Aminophylline

AMINOPHYLLINE- aminophylline dihydrate tablet
West-ward Pharmaceutical Corp

DESCRIPTION

Aminophylline is a 2:1 complex of theophylline and ethylenediamine. Theophylline is structurally classified as a methyxanthine. Aminophylline occurs as a white or slightly yellowish granule or powder, with a slight ammoniacal odor. Aminophylline has the chemical name 1H -Purine-2,6-dione,3,7- dihydro-1,3-dimethyl-,compound with 1,2 ethanedamine (2:1) and is represented by the following structural formula:

Chemical Structure

The molecular formula of aminophylline dihydrate is C16 H24 N10 O4 •(H2 O)2 with a molecular weight of 456.46.

Aminophylline is available as tablets intended for oral administration, containing 100 mg or 200 mg of Aminophylline, USP (calculated as the dihydrate) per tablet (equivalent to 79 mg or 158 mg of theophylline anhydrous).

Inactive ingredients: Magnesium Stearate and Microcrystalline Cellulose.

CLINICAL PHARMACOLOGY

Mechanism of Action:

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.

Serum Concentration-Effect Relationship:

Bronchodilation occurs over the serum theophylline concentration range of 5-20 mcg/mL. Clinically important improvement in symptom control has been found in most studies to require peak serum theophylline concentrations > 10 mcg/mL, but patients with mild disease may benefit from lower concentrations. At serum theophylline concentrations > 20 mcg/mL, both the frequency and severity of adverse reactions increase. In general, maintaining peak serum theophylline concentrations between 10 and 15 mcg/mL will achieve most of the drug’s potential therapeutic benefit while minimizing the risk of serious adverse events.

Pharmacokinetics:

Overview

Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver.

The pharmacokinetics of theophylline vary widely among similar patients and cannot be predicted by age, sex, body weight or other demographic characteristics. In addition, certain concurrent illnesses and alterations in normal physiology (see Table I) and co-administration of other drugs (see Table II) can significantly alter the pharmacokinetic characteristics of theophylline. Within-subject variability in metabolism has also been reported in some studies, especially in acutely ill patients. It is, therefore, recommended that serum theophylline concentrations be measured frequently in acutely ill patients (e.g., at 24-hr intervals) and periodically in patients receiving long-term therapy, e.g., at 6-12 month intervals. More frequent measurements should be made in the presence of any condition that may significantly alter theophylline clearance (see PRECAUTIONS, Laboratory tests).

Table I. Mean and range of total body clearance and half-life of theophylline related to age and altered physiological states.¶

¶ For various North American patient populations from literature reports. Different rates of elimination and consequent dosage requirements have been observed among other peoples.

* Clearance represents the volume of blood completely cleared of theophylline by the liver in one minute. Values listed were generally determined at serum theophylline concentrations <20 mcg/mL; clearance may decrease and half-life may increase at higher serum concentrations due to non-linear pharmacokinetics.

++ Reported range or estimated range (mean ± 2 SD) where actual range not reported.

+ NR = not reported or not reported in a comparable format.

** Median

Population Characteristics Total body clearance* mean (range)++ (mL/kg/min) Half-life mean (range)++ (hr)
Age
Premature neonates
postnatal age 3-15 days 0.29 (0.09-0.49) 30(17-43)
postnatal age 25-57 days 0.64(0.04-1.2) 20 (9.4-30.6)
Term infants
postnatal age 1-2 days NR+ 25.7 (25-26.5)
postnatal age 3-30 weeks NR+ 11 (6-29)
Children
1-4 years 1.7(0.5-2.9) 3.4(1.2-5.6)
4-12 years 1.6 (0.8-2.4) NR+
13-15 years 0.9 (0.48-1.3) NR+
6-17 years 1.4(0.2-2.6) 3.7(1.5-5.9)
Adults (16-60 years)
otherwise healthy non-smoking asthmatics 0.65(0.27-1.03) 8.7(6.1-12.8)
Elderly (>60 years)
non-smokers with normal cardiac, liver, 0.41 (0.21-0.61) 9.8(1.6-18)
and renal function
Concurrent illness or altered physiological state
Acute pulmonary edema 0.33** (0.07-2.45) 19** (3.1-82)
COPD->60 years, stable non-smoker >1 year 0.54 (0.44-0.64) 11 (9.4-12.6)
COPD with cor pulmonale 0.48 (0.08-0.88) NR+
Cystic fibrosis
(14-28 years) 1.25(0.31-2.2) 6.0(1.8-10.2)
Fever associated with acute viral respiratory illness(children 9-15 years) NR+ 7.0(1.0-13)
Liver disease -
cirrhosis 0.31** (0.1-0.7) 32** (10-56)
acute hepatitis 0.35 (0.25-0.45) 19.2(16.6-21.8)
cholestasis 0.65 (0.25-1.45) 14.4(5.7-31.8)
Pregnancy – 1st trimester NR+ 8.5 (3.1-13.9)
2nd trimester NR+ 8.8 (3.8-13.8)
3rd trimester NR+ 13.0 (8.4-17.6)
Sepsis with multi-organ failure 0.47(0.19-1.9) 18.8(6.3-24.1)
Thyroid disease -
hypothyroid 0.38(0.13-0.57) 11.6(8.2-25)
hyperthyroid 0.8 (0.68-0.97) 4.5 (3.7-5.6)

Note: In addition to the factors listed above, theophylline clearance is increased and half-life decreased by low carbohydrate/high protein diets, parenteral nutrition, and daily consumption of charcoal-broiled beef. A high carbohydrate/low protein diet can decrease the clearance and prolong the half-life of theophylline.

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