Methylxanthines are a purine-derived group of pharmacologic agents that have clinical use because of their bronchodilatory and stimulatory effects. This class includes several drugs, including the world’s most widely used caffeine. The FDA has approved the use of several methylxanthine derivatives for the treatment of reversible airway obstruction diseases such as chronic bronchitis, emphysema, and asthma. However, it is worth noting that the new GOLD criteria for the treatment of COPD (released in 2018) relegated methylxanthines from its treatment algorithm due to an imbalance between benefits and side effect profile. Non-FDA approved indications currently include sleep apnea and infant apnea (due to theoretical benefits from bronchodilation), cardiogenic pulmonary, and anosmia (according to one 2008 study, they showed potential benefits in improving the sense of smell in anosmic patients).
Methylxanthines are well-documented competitive inhibitors of the enzyme phosphodiesterase (isoenzyme types III and IV), nonselective antagonists of adenosine receptors (subtypes A1, A2, and A3), and activators of histone deacetylase (isoenzyme type II), however, the complete mechanism of action of methylxanthines is not known. Moreover, not all of these effects are achievable within the therapeutic window of the drug. The three known primary mechanisms by which methylxanthines exert their effects appear in more detail below:
Through non-competitive inhibition of the phosphodiesterase enzyme (PDE), methylxanthines cause an intracellular increase in levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). This signal results in bronchial smooth muscle relaxation, pulmonary vessel vasodilation, diuresis, CNS stimulation, and cardiac stimulation.
Adenosine receptor antagonist
Adenosine receptors in the basal forebrain are essential in signaling mental fatigue to the brain as adenosine accumulates and increasingly binds receptors the longer one stays awake. Methylxanthines bind these receptors with nearly identical affinity to adenosine, and this antagonism is the drug’s primary means of CNS stimulation. Methylxanthines also increase calcium uptake in diaphragmatic muscles via adenosine-mediated calcium channels, thus increasing their force of contraction.
Histone deacetylase activator
During inflammation, histone deacetylase becomes a key regulator of inflammatory mediators. An enzyme called phosphoinisitide-3-kinase-delta prevents recruitment of histone deacetylase to sites of inflammation, and methylxanthines have more recently shown to inhibit phosphoinisitide-3-kinase-delta. Increased recruitment of histone deacetylase to areas of inflammation prevents the transcription of genes for inflammatory mediators and thus exerts an anti-inflammatory effect.
Methylxanthines are available as tablets, extended-release tablets, and an oral solution. When administered orally, the drug is absorbed rapidly. However, broadly fluctuating plasma drug concentrations are a well-documented disadvantage to this route of administration. Despite the development of extended-release formulations, variability in plasma drug levels has led oral administration of methylxanthines to fall out of favor clinically.
Intravenous administration of methylxanthines yields a more consistent plasma drug concentration than does oral administration. IV methylxanthines are indicated for the termination of acute bronchospasm secondary to asthma or COPD exacerbation; however, inhaled beta-2-agonists (such as albuterol) are more effective treatments. The drug is administered as a loading dose followed by a constant maintenance infusion with a goal therapeutic range of 10-15mcg/ml. Dosage must be adjusted if the individual has taken a methylxanthine dose within the past 24 hours, is a smoker, or has renal or hepatic impairment.
Other routes of administration include inhalation and intramuscular injection. Inhalation has poor bioavailability and is typically not well tolerated. Intramuscular injection is painful and not recommended.
Methylxanthines have a narrow therapeutic range and, therefore, a high incidence of adverse effects. More mild adverse effects typically occur when serum drug concentrations are below 20 mcg/ml and may include nausea, vomiting, increased gastric acid secretion (and subsequent gastroesophageal reflux), polyuria, insomnia, palpitations, headaches, and tremors. Many of these mirror effects seen with excess caffeine. Generally, with serum concentrations that exceed 20 mcg/ml, severe effects include intractable vomiting, arrhythmias, irregular heartbeat (slow or fast), cardiac arrest, allergic skin reactions, or seizures.
It is because of this dose-related appearance of adverse effects that dosing is administered at the lowest possible rate to begin and titrated up until achieving a therapeutic effect.
Methylxanthines are contraindicated in any patient with a history of hypersensitivity reaction to any medication with a xanthine-derivative component (including aminophylline, theophylline, ethylenediamine).
Precautions are necessary when any of the following conditions apply to the patient in question: cardiovascular disease, cystic fibrosis, hepatic impairment, hypo or hyperthyroidism, peptic ulcer disease, seizure disorder, or pregnancy.
Methylxanthines are pregnancy category C drugs (risk cannot be ruled out). The drug crosses the placenta and infiltrates breast milk. It may be used in pregnancy only if the benefit to stand outweighs the potential of causing harm to the fetus. In these individuals, careful dose adjustment and monitoring are essential.
Monitoring for methylxanthine toxicity is crucial in patients receiving the drug. Serum drug concentration requires measurement before the initiation of the loading dose. In patients receiving ongoing dosing of methylxanthines, physicians should closely monitor the following: serum drug levels, heart rate (tachycardia), respiratory rate (tachypnea), CNS symptoms (tremor, insomnia, headache), venous or arterial blood gasses (evidence of respiratory alkalosis or acid/base imbalance), electrolytes (various abnormalities due to diuretic effect).
Methylxanthine toxicity can present with any of the following symptoms: intractable nausea, cardiac arrhythmias, rhabdomyolysis, seizures, or cardiac arrest. Charcoal or sorbitol may be administered to reduce further GI absorption of the drug (however, this is only effective with oral dosing of the drug). There is some evidence to suggest that beta-blocker administration may decrease cardiac adverse events in patients with methylxanthine toxicity. Intravenous administration of benzodiazepines may be employed to abort seizure activity induced by toxicity. Hemodialysis is proven to be efficacious in removing the drug from circulation by drastically expediting elimination (though usually only reserved for extremely severe cases).
Methylxanthines have a narrow therapeutic index, and as such, patients receiving them must be watched closely by all members of the care team. Effective communication regarding harbingers of toxicity is crucial. Careful monitoring and awareness of changes in patient condition may play a significant role in early recognition of and intervention for methylxanthine toxicity. However, with the advent of safer, more effective bronchodilating therapies, clinicians should not use methylxanthines routinely.
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