Aminophylline

Aminophylline is a drug combination of theophylline and ethylenediamine in a ratio of 2 to 1. It is FDA approved for relieving symptoms of reversible airway obstruction due to asthma or other chronic lung diseases like chronic bronchitis and emphysema. It is also used to prevent apnea in preterm infants.[1]

Non-FDA approved uses include:

• Cardiogenic pulmonary edema
• Thigh cellulite creams
• Sleep apnea  

Aminophylline's mechanism of action is not entirely understood. Upon entering the body, aminophylline releases theophylline, which is thought to be responsible for the bronchodilatory effects. There are various proposals for the molecular mechanism for theophylline, but not all of them take place at clinically effective concentrations. Theophylline works in three distinct ways as:

Phosphodiesterase Inhibitor 

Theophylline causes non-selective inhibition of type III and type IV isoenzymes of phosphodiesterase, which leads to increased tissue cyclic adenine monophosphate (cAMP) and cyclic 3′,5′ guanosine monophosphate concentrations, resulting in smooth muscle relaxation in lungs and pulmonary vessels, diuresis, CNS and cardiac stimulation. The bronchodilatory effect is not maximal at therapeutically effective dosages.[2] Inhibition of type IV isoenzyme is responsible for inhibiting the release of mediators from the alveolar macrophages but requires much higher serum concentrations.[3]

Adenosine receptor antagonist

Theophylline antagonizes adenosine receptor A1, A2 strongly, and  A3 less potently. It binds to adenosine A2B receptors to prevent bronchoconstriction by inhibiting the release of mediators like histamine and leukotrienes from mast cells.[4][5] This activity is thought to play an indirect role in the bronchodilation. Theophylline also increases calcium uptake through the adenosine-mediated calcium channels in the diaphragm leading to increased contraction and reversal of diaphragm fatigue.[6][7] This antagonism of the adenosine receptors, specifically A1 receptors, is responsible for some of the side effects of theophylline like seizures and cardiac arrhythmias.

Histone deacetylase activator

In inflammatory states, the activity of histone deacetylase becomes reduced due to oxidative stress via the activation of phosphoinositide-3-kinase-delta (PI3K-delta).[8] Theophylline increases the activity and recruitment of histone deacetylases to the site of active inflammation at therapeutic concentrations.[9] This action prevents the transcription of inflammatory genes that require acetylation of histones to activate their transcription and also decreases the resistance to steroids of COPD macrophages. This mechanism is distinct from PDE and adenosine receptor inhibition.[10]

A new study indicates that aminophylline plays an essential role in mitochondrial biogenesis in epithelial cells of the lung. Treatment with aminophylline induces the expression of transcriptional coactivator PGC-1α and transcriptional factors NRF1 and TFAM, which requires the activation of the CREB-PGC-1a signaling pathway by aminophylline.[11]

Pharmacokinetics

Aminophylline is rapidly and completely absorbed by the body and converted to theophylline, which is up to 40% bound by albumin. The remaining unbound theophylline distributes freely throughout the body except for body fat. The volume of distribution ranges from 0.3 to 0.7 L/kg. It passes across the placenta and is present in breast milk. Theophylline metabolism occurs in the liver via the cytochrome CYP450 system. At lower concentration's it is a substrate of CYP1A2, and at higher concentrations, CYP2E1 may also have involvement. Pharmacokinetics of theophylline are not predictable by sex, age, or other characteristics. Besides, various other factors like certain illnesses, tobacco use, marijuana use, and co-administration of other drugs can significantly alter its clearance. Below is a list of factors affecting the clearance of theophylline.

 Factors that increase clearance are:

• CYP450 enzyme induction by drugs like phenobarbital, carbamazepine
• Smoking 
• High protein and low carbohydrates diet
• Barbecued meat
• Age range 4 to 16

 Factors that decrease clearance are:

• Old age
• P450 enzyme inhibition
• Liver disease
• Infectious diseases like pneumonia or viral infection
• Congestive heart failure

Oral Administration

Aminophylline comes in the form of an oral solution, oral tablets, and extended-release- tablets. The absorption of the solution and oral tablets give wide fluctuations of serum concentrations and therefore are usually not recommended. The extended-release tablets are absorbed slowly over 12 to 24 hours and provide a steady plasma concentration. The recommended dose ranges from 400 to 600 mg/day.

Intravenous Administration

Intravenous administration of aminophylline occurs via two methods. A loading dose is given to achieve a serum concentration of 10 mcg/ml. Once the serum concentration has reached 10 to 15 mcg/ml, the maintenance constant infusion follows. The dosage given depends on the clearance of theophylline and whether the person has taken theophylline in the last 24 hours. These dosages vary by age, body weight, and the health status of the patient. 

Loading Dose 

The loading dose is 5.7 mg/kg based on the ideal body weight for all age groups. 

Loading doses should be administered over 30 minutes at a rate not to exceed 21 mg/hr and should be calculated using ideal body weight. This dose is for patients who have not taken aminophylline in the past 24 hours. The loading dose calculation must use the formula given below for patients who have taken aminophylline in the last 24 hours.

Loading dose = (Desired concentration - measured concentration) (volume of distribution) 

Mean volume of distribution:  0.3 to 0.7 ml/kg 

Maintenance Dose

Up to 1 mg/kg/hour as a constant infusion can be given depending on the ideal body weight and clearance rates. 

Intramuscular Administration:

IM administration is not recommended due to severe pain at the injection site.

Rectal suppositories:

These dosage forms are not widely used due to unreliable absorption and the occurrence of proctitis.

Dosing Considerations:

• Hepatic Impairment

Patients with hepatic dysfunction due to cirrhosis or any other cause require a dose adjustment. The maximum dose for such patients can't exceed 400 mg/day.

• Renal Impairment

There are no dose adjustments needed for renal impairment in adults or children older than 3 months. However, in infants younger than 3 months, a large amount of theophylline is excreted in the urine, and they require a dose adjustment.

• Concurrent Illness

Due to varying clearance rates for different concurrent illnesses, a good rule of thumb is that the maximum dose should not exceed 400 mg daily.

• Smokers

Smokers require a higher dose as their clearance rates of theophylline are faster than non-smokers.

Aminophylline has a narrow therapeutic index and is associated with a wide range of adverse effects. The adverse effects depend on the peak serum concentrations of theophylline in the body.[12]

With peak serum concentrations under 20 mcg/ml, the most common adverse effects are similar to the transient effects of caffeine (structurally similar) and include: 

• Nausea
• Vomiting
• Headache
• Insomnia
• Irritability
• Restlessness
• Increase in urine volume
• Shakiness
• Increased gastric acid secretion
• Gastroesophageal reflex

Once the serum theophylline exceeds 20 mcg/mL, the chances of adverse events increases and include :

• Persistent vomiting
• Cardiac arrhythmias
• Intractable seizures
• Fast, slow, or irregular heartbeat
• CNS depression
• Allergic skin reaction
• Yellowing of skin and eye
• Elevated liver enzymes  

Some of the more serious side effects along with their symptoms from the above mentioned are:

• Symptoms related to Irregular heartbeat can include (dizziness, chest pain, shortness of breath)
• Symptoms related to seizures can include (twitching, confusion, stiff muscles, difficulty talking)
• Allergic skin reaction (itching, skin rash, hives, blistering, tightness in the chest, facial swelling)

Aminophylline contraindications include patients with hypersensitivity to theophylline, ethylenediamine, or any component of the drug formulation. 

Precautions are necessary for patients with concurrent illnesses like:

• Cardiac disease
• Renal Impairment
• Hepatic dysfunction due to any cause
• Hypo/hyperthyroidism
• Epilepsy

Aminophylline is a pregnancy category C drug and passes into breast milk and across the placenta. Consistent monitoring and dose adjustment can help prevent adverse effects in this population.