Aminophylline

420.43

420.198212

206-264-5

27Y3KJK423

C47393

White or slightly yellowish granules or powder

R - Respiratory system

2933990090

191

-3.03

white to off-white powder

269-270 °C

869.7°C at 760 mmHg

H2O: 3.7 mg/mL solutions should be freshly prepared.

−20°C

LD50 orally in mice: 540 mg/kg (Thompson, Warren)

Slight ammoniacal

Bitter

Occurs as the dihydrate|Upon exposure to air, gradually loses ethylene diamine and absorbs carbon dioxide with liberation of theophylline

Ⅲ

6.1(b)

UN 2811 6.1/PG 3

3

22-42/43-34-36/37/38-20/21/22

45-36/37/39-26-23-36

XH5600000

Xn,C

Aminophylline injections reportedly are not stable in soln having a pH substantially less than 8; however, the drug appears to be relatively stable in large volume parenteral soln over a wide pH range (3.5-8.6) if aminophylline concn do not exceed 40 mg (31.6 mg of anhydrous theophylline) per mL.

P301 + P310

H301

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber; Contaminated packaging: Dispose of as unused product.

Incompatible materials: Strong oxidizing agents.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including aminophylline, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.|Drug products containing certain active ingredients offered over-the-counter (OTC) for certain uses. A number of active ingredients have been present in OTC drug products for various uses, as described below. However, based on evidence currently available, there are inadequate data to establish general recognition of the safety and effectiveness of these ingredients for the specified uses: aminophylline is included in bronchodilator drug products.

|Danger|H301: Toxic if swallowed [Danger Acute toxicity, oral]|P264, P270, P301+P310, P321, P330, P405, and P501|H317: May cause an allergic skin reaction [Warning Sensitization, Skin]|P201, P202, P260, P261, P263, P264, P270, P272, P280, P281, P302+P352, P307+P311, P308+P313, P314, P321, P333+P313, P363, P405, and P501

Eye/face protection: Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Skin protection: Handle with gloves.|Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N99 (US) or type P2 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical, or carbon dioxide.|Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.|Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.|Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

IDENTIFICATION AND USE: Aminophylline is white or slightly yellowish granules or powder. Aminophylline is prepared from theophylline and aqueous ethylenediamine. It is used as bronchodilator agent. HUMAN EXPOSURE AND TOXICITY: Aminophylline can trigger seizures in patients without known underlying epilepsy or added risk factor for seizure exacerbation in epilepsy. Most of these seizures are difficult to control and are underappreciated compared to other drug toxicities. Despite a long clinical history of aminophylline-induced seizures, relatively little is known about the underlying molecular mechanisms that contribute to methylxanthine-induced seizure generation. Fatalities in adults have generally occurred during or following IV administration of large doses of aminophylline in patients with renal, hepatic, or cardiovascular complications. In other patients, the rapidity of the injection, rather than the dose used, appears to be the more important factor precipitating acute hypotension, seizures, coma, cardiac standstill, ventricular fibrillation, and death. IV aminophylline or theophylline should therefore be given slowly. In children, fatalities usually are a result of overdosage and marked sensitivity to the CNS stimulation of theophylline. There are some reports of aminophylline hypersensitivity reaction and the most cases were delayed type reaction in English literatures. However, most of Japanese cases were immediate type. Acetylation is a main metabolic pathway of ethylenediamine. Most of Japanese have a rapid or intermediate acetylators on the other hand. Caucasian have a 50% likelihood of being slow acetylators. This difference suggest the different incidences of immediate and delayed reaction of aminophylline hypersensitivity reaction in Japanese and Caucasian respectively. Aminophylline treatment might be associated with elevated levels of myocardial enzymes. In vitro, aminophylline protected apoptosis of MRC-5 cells through the inactivation of caspases 3 and 8. ANIMAL STUDIES: Aminophylline (100-250 mg/kg) consistently induced seizures and post-ictal mortality in mice, and conventional anticonvulsants and adenosine agonists were ineffective in antagonizing them. Biochemical assay of brain homogenates showed that aminophylline seizures were associated with enhancements in brain malone dialdehyde and nitric oxide metabolites levels, whereas, superoxide dismutase activity was reduced, and these changes were attenuated after melatonin and L-NAME pretreatment. Aminophylline induced convulsions in rats in a dose-dependent manner, and both incidence of seizure and mortality were maximum at 300 mg/kg and there was significant increase of free radical generation. Pre-treatment with antioxidants showed differential attenuating effects on aminophylline induced free radical generation, but they were very much ineffective in antagonizing aminophylline induced seizures and post-seizure mortality by any appreciable extent. In pregnant rabbits, aminophylline treatment produced no acceleration in general anatomic lung development, as reflected in the ratio of lung air-space capacity to lung tissue weight. Under similar experimental conditions, maternal caffeine treatment had no effect on fetal rabbit lungs. In other experiment, pregnant rabbit does were treated intravenously with aminophylline (6 mg/kg/day) from the twenty-fifth day after the day of mating, and the fetuses were delivered by hysterotomy on the twenty-eighth day. One group of neonates was breathing air, and another group 100% oxygen. Lung mechanics were evaluated in the newborn animals during spontaneous or artificial ventilation, and the lungs were studied histologically with particular reference to the alveolar volume density. Aminophylline-treated litters had greater body weights, an improved survival rate, and an increased amount of phosphatidylglycerol in lung lavage fluid. Respiratory frequency was increased in aminophylline-treated animals breathing air, but data on lung compliance showed no significant difference between treated and control animals. It was concluded that the beneficial effect of aminophylline can be attributed largely to a combination of accelerated fetal growth and improved postnatal regulation of breathing and less to a specific influence on the biochemical and functional maturation of the lung. Aminophylline, exacerbated seizure-induced damage in the developing brain in rats.

This study aimed to characterize pharmacodynamic interaction between propofol and aminophylline. Nine beagle dogs were randomly allocated at the propofol rates of 0.75 (group A), 1.00 (group B), and 1.25 (group C) mg/kg/min. During period 1, propofol only was infused, while during period 2, aminophylline only, at the rate of 0.69 (group A), 1.37 (group B), and 2.62 (group C) mg/kg/hr. During periods 3-5, the two drugs were co-administered. The aminophylline infusion rate was 0.69 (period 3), 1.37 (period 4), and 2.62 (period 5) mg/kg/hr. The aminophylline was infused from 0 to 30 h, and the propofol was infused at 24 hr for 20 min. Blood samples and electroencephalograms were obtained at preset intervals. In the linear regression between log-transformed doses of aminophylline and AUC inf, the slope was 0.6976 (95% CI 0.5242-0.8710). Pharmacokinetics of aminophylline was best described by a one-compartment, with enzyme auto-induction, model. Pharmacokinetics and pharmacodynamics of propofol were best described by a three-compartment model and a sigmoid Emax model, respectively. Pharmacodynamic parameter estimates of propofol were: k(e0) = 0.805/min, E0 = 0.76, Emax = 0.398, Ce(50 na) = 2.38 ug/mL (without aminophylline-exposure), C(e50 wa) = 4.49 ug/mL (with aminophylline-exposure), and gamma = 2.21. Propofol becomes less potent when exposed to aminophylline. Pharmacodynamic antagonistic interaction of aminophylline with propofol sedation, may occur, not in a dose-dependent manner, but in an all-or-none response.|There is some evidence from animal studies that concomitant administration of a beta-adrenergic agonist (e.g., isoproterenol) and a theophylline derivative (e.g., aminophylline) may produce increased cardiotoxic effects. Although such an interaction has not been established in humans, a few reports have suggested that such a combination may have the potential for producing cardiac arrhythmias. Further accumulation of clinical data is needed to determine whether this potential interaction exists in humans.|Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to theophylline or another drug or occurrence of adverse effects without a change in serum theophylline concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of theophylline clearance is altered by another drug resulting in increased or decreased serum theophylline concentrations. Theophylline only rarely alters the pharmacokinetics of other drugs. The drugs listed in Table have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the "Effect" column of Table assumes that the interacting drug is being added to a steady-state theophylline regimen. If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller. Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger. Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially toxic levels, unless the theophylline dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased. /Theophylline/|Cimetidine, high-dose allopurinol (e.g., 600 mg daily), oral contraceptives, propranolol, ciprofloxacin, erythromycin, and troleandomycin may increase serum theophylline concentrations by decreasing theophylline's hepatic clearance. /Theophylline/|For more Interactions (Complete) data for AMINOPHYLLINE (12 total), please visit the HSDB record page.

LD50 Mouse iv 146 mg/kg|LD50 Mouse sc 186 mg/kg|LD50 Mouse ip 217 mg/kg|LD50 Mouse oral 150 mg/kg|For more Non-Human Toxicity Values (Complete) data for AMINOPHYLLINE (9 total), please visit the HSDB record page.

The drugs should be used with caution in patients with peptic ulcer, hyperthyroidism, glaucoma, diabetes mellitus, severe hypoxemia, hypertension, or in patients with compromised cardiac or circulatory function. Theophylline preparations should be used cautiously in patients with angina pectoris or acute myocardial injury when myocardial stimulation would be harmful. Since theophylline may cause dysrhythmia and/or worsen preexisting arrhythmias, any substantial change in rate and/or rhythm warrants electrocardiographic (ECG) monitoring and further investigation. /Theophyllines/|Theophyllines are contraindicated in patients who are allergic to any of the theophyllines, caffeine, or theobromine; aminophylline should not be used in patients hypersensitive to ethylenediamine. At least one manufacturer states that theophyllines also are contraindicated in patients with active peptic ulcer disease and in those with underlying seizure disorders, unless the latter patients are receiving adequate anticonvulsant therapy. /Theophyllines/|Elderly patients are at a significantly greater risk of experiencing serious toxicity from theophylline than younger patients due to pharmacokinetic and pharmacodynamic changes associated with aging. ... /Theophylline/|Tobacco and marijuana smoking appears to increase the clearance of theophylline by induction of metabolic pathways. Theophylline clearance has been shown to increase by approximately 50% in young adult tobacco smokers and by approximately 80% in elderly tobacco smokers compared to non-smoking subjects. Passive smoke exposure has also been shown to increase theophylline clearance by up to 50%. Abstinence from tobacco smoking for one week causes a reduction of approximately 40% in theophylline clearance. Careful attention to dose reduction and frequent monitoring of serum theophylline concentrations are required in patients who stop smoking. Use of nicotine gum has been shown to have no effect on theophylline clearance. /Theophylline/

60%

For the treatment of bronchospasm due to asthma, emphysema and chronic bronchitis.

Bronchodilator Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Aminophylline is included in the database.|IV theophylline (often as aminophylline) has been used to relieve the periodic apnea and increase arterial blood pH in patients with Cheyne-Stokes respiration. /NOT included in US product labeling/|MEDICATION (VET): Aminophylline is indicated for control of reversible airway constriction, to prevent bronchoconstriction, and as an adjunct with other respiratory disease treatment. The uses are are similar to the indications for theophylline because it is a salt form of theophylline. It is used for inflammatory airway disease in cats (feline asthma), dogs, and horses. In dogs, the uses include collapsing trachea, bronchitis, and other airway disease. It has not been effective for respiratory diseases in cattle.|For more Therapeutic Uses (Complete) data for AMINOPHYLLINE (10 total), please visit the HSDB record page.

Fatalities in adults have generally occurred during or following IV administration of large doses of aminophylline in patients with renal, hepatic, or cardiovascular complications. In other patients, the rapidity of the injection, rather than the dose used, appears to be the more important factor precipitating acute hypotension, seizures, coma, cardiac standstill, ventricular fibrillation, and death. IV aminophylline or theophylline should therefore be given slowly. In children, fatalities usually are a result of overdosage and marked sensitivity to the CNS stimulation of theophylline.|When administered rectally as suppositories (dosage form no longer commercially available in the US), theophyllines have caused rectal irritation and inflammation. /Theophyllines/|Rapid IV injection of aminophylline may produce dizziness, faintness, lightheadedness, palpitation, syncope, precordial pain, flushing, profound bradycardia, ventricular premature complexes (VPCs, PVCs), severe hypotension, or cardiac arrest. IM injection of aminophylline produces intense local pain and sloughing of tissue ... .|Theophyllines may also produce transiently increased urinary frequency, dehydration, twitching of fingers and hands, tachypnea, and elevated serum AST (SGOT) concentrations. Hypersensitivity reactions characterized by urticaria, generalized pruritus, and angioedema have been reported with aminophylline administration. A contact-type dermatitis, caused by hypersensitivity to the ethylenediamine component of aminophylline, has also been reported. Bone marrow suppression, leukopenia, thrombocytopenia, and hemorrhagic diathesis have also been reported, but their association with theophylline therapy is questionable. Other adverse effects of theophyllines include albuminuria, increased urinary excretion of renal tubular cells and erythrocytes, hyperglycemia, and syndrome of inappropriate secretion of antidiuretic hormone (SIADH). /Theophyllines/|For more Drug Warnings (Complete) data for AMINOPHYLLINE (22 total), please visit the HSDB record page.

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.

Agents that cause an increase in the expansion of a bronchus or bronchial tubes. (See all compounds classified as Bronchodilator Agents.)|Compounds which inhibit or antagonize the biosynthesis or actions of phosphodiesterases. (See all compounds classified as Phosphodiesterase Inhibitors.)|Compounds that bind to and block the stimulation of PURINERGIC P1 RECEPTORS. (See all compounds classified as Purinergic P1 Receptor Antagonists.)|Agents that have a strengthening effect on the heart or that can increase cardiac output. They may be CARDIAC GLYCOSIDES; SYMPATHOMIMETICS; or other drugs. They are used after MYOCARDIAL INFARCT; CARDIAC SURGICAL PROCEDURES; in SHOCK; or in congestive heart failure (HEART FAILURE). (See all compounds classified as Cardiotonic Agents.)

0.3 to 0.7 L/kg|0.29 mL/kg/min [postnatal age 3-15 days]|IV theophylline produces the highest and most rapid serum theophylline concentration. Following a single IV dose of theophylline (as aminophylline) of about 5 mg/kg over 30 minutes to healthy adults, mean peak serum theophylline concentrations of about 10 ug/mL are reached.|In neonates, approximately 50% of the theophylline dose is excreted unchanged in the urine. Beyond the first three months of life, approximately 10% of the theophylline dose is excreted unchanged in the urine. /Theophylline/|When administered IM, theophylline is usually absorbed slowly and incompletely. Rectal suppositories (no longer commercially available in the US) are slowly and erratically absorbed, regardless of whether the suppository base is hydrophilic or lipophilic. /Theophylline/|Dissolution appears to be the rate-limiting step in the absorption of oral theophylline. Under the acidic conditions of the stomach, the theophylline salts and compounds release free theophylline. ... Microcrystalline dosage forms and oral solutions of theophyllines are absorbed more rapidly, but not to a greater extent, than are uncoated tablets. Although the rate of absorption is slower, extended-release preparations (capsules and tablets) of theophylline are generally absorbed to the same extent as uncoated tablets; however, the actual rate of absorption of extended-release preparations may differ. Extended-release preparations of theophyllines have been formulated to release the drug at various rates suitable for dosing every 8-12, 12, or 24 hours; however, the actual dosing frequency for a given patient depends on their individual pharmacokinetic parameters. Since the rate and extent of absorption may differ between various extended-release preparations and sometimes between different dosage sizes of the same preparation, patients should generally be stabilized on a given preparation; substitution of one extended-release preparation for another should generally only be made when the preparations have been shown to be equivalent and/or the patient is evaluated pharmacokinetically during the transition period. Absorption of theophyllines may also be delayed, but is generally not reduced, by the presence of food in the GI tract; however, the effect of food on the absorption of extended-release preparations appears to be variable, and the manufacturer's recommendations for administration of specific preparations should be followed. /Theophyllines/|For more Absorption, Distribution and Excretion (Complete) data for AMINOPHYLLINE (12 total), please visit the HSDB record page.

Both the N-demethylation and hydroxylation pathways of theophylline biotransformation are capacity-limited. Due to the wide intersubject variability of the rate of theophylline metabolism, non-linearity of elimination may begin in some patients at serum theophylline concentrations <10 mcg/mL. Since this non-linearity results in more than proportional changes in serum theophylline concentrations with changes in dose, it is advisable to make increases or decreases in dose in small increments in order to achieve desired changes in serum theophylline concentrations. Accurate prediction of dose-dependency of theophylline metabolism in patients a priori is not possible, but patients with very high initial clearance rates (i.e., low steady-state serum theophylline concentrations at above average doses) have the greatest likelihood of experiencing large changes in serum theophylline concentration in response to dosage changes. /Theophylline/|Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. 3-methylxanthine has approximately one tenth the pharmacologic activity of theophylline and serum concentrations in adults with normal renal function are <1 ug/mL. In patients with end-stage renal disease, 3-methylxanthine may accumulate to concentrations that approximate the unmetabolized theophylline concentration. Caffeine concentrations are usually undetectable in adults regardless of renal function. In neonates, caffeine may accumulate to concentrations that approximate the unmetabolized theophylline concentration and thus, exert a pharmacologic effect. /Theophylline/|Theophylline is metabolized by the liver to 1,3-dimethyluric acid, 1-methyluric acid, and 3-methylxanthine. ... Individuals metabolize theophylline at different rates; however, individual metabolism of the drug is generally reproducible. Theophylline and its metabolites are excreted mainly by the kidneys. Renal clearance of the drug, however, contributes only 8-12% of the overall plasma clearance of theophylline. Small amounts of theophylline are excreted in feces unchanged. /Theophylline/|Theophylline is metabolized via the microsomal cytochrome p450 system, primarily by the isozyme CYP1A2. The major pathway is demethylation to 3-methylxanthine in addition to being demethylated or oxidized to other metabolites. Less than 10% of theophylline is excreted in the urine unchanged. /Theophylline/|Following oral dosing, theophylline does not undergo any measurable first-pass elimination. In adults and children beyond one year of age, approximately 90% of the dose is metabolized in the liver. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine. Theophylline demethylation to 3-methylxanthine is catalyzed by cytochrome P-450 1A2, while cytochromes P-450 2E1 and P-450 3A3 catalyze the hydroxylation to 1,3-dimethyluric acid. Demethylation to 1-methylxanthine appears to be catalyzed either by cytochrome P-450 1A2 or a closely related cytochrome. In neonates, the N-demethylation pathway is absent while the function of the hydroxylation pathway is markedly deficient. The activity of these pathways slowly increases to maximal levels by one year of age. /Theophylline/

7-9 hours|Theophylline clearance rates and half-life values were measured in 15 infants aged three to 23 months, after infusion of aminophylline by the intravenous route for at least 24 hours. ... The mean half-life was 4.4 +/- 2.2 hours. There was a tenfold variability in half-life, suggesting that individualization of theophylline dose is especially important in infants if undertreatment and toxicity are to be avoided.

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/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Anticipate Need for Anticonvulsants. In patients with theophylline overdose who are at high risk for theophylline-induced seizures, e.g., patients with acute overdoses and serum theophylline concentrations >100 ug/mL or chronic overdosage in patients >60 years of age with serum theophylline concentrations >30 ug/mL, the need for anticonvulsant therapy should be anticipated. A benzodiazepine such as diazepam should be drawn into a syringe and kept at the patient's bedside and medical personnel qualified to treat seizures should be immediately available. In selected patients at high risk for theophylline-induced seizures, consideration should be given to the administration of prophylactic anticonvulsant therapy. Situations where prophylactic anticonvulsant therapy should be considered in high risk patients include anticipated delays in instituting methods for extracorporeal removal of theophylline (e.g., transfer of a high risk patient from one healthcare facility to another for extracorporeal removal) and clinical circumstances that significantly interfere with efforts to enhance theophylline clearance (e.g., a neonate where dialysis may not be technically feasible or a patient with vomiting unresponsive to antiemetics who is unable to tolerate multiple-dose oral activated charcoal). In animal studies, prophylactic administration of phenobarbital, but not phenytoin , has been shown to delay the onset of theophylline-induced generalized seizures and to increase the dose of theophylline required to induce seizures (i.e., markedly increases the LD 50 ). Although there are no controlled studies in humans, a loading dose of intravenous phenobarbital (20 mg/kg infused over 60 minutes) may delay or prevent life-threatening seizures in high risk patients while efforts to enhance theophylline clearance are continued. Phenobarbital may cause respiratory depression, particularly in elderly patients and patients with COPD. /Theophylline/|For more Antidote and Emergency Treatment (Complete) data for AMINOPHYLLINE (12 total), please visit the HSDB record page.

/HUMAN EXPOSURE STUDIES/ ... Theophylline has been recognized as an important drug for not only asthma but also corticosteroid-insensitive chronic obstructive pulmonary disease (COPD). To clarify the role of theophylline in hypercapnic ventilatory responses in humans, we analyzed the effects of aminophylline administered at the usual clinical therapeutic doses on ventilation and augmentation of respiratory muscle contractility in room air and under 3 conditions of hypercapnia. We performed electromyography (EMG) of the parasternal intercostal muscle (PARA) and transversus abdominis muscle (TA) in 7 healthy subjects and recorded both ventilatory parameters and EMG data in room air and under 3 conditions of hypercapnia before (control) and during aminophylline administration. Before aminophylline administration (control), hypercapnic stimulation elicited ventilatory augmentation in a hypercapnia intensity-dependent manner. Ventilatory parameters (tidal volume, frequency of respiration, and minute ventilation) showed significant increases from lower PaCO2 levels during aminophylline administration when compared with the corresponding values before aminophylline administration. EMG activity of both PARA and TA increased significantly at each level of hypercapnia, and those augmentations were shown from lower PaCO2 levels during aminophylline administration. Aminophylline administered at the usual clinical therapeutic dose increases ventilation and EMG activity of both inspiratory and expiratory muscles during hypercapnia in healthy humans.|/HUMAN EXPOSURE STUDIES/ We investigated the effect of intravenous infusions of aminophylline on plasma glucose, insulin (IRI), glucagon (IRG), growth hormone (HGH), cortisol, and free fatty acid (FFA) levels in healthy young subjects. Six received an intravenous loading dose of aminophylline (6.0 mg/kg over 20 min) followed by a maintenance dose (0.9 mg/kg/hr) for 100 min. Another 7 subjects initially received smaller loading (3.0 mg/kg) and maintenance (0.45 mg/kg/hr) doses, and after 60 min they received a second loading dose (3.0 mg/kg) followed by a larger maintenance dose (0.9 mg/kg/hr) over 120 min. In these fasting volunteers, infusion of aminophylline, which produced theophylline levels in the usual therapeutic range (10 to 20 microgram/ml) caused small increases in plasma glucose levels without changing IRI, IRG, HGH, or cortisol. There were rapid, pronounced, and prolonged rises in FFA associated with the aminophylline infusion. Increases in FFA paralleled the rise in theophylline levels. It is concluded that routine therapeutic doses of theophylline, i.e., doses that achieve serum levels normally encountered in treatment for bronchial asthma, cause a marked rise in FFA and a slight rise in glucose (8 +/- 3 mg/dL) without changing levels of IRI, IRG, HGH, or cortisol.|/SIGNS AND SYMPTOMS/ Several studies have described the clinical manifestations of theophylline overdose and attempted to determine the factors that predict life-threatening toxicity. In general, patients who experience an acute overdose are less likely to experience seizures than patients who have experienced a chronic overdosage, unless the peak serum theophylline concentration is >100 ug/mL. After a chronic overdosage, generalized seizures, life-threatening cardiac arrhythmias, and death may occur at serum theophylline concentrations >30 ug/mL. The severity of toxicity after chronic overdosage is more strongly correlated with the patient's age than the peak serum theophylline concentration; patients >60 years are at the greatest risk for severe toxicity and mortality after a chronic overdosage. Pre-existing or concurrent disease may also significantly increase the susceptibility of a patient to a particular toxic manifestation, e.g., patients with neurologic disorders have an increased risk of seizures and patients with cardiac disease have an increased risk of cardiac arrhythmias for a given serum theophylline concentration compared to patients without the underlying disease. /Theophylline/|/SIGNS AND SYMPTOMS/ The chronicity and pattern of theophylline overdosage significantly influences clinical manifestations of toxicity, management and outcome. There are two common presentations: (1) acute overdose, i.e., ingestion of a single large excessive dose (>10 mg/kg) as occurs in the context of an attempted suicide or isolated medication error, and (2) chronic overdosage, i.e., ingestion of repeated doses that are excessive for the patient's rate of theophylline clearance. The most common causes of chronic theophylline overdosage include patient or care giver error in dosing, clinician prescribing of an excessive dose or a normal dose in the presence of factors known to decrease the rate of theophylline clearance, and increasing the dose in response to an exacerbation of symptoms without first measuring the serum theophylline concentration to determine whether a dose increase is safe. /Theophylline/|For more Human Toxicity Excerpts (Complete) data for AMINOPHYLLINE (13 total), please visit the HSDB record page.

Afonilum

Table: Aminophylline (Hydrous) Preparations [Table#843]|Table: Aminophylline (Anhydrous) Preparations [Table#844]

1H-Purine-2,6-dione, 3,9-dihydro-1,3-dimethyl-, compd. with 1,2-ethanediamine (2:1): ACTIVE|The solubility of the methylxanthines is low and is much enhanced by the formation of complexes (usually 1:1) with a wide variety of compounds. The most notable of such complexes is that between theophylline and ethylenediamine (to form aminophylline).|Aminophylline is a 2:1 complex of theophylline and ethylenediamine.

THEOPHYLLINE CONTENT OF AMINOPHYLLINE INJECTION BP & AMINOPHYLLINE TABLETS BP WERE DETERMINED BY HIGH-PRESSURE LIQUID CHROMATOGRAPHY USING CAFFEINE (500 MUG/ML AS INTERNAL STD.|AOAC Method 955.54, Phenobarbital and Aminophylline in drugs, spectrophotometric method, detection limit not reported.

THEOPHYLLINE...EXTRACTED FROM SERUM OR SALIVA. IDENTIFIED BY UV SPECTROPHOTOMETRY OR GAS CHROMATOGRAPHY.|MEASUREMENT USING HIGH-PRESSURE LIQUID CHROMATOGRAPHY IS SIMPLE & REQUIRES ONLY SMALL VOLUME OF BLOOD.

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients