Aminophylline is a methylxanthine and derivative of theophylline. Aminophylline relaxes smooth muscles, particularly bronchial muscles. This xanthine most likely exerts its effect by inhibiting cAMP or cGMP phosphodiesterases, thereby increasing levels of the second messenger cAMP or cGMP intracellularly. Other modes of actions include an adenosine antagonistic effect on the activity of CD4 lymphocytes and mediator release from mast cells thereby decreasing lung sensitivity to allergens and other substances that cause inflammation. Aminophylline also acts as a CNS stimulant and exerts a positive chronotropic and inotropic effect on the heart.
Aminophylline is a drug combination that contains theophylline and ethylenediamine in a 2:1 ratio. Once in the body, theophylline is released and acts as a phosphodiesterase inhibitor, adenosine receptor blocker, and histone deacetylase activator. Similar to other theophyllines, aminophylline is indicated for the treatment of lung diseases such as asthma, chronic bronchitis, and COPD.
Mechanism of Action of Aminophylline
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, an 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.
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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.
Indications of Aminophylline
- Apnea of Prematurity
- Asthma, acute
- Acute Exacerbation of Chronic Bronchitis
- asthma
- Chronic Bronchitis
- Exacerbation of asthma
- For the treatment of bronchospasm due to asthma, emphysema and chronic bronchitis
Contraindications of Aminophylline
- Allergic reactions
- Asthma exacerbations
- Hypersensitivity
- Hyperthyroidism
- Kidney or liver disease
- Hypoxemia (low level of oxygen in the blood)
- Cardiac arrhythmias
- History of peptic ulcer
- Acute myocardial infarction and
- Hypotension.
Dosages of Aminophylline
Strengths: 100 mg ; 200 mg ;225 mg ; 250 mg ; 500 mg;25 mg/mL ; 105 mg/5 mL ;
Asthma – Acute
Loading dose
- 6 mg/kg in 100 to 200 mL of IV fluid intravenously once over 20 to 30 minutes.
Maintenance dose (following loading dose)
- Otherwise healthy nonsmoking adult: 0.7 mg/kg/hr continuous intravenous infusion.
- Young adult smoker: 0.9 mg/kg/hr continuous intravenous infusion.
- Patient with cor pulmonale or congestive heart failure: 0.25 mg/kg/hr continuous intravenous infusion.
Oral: (Patient not receiving aminophylline or theophylline)
- Loading dose: 6.3 mg/kg orally once.
Maintenance dose (following loading dose)
- Otherwise healthy nonsmoking adult: 12.5 mg/kg/day in divided doses. Do not exceed 1,125 mg/day.
- Young adult smoker: 19 mg/kg/day in divided doses.
- Patient with cor pulmonale or congestive heart failure: 6.25 mg/kg/day in divided doses. Do not exceed 500 mg/day.
Pediatric Apnea of Prematurity
Loading dose
- (Patient not receiving aminophylline or theophylline): 5 to 6 mg/kg once – if IV, dilute in IV fluid and give intravenously once over 20 to 30 minutes.
- Maintenance dose: 3 to 8 mg/kg/day divided every 6 to 12 hours.
Pediatric Asthma – Acute
Loading dose
- 6 mg/kg diluted in IV fluid intravenously once over 20 to 30 minutes.
Maintenance dose (following loading dose)
- 6 weeks to 6 months: 0.5 mg/kg/hour continuous intravenous infusion.
- 6 months to 1 year: 0.6 to 0.7 mg/kg/hr continuous intravenous infusion.
- 1 year to 9 years: 1 to 1.2 mg/kg/hr continuous intravenous infusion.
- 9 years to 12 years: 0.9 mg/kg/hr continuous intravenous infusion.
- >12 years: 0.7 mg/kg/hr continuous intravenous infusion.
Oral
- Loading dose: 6.3 mg/kg orally once.
Maintenance dose (following loading dose)
- >=42 < 182 days: 12 to 13.5 mg/kg/day in divided doses.
- >= 6 < 12 months: 15 to 22.5 mg/kg/day in divided doses.
- >=1 year to <9 years: 25 to 30 mg/kg/day in divided doses.
- >=9 years to <12 years: 17 to 20 mg/kg/day in divided doses.
- >=12 to <16 years: 15 to 17 mg/kg in divided doses.
- >=16 years: 6.25 to 20 mg/kg orally divided every 6 hours.
| Children aged 6 months to 9 years: | 1 .2mg/kg/hour (reducing to lmg/kg/hour beyond 12 hours). |
| Children aged 9 years to 16 years and young adult smokers: | 1mg/kg/hour (reducing to 0.8mg/kg/hour beyond 12 hours). |
| Otherwise healthy non-smoking adults: | 0.7mg/kg/hour (reducing to 0.5mg/kg/hour beyond 12 hours). |
| Older patients and those with cor pulmonale: | 0.6mg/kg/hour (reducing to 0.3mg/kg/ hour beyond 12 hours). |
| Patients with congestive cardiac failure | 0.5mg/kg/hour (reducing to 0.1 – |
| or hepatic disease: | 0.2mg/kg/hour beyond 12 hours). |
Side Effects of Aminophylline
The most common
- a headache
- sore throat
- a cough
- stomach pain
- diarrhea
- a runny nose
- fluid retention
- a headache,
- dizziness, drowsiness
- feeling unusually weak or tired
- upper respiratory tract infection.
Common
- stomach pain
- nausea, vomiting
- diarrhoea.
- agitation, including aggressive behaviour and/or hostility
- irritability, restlessness, feeling anxious
- depression
- seeing, feeling or hearing things that are not there (also called hallucinations)
- dream abnormalities, difficulty sleeping
- sleep walking.
- muscle aches or cramps, joint pain
- stomach pain
- nausea, vomiting
- diarrhea.
Less common
- Abdominal or stomach pain
- the general feeling of discomfort or illness
- a headache
- joint pain
- pain or tenderness around the eyes and cheekbones
- shortness of breath or troubled breathing
- sweating
- the tightness of the chest
- trouble with swallowing
Drug Interactions of Aminophylline
Aminophylline may interact with following drugs, supplement & may change the efficacy of drugs
- antipsychotics (e.g., chlorpromazine, clozapine, haloperidol, olanzapine, quetiapine, risperidone)
- antiseizure medications (e.g., clobazam, phenobarbital, phenytoin, valproic acid, )
- aripiprazole
- “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- baclofen
- barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
- benzodiazepines (e.g., alprazolam, diazepam, lorazepam)
- Calcium channel blockers, diltiazem, verapamil
- domperidone
- famotidine
- gabapentin
- ipratropium
- ketotifen
- levodopa
- macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
- magnesium sulfate
- methylphenidate
- mirtazapine
- monoamine oxidase inhibitors (MAOIs; e.g., moclobemide, rasagiline, selegiline, tranylcypromine)
- quinolone antibiotics (e.g., levofloxacin, norfloxacin, moxifloxacin)
- selective serotonin reuptake inhibitors (SSRIs; e.g., paroxetine, fluoxetine, citalopram)
- serotonin antagonists (anti-emetic medications; e.g., granisetron, ondansetron)
- sotalol
- tapentadol
- thiazide diuretics (water pills; e.g., hydrochlorothiazide, indapamide, )
- thioridazine
- tolterodine
- tramadol
- trimethoprim
- tricyclic antidepressants (e.g., amitriptyline, clomipramine, desipramine, trimipramine)
- “triptan” migraine medications (e.g., eletriptan, sumatriptan)
- tryptophan
- tyrosine kinase inhibitors (e.g., dasatinib, imatinib, nilotinib, sunitinib)
- Zafirlukast
- Oral contraceptive
- Xanthines
Pregnancy & Lactation of Aminophylline
FDA Pregnancy Category C
Pregnancy
It is not known whether theophyllines can cause fetal harm when administered to pregnant women. Although the safe use of theophylline during pregnancy has not been established relative to the potential risk to the fetus, theophyllines have been used during pregnancy without teratogenicity or other adverse fetal effects. Because of the risk of uncontrolled asthma, their safety during pregnancy when clearly needed is generally not seriously questioned. As with other drugs, aminophylline should only be used during pregnancy if considered essential by the physician. Theophylline crosses the placenta.
Lactation
Theophylline is distributed into breast milk and may occasionally induce irritability or other signs of toxicity in nursing infants, and therefore should not be used if the mother is breastfeeding her infant.
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