Theophylline Poisoning

• Theophylline (1,3-dimethylxanthins) can indirectly stimulate both β1 and β2 receptors through release of endogenous catecholamines.
• It is used for the treatment of pulmonary conditions, including asthma and chronic obstructive pulmonary disease (COPD). 
• In neonates, theophylline can be used for the treatment of apnea.
• Theophilline causes release of endogenous catecholamines and prolong their effects by inhibiting degradation of cyclic AMP by phosphodiesterase.

Theophylline toxicokinetics (‘ADME’):

Absorption –

• Orally administered theophylline is well absorbed, but peak levels may not be reached for up to ~15 hours post-ingestion if the preparation is slow-release (compared to about 2 hours for therapeutic doses of standard preparations).

Distribution –

• Theophylline is rapidly distributed and has a small volume of distribution (~0.5 L/kg).

Metabolism –

• Theophylline is metabolised by cytochrome P450 liver enzymes (mostly 1A2, 3A4, and 2E1 isozymes) and has active (e.g. 1,3-dimethyluric acid) and inactive (e.g. methyl xanthine, 1-methyl uric acid)metabolites. 
• Metabolism is saturable and may be affected by interactions with drugs that affect CYP450 activity.

Elimination –

• The elimination half-life can vary greatly, in a large overdose elimination is greatly prolonged.

In acute theophylline toxicity predicted severity is as follows:

1. therapeutic — 55-110 micromol/L or 10-20 mg/L
2. minor toxicity — 110-220 micromol/L or 20-40 mg/L
3. moderate toxicity — 220-440 micromol/L or 40-80 mg/L
4. severe toxicity — 440 micromol/L or >80 mg/L
5. fatal — 550 micromol/L or >100 mg/L

There are important differences between acute and chronic theophylline toxicity. Characteristics of chronic theophylline toxicity include:

1. tendency to occur in infants or the elderly
2. generally presents with vomiting and tachycardia.
3. metabolic effects are les pronounced.
4. seizures and cardiac dysrhythmias occur frequently and at lower serum theophylline levels.
5. Severe toxicity may occur at levels as low as >220 micromol/L (40 mg/L).
6. Haemodialysis should be commenced at a lower serum theophylline level: >330 micromol/L (60 mg/L) is commonly accepted (haemodialysis should be commenced regardless of the level if there are features of severe toxicity).

Clinical Features:

>18mg/L: Nausea, vomiting

>40mg/L: Tachycardia premature atrial and ventricular contraction

>50mg/L: Seizure

• CVS effects: Atrial arrhythmias, multifocal ventricular ectopics, idioventricular rhythms, ventricular tachycardia and ventricular fibrillation.
• Metabolic abnormalities: metabolic acidosis, hyperglycemia, decreased serum potassium and calcium
• Chronic theophylline overdose has minimal GI signs or symptoms.
• Seizures, hypotension, and significant dysrhythmias usually are observed when serum levels approach 80 mcg/mL.
• Seizures are more common with acute overdose than with chronic overdose. 
• In chronic exposures, seizures may develop at lower serum concentrations (40-60 mcg/mL).
• Cardiac dysrhythmias are more common following a chronic overdose rather than acute overdose and with lower serum concentrations.

Management:

Gastric lavage

• if within 1-2 hours of ingestion and multiple doses of activated charcoal should be given
• This will increase elimination of theophylline from the gut
• Consider whole-bowel irrigation with polyethylene glycol for overdose with sustained release preparations.

According to The Royal Children Hospital Melbourne:

Asymptomatic

• Give Charcoal 1g/kg
• Observe 4 hours. If no symptoms, discharge if not slow release medication.
• If ingestion of slow release preparation, admit for observation and serial drug levels

Symptomatic

• Charcoal 1g/kg initially unless altered conscious state (protect airway first)
• then 0.5g/kg 4 hourly, and whole bowel irrigation with colonic lavage solution 30ml/kg/hr.

Hypotension:

• Hypotension is treated with volume expansion and vasopressor.
• IV crystalloid (10-20 mL/kg) bolus
• noradrenaline infusion if resistant to fluid administration

Supraventricular tachycardia: 

• beta-blockade – e.g. metoprolol (5 mg IV slow then repeat in 5 min if needed), 
• propanolol (0.5-1 mg IV slow then repeat in 5 min if needed), or 
• esmolol infusion (0.05mg/kg/min then titrated up; 10 mg/mL in 5% dextrose)
• beware of bronchospasm in asthma patients!

Electrolytes imbalance:

• Serum potassium level should be measured and monitored regularly.
• Potassium supplements are nearly needed.

Seizure:

• Benzodiazepines and barbiturates are useful for convulsions and hyperactivity.
• e.g. IV Diazepam 5-10mg
• Phenytoin is ineffective

Gastrointestinal tract:

• Upper GI haemorrhage may follow theophylline-induced peptic ulceration and proton pump inhibitor or H2-antagonist 
• Other than cimetidine should be given since cimetidine inhibits metabolism of theophylline

Haemodialysis, peritoneal dialysis and haemoperfusion 

• are effective in removing theophylline and are indicated in patients with severe toxicity regardless of serum level (e.g. intractable seizure or life threatening cardiovascular complications) or after acute ingestion with serum level >440µmol/L (80mg/L), and in chronic ingestion, with serum level >200-300µmol/L (40-60mg/L)

 Antidotes: NIL

References:

http://lifeinthefastlane.com/toxicology-conundrum-014/

Sarawak Handbook 3rd Edition

http://www.rch.org.au/clinicalguide/guideline_index/Acute_Poisoning_Guidelines_For_Initial_Management/

http://www.rch.org.au/clinicalguide/guideline_index/Theophylline_Poisoning/

http://www.ncbi.nlm.nih.gov/pubmed/3534061