SN5 SHORT NOTE 5M ★ High-yield

Describe theophylline with its mechanism, interactions, toxicity and place in therapy.

Pharmacology · 2nd Professional — Para-Clinical

Pharmacology

Theophylline is a methylxanthine bronchodilator with a narrow therapeutic index; aminophylline is its more soluble complex with ethylenediamine, used intravenously.

Mechanisms — (1) adenosine receptor antagonism (adenosine is a bronchoconstrictor and mediates several of the toxic effects, including seizures and arrhythmia); (2) phosphodiesterase inhibition, raising cAMP; and (3) at low doses, activation of histone deacetylase, giving an anti-inflammatory effect and restoring steroid sensitivity
Actions — bronchodilatation; increased diaphragmatic contractility (useful in COPD); CNS stimulation; cardiac stimulation; diuresis; increased gastric acid secretion
Therapeutic range 10 to 20 mg/L, and toxicity may begin within it; metabolised by CYP1A2

CLINICAL PEARL

Levels rise when a smoker is admitted to hospital and stops smoking, and this catches people out. Tobacco smoke is a strong CYP1A2 inducer, so a smoker needs a higher theophylline dose. Stop smoking — on admission, in an intensive care unit, or after a successful quit attempt — and induction wanes over about a week while the dose stays the same. The result is toxicity in a patient who has changed nothing except a habit nobody recorded.

Interactions

Effect on level	Cause
Raised (risk of toxicity)	Ciprofloxacin, erythromycin and clarithromycin, cimetidine, allopurinol, fluvoxamine, oral contraceptives, verapamil, propranolol; cardiac failure, liver disease, viral infection, old age
Lowered (risk of failure)	Smoking (including cannabis), rifampicin, phenytoin, carbamazepine, phenobarbitone, chronic alcohol; childhood

Toxicity

Early — nausea, vomiting, abdominal pain, headache, insomnia, restlessness, tremor
Serious — tachyarrhythmias (including supraventricular and ventricular tachycardia), seizures which are often refractory, hypokalaemia, hyperglycaemia, metabolic acidosis, hypotension and rhabdomyolysis
Seizures and arrhythmia may occur without preceding gastrointestinal warning in chronic overdose, particularly in the elderly — so a normal symptom profile does not exclude a dangerous level
Management — stop the drug; activated charcoal (repeated doses enhance elimination, since theophylline undergoes enteroenteric recirculation); correct potassium; benzodiazepines for seizures; beta-blockers for arrhythmia (cautiously in asthmatics); and haemodialysis or charcoal haemoperfusion in severe poisoning, since it has a small volume of distribution and low protein binding

Place in Therapy

Now a later-line option in asthma and COPD, after inhaled corticosteroids, LABAs and LAMAs, because of its narrow index and interactions
Retains a role where cost matters — it is very cheap and orally active, which keeps it in wide use in India, particularly in sustained-release form
Intravenous aminophylline in acute severe asthma unresponsive to nebulised therapy, with cardiac monitoring; a loading dose is omitted if the patient is already on oral theophylline
Other uses — neonatal apnoea (where caffeine, a related methylxanthine, is now preferred and is safer)

Applied Aspects

Measure levels when starting, after any dose change, and whenever an interacting drug is added or stopped — theophylline is one of the few drugs where therapeutic monitoring genuinely changes management
Ask about smoking status at every review, and reduce the dose when a patient stops
Check before adding ciprofloxacin or a macrolide to a patient on theophylline; this combination is a classic and entirely avoidable cause of seizures
Do not give a loading dose without knowing the current level in someone already taking it
Sustained-release preparations are not interchangeable between brands, and switching can alter levels significantly
Where inhaled therapy is unaffordable or unavailable, theophylline remains a reasonable option — but it demands the monitoring and interaction vigilance that a safer inhaled drug does not

All questions in Gastrointestinal & Respiratory Drugs

Every Pharmacology chapter →