, and has been studied for the treatment of other diseases, including acute mountain sickness and contrast-induced nephropathy.6,7
Theobromine (3,7-dimethylxanthine) is found in the seeds of Theobroma cacao, from which chocolate and cocoa are derived; and Commelia thea, from which teas are steeped; and is an ingredient in numerous “energy drinks” in addition to caffeine. There are very few cases of human toxicity, but theobromine has been associated with atrial fibrillation.8
Caffeine is most commonly consumed orally; however, it can be administered rectally or parenterally. Theophylline is usually taken orally, although its absorption may be affected by food. It is available as an elixir or as extended-release and controlled-release tablets. Controlled-release tablets can result in erratic or rapid absorption. Theophylline can also be administered IV as aminophylline.
All methylxanthines are rapidly absorbed with early peak levels; they cross the blood–brain barrier and placenta and are excreted in breast milk (Table 192-2). Half-lives are only accurate at therapeutic concentrations and vary based on several factors, including drug level, age extremes, smoking, organ system dysfunction (e.g., cirrhosis), infection, and cytochrome P-450 inhibition (Table 192-3).
| Parameter | Caffeine | Theophylline |
|---|---|---|
| Therapeutic serum concentration | 5–20 micrograms/mL (25–100 micromoles/L) | 8–20 micrograms/mL (44–110 micromoles/L) |
| Bioavailability (oral) | ~100% | ~100% |
| Oral peak absorption (h) (delayed in overdose) | 0.5–1.0 | 1–2 (up to 8 h with sustained release preparations) |
| Volume of distribution (L/kg) | ~0.6 | ~0.5 |
| Protein binding | ~35% | ~60% |
| Major active metabolites | Paraxanthine Theobromine Theophylline | Caffeine (only if <6 mo old) |
| Clearance | Hepatic | <1 y old: 50% hepatic and 50% renal >1 y old: 90% hepatic and 10% renal |
| Half-life (accurate only at therapeutic concentrations) | Neonates: >50 h <1 y old: 20 h >1 y old: 5 h | Neonates: 20–30 h Children and adults: 5 h > 60 y old: 10 h |
| Increases Theophylline Clearance | Decreases Theophylline Clearance | |
|---|---|---|
| Medications | Barbiturates Benzodiazepines (suspected) Carbamazepine Phenytoin St. John’s wort | Cimetidine Ethanol (coingested) Erythromycin (all macrolides suspected) Oral contraceptives Propranolol (metoprolol suspected) Fluoroquinolones (most) Verapamil |
| Medical conditions | Cirrhosis Heart failure Pneumonia (other infections suspected) | |
| Other | Hyperthyroid Tobacco Marijuana (cannabis) | Pregnancy Obesity Fever (suspected) |
Methylxanthines exhibit Michaelis-Menten kinetics; that is, metabolism changes from first-order to zero-order kinetics at increased concentrations such that a fixed amount, not percentage, of drug is eliminated per unit of time, making accurate half-life calculations impossible following an overdose. This also explains why patients who chronically use theophylline may develop a large increase in serum theophylline concentration with only a small increase in dose. Methylxanthines are metabolized in the liver by the cytochrome P-450 1A2 pathway. Theophylline undergoes significant enterohepatic recirculation, so toxic serum levels can be maintained longer than anticipated.
Theophylline has the most potential for significant toxicity, followed by caffeine and then theobromine. The underlying pathophysiology involves adenosine antagonism, increased endogenous adrenergic stimulation, and, at toxic levels, phosphodiesterase inhibition (Table 192-4).
| Adenosine Antagonism | Increased Catecholamines | Inhibition of Phosphodiesterase | |
|---|---|---|---|
| Mechanism | Inhibition of adenosine-1 and adenosine-2 > adenosine-3 receptors | Increased circulating catecholamines (epinephrine and norepinephrine) | Phosphodiesterase inhibition (at toxic levels) |
| Effect | Decreased adenosine activity Increased excitatory neurotransmitters activity | Stimulation of β1 and β2 receptors | Increased concentration of cyclic adenosine monophosphate and catecholamine effects |
| Therapeutic effect | Bronchodilation | Bronchodilation | No role at therapeutic doses |
| Clinical toxicity | Vasoconstriction Arrhythmias Seizures | Tachycardia Vasodilation Hypotension | Enhanced β-adrenergic effects |
The main organ systems involved in methylxanthine toxicity are GI, neurologic, cardiovascular, and metabolic (Table 192-5).
| Organ System | Manifestation |
|---|---|
| GI | Nausea Vomiting Gastritis |
| Neurologic | Headache Tremor Agitation Seizure |
| Cardiovascular | Hypotension Tachycardia Atrial arrhythmias Ventricular ectopy |
| Metabolic | Hypokalemia Metabolic acidosis Hyperglycemia Hyperthermia Rhabdomyolysis |
Nausea and vomiting are reported in >70% of acute overdoses.9 Theophylline can also induce esophageal reflux by decreasing lower esophageal sphincter pressure.
Methylxanthine-induced seizures can be severe and refractory to treatment. First-time seizures in the setting of heavy caffeinated “energy drink” consumption have been reported.4,10 In theophylline toxicity, incidence of seizures is approximately 50% when serum levels are >40 micrograms/mL (>200 micromoles/L) during chronic therapy and >120 micrograms/mL (>600 micromoles/L) after an acute ingestion.9 Seizures at a lower serum concentration, even as low as 20 micrograms/mL (100 micromoles/L), are more likely in chronic toxicity due to relatively higher tissue levels. In chronic toxicity, seizures can occur without prior neurologic symptoms of tremor or agitation.
Methylxanthines induce the release of endogenous catecholamines, stimulating β-adrenergic receptors, resulting in increased inotropy and chronotropy, vasodilation, hypotension, and reflex tachycardia. Sinus tachycardia is the most common cardiac manifestation of both caffeine and theophylline use and toxicity. Atrial fibrillation and supraventricular tachycardia are described with excessive caffeine intake.11,12 Theophylline toxicity may result in atrial arrhythmias such as multifocal tachycardia and fibrillation/flutter. Ventricular ectopy are more common with chronic toxicity and in patients with advanced age or underlying cardiac dysfunction.13 Ventricular fibrillation and tachycardia are rare.
