Methylxanthines

GENERAL PRINCIPLES

• The methylxanthines include caffeine, theophylline, and theobromine.

• Caffeine is widely consumed in the form of coffee or tea and is used medically in the treatment of headaches.

Caffeine is commercially available in highly concentrated powdered form for use as a preworkout supplement or food additive.

• Theophylline was once commonly used to treat asthma and chronic obstructive pulmonary diseasebut has generally fallen out of favor with the emergence of safe and effective inhaled agents.

Pathophysiology

• The methylxanthines are adenosine receptor antagonists and phosphodiesterase inhibitors.

î In combination, these effects lead to the enhanced release of catecholamines and enhancement of the

receptor effects of catecholamines, especially at the beta-adrenoceptors.

î Adenosine antagonism in the central nervous system promotes wakefulness and decreases fatigue.

• In poisoning, these effects lead to tachycardia (via beta-1 stimulation), hypotension (via beta-2 stimulation), hypokalemia (via beta-1 stimulation), and seizures (via central nervous system adenosine antagonism).

DIAGNOSIS

Clinical Presentation

• Methylxanthine poisoning produces tachycardia, hypotension, GI upset, anxiety and agitation, and seizures.

• Most severe caffeine poisoning involves the highly concentrated powdered form.

• Patients taking theophylline are at risk of accidental poisoning with abrupt smoking cessation (due to induction of CYP1A2 by smoking).

Diagnostic Testing

LABORATORIES

• Obtain a BMP to evaluate for hypokalemia and hyperglycemia.

î Hypokalemia due to excessive beta-1 adrenergic signaling is characteristic of methylxanthine poisoning.

• In the case of theophylline poisoning, obtain a theophylline concentration.

° Therapeutic concentrations are typically 5-15 #956;g#8725;mL.

î In the rare case of acute overdose, concentrations should be trended over time.

• Most hospital laboratories do not have access to rapid testing of caffeine concentrations.

ELECTROCARDIOGRAPHY

• The ECG may show sinus tachycardia or atrial or ventricular dysrhythmias.

• Supraventricular tachycardia and atrial or ventricular ectopy are particularly common.

TREATMENT

• Treat seizures with benzodiazepines or other directly GABAergic agents such as barbiturates or propofol.

• Significant dysrhythmias should be treated with esmolol.

î Adenosine will likely be ineffective.

• Hypotension refractory to fluid resuscitation should be treated with esmolol (if there is significant tachycardia impairing cardiac output) and norepinephrine or phenylephrine (for alpha-1 agonism mediating beta-2 peripheral vasodilation).

• MDAC enhances theophylline elimination and should be considered in theophylline-poisoned patients without contraindication to AC.

• Hemodialysis effectively clears methylxanthines and may be indicated in certain circumstances.

î In theophylline poisoning, indications for hemodialysis include high concentrations (gt;100 mg/L in acute poisoning or gt;60 mg/L in chronic poisoning), patient at extremes of age or with significant medical comorbidities, and the presence of life-threatening dysrhythmias, shock, and/or seizures.

î In caffeine poisoning, indications for hemodialysis are not well-developed, but hemodialysis would