Chapter 107. Xanthines and Nicotine

Theophylline, theobromine, and caffeine are methylxanthines. Theophylline was once widely used for the management of asthma and chronic obstructive pulmonary disease. Theobromine is found in chocolate and cocoa as well as numerous “energy drinks.” Caffeine is the most commonly used psychoactive drug in the world and can be legally purchased by children. It is used medically in the management of apnea of prematurity, as an analgesic adjunct, and in some over-the-counter weight loss preparations.

Nicotine is rapidly absorbed through the lungs, mucous membranes, intestinal tract, and skin. Once absorbed, it binds to nicotinic receptors throughout the body including the central nervous system, autonomic system, and neuromuscular junction.

Methylxanthine toxicity can cause life-threatening cardiac, neurologic, and metabolic abnormalities. Even therapeutic concentrations of theophylline can cause significant side effects in some individuals. Elderly patients with concomitant medical problems are more susceptible to life-threatening toxicity with chronic use than are younger patients with acute overdose.

Cardiac side effects include sinus tachycardia, premature atrial contractions, atrial flutter, and atrial fibrillation. Ventricular arrhythmias are more common with chronic toxicity, in the elderly, and those with underlying cardiac dysfunction. Hypotension may also occur.

Neurologic toxicity includes agitation, headache, irritability, sleeplessness, tremors, hallucinations, and seizures. Methylxanthine-induced seizures can be severe and refractory to treatment.

Metabolic side effects include hypokalemia, hyperglycemia, and metabolic acidosis. Rhabdomyolysis has been reported with theophylline and caffeine overdose. Gastrointestinal effects commonly include nausea and vomiting.

Nicotine toxicity affects the GI, neurologic, cardiovascular, and respiratory systems. Nausea, vomiting, bradycardia, arrhythmias, hypoventilation, coma, and seizures can occur. In severe poisoning, nicotine can result in paralysis and respiratory arrest. Table 107-1 lists the clinical effects of nicotinic receptor stimulation.

Therapeutic serum theophylline levels of 10 to 15 micrograms/mL can produce toxic effects and the severity of symptoms may not correlate with serum levels, especially in the setting of chronic use. Life-threatening side effects can occur with little warning and before lesser symptoms manifest. Smoking cessation, cirrhosis, and numerous medications, such as cimetidine and erythromycin, increase the half-life of theophylline and may precipitate toxicity. Laboratory evaluation for theophylline toxicity includes serum theophylline level, and electrolytes and an ECG should be obtained in cases of all methylxanthine toxicity. The differential diagnosis includes other stimulant drug overdose (eg, amphetamines, cocaine) and electrolyte abnormalities.

Diagnosis of acute nicotine toxicity is largely based on history and physical examination. Qualitative urine toxicological screen is of little value. Poisoning by pesticides such as organophosphates and carbamates can lead initially to nicotinic receptor stimulation that can mimic nicotine poisoning.

Methylxanthine Poisoning Treatment

Treatment of methylxanthine poisoning consists of stabilization, gastric decontamination and elimination, treatment of life-threatening toxic effects, and, in severe cases, hemoperfusion or dialysis.

1. Table 107-2 lists appropriate methods of GI decontamination and elimination in methylxanthine toxicity.

2. Place all patients on monitors and establish intravenous (IV) or intraosseous (IO) access.

3. Treat nausea and vomiting with ondansetron 4 milligrams IV or PO (0.1 to 0.15 milligram/kilogram). Consider ranitidine for gastric hypersecretion but avoid cimetidine, which can prolong the half-life of theophylline.

4. Treat seizures with lorazepam 1 to 2 milligrams IV (0.1 milligram/kilogram). Give phenobarbital 10 to 20 milligrams/kilogram IV if benzodiazepines are ineffective. Anticipate respiratory depression and the need for ventilator assistance. Phenytoin is contraindicated in theophylline toxicity.

5. Administer IV isotonic crystalloid for hypotension. Consider cardio-selective β-blockers such as esmolol or metoprolol in patients with hypotension unresponsive to IV fluids or conventional vasopressors.

6. Treat cardiac arrhythmias with cardio-selective β-blockers such as metoprolol and esmolol. Consider a calcium channel blocker such as diltiazem for atrial fibrillation. Identify and treat electrolyte abnormalities such as hypokalemia, which may contribute to arrhythmias.

7. Consider hemodialysis or hemoperfusion in a symptomatic patient with a serum theophylline level >90 micrograms/mL after acute ingestion, or >40 micrograms/mL in the setting of chronic toxicity and in patients with life-threatening seizures or arrhythmias.

8. Admit patients with seizures or ventricular dysrhythmias to intensive care. Patients with mild symptoms and theophylline levels below 25 micrograms/mL do not require specific treatment or admission, but their medication dosing should be decreased or discontinued. Patients with levels >30 micrograms/mL should be treated with oral activated charcoal and monitored for toxic side effects.

Nicotine Toxicity Treatment

1. Place patients on a cardiac monitor and establish intravenous or intraosseous access.

2. Consider dermal decontamination with soap and water for skin exposure (eg, transdermal patches). Activated charcoal and enhanced elimination are not recommended. Urine acidification is contraindicated.

3. Treat nausea and vomiting with ondasetron 4 milligrams IV or PO (0.1 to 0.15 milligram/kilogram).

4. Treat seizures with lorazepam 1 to 2 milligrams IV (0.1 milligram/kilogram).

5. Administer isotonic crystalloid for hypotension.

6. Anticipate neuromuscular weakness or respiratory depression in severe toxicity and be prepared for endotracheal intubation and mechanical ventilation.

7. Patients who remain asymptomatic at least 3 hours after ingestion of nicotine-containing products, except after intact transdermal patch ingestion, can be discharged. Patients who ingest transdermal patches should be monitored for at least 6 hours.