Aminophylline

Aminophylline belongs to the pharmacological class Methylxanthines. Aminophylline appears to have a bronchodilatory effect.

Aminophylline had been approved for relieving the symptoms as well as for the treatment and maintenance of episodes of reversible airflow obstruction, acute symptoms, and dipyridamole- or regadenoson-induced adverse reactions such as aging and hypotension (off-label indication).

Aminophylline is completely dissociated into theophylline. this theophylline is distributed into the non adipose tissue and it is found in breast milk about 70%.The apparent volume of distribution of aminophylline is found to be 0.3 to 0.7 L/kg.Theophylline is said to undergo hepatic metabolism via the cytochrome P450 system. In adults, theophylline and its metabolites undergo renal excretion.The main metabolites of aminophylline are 1,3-dimethyl uric acid, 1-methyl uric acid, and 3-methylxanthine.

The common side effects associated with Aminophylline are increase in urine volume, lightheadedness, persistent vomiting, chest pain or discomfort, dizziness, fainting ,fast, slow, or irregular heartbeat, pounding or rapid pulse etc.

Aminophylline is available in the form of systemic intravenous administration. Aminophylline is available in the U.S., Canada, E.U. , India, Australia, Japan.

Aminophylline belongs to the pharmacological class Methyl Xanthines. Aminophylline is said to be the ethylenediamine salt of theophylline. After ingestion of aminophylline, theophylline is released, and theophylline relaxes the bronchial smooth muscle of the bronchial airways as well as pulmonary blood vessels thereby reducing airway responsiveness to , adenosine, histamine, methacholine, and allergen. Theophylline is said to competitively inhibit the type III and type IV phosphodiesterase (PDE), which is the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, thereby possibly resulting in bronchodilation. Theophylline is said to also bind to the adenosine A2B receptor as well as block adenosine mediated bronchoconstriction. In the inflammatory states, theophylline is said to activate histone deacetylase in order to prevent transcription of inflammatory genes that require the acetylation of histones for transcription to begin.

Aminophylline had been approved for relieving symptoms and also for the maintenance and treatment of episodes of reversible airflow obstruction, acute symptoms, dipyridamole- or regadenoson-induced adverse reactions such as aging and hypotension (off label indication).

The half-life of administered aminophylline which gets dissociated and form theophylline varies from 3 to 12.8 hours (mean 7.5 hours) in adults and from 1.5 to 7.8 hours (mean 3.4 hours) in children.

The onset of action of aminophylline is 30 minutes. The duration of action of aminophylline is 4-6 hours.

Aminophylline can be used in the treatment of:

• Reversible airflow obstruction, acute symptoms
• Dipyridamole- or regadenoson-induced adverse reactions such as aging and hypotension (off label indication)

Aminophylline is approved for use in the following clinical indications:

• Reversible airflow obstruction, acute symptoms
• Dipyridamole- or regadenoson-induced adverse reactions such as aging and hypotension (off label indication)

Systemic

Intravenously administered by a registered medical practitioner.

225 mg; or 105 mg/5 mL; or 100 mg; or 200 mg; or 25 mg/mL; or 250 mg; or 500 mg

Systemic intravenous

• Dosage Adjustments in Hepatic Impairment Patients:

Initial: 0.25 mg/kg/hour; maximum dose: 500 mg/day unless serum concentrations indicate the need for a larger dose. Use with caution and monitor serum theophylline concentrations frequently.

• Dosage Adjustments in Pediatric Patients:

Infants 4 to 6 weeks: IV: 1.9 mg/kg/dose every 12 hours.

Infants 6 to 52 weeks: Continuous IV infusion: Dose (mg/kg/hour) = [(0.008 × age in weeks) + 0.21] divided by 0.8.

Maintaining health and cessation of smoking is a must.

Caffeine should be limited to use or avoided as it might lead to the risk of nervousness, rapid heartbeat, nausea, palpitations, etc.

Patients with an underlying liver disorder or liver dysfunction must avoid drinking alcohol.

Diet containing food with a high refined and high energy-dense foods, glycemic index, red and processed meat, saturated and trans fat food, added sugar, salt, preservatives, low fiber, low antioxidants, and vitamins needs to be restricted.

The dietary restrictions need to be individualized as per the patient's requirements.

Aminophylline may be contraindicated under the following conditions:

• Aminophylline Injection is said to be contraindicated in patients who are hypersensitive to xanthines or to ethylenediamine.
• Aminophylline Injection is also found to be contraindicated in patients who have coronary artery disease where myocardial stimulation may prove harmful.
• Aminophylline Injection is also contraindicated in patients suffering from bronchiolitis (bronchopneumonia).

The treating physician should be closely monitoring the patients and keep pharmacovigilance as follows:

Theophylline toxicity: Potentially fatal and severe theophylline toxicity might occur if reduced theophylline clearance occurs. Theophylline clearance might be decreased in patients suffering with acute pulmonary edema, heart failure, cor pulmonale, fever (≥102°F for ≥24 hours or the lesser temperature elevations for longer periods) , sepsis with multiorgan failure, hepatic disease, acute hepatitis, cirrhosis, hypothyroidism shock, infants <1 year,neonates (term and premature), infants <3 months of age with decreased renal function, elderly >60 years, and patients following cessation of smoking. The benefits should be considered versus risks and the need for more intensive monitoring in these patients; reduced dosing may be required. If a patient develops symptoms or signs of theophylline toxicity such as nausea or persistent, repetitive vomiting, a serum theophylline level should be measured immediately and subsequent doses should be withheld.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiac arrhythmias (excluding bradyarrhythmias); use might exacerbate arrhythmias.

• Cystic fibrosis: In patients with cystic fibrosis aminophylline should be used cautiously; increased theophylline clearance might occur.

• Hepatic impairment: In patients with hepatic impairment aminophylline should be used cautiously. The risk of severe and potentially fatal theophylline toxicity is found to be increased. Theophylline clearance is reported to be decreased ≥50% in these patients. It is advised to frequently monitor of serum theophylline concentrations.

• Hyperthyroidism: Use with caution in patients suffering from hyperthyroidism; increased theophylline clearance might occur.

• Peptic ulcer disease: Use with caution in patients suffering from active peptic ulcer disease; use might exacerbate peptic ulcer.

• Seizure disorder: Use with caution in patients suffering from seizure disorders; use might exacerbate seizure disorder.

Avoid alcohol usage while on Aminophylline medication as alcohol can worsen the effects of any other underlying disease condition, including conditions such as blurred vision, dizziness, etc.

Aminophylline, as theophylline, is found to be distributed into breast milk, and might occasionally induce irritability or the other signs of toxicity in the breast fed infants of mothers who are undergoing aminophylline therapy. The concentration of theophylline in breast milk is found to be about equivalent to the maternal serum concentration. An infant ingesting a liter of breast milk containing 10 - 20 mcg/mL of theophylline per day is likely to receive about 10 - 20 mg of theophylline on a daily basis. Serious adverse effects in the infant are less likely to occur unless the mother has toxic serum theophylline concentrations.

Category A1

The pharmacokinetics of aminophylline might be altered during pregnancy, and therefore serum theophylline concentrations might need to be measured more frequently in patients who are undergoing aminophylline therapy during pregnancy.

There has been found to be no sufficient evidence on the scientific basis traceable regarding the use and safety of Aminophylline in concurrent use with any particular food.

The adverse reactions related to Aminophylline can be categorized as:

Less Common

• Difficulty Sleeping
• Decreased Appetite
• Stomach Cramps
• Fast Heartbeat
• Nausea
• Nervousness

Rare

• Atrial Flutter
• Sinus Tachycardia
• Low Blood Pressure
• Seizures
• Headache
• Heart Throbbing Or Pounding
• Rapid Breathing
• Chest Pain
• Multifocal Atrial Tachycardia

The clinically relevant drug interactions of Aminophylline is briefly summarized here:

The following drugs might inhibit theophylline metabolism and decrease aminophylline

clearance thereby resulting in increased serum levels and the potential for increased toxicity: alcohol, high dose allopurinol (> 600 mg/day), cimetidine, oestrogen containing oral contraceptives, diltiazem, thyroid hormones, beta-blockers,disulfuram, recombinant alpha-interferon, methotrexate, mexiletine, propranolol, tacrine, thiabendazole,ticlopidine, verapamil, and macrolide antibiotics and quinolones which including erythromycin, clarithromycin, ciprofloxacin and enoxacin.

The following drugs may interact with aminophylline:

Adenosine Aminophylline might antagonise the cardiovascular effects of adenosine.

Halothane Concurrent use of aminophylline and halothane might result in ventricular arrythmias.

Ketamine Concurrent use of aminophylline and ketamine might result in a lowered seizure threshold.

Lithium Concurrent use of aminophylline and lithium might result in an increased excretion of lithium, and hence resulting in a reduction in the therapeutic effect of lithium. Adjustment of the lithium dosage might be required.

Beta-agonists Concurrent use of aminophylline and beta-agonists might produce increased cardiotoxic effects. Also, aminophylline might potentiate the hypoglycaemia which might be associated with administration of beta-agonists.

Beta-blocking agents (including ophthalmic agents) Concurrent use of the aminophylline with beta-blockers might result in an inhibition of the bronchodilatory effects of aminophylline.

Benzodiazepines Concurrent use of aminophylline and benzodiazepines might result in a reversal or reduction of the sedative effects of benzodiazepines.

Cardiac glycosides Version: Aminophylline might enhance the sensitivity of the myocardium to as well as the toxic potential of cardiac glycosides.

Ephedrine and other sympathomimetic amines The Concurrent use of aminophylline and sympathomimetic amines might result in increased nausea, nervousness or insomnia.

Neuromuscular blocking agents, non-depolarizing Aminophylline might antagonize the neuromuscular blocking effects of these agents.

Xanthines The concurrent use of aminophylline and other xanthine containing medications might result in additive toxicity and should be avoided

The common side effects of Aminophylline include the following:

• Increase in urine volume
• Lightheadedness
• Persistent vomiting
• Chest pain or discomfort
• Dizziness
• Fainting
• Fast, slow, or irregular heartbeat
• Pounding or rapid pulse
• Seizures
• Shakiness

Pregnancy

Category A1

The pharmacokinetics of aminophylline might be altered during pregnancy, and therefore serum theophylline concentrations might need to be measured more frequently in patients who are undergoing aminophylline therapy during pregnancy.

• Nursing Mothers

Aminophylline, as theophylline, is found to be distributed into breast milk, and might occasionally induce irritability or the other signs of toxicity in the breast fed infants of mothers who are undergoing aminophylline therapy. The concentration of theophylline in breast milk is found to be about equivalent to the maternal serum concentration. An infant ingesting a litre of breast milk containing 10 - 20 mcg/mL of theophylline per day is likely to receive about 10 - 20 mg of theophylline on daily basis. Serious adverse effects in the infant are less likely to occur unless the mother has toxic serum theophylline concentrations.

• Pediatric Use

Aminophylline Injection should be administered cautiously in premature or neonatal infants and children aged <1 year. The constant infusion rate of intravenous theophylline should be selected cautiously in pediatric patients since the rate of theophylline clearance is found to be highly variable across the age range of neonates to adolescents.

Due to the immaturity of theophylline metabolic pathways in the pediatric patients under the age of 1 year, particular attention to dosage selection and frequency of monitoring of serum theophylline concentrations are highly required when theophylline is prescribed to pediatric patients in this age group. Children are found to be particularly sensitive to xanthines, especially the CNS stimulant effects. The margin of safety above therapeutic doses is found to be small.The Rapid intravenous injection is not recommended in children.

• Geriatric Use

Aminophylline Injection should be administered with caution. Older patients are at significantly greater risk of experiencing serious toxicity from theophylline as compared to the younger patients due to pharmacodynamic and pharmacokinetic changes associated with aging. Theophylline clearance is reduced in patients aged greater than 60 years, resulting in an increased serum theophylline concentrations in response to a given theophylline infusion rate. Protein binding might be decreased in the elderly hence resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. Older patients also seem to appear to be more sensitive to the toxic effects of theophylline after chronic overdosage as compared to younger patients. For these reasons, the maximum infusion rate in patients aged more than 60 years, ordinarily should not exceed 17 mg/hr which is 21 mg/hr as aminophylline unless the patient continues to be symptomatic and the peak steady state serum theophylline concentration is about <10 mcg/mL. Theophylline infusion rates greater than 17 mg/hr i.e. 21 mg/hr as aminophylline, should be prescribed cautiously in elderly patients.

Physicians should be vigilant and knowledgeable about the treatment pertaining to the treatment and identification of overdosage of Aminophylline.

There are 2 common presentations: 1)acute overdose, which is infusion of an excessive loading dose or excessive maintenance infusion rate for less than 24 hours, and 2) chronic overdosage,which is excessive maintenance infusion rate for greater than 24 hours.

The most common causes of chronic aminophylline overdosage include clinician prescribing of an excessive dose or a normal dose of aminophylline in the presence of factors which are known to decrease the rate of the clearance of theophylline as well as increasing the dose of aminophylline in response to an exacerbation of symptoms without measuring first the serum theophylline concentration to determine whether a dose increase is safe.

Pharmacodynamics

Aminophylline is said to be the ethylenediamine salt of theophylline. Aminophylline is found to stimulate the CNS, skeletal muscles, and cardiac muscle. Aminophylline relaxes certain smooth muscles, produces diuresis,relaxes bronchi, and causes an increase in gastric secretion

Pharmacokinetics

Aminophylline is said to be rapidly and completely absorbed by the body and gets converted to theophylline, which is up to 40% bound by albumin. The remaining unbound theophylline freely distributed throughout the body except for body fat. The volume of distribution of aminophylline ranges from 0.3 to 0.7 L/kg. It passes across the placenta and is also present in breast milk. Theophylline metabolism is found to occur in the liver via the cytochrome CYP450 enzyme system. At lower concentration's it is said to be a substrate of CYP1A2 enzyme, and at higher concentrations, CYP2E1 might also have involvement.

1. https://www.webmd.com/drugs/2/drug-13863/aminophylline-intravenous/details/list-sideeffects
2. https://www.drugs.com/sfx/aminophylline-side-effects.html
3. https://www.mayoclinic.org/drugs-supplements/aminophylline-intravenous-route/side-effects/drg-20073584?p=1
4. https://www.medsafe.govt.nz/profs/datasheet/a/Aminophyllineinj.pdf
5. https://archive.hshsl.umaryland.edu/bitstream/handle/10713/14937/Aminophylline_Final_2020_12.pdf?sequence=1&isAllowed=n
6. https://www.ncbi.nlm.nih.gov/books/NBK545175/
7. https://go.drugbank.com/drugs/DB01223
8. https://medlineplus.gov/ency/article/002572.htm
9. https://www.mayoclinic.org/drugs-supplements/aminophylline-oral-route/proper-use/drg-20073https://www.medicines.org.uk/emc/product/6560/smpc#gref578
10. https://www.drugs.com/dosage/aminophylline.html#Usual_Adult_Dose_for_Asthma___Acute