aminophylline (theophylline ethylenediamine)
(am in off' i lin)
Truphylline

Pregnancy Category C

Drug classes
Bronchodilator
Xanthine

Therapeutic actions
Relaxes bronchial smooth muscle, causing bronchodilation and increasing vital capacity, which has been impaired by bronchospasm and air trapping; in higher concentrations, it also inhibits the release of slow-reacting substance of anaphylaxis (SRS-A) and histamine.

Indications
· Symptomatic relief or prevention of bronchial asthma and reversible bronchospasm associated with chronic bronchitis and emphysema
· Unlabeled uses: respiratory stimulant in Cheyne-Stokes respiration; treatment of apnea and bradycardia in premature babies

Contraindications and cautions
· Contraindicated with hypersensitivity to any xanthine or to ethylenediamine, peptic ulcer, active gastritis; rectal or colonic irritation or infection (use rectal preparations).
· Use cautiously with cardiac arrhythmias, acute myocardial injury, CHF, cor pulmonale, severe hypertension, severe hypoxemia, renal or hepatic disease, hyperthyroidism, alcoholism, labor, lactation.

Available forms
Tablets--100, 200 mg; CR tablets--225 mg; liquid--105 mg/5 mL; injection--250 mg/10 mL; suppositories--250, 500 mg

Dosages
Individualize dosage, base adjustments on clinical responses; monitor serum theophylline levels; maintain therapeutic range of 10–20 mcg/mL; base dosage on lean body mass; 127 mg aminophylline dihydrate = 100 mg theophylline anhydrous.
ADULTS
· Acute symptoms requiring rapid theophyllinization in patients not receiving theophylline: An initial loading dose is required, as indicated below:

Patient Group
Oral Loading
Followed by
Maintenance
Non-smoking adults who are otherwise healthy
7.6 mg/kg
3.8 mg/kg q 4 hr × 3 doses
3.8 mg/kg q 6 hr
Young adult smokers
7.6 mg/kg
3.8 mg/kg q 6 hr × 2 doses
3.8 mg/kg q 8 hr


· Long-term therapy: Usual range is 600–1,600 mg/day PO in three to four divided doses.
· Rectal: 500 mg q 6–8 hr by rectal suppository or retention enema.
PEDIATRIC PATIENTS
Use in children < 6 mo not recommended; use of timed-release products in children < 6 yr not recommended. Children are very sensitive to CNS stimulant action of theophylline; use caution in younger children who cannot complain of minor side effects.
· Acute therapy: For acute symptoms requiring rapid theophyllinization in patients not receiving theophylline, a loading dose is required. Dosage recommendations are as follows:

Patient Group
Oral Loading
Followed by
Maintenance
Children 6 mo–9 yr
7.6 mg/kg
5.1 mg/kg q 4 hr × 3 doses
5.1 mg/kg q 6 hr
Children 9–16 yr
7.6 mg/kg
3.8 mg/kg q 4 hr × 3 doses
3.8 mg/kg q 6 hr


· Long-term therapy: 12 mg/kg per 24 hr PO; slow clinical adjustment of the oral preparations is preferred; monitor clinical response and serum theophylline levels. In the absence of serum levels, adjust up to the maximum dosage shown below, providing the dosage is tolerated.

Age
Maximum Daily Dose
< 9 yr
30.4 mg/kg/day
9–12 yr
25.3 mg/kg/day
12–16 yr
22.8 mg/kg/day
> 16 yr
16.5 mg/kg/day or 1,100 mg, whichever is less


GERIATRIC PATIENTS OR IMPAIRED ADULTS
Use caution, especially in elderly men and in patients with cor pulmonale, CHF, liver disease (half-life of aminophylline may be markedly prolonged in CHF, liver disease). For acute symptoms requiring rapid theophyllinization in patients not receiving theophylline, a loading dose is necessary as follows:

Patient Group
Oral Loading
Followed by
Maintenance
Older patients and cor pulmonale
7.6 mg/kg
2.5 mg/kg q 6 hr × 2 doses
2.5 mg/kg q 8 hr
CHF
7.6 mg/kg
2.5 mg/kg q 8 hr × 2 doses
1.3–2.5 mg/kg q 12 hr


Pharmacokinetics
Route
Onset
Peak
Duration
Oral
1–6 hr
4–6 hr
6–8 hr
IV
Immediate
30 min
4–8 hr


Metabolism: Hepatic; T1/2: 3–15 hr
Distribution: Crosses placenta; passes into breast milk
Excretion: Urine

IV facts
Preparation: May be infused in 100–200 mL of 5% dextrose injection or 0.9% sodium chloride injection.
Infusion: Do not exceed 25 mg/min infusion rate. Substitute oral therapy or IV therapy as soon as possible; administer maintenance infusions in a large volume to deliver the desired amount of drug each hour.
Adult: 6 mg/kg. For acute symptoms requiring rapid theophyllinization in patients receiving theophylline: a loading dose is required. Each 0.6 mg/kg IV administered as a loading dose will result in about a 1 mcg/mL increase in serum theophylline. Ideally, defer loading dose until serum theophylline determination is made; otherwise, base loading dose on clinical judgment and the knowledge that 3.2 mg/kg aminophylline will increase serum theophylline levels by about 5 mcg/mL and is unlikely to cause dangerous adverse effects if the patient is not experiencing theophylline toxicity before this dose. Aminophylline IV maintenance infusion rates (mg/kg/hr) are given below:

Patient Group
First 12 hr
Beyond 12 hr
Young adult smokers
1
0.8
Nonsmoking adults otherwise healthy
0.7
0.5


Pediatric: After an IV loading dose, these maintenance rates (mg/kg/hr) are recommended:

Patient Group
First 12 hr
Beyond 12 hr
Children 6 mo–9 yr
1.2
1
Children 9–16 yr
1
0.8


Geriatric: After a loading dose, these maintenance infusion rates (mg/kg/hr) are recommended:

Patient Group
First 12 hr
Beyond 12 hr
Other patients, cor pulmonale
0.6
0.3
CHF, liver disease
0.5
0.1–0.2


Compatibility: Aminophylline is compatible with most IV solutions, but do not mix in solution with other drugs, including vitamins.
Y-site incompatibility: dobutamine, hydralazine, ondansetron.

Adverse effects
· Serum theophylline levels < 20 mcg/mL: adverse effects uncommon
· Serum theophylline levels > 20–25 mcg/mL: nausea, vomiting, diarrhea, headache, insomnia, irritability (75% of patients)
· Serum theophylline levels > 30–35 mcg/mL: hyperglycemia, hypotension, cardiac arrhythmias, tachycardia (> 10 mcg/mL in premature newborns); seizures, brain damage
· CNS: Irritability (especially children); restlessness, dizziness, muscle twitching, convulsions, severe depression, stammering speech; abnormal behavior characterized by withdrawal, mutism, and unresponsiveness alternating with hyperactive periods
· CV: Palpitations, sinus tachycardia, ventricular tachycardia, life-threatening ventricular arrhythmias, circulatory failure
· GI: Loss of appetite, hematemesis, epigastric pain, gastroesophageal reflux during sleep, increased AST
· GU: Proteinuria, increased excretion of renal tubular cells and RBCs; diuresis (dehydration), urinary retention in men with prostate enlargement
· Respiratory: Tachypnea, respiratory arrest
· Other: Fever, flushing, hyperglycemia, SIADH, rash

Interactions
Drug-drug
· Increased effects with cimetidine, erythromycin, troleandomycin, clindamycin, lincomycin, influenza virus vaccine, oral contraceptives
· Possibly increased effects with thiabendazole, rifampin, allopurinol
· Increased cardiac toxicity with halothane; increased likelihood of seizures when given with ketamine; increased likelihood of adverse GI effects when given with tetracyclines
· Increased or decreased effects with furosemide, levothyroxine, liothyronine, liotrix, thyroglobulin, thyroid hormones
· Decreased effects in patients who are cigarette smokers (1–2 packs per day); theophylline dosage may need to be increased 50%–100%
· Decreased effects with phenobarbital, aminoglutethimide
· Increased effects, toxicity of sympathomimetics (especially ephedrine) with theophylline preparations
· Decreased effects of phenytoin and theophylline preparations when given concomitantly
· Decreased effects of lithium carbonate, nondepolarizing neuromuscular blockers given with theophylline preparations
· Mutually antagonistic effects of beta-blockers and theophylline preparations
Drug-food
· Elimination is increased by a low-carbohydrate, high-protein diet and by charcoal broiled beef
· Elimination is decreased by a high-carbohydrate, low-protein diet
· Food may alter bioavailability and absorption of timed-release theophylline preparations, causing toxicity. These forms should be taken on an empty stomach
Drug-lab test
· Interference with spectrophotometric determinations of serum theophylline levels by furosemide, phenylbutazone, probenecid, theobromine; coffee, tea, cola beverages, chocolate, acetaminophen cause falsely high values
· Alteration in assays of uric acid, urinary catecholamines, plasma free fatty acids by theophylline preparations

Nursing considerations
Assessment
· History: Hypersensitivity to any xanthine or to ethylenediamine, peptic ulcer, active gastritis, cardiac arrhythmias, acute myocardial injury, CHF, cor pulmonale, severe hypertension, severe hypoxemia, renal or hepatic disease, hyperthyroidism, alcoholism, labor, lactation, rectal or colonic irritation or infection (aminophylline rectal preparations)
· Physical: Bowel sounds, normal output; P, auscultation, BP, perfusion, ECG; R, adventitious sounds; frequency of urination, voiding, normal output pattern, urinalysis, renal function tests; liver palpation, liver function tests; thyroid function tests; skin color, texture, lesions; reflexes, bilateral grip strength, affect, EEG

Interventions
· Administer to pregnant patients only when clearly needed--neonatal tachycardia, jitteriness, and withdrawal apnea observed when mothers received xanthines up until delivery.
· Caution patient not to chew or crush enteric-coated timed-release forms.
· Give immediate-release, liquid dosage forms with food if GI effects occur.
· Do not give timed-release forms with food; these should be given on an empty stomach 1 hr before or 2 hr after meals.
· Maintain adequate hydration.
· Monitor results of serum theophylline levels carefully, and arrange for reduced dosage if serum levels exceed therapeutic range of 10–20 mcg/mL.
· Take serum samples to determine peak theophylline concentration drawn 15–30 min after an IV loading dose.
· Monitor for clinical signs of adverse effects, particularly if serum theophylline levels are not available.
· Maintain diazepam on standby to treat seizures.

Teaching points
· Take this drug exactly as prescribed; if a timed-release product is prescribed, take this drug on an empty stomach, 1 hr before or 2 hr after meals.
· Do not to chew or crush timed-release preparations.
· Administer rectal solution or suppositories after emptying the rectum.
· It may be necessary to take this drug around the clock for adequate control of asthma attacks.
· Avoid excessive intake of coffee, tea, cocoa, cola beverages, chocolate.
· Smoking cigarettes or other tobacco products impacts the drug's effectiveness. Try not to smoke. Notify the care provider if smoking habits change while taking this drug.
· Be aware that frequent blood tests may be necessary to monitor the effect of this drug and to ensure safe and effective dosage; keep all appointments for blood tests and other monitoring.
· These side effects may occur: nausea, loss of appetite (taking this drug with food may help if taking the immediate-release or liquid dosage forms); difficulty sleeping, depression, emotional lability (reversible).
· Report nausea, vomiting, severe GI pain, restlessness, convulsions, irregular heartbeat.

Adverse effects in Italic are most common; those in Bold are life-threatening.