Methylxanthines

Continuing Education Activity

Methylxanthines are drugs primarily employed in the treatment of non-obstructive

lung pathology. This activity will highlight the indications, mechanism of action,
and adverse effects of methylxanthines. It will also investigate early signs of
toxicity and how its narrow therapeutic range alters the monitoring of patients
receiving these drugs.

Indications

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 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

Mechanism of Action

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:

Phosphodiesterase inhibition
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.

Administration

Oral

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.

IV
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

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

Adverse Effects

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.

Contraindications

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.
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

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 effecCT.

Toxicity

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

Enhancing Healthcare Team Outcomes

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.