Aminophylline

Mechanism of Action

Aminophylline's mechanism of action is not entirely understood. Upon entering the body, aminophylline releases theophylline, which is 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:

Phosphodiesterase Inhibitor 

Theophylline causes non-selective inhibition of type III and types 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.[5] Inhibition of type IV isoenzyme is responsible for inhibiting the release of mediators from the alveolar macrophages but requires much higher serum concentrations.[6]

Adenosine Receptor Antagonist

Theophylline antagonizes adenosine receptors 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.[7][8] This activity is thought to play an indirect role in bronchodilation. Theophylline also increases calcium uptake through the adenosine-mediated calcium channels in the diaphragm leading to increased contraction and reversal of diaphragm fatigue. This antagonism of the adenosine receptors, specifically A1 receptors, is responsible for some of the side effects of theophylline, like seizures and cardiac arrhythmias.[9][10]

Histone Deacetylase Activator

In inflammatory states, histone deacetylase activity becomes reduced due to oxidative stress via the activation of phosphoinositide-3-kinase-delta (PI3K-Delta).[11] Theophylline increases the action and recruitment of histone deacetylases to the site of active inflammation at therapeutic concentrations.[12] This action prevents the transcription of inflammatory genes that require acetylation of histones to activate their transcription and decreases the resistance to steroids of COPD macrophages. This mechanism is distinct from PDE and adenosine receptor inhibition.[13]

Recently, mitochondrial dysfunction has been linked to the development of chronic obstructive pulmonary disease (COPD) and asthma. A new study indicates that aminophylline plays an essential role in mitochondrial biogenesis in epithelial cells of the lung. It increases the ratio of mitochondrial DNA to nuclear DNA. Consequently, aminophylline is believed to have a beneficial effect on epithelial mitochondrial function in lung diseases.[14]

Pharmacokinetics

Aminophylline is rapidly and completely absorbed by the body and converted to theophylline, 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, 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

Administration

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. First, a loading dose is given to achieve a serum concentration of 10 mcg/ml. Then, the constant maintenance infusion follows once the serum concentration has reached 10 to 15 mcg/ml. The dosage depends on theophylline clearance 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 inconsistent 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: No dose adjustments are needed for renal impairment in adults or children older than three months. However, in infants younger than three months, a large amount of theophylline is excreted in the urine, requiring a dose adjustment.
• Concurrent Illness: A good rule of thumb is that the maximum dose should not exceed 400 mg daily due to varying clearance rates for different concurrent illnesses.
• Smokers: Smokers require a higher dose as their clearance rates of theophylline are faster than non-smokers.[15]

Adverse Effects

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.[16] 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 including multifocal atrial tachycardia[17][18]
• 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)

Contraindications

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
• Active peptic ulcer disease[19]

Pregnancy Consideration

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

Breastfeeding Consideration

Breastfeeding Avoid breastfeeding for 2 hours after intravenous or 4 hours after an oral aminophylline product to reduce the dose received by the breastfed infant.[20]

Monitoring

• Patients receiving aminophylline require monitoring for CNS effects, respiratory rate, arterial blood gasses, and serum theophylline concentrations.
• Clinicians must measure serum concentrations before initiating a loading dose in a person who has taken theophylline in the last 24 hours. A repeat serum concentration is necessary before starting the maintenance dose, as well.
• In children, the therapeutic range of aminophylline is 5 to 15 mcg/mL.
• Ensure a therapeutic range of aminophylline in adults, which is 10 to 20 mcg/mL.[21]

Toxicity

The concentration of theophylline in acute toxicity is greater than 20 mcg/mL. Aminophylline toxicity can present with the following clinical features. 

• Nausea and intractable vomiting
• Seizures
• Cardiac arrhythmias 
• Multifocal atrial tachycardia
• Cardiac arrest
• Rhabdomyolysis[22]
• Death[23]

Overdose Management

• Institute supportive care, including establishing intravenous access, maintenance of the airway, and electrocardiographic monitoring.
• Serum electrolytes and glucose should be measured on presentation and at appropriate intervals indicated by clinical circumstances. Clinicians should promptly correct fluid and electrolyte abnormalities.
• Serum Theophylline Concentration Monitoring: Measure the serum theophylline concentration immediately upon presentation and every 4 hours to guide treatment decisions. 
• Because of the increased morbidity and mortality associated with theophylline-induced seizures, treatment should be aggressive. Administer intravenous benzodiazepines such as lorazepam or diazepam. In addition, clinicians should consider phenobarbital for refractory seizures.
• Treat cardiac arrhythmias as per ACLS and PALS guidelines. 
• Enhance clearance of theophylline with the use of multiple-dose oral activated charcoal.[24]
• Extracorporeal Removal: Charcoal hemoperfusion is the most effective method of extracorporeal removal. Monitor for severe complications such as bleeding diathesis, hypotension, hypocalcemia. 
• Hemodialysis is as effective as charcoal hemoperfusion for eliminating theophylline. Additionally, it has a lower complication rate than hemoperfusion.[25]
• Clinicians should continue monitoring and treatment until the serum concentration decreases below 20 mcg/mL.[21] 

Enhancing Healthcare Team Outcomes

Aminophylline is an adjunct to beta2-agonists and corticosteroids in treating reversible bronchoconstriction caused by asthma and chronic lung conditions. However, the drug demonstrates a narrow therapeutic index, and even with regular monitoring, it can lead to adverse effects. Without precise management, the morbidity and mortality from aminophylline overdose are high. Therefore Healthcare workers, including nurses, pharmacists, and prescribing clinicians, should be aware of the complications of aminophylline toxicity.

Clinicians should prescribe aminophylline after risk-benefit evaluation for appropriate indications considering the recent global initiative for asthma(GINA) guidelines and global initiative for chronic obstructive lung disease(GOLD) guidelines.[26] Patients who receive aminophylline must be monitored for serum concentrations of the drug to ensure they are within therapeutic serum concentrations. There is no specific antidote to reverse toxicity, so it is vital to avoid taking high doses without approval from the clinician.

Nursing staff can monitor vital signs and treatment effectiveness and communicate with the healthcare team if they notice any adverse event. The pharmacist should suggest a safer option for treating asthma to clinicians who prescribe this drug, verify dosing, perform thorough medication reconciliation, alert the team to any issues. Also, drug interactions and concurrent illnesses require strong consideration before initiating treatment as clearance rates vary widely.

In cases of acute overdose, tirage nurses and emergency department physicians should rapidly stabilize patients and promptly initiate treatment. Clinicians should consult intensivists for refractory seizures, arrhythmias, and hypotension. Nephrologist consultation is necessary for hemodialysis. As illustrated above, multiple healthcare providers, including clinicians(MDs, DOs, NPs, PAs), specialists, nurses, pharmacists, are involved in taking care of the patient receiving aminophylline therapy. Hence, only through a collaborative, interprofessional team approach can the morbidity of this medication be lowered while achieving improved outcomes. [Level 5]