Theophylline toxicity

Theophylline Ciprofloxacin, fluvoxamine, etc. CYP1A2 Theophylline toxicity... 

Additive sympathomimetic effects may develop when decongestants are administered with other sympathomimetic drug s (see Chap. 22). Use of the nasal decongestants with the MAOIs may cause hypertensive crisis. Use of a decongestant with beta-adrenergic blocking dragp may cause hypertension or bradycardia. When ephedrine is administered with theophylline, the patient is at increased risk for theophylline toxicity. 

Notify the primary health care provider immediately if any of the following signs of theophylline toxicity develop anorexia, nausea, vomiting, diarrhea, confusion, abdominal cramping, headache, restlessness insomnia, tachycardia, arrhythmias or seizures... 

L Hendeles, M Weinberger, G Milavetz, M Hill III, L Vaughan. Food-induced dose-dumping from a once-a-day theophylline product as a cause of theophylline toxicity. Chest 87 758-765, 1985. 

All quinolones interact with multivalent cations, forming chelation complexes resulting in reduced absorption. Major offenders are antacids vitamins containing calcium and iron can also be problematic. All fluoroquinolones interact with warfarin, didanosine (ddi), and phenytoin, resulting in decreased absorption or metabolism. Ciprofloxacin and other second-generation drugs interact with theophylline by decreasing its clearance, which leads to theophylline toxicity. 

The dangers of theophylline toxicity in hypothyroidism have been described (1120). 

In contrast, decreases in theophylline metabolism by selective inhibitors of CYP1A2, such as fluvoxamine and some quinolone antibiotics, or by selective and potent inhibitors of CYP3A4, such as the macrolide antibiotics, have resulted in serious theophylline toxicity (22). It is postulated that taken over time, the macrolide antibiotics act as mechanism-based inhibitors of CYP isoforms other than just CYP3A4. Some nonselective inhibitors of P450s, such as cimetidine, some p-blockers and calcium channel blockers, and others (19,22), also appear to inhibit the metabolism of theophylline enough to cause toxicity. 

AMIODARONE BRONCHODILATORS- THEOPHYLLINE Theophylline levels may be t by amiodarone (single case report of theophylline levels doubling) Uncertain amiodarone probably inhibits the metabolism of theophylline Watch for theophylline toxicity monitor levels regularly until stable... 

MEXILETINE BRONCHODILATORS -THEOPHYLLINE Theophylline levels may be t by mexiletine cases of theophylline toxicity have been reported Mexiletine inhibits CYP1A2-mediated metabolism of theophylline 1 the theophylline dose (by up to 50%). Monitor theophylline levels and watch for toxicity... 

PROPAFENONE BRONCHODILATORS -THEOPHYLLINE Cases oft theophylline levels with toxicity when propafenone added Uncertain at present Watch for signs of theophylline toxicity... 

DILTIAZEM, VERAPAMIL THEOPHYLLINE t theophylline levels with diltiazem and verapamil. Mostly not clinically significant but two cases of theophylline toxicity with verapamil have been reported Uncertain, but thought to be due to inhibition of CYP1A2-mediated metabolism of theophylline Be aware of the small possibility of theophylline toxicity when commencing calcium channel blockers check levels if any problems occur, and consider either reducing the dose of theophylline or using an alternative calcium channel blocker... 

METHOTREXATE BRONCHODILATORS -THEOPHYLLINE Possible t in theophylline levels Possibly inhibition of CYP2D6-mediated metabolism of theophylline Monitor clinically for toxic effects and advise patients to seek medical attention if they have symptoms suggestive of theophylline toxicity. Measure theophylline levels before, during and after co-administration... 

THYROID HORMONES BRONCHODILATORS- THEOPHYLLINE Altered theophylline levels (T or f) when thyroid status was altered therapeutically Uncertain Monitor theophylline levels closely during changes in treatment of abnormal thyroid function. Watch for early features of theophylline toxicity... 

THEOPHYLLINE LEUKOTRIENE RECEPTOR ANTAGONISTS -ZAFIRLUKAST Possibly t theophylline levels. Also possibly 4 zafirlukast levels Mutual alteration of metabolism Be aware watch for features of theophylline toxicity and measure levels... 

Toxicity. The estimated minimum lethal dose after intravenous administration is 0.1 g fatalities have occurred after oral doses of 8.4 mg/kg in a child and after 25 to 100 mg/kg of aminophylline given as a suppository. Recovery has been reported after ingestion of choline theophyllinate equivalent to 12.8 g of theophylline. Toxic effects are usually associated with plasma concentrations greater than 30 pg/ml and fatalities with concentrations above 50pg/ml premature neonates appear to be relatively resistant to theophylline poisoning. 

Theophylline neurotoxicity and cardiotoxicity are increased in older patients. Although it is unclear whether decreased theophylline clearance and increased exposure in older patients fully explain this apparent sensitivity, clinical reports are uniform in identifying age as a major contributing risk factor for theophylline toxicity (95,96). This has resulted in much less use of theophylline in older patients. 

Schiff GD, Hegde HK, LaCloche L, Hryhoczuk DO. Inpatient theophylline toxicity Preventable factors. Ann Intern Med 1991 114 748-53. 

Hendeles, L. Weinberger, M. Milavetz, G. Hill, M. Vaughan, L. Food induced dumping from once-a-day theophylline product as cause of theophylline toxicity. Chest... 

Theophylline toxicity has been reported in several patients, apparently stabilized on theophylline, after the introduction of verapamil (205) or nifedipine (206). 

The toxic concentrations for theophylline in neonates have not been well defined, and can vary from infant to infant. Other pharmacokinetic factors, such as low plasma protein binding and limited capacity for excretion could make neonates prone to aminophylline toxicity. Fetuses and neonates can develop theophylline toxicity even with plasma concentrations in the target range, since they can metabolize theophylline to caffeine, adding to the methyl-xanthine load. 

The use of hemodialysis or hemoperfusion in the management of theophylline toxicity was initially controversial (SEDA-8, 11) (SEDA-9, 10) (SEDA-11, 5). In one study... 

The most frequently observed effects of macrolides on theophylline pharmacokinetics are increases in half-life and serum theophylline concentrations and reduced clearance (62). The interaction with theophylline is mainly seen with higher doses of macrolides and can result in theophylline toxicity (63). 

Serious theophylline toxicity has been attributed to ciprofloxacin (64). 

These cases of interactions of aminophylline with macro-lide antibiotics illustrate that serious, even fatal, adverse effects can occur when possible interactions are not considered. In both cases, experienced physicians prescribed appropriate antimicrobial drugs, but omitted to consider the possibility of interactions with aminophylline, and failed to reduce the dose of aminophyUme or to measure theophylline concentrations. In the first case the development of tachycardia, hypokalemia, acidosis, vomiting, and convulsions can be explained on the basis of theophylline toxicity caused by ciprofloxacin, while in the second the anxiety, tremor, and cardiac arrests could all have resulted from an interaction of aminophylline and erythromycin. These cases add to an extensive literature that emphasizes the potential for interaction between aminophylline and drugs metabolized by CYP1A2. 

A 59-year-old Japanese man taking theophylline for emphysema had stimulation, insomnia, and tachycardia owing to theophylline toxicity after he also took levofloxacin and clarithromycin (76). His theophylline clearance returned to normal and his symptoms resolved after withdrawal of levofloxacin, while clarithromycin was continued. 

Aitken ML, Martin TR. Life-threatening theophylline toxicity is not predictable by serum levels. Chest 1987 91(1) 10-14. 

Henderson JH, McKenzie CA, Hilton PJ, Leach RM. Continuous venovenous haemofiltration for the treatment of theophylline toxicity. Thorax 2001 56(3) 242-3. 

Gitomer JJ, Khan AM, Ferris ME. Treatment of severe theophylline toxicity with hemodialysis in a preterm neonate. Pediatr Nephrol 2001 16(10) 784-6. 

D Arcy PF. Theophylline toxicity from dose-dumping. Pharm Int 1985 6 289. 

In acute overdose, peak serum levels > 100 pg ml may be predictive of arrhythmias and seizures. The use of sustained-release formulations and the presence of pharmacobezors in the gut may make it difficult to determine peak serum levels. Sinus tachycardia is the most common cardiac sign of theophylline toxicity. Ventricular and supraventricular tachycardia, ectopic beats, hypotension, and cardiac arrest may occur. Metabolic acidosis, hypokalemia, hypercalcemia, and hyperglycemia may be seen. Tremulousness and agitation frequently occur. Intractable seizures may occur in severe intoxications, probably secondary to adenosine receptor antagonism in the brain. Onset of seizures is a poor prognostic indicator. Persistent vomiting is commonly seen and may interfere with attempts at therapy. 

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