What are the drug classes of cimetidine and theophylline, and how should their concomitant use be managed to avoid toxicity?

Cimetidine and Theophylline: Drug Classes and Management of Concomitant Use

Cimetidine is an H2-receptor antagonist (H2RA) and theophylline is a methylxanthine bronchodilator; when used together, cimetidine significantly inhibits theophylline metabolism through CYP450 enzyme inhibition, requiring a 25-50% reduction in theophylline dose to prevent toxicity. 1, 2

Drug Classifications

Cimetidine:

• H2-receptor antagonist that reduces gastric acid secretion 3
• Metabolized primarily hepatically (60% of oral dose) 3
• Potent inhibitor of multiple cytochrome P-450 enzymes including CYP1A2, 2C9, 2C19, 2D6, 2E1, and 3A4 3, 4, 2

Theophylline:

• Methylxanthine bronchodilator used for asthma and COPD 3
• Mild to moderate bronchodilator through phosphodiesterase 3 inhibition at therapeutic levels 3
• Metabolized by hepatic cytochrome P-450 system, making it highly susceptible to drug interactions 3, 1
• Therapeutic serum concentration range: 10-20 mcg/mL (or 5-15 mcg/L for COPD) 3, 1

Mechanism of Drug Interaction

The interaction is pharmacokinetic, not pharmacodynamic:

• Cimetidine decreases theophylline clearance by 25-70% through competitive inhibition of CYP1A2 and other P-450 enzymes 1, 2, 5
• This results in increased theophylline half-life by 36-64% and elevated serum concentrations 5, 6
• The effect is immediate upon cimetidine initiation and progresses over 8 days of treatment 6
• Theophylline volume of distribution remains unchanged 5, 6
• Higher theophylline doses show more pronounced interaction effects 5

Clinical Management Algorithm

When cimetidine must be added to existing theophylline therapy:

1. Reduce theophylline dose by 25-30% immediately upon cimetidine initiation 7, 6
2. Measure serum theophylline levels within 3-5 days of starting cimetidine 1, 2
3. Monitor for toxicity symptoms: nausea, vomiting, persistent headache, insomnia, tachycardia, seizures 1
4. Adjust theophylline dose based on serum levels to maintain therapeutic range (10-20 mcg/mL) 1
5. Recheck levels after 8 days as the interaction effect continues to increase 6

When initiating theophylline in patients already on cimetidine:

• Start with 25-30% lower theophylline dose than would otherwise be prescribed 1
• Measure serum levels after achieving steady state (typically 3-5 days) 1

When discontinuing cimetidine:

• Increase theophylline dose back to original levels to prevent subtherapeutic concentrations 1
• Monitor for loss of symptom control 1

Preferred Alternative: Use Different H2RA

The safest approach is to avoid this combination entirely by using alternative H2RAs:

• Ranitidine interacts weakly with cytochrome P-450 and has minimal effect on theophylline clearance 3, 5
• Famotidine and nizatidine do not bind to cytochrome P-450 and have low potential for interaction 3
• However, note that rare case reports exist of ranitidine-theophylline interaction in elderly patients, though this is far less common than with cimetidine 8, 9

Critical Pitfalls to Avoid

Common errors in managing this interaction:

• Failing to reduce theophylline dose proactively when adding cimetidine leads to rapid toxicity development 5, 7
• Assuming the interaction is minor because both drugs are commonly used—the 70% increase in theophylline levels can cause serious toxicity including seizures 1, 2
• Not monitoring elderly patients more closely, as they are at higher risk for confusional states from both drugs 2, 8
• Forgetting to adjust doses when discontinuing cimetidine, leading to loss of therapeutic effect 1
• Using once-daily cimetidine dosing (800 mg at bedtime) may produce less interaction than divided dosing, particularly in patients over 54 years, but monitoring is still essential 2

Special Populations

Elderly patients and those with hepatic/renal disease:

• Are at increased risk for both theophylline toxicity and cimetidine-induced confusional states 2, 8
• Require more aggressive dose reductions (up to 50%) and closer monitoring 2, 7
• Consider alternative H2RA from the outset in these populations 3, 9

Patients with COPD or asthma:

• Theophylline has narrow therapeutic index in these populations 3
• Serum level monitoring is mandatory when any interacting drug is added or removed 1
• Alternative bronchodilators (long-acting beta-agonists, anticholinergics) should be considered before adding cimetidine 3