Aminophylline inhibits the enzyme phosphodiesterase and enhances the influx of calcium ions. It is used to treat the following conditions:

• Symptoms of acute airway obstruction in patients with Asthma, emphysema, and chronic bronchitis in addition to bronchodilators and other agents like corticosteroids.
• Off-label use for the reversal of dipyridamole or regadenoson-induced adverse reactions (angina and hypotension) during nuclear cardiac stress testing.

Note: The 2007 National Heart, Lung, and Blood Institute Asthma Guidelines and the 2018 Global Initiative for Asthma Guidelines (GINA) recommend against the use of theophylline in patients with Asthma and other chronic lung conditions like COPD because of the significant adverse drug reactions.

Aminophylline Dose in Adults

Note: Calculating aminophylline dose should be based on the ideal body weight. Theophylline and aminophylline doses are not equivalent. Theophylline dose is about 79% of the aminophylline dose.

Aminophylline Dose in acute symptomatic bronchoconstriction:

• An intravenous loading dose of 5.7 mg/kg of aminophylline in patients who have not received aminophylline or theophylline in the previous 24 hours.
• Loading dose should be calculated based on the serum aminophylline levels in patients who have used it in the last 24 hours and calculated as follows:
  • Aminophylline Loading dose = (desired serum theophylline concentration - measured serum theophylline concentration) (V )

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Maintenance dose of intravenous aminophylline:

• The maintenance dose should target plasma theophylline levels of 10 mcg/mL.
• Adults 60 years of age or younger:
  • 0.51 mg/kg/hour to a maximum dose of 1,139 mg/day or when the serum target levels are achieved.
• Adults older than 60 years of age
  • 0.38 mg/kg/hour to a maximum dose of 507 mg/day or until target levels indicate the need for a larger dose.
• Patients with decompensated cardiac disease, cor pulmonale, sepsis with multiorgan failure, and shock:
  • 0.25 mg/kg/hour to a maximum dose of 507 mg/day or unless serum levels indicate the need for a larger dose.

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Dosage adjustment based on serum theophylline concentrations:

• Serum levels of less than 9.9 mcg/mL:
  • If tolerated, increase the infusion rate by 25 %.
• Serum levels of 10 to 14.9 mcg/mL:
  • Continue the same dose if the patient is tolerating it.
• Serum levels of 15 to 19.9 mcg/mL:
  • Reduce the dose by 10 % even if the patient is tolerating it to avoid adverse drug reactions.
• Serum levels of 20 to 24.9 mcg/mL:
  • Reduce the infusion rate by 25% even if the patient is tolerating it.
• Serum levels of 25 to 30 mcg/mL:
  • Stop aminophylline infusion for 24 hours and reduce the subsequent infusion rate by 25%.
• Serum aminophylline dose of more than 30 mcg/mL:
  • Stop the infusion, treat the patient for aminophylline overdose, and reduce the subsequent infusion rate by 50%.

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Reversal of dipyridamole- or regadenoson-induced adverse reactions (angina and hypotension) during nuclear cardiac stress testing:

• 50 to 250 mg administered intravenously over 30 to 60 minutes. The dose may be repeated if necessary. If Intravenous aminophylline is not available, intravenous theophylline or caffeine may be used as alternatives 

Aminophylline Dose in Childrens

Aminophylline Dose in acute symptomatic bronchoconstriction:

Infants, children, and adolescents:

• An intravenous loading dose of 5.7 mg/kg of aminophylline in patients who have not received aminophylline or theophylline in the previous 24 hours.
• Loading dose should be calculated based on the serum aminophylline levels in patients who have used it in the last 24 hours and calculated as follows:
  • Aminophylline Loading dose = (desired serum theophylline concentration - measured serum theophylline concentration) (V )

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Maintenance dose of aminophylline:

• Infants 4 to 6 weeks of age:
  • 1.9 mg/kg/dose every twice daily.
• Infants 6 to 52 weeks of age:
  • Dose (mg/kg/hour) = [(0.008 X age in weeks) + 0.21] divided by 0.79
• Children 1 to less than 9 years of age:
  • 1.01 mg/kg/hour
• Children 9 to less than 12 years of age:
  • 0.89 mg/kg/hour
• Adolescents 12 to less than 16 years of age:
  • 0.63 mg/kg/hour
• Adolescents 12 to less than 16 years of age and smoking cigarette or marijuana smokers:
  • 0.89 mg/kg/hour
• Adolescents older than 16 years of age (non-smokers):
  • 0.51 mg/kg/hour
• Decompensated cardiac disease, cor pulmonale, liver disease, sepsis with multiorgan failure, and shock:
  • 0.25 mg/kg/hour to a maximum dose of 507 mg/day unless the serum concentrations indicate the need for a larger dose.

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Dosage adjustment based on serum theophylline concentrations:

• Serum levels of less than 9.9 mcg/mL:
  • If tolerated, increase the infusion rate by 25 %.
• Serum levels of 10 to 14.9 mcg/mL:
  • Continue the same dose if the patient is tolerating it.
• Serum levels of 15 to 19.9 mcg/mL:
  • Reduce the dose by 10 % even if the patient is tolerating it to avoid adverse drug reactions.
• Serum levels of 20 to 24.9 mcg/mL:
  • Reduce the infusion rate by 25% even if the patient is tolerating it.
• Serum levels of 25 to 30 mcg/mL:
  • Stop aminophylline infusion for 12 hours (in patients aged less than 16 years), for 24 hours ( in patients aged more than 16 years ), and reduce the subsequent infusion rate by 25%.
• Serum aminophylline dose of more than 30 mcg/mL:
  • Stop the infusion, treat the patient for aminophylline overdose, and reduce the subsequent infusion rate by 50%.

Pregnancy Risk Factor C

• Theophylline crosses into the placenta, and adverse drug reactions have been observed in animal studies. 
• Theophylline monographs in pregnancy are important to consider.

Use of theophylline during breastfeeding

• AAP has designated theophylline compatible with breastfeeding. 
• Theophylline is excreted in breastmilk so dose adjustments should be made according to the monograph.

Aminophylline Dose in kidney impairment:

• No dosage adjustment is necessary in renal disease.

Aminophylline dose in patients with liver disease:

• 0.25 mg/kg/hour as an initial starting dose to a maximum dose of 507 mg/day unless serum concentrations indicate the need for a larger dose.
• Aminophylline should be used with caution in patients with liver disease and the serum concentrations should be routinely measured.

Side Effects of Aminophylline:

Adverse reactions at therapeutic serum levels:

• Central nervous system:
  • Headache, irritability, insomnia, restlessness, and seizure.
• Dermatologic:
  • Allergic skin reactions and exfoliative dermatitis
• Gastrointestinal:
  • Diarrhea, nausea, and vomiting
• Genitourinary:
  • Transient Diuresis
• Neuromuscular & skeletal:
  • Tremor

Contraindications to Aminophylline:

• Hypersensitivity or allergy to theophylline or aminophylline or any other component of the formulation.
• Patients at high risk for arrhythmias and coronary artery disease
• Active peptic ulcer disorder.

Precautions and warnings

• Because of possible skin reactions, it is important to avoid extravasation.
• Overdosing can lead to theophylline toxicities, which can be fatal.
  • Patients with:
    • Acute pulmonary edema
    • heart failure,
    • Cor pulmonale
    • febrile state
    • Liver disease
    • hypothyroidism,
    • Sepsis with multiorgan failure
    • shock
    • neonates,
    • impaired renal function
    • Patients who smoke marijuana or tobacco.
• Patients with epilepsy may experience Seizures that are exacerbated by theophylline.

Aminophylline: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring Parameters:

Monitor theophylline levels 30 minutes after the initial loading dose and 24 hours of the maintenance dose or after dose adjustment. During therapy with theophylline, monitor:

• Heart rate
• CNS effects like insomnia and irritability
• Respiratory rate
• arterial or capillary blood gases in patients with chronic lung diseases like asthma
• Observe the infusion site for extravasation of the drug.

How to administer aminophylline?

• The intravenous loading doses should be administered over 30 minutes.
• For patients with cor pulmonale, decompensated heart disease, liver disease, patients older than 60 years of age, or patients on certain medications that impair clearance of aminophylline, the infusion rate should not exceed 21 mg/hour.
• Avoid extravasation of the drug as it may cause serious skin-related adverse effects. If extravasation of theophylline into the skin occurs, follow these steps:
  • stop the infusion,
  • aspirate the fluid with the same IV line (DO NOT FLUSH THe LINE)
  • administer hyaluronidase antidote (intradermal/ subQ 1 to 1.7 ml as five separate injections of 0.2 to 0.3 ml with a 25 gauge needle injected in a clockwise manner.
  • Remove the needle,
  • Apply cold compresses, and
  • Elevate the limb.

Mechanism of action of Aminophylline:

• Bronchodilation is caused by the aminophylline and theophylline.
• It can also reduce the body's response to allergens through unknown mechanisms. 
• It is used to prevent allergic airways disease.
• Theophylline increases calcium uptake via adenosine-mediated channel and also causes diaphragmatic muscle contraction to be increased.

It is bound to protein primarily albumin at 40% and is metabolized by the liver to active metabolites (caffeine, methylxanthine).

The half-life of a substance is variable. Half-life is affected by age, heart function, lung disease, smoking, and liver function.

• Premature infants, aged 3 to 15 days:
  • 30 hours ranging from 17 to 43 hours
• Premature infants, postnatal age 25 to 57 days:
  • 20 hours ranging from 9.4 to 30.6 hours
• Term infants (postnatal age 1-2 days):
  • 25.7 hours ranging from 25 to 26.5 hours.
• Term infants postnatal age 3 to 30 weeks:
  • 11 hours ranging from 6 to 29 hours
• Children 1 to 4 years:
  • 3.4 hours ranging from 1.2 to 5.6 hours
• Children and Adolescents 6 to 17 years:
  • 3.7 hours ranging from 1.5 to 5.9 hours
• Adults older than 18 years to less than 60 years of age:
  • 8.7 hours ranging from 6.1 to 12.8 hours
• Elderly older than 60 years:
  • 9.8 hours (range: 1.6 to 18 hours)

Time to reach the peak plasma concentration: 30 minutes

Excretion of Theophylline is via Urine ( 50% as unchanged drug). Smokers clear theophylline from the body twice as rapidly as non-smokers.

Aminophylline International Brand Names:

• Aminocont
• Aminofilina
• Aminomal
• Aminophyllin
• Aminophylline Renaudin
• Aminophyllinum
• Aminophyllinum Prolongatum
• Aminoslow
• Aminosol
• Amlin
• Asiphylline
• Asmafin
• Asmapen
• Asthcontin
• Brolin
• Cardiomin
• Cardirenal
• Cardophyllin
• Carine
• Clonofillin SR
• Diaphyllin
• Escophyllin
• Euphyllin Retard
• Filin
• Filotempo
• Lanrox
• Minoton
• Miofilin
• Neophyllin
• Pediatric Asthcontin for Children SR
• Peterphyllin
• Phaminov
• Pharmafil
• Phylin
• Phyllocontin
• Phyllotemp
• Retafilin
• Sofafyllin
• Syntophyllin
• Tefamin
• Teofyllamin Ipex
• Xing You Shan

Aminophylline Brand Names in Pakistan: