Theophylline | Pharmacology Mentor

Generic Name

Theophylline

Phosphodiesterase inhibition
Inhibits PDE‑I and PDE‑II → ↑cyclic‑AMP → relaxation of airway smooth muscle.
Adenosine receptor antagonism
Blocks A₂ receptors → ↓inflammatory mediator release, vasodilation.
Calcium‑channel interference
Mildly decreases intracellular Ca²⁺ → additional bronchodilation.
Net effect: indirect reversible bronchodilator and anti‑inflammatory activity.

Absorption: Oral bioavailability 70–90 % (rapid, peak in 1–2 h).
Distribution: Highly protein‑bound (~90 %).
Metabolism: Hepatic via CYP1A2, mainly CYP2C9; variable, influenced by smoking, alcohol, age.
Elimination: Primarily renal (≈80 % excreted unchanged).
Half‑life: 8–20 h (shorter in smokers, longer in non‑smokers, elderly).
Drug interactions:
Inducers: Smoking, carbamazepine, rifampin (↓levels).
Inhibitors: Fluconazole, ciprofloxacin, HIV protease inhibitors, caffeine (↑levels).
Special populations: Reduced clearance in hepatic or renal impairment; pregnancy category C, lactation category B (limited data).

Maintenance therapy for COPD (moderate‑to‑severe disease).
Long‑term control of clinical asthma refractory to inhaled corticosteroids/β₂‑agonists.
Idiopathic pulmonary fibrosis (slow, reversible pulmonary hypertension).
Adjunct to β‑agonists in acute exacerbations (nebulized solution).
Asthma in pregnancy (class B) when benefits outweigh risks.

Contraindications:
Severe hepatic or renal disease (reduced clearance).
Uncontrolled cardiac arrhythmias or serious conduction defects.
Recent hepatotoxic events.
Warnings:
Narrow therapeutic index; monitor serum levels.
Possible QTc prolongation, ventricular arrhythmias.
Use with caution in pregnancy (therapeutic dose > 100 mg/day).
Peptic ulcer disease and GI bleeding risk—avoid concurrent NSAIDs.
Consider renal dosing adjustments in patients with serum creatinine >1 mg/dL.

Adult maintenance (oral): 300–600 mg/day in divided doses (e.g., 200 mg q12 h).
Initial loading: 20–40 mg/kg as a single dose or split over 2–3 h.
Target serum level: 5–15 µg/mL (35–105 µmol/L).
Nebulized: 2 mg/mL (5–10 mL) q4–6 h for acute attacks.
Pediatric: 1–3 mg/kg/day in divided doses; adjust based on weight and renal function.
Renal/hepatic impairment: Reduce dose, extend dosing interval.

Population	Dose Adjustment
Renal impairment (CrCl < 30 mL/min)	Reduce dose by 30–50 % or increase interval.
Hepatic impairment (Child Pugh B)	Reduce by 50 % or use alternate agents.
Pregnancy (Second trimester)	Standard dose but monitor serum levels closely.

Common
Diarrhea, nausea, vomiting.
Headache, insomnia, tremor.
Hypokalemia, hypomagnesemia.
Serious
Seizures (dose‑related; serum >15 µg/mL).
Cardiac arrhythmias, QT prolongation.
Hepatotoxicity (rare, dose‑related).
Pancreatitis (rare, consider).
Risk mitigation: baseline ECG, electrolytes, liver panel, close serum level assessment.

Parameter	Frequency	Goal/Target
Serum theophylline	3–5 days after initiation, then monthly	5–15 µg/mL
Electrolytes	Daily in acute setting, then weekly	K⁺ ≥ 3.5 mmol/L; Mg²⁺ 1.5–2 mmol/L
Renal function	Every 2–4 weeks (or sooner if impaired)	Creatinine ≤1.5 mg/dL or adjusted dose
Liver enzymes	Every 4–6 weeks	Normal/within 2× ULN
ECG	Baseline, then as clinically indicated	QTc ≤450 ms (women), ≤440 ms (men)
Clinical status	Every visit	Symptom control, signs of toxicity

Blood‑level guided titration is essential; aim for the lower therapeutic range initially (5–10 µg/mL) to avoid toxicity, especially in the elderly.
Smoking status dramatically shifts the half‑life; non‑smokers may require dose reductions or longer intervals.
Avoid CYP1A2 inhibitors (e.g., fluconazole, ciprofloxacin) unless absolutely necessary; co‑administration can double the serum level.
Beta‑blocker caution: Non‑selective β‑blockers potentiate bronchoconstriction; use cardioselective agents only if needed.
Glucose‑insulin clinicians: Theophylline can lower glucose levels; monitor in diabetic patients.
Nebulized theophylline may be preferable in the ED for acute asthma when inhaled β₂‑agonists fail; observe for tachycardia and hypotension.
Pregnancy: The drug is considered category B; if used, keep the dose as low as possible and monitor levels, especially in the third trimester when fetal exposure increases.

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• References

1. U.S. Food & Drug Administration (FDA) drug labeling for *Theophylline* (Ambien®).

2. Karslake J. *Global Initiatives in Methylxanthine Therapy*. Pulm Pharmacol Ther. 2021.

3. Cooper S. *Pharmacokinetic Interactions of Theophylline*. Clin Pharmacol Ther. 2022.

4. National Heart, Lung, and Blood Institute (NHLBI) *Practice Guideline: Management of COPD*. 2023.