Aminophylline

Indications

• Severe acute asthma
• Chronic asthma
• Chronic obstructive pulmonary disease (COPD)

Dosage

Children: For children aged 14–17 years, initially 200 mg four times a day for severe acute asthma, adjusted up to 40 mg/kg. For children 1 month to 11 years, 1 mg/kg/hour adjusted according to plasma-theophylline concentration.

Adults: Dosage should be individualized based on plasma theophylline concentrations. Generally, doses are given intravenously for acute situations and adjusted accordingly.

Mechanism of action

Aminophylline works by relaxing the smooth muscles of the airways, leading to bronchodilation. It also has anti-inflammatory properties and may increase the contraction of the diaphragm.

Pharmacodynamics

Aminophylline enhances the action of certain neurotransmitters and decreases the release of inflammatory mediators. The therapeutic dose range is narrow, necessitating careful monitoring of plasma theophylline concentrations.

Pharmacokinetics

Aminophylline is metabolised in the liver, with its half-life affected by various factors including smoking and liver function. The plasma concentration is increased in conditions like heart failure and hepatic impairment, and decreased in smokers.

Adverse effects

• Cough
• Headache
• Pneumonia
• Eosinophilic pneumonia
• Eosinophilic rhinitis
• Throat irritation
• Arthralgia
• Nausea
• Rash
• Abdominal pain
• Anxiety
• Arrhythmia

Interactions

• Beta-blockers (increases risk of bronchospasm)
• Phosphodiesterase type- (increases exposure)
• Stiripentol (increases exposure)
• Deferasirox (increases exposure)
• Roflumilast (increases exposure)
• Aciclovir (increases exposure)
• Macrolides (decreases exposure)
• Erythromycin (decreases exposure)
• Mexiletine (increases exposure)
• Monoclonal antibodies (decreases exposure)

Precautions

• Discontinue if eosinophilic pneumonia occurs
• Dose adjustment may be necessary if smoking started or stopped during treatment
• Patient counselling is advised for patients with cardiac arrhythmias or other cardiac disease

Pregnancy

Not known to be harmful. Can be taken as normal during pregnancy.

Breast-feeding

Unlikely to be present in milk. Can be taken as normal during breastfeeding.

Storage

Store in a cool, dry place away from direct sunlight.

Formulations

• Oral solution
• Capsule
• Modified-release tablets
• Intravenous infusion

Mechanism of action

Aminophylline is the ethylenediamine salt of theophylline. After ingestion, theophylline is released from aminophylline, and theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction. In inflammatory states, theophylline activates histone deacetylase to prevent transcription of inflammatory genes that require the acetylation of histones for transcription to begin. Theophylline and aminophylline have been widely used as inhibitors of phosphodiesterase when examining the role of cAMP in regulating cell function. In reality, however, these phosphodiesterase inhibitors may have additional sites of action that could complicate the interpretation of the results. These additional sites of action could include antagonism of inhibitory adenosine autoreceptors and release of intracellular calcium. The purpose of the present study was to determine which of the above three is the primary mechanism by which theophylline and aminophylline affect transmitter release at the mammalian neuromuscular junction. Quantal release measurements were made using intracellular recording techniques. A variety of drugs were used to elucidate this pathway. Isoproterenol, an adenylate cyclase activator, was first used to establish the effect of enhanced levels of cAMP. Theophylline application on its own or in the presence of a drug combination that blocked the adenosine receptor and phosphodiesterase pathways caused significant release depression, opposite to what is expected if it was functioning to enhance cAMP levels. However, when applied in the presence of a drug combination that blocked the adenosine receptor, phosphodiesterase and intracellular ryanodine calcium pathways, theophylline was unable to depress release. Therefore, it was concluded that the major mechanism of action of theophylline is depression of transmitter release by causing the release of intracellular calcium. Aminophylline application alone resulted in a significant enhancement of release. However, when coupled with an adenosine receptor blocker, the ability of aminophylline to enhance transmitter release was blocked, suggesting that its dominant mechanism of action is adenosine receptor inhibition. Taken together, these results indicate that the use of theophylline and aminophylline is inappropriate when examining the role of cAMP at the mammalian neuromuscular junction. Theophylline has two distinct actions in the airways of patients with reversible obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic effects). While the mechanisms of action of theophylline are not known with certainty, studies in animals suggest that bronchodilatation is mediated by the inhibition of two isozymes of phosphodiesterase (PDE III and, to a lesser extent, PDE IV) while non-bronchodilator prophylactic actions are probably mediated through one or more different molecular mechanisms, that do not involve inhibition of PDE III or antagonism of adenosine receptors. Some of the adverse effects associated with theophylline appear to be mediated by inhibition of PDE III (e.g., hypotension, tachycardia, headache, and emesis) and adenosine receptor antagonism (e.g., alterations in cerebral blood flow). Theophylline increases the force of contraction of diaphragmatic muscles. This action appears to be due to enhancement of calcium uptake through an adenosine-mediated channel. /Theophylline/

Pharmacodynamics

Aminophylline is the ethylenediamine salt of theophylline. Theophylline stimulates the CNS, skeletal muscles, and cardiac muscle. It relaxes certain smooth muscles in the bronchi, produces diuresis, and causes an increase in gastric secretion.