Methylxanthines

Source Xanthines e.g. theophylline are used as bronchodilators (and very rarely for their positive inotropic effects on the cardiac muscle). There is also themethylated form, the methylxanthines e.g. theobromine (in chocolate) and caffeine. All of the xanthines are phosphodiesterase inhibitors (thus increasing the levels of cylcic AMP) and are also adenosine receptor antagonists.

The most common form of xanthine toxicity is theobromine (found in chocolate, cocoa, soft drinks and tea)however the ingestion of stimulants is another cause.

Mechanism of action As phosphodiesterase inhibitors, the methylxanthines lead to an increase n cAMP. This in turn leads to a rise in intracellular calcium and also a decrease in calcium sequestration. Hence, there is increased activity of the cardiac and skeletal muscles. There is also competitive antagonism of the intracellular adenosine receptors. This causes CNS stimulation, vasoconstriction and tachycardia Finally, the methylxanthines tend to cause a degree of sensory cortex 'irritation' leading to excitation.

Toxicokinetics It is readily absorbed, both orally and parentrally, and becomes widely distributed throughout the body. Metabolism is in the liver and it is renally excreted. This is enahanced by acidic urine due to the relative alkalinity of the methylxanthines.

Clinical signs -Increased urination -Vomiting -Diarrhoea -Tachycardia (up to 300bpm) -Tachypnoea (up to 150-200bpm) -Arrhythmias -Restlessness, hyperactivity, stiffness, twitching, hyperreflexia. -Ataxia -Seizures -Hyperthermia

Toxicity Lethal range in dogs = 100-250mg/kg LD50 of caffeine and theobromine = 100-200mg/kg LD50 of theophylline = 300mg/kg dogs, 700mg/kg cats

The highest concentration of theobromine is found in unsweetened baking chocolate and dark chocolate.

Diagnosis Clinical signs and history of exposure

Treatment -There is no specific antidote -Attempt gastric decontamination:

       - Emesis, gastric lavage if a small dog. N.B. avoid emesis if there is any evidence of hypereflexia or seizures.
       - Activated charcoal (every 3-4hours to reduce the half life of the toxin)
       - Cathartics 

-Supportive therapy and reduction of side effects:

       - Respiratory e.g. oxygen
       - Cardiovascular --> need to control arrhythmias (lidocaine, propanolol) and correct any acid/base or electrolyte abnormalities.
       - CNS --> may need to control any excitement or seizures using diazepam.
       - Insulin will antagonise the effects of caffeine