AMINOPHYLLINE, THEOPHYLLINE
Chemistry - Xanthine derivatives, aminophylline and theophylline are considered to be respiratorysmooth muscle relaxants, but also have other pharmacologic actions. Aminophylline differs fromtheophylline only by the addition of ethylenediamine to its structure and may have differentamounts of molecules of water of hydration. 100 mg of aminophylline (hydrous) contains approximately 79 mg of theophylline (anhydrous) and 100 mg of aminophylline (anhydrous) contains approximately 86 mg theophylline (anhydrous). Conversely, 100 mg of theophylline(anhydrous) is equivalent to 116 mg of aminophylline (anhydrous) and 127 mg aminophylline(hydrous).
Aminophylline occurs as bitter-tasting, white or slightly yellow granules or powder with a slightammoniacal odor and a pKa of 5. Aminophylline is soluble in water and insoluble in alcohol.
Theophylline occurs as bitter-tasting, odorless, white, crystalline powder with a melting pointbetween 270-274°C. It is sparingly soluble in alcohol and only slightly soluble in water at a pH of7, but solubility increases with increasing pH.
Aminophylline for injection is reportedly compatible when mixed with all commonly used IVsolutions, but may be incompatible with 10% fructose or invert sugar solutions.
Aminophylline is reportedly compatible when mixed with the following drugs: amobarbitalsodium, bretylium tosylate, calcium gluconate, chloramphenicol sodium succinate, dexamethasonesodium phosphate, dopamine HCl, erythromycin lactobionate, heparin sodium, hydrocortisonesodium succinate, lidocaine HCl, mephentermine sulfate, methicillin sodium, methyldopate HCl, metronidazole with sodium bicarbonate, pentobarbital sodium, phenobarbital sodium, potassiumchloride, secobarbital sodium, sodium bicarbonate, sodium iodide, terbutaline sulfate, thiopentalsodium, and verapamil HCl.
Aminophylline is reportedly incompatible (or data conflicts) with the following drugs: amikacinsulfate, ascorbic acid injection, bleomycin sulfate, cephalothin sodium, cephapirin sodium, clindamycin phosphate, codeine phosphate, corticotropin, dimenhydrinate, dobutamine HCl, doxorubicin HCl, epinephrine HCl, erythromycin gluceptate, hydralazine HCl, hydroxyzine HCl, insulin (regular), isoproterenol HCl, levorphanol bitartrate, meperidine HCl, methadone HCl, methylprednisolone sodium succinate, morphine sulfate, nafcillin sodium, norepinephrine bitartrate, oxytetracycline, penicillin G potassium, pentazocine lactate, procaine HCl, prochlorperazineedisylate or mesylate, promazine HCl, promethazine HCl, sulfisoxasole diolamine, tetracycline HCl, vancomycin HCl, and vitamin B complex w/C. Compatibility is dependent upon factors such as pH, concentration, temperature, and diluents used and it is suggested to consult specialized referencesfor more specific information.
The theophyllines directly relax smooth muscles in the bronchi and pulmonary vasculature, inducediuresis, increase gastric acid secretion and inhibit uterine contractions. They also have weakchronotropic and inotropic action, stimulate the CNS and can cause respiratory stimulation(centrally-mediated).
Uses, Indications - The theophyllines are used primarily for their bronchodilitory effects, often inpatients with myocardial failure and/or pulmonary edema.
Theophylline is distributed throughout the extracellular fluids and body tissues. It crosses theplacenta and is distributed into milk (70% of serum levels). In dogs, at therapeutic serum levels, only about 7-14% is bound to plasma proteins. The volume of distribution of theophylline for dogshas been reported to be 0.82 L/kg. The volume of distribution in cats is reported to be 0.46 L/kg, and in horses, 0.85 - 1.02 L/kg. Because of the low volumes of distribution and theophylline's lowlipid solubility, obese patients should be dosed on a lean body weight basis.
Theophylline is metabolized primarily in the liver (in humans) to 3-methylxanthine, which hasweak bronchodilitory activity. Renal clearance contributes only about 10% to the overall plasmaclearance of theophylline. The reported elimination half-lives (mean values) in various species are:dogs » 5.7 hours; cats » 7.8 hours, pigs » 11 hours; and horses » 11.9 to 17 hours. In humans, there are very wide interpatient variations in serum half lives and resultant serum levels. It could beexpected that similar variability exists in veterinary patients, particularly those with concurrentillnesses.
Contraindications/Precautions - The theophyllines are contraindicated in patients who are hypersensitive to any of the xanthines, including theobromine or caffeine. Patients who are hypersensitive to ethylenediamine should not take aminophylline.
The theophyllines should be administered with caution in patients with severe cardiac disease, gastric ulcers, hyperthyroidism, renal or hepatic disease, severe hypoxia, or severe hypertension.
Becuase it may cause or worsen preexisting arrhythmias, patients with cardiac arrhythmias shouldreceive theophylline only with caution and enhanced monitoring. Neonatal and geriatric patientsmay have decreased clearances of theophylline and be more sensitive to its toxic effects. Patientswith CHF may have prolonged serum half-lifes of theophylline.
Dogs and cats can exhibit symptoms of nausea and vomiting, insomnia, increased gastric acidsecretion, diarrhea, polyphagia, polydipsia, and polyuria. Side effects in horses are generally doserelated and may include: nervousness, excitability (auditory, tactile, and visual), tremors, diaphoresis, tachycardia, and ataxia. Seizures or cardiac dysrhythmias may occur in severe intoxications.
Overdosage - Symptoms of toxicity (see above) are usually associated with levels greater than 20micrograms/ml in humans and become more severe as the serum level exceeds that value.
Tachycardias, arrhythmias, and CNS effects (seizures, hyperthermia) are considered to be the mostlife-threatening aspects of toxicity.
Treatment of theophylline toxicity is basically supportive. The gut should be emptied, charcoal anda cathartic administered after an oral ingestion, using the standardized methods and cautionsassociated with these practices. Patients suffering from seizures should have an adequate airwaymaintained and treated with IV diazepam. The patient should be constantly monitored for cardiacarrhythmias and tachycardia. Fluid and electrolytes should be monitored and corrected as necessary. Hyperthermia may be treated with phenothiazines and tachycardia treated with propranolol ifeither condition is considered life-threatening.
Agents which may increase theophylline effects, include cimetidine, erythromycin, allopurinol, thiabendazole, clindamycin, lincomycin.
Theophylline may decrease the effects of phenytoin, lithium carbonate, or pancuronium.
Theophylline and beta-adrenergic blockers (propranolol, etc.) may antagonize each other'seffect.
Toxic synergism (arrhythmias) can occur if theophylline is used concurrently with sympathomimetics (especially ephedrine) or possibly isoproterenol. Theophylline with halothane maycause increased incidence of cardiac dysrhythmias.
Theophylline with ketamine can cause an increased incidence of seizures.
Laboratory Interactions - Theophylline can cause falsely elevated values of serum uric acid ifmeasured by the Bittner or colorimetric methods. Values are not affected if using the uricasemethod.
Theophylline serum levels can be falsely elevated by furosemide, phenylbutazone, probenecid, theobromine, caffeine, sulfathiazole, chocolate, or acetominophen if using aspectrophotometric method of assay.
Aminophylline occurs as bitter-tasting, white or slightly yellow granules or powder with a slightammoniacal odor and a pKa of 5. Aminophylline is soluble in water and insoluble in alcohol.
Theophylline occurs as bitter-tasting, odorless, white, crystalline powder with a melting pointbetween 270-274°C. It is sparingly soluble in alcohol and only slightly soluble in water at a pH of7, but solubility increases with increasing pH.
Storage, Stability, Compatibility
Aminophylline for injection should be stored in single-usecontainers in which carbon dioxide has been removed. It should also be stored at temperaturesbelow 30°C and protected from freezing and light. Upon exposure to air (carbon dioxide), aminophylline will absorb carbon dioxide, lose ethylenediamine and liberate free theophylline whichcan precipitate out of solution. Do not inject aminophylline solutions that contain a precipitate orvisible crystals.Aminophylline for injection is reportedly compatible when mixed with all commonly used IVsolutions, but may be incompatible with 10% fructose or invert sugar solutions.
Aminophylline is reportedly compatible when mixed with the following drugs: amobarbitalsodium, bretylium tosylate, calcium gluconate, chloramphenicol sodium succinate, dexamethasonesodium phosphate, dopamine HCl, erythromycin lactobionate, heparin sodium, hydrocortisonesodium succinate, lidocaine HCl, mephentermine sulfate, methicillin sodium, methyldopate HCl, metronidazole with sodium bicarbonate, pentobarbital sodium, phenobarbital sodium, potassiumchloride, secobarbital sodium, sodium bicarbonate, sodium iodide, terbutaline sulfate, thiopentalsodium, and verapamil HCl.
Aminophylline is reportedly incompatible (or data conflicts) with the following drugs: amikacinsulfate, ascorbic acid injection, bleomycin sulfate, cephalothin sodium, cephapirin sodium, clindamycin phosphate, codeine phosphate, corticotropin, dimenhydrinate, dobutamine HCl, doxorubicin HCl, epinephrine HCl, erythromycin gluceptate, hydralazine HCl, hydroxyzine HCl, insulin (regular), isoproterenol HCl, levorphanol bitartrate, meperidine HCl, methadone HCl, methylprednisolone sodium succinate, morphine sulfate, nafcillin sodium, norepinephrine bitartrate, oxytetracycline, penicillin G potassium, pentazocine lactate, procaine HCl, prochlorperazineedisylate or mesylate, promazine HCl, promethazine HCl, sulfisoxasole diolamine, tetracycline HCl, vancomycin HCl, and vitamin B complex w/C. Compatibility is dependent upon factors such as pH, concentration, temperature, and diluents used and it is suggested to consult specialized referencesfor more specific information.
Pharmacology - AMINOPHYLLINE, THEOPHYLLINE
The theophyllines competitively inhibit phosphodiesterase, thereby increasingamounts of cyclic AMP which increases the release of endogenous epinephrine. The increasedlevels of cAMP may also inhibit the release of histamine and slow reacting substance of anaphylaxis (SRS-A). The myocardial and neuromuscular transmission effects that the theophyllinesposses may be a result of translocating intracellular ionized calcium.The theophyllines directly relax smooth muscles in the bronchi and pulmonary vasculature, inducediuresis, increase gastric acid secretion and inhibit uterine contractions. They also have weakchronotropic and inotropic action, stimulate the CNS and can cause respiratory stimulation(centrally-mediated).
Uses, Indications - The theophyllines are used primarily for their bronchodilitory effects, often inpatients with myocardial failure and/or pulmonary edema.
Pharmacokinetics - AMINOPHYLLINE, THEOPHYLLINE
The pharmacokinetics of theophylline have been studied in several domesticspecies. After oral administration, the rate of absorption of the theophyllines is limited primarily bythe dissolution of the dosage form in the gut. In studies in cats, dogs, and horses, bioavailabilitiesafter oral administration are nearly 100% when non-sustained release products are used. One studyin dogs that compared various sustained-release products (Koritz, Neff-Davis, and Munsiff 1986), found bioavailabilities to range from approximately 30 - 76%, depending on the product used.Theophylline is distributed throughout the extracellular fluids and body tissues. It crosses theplacenta and is distributed into milk (70% of serum levels). In dogs, at therapeutic serum levels, only about 7-14% is bound to plasma proteins. The volume of distribution of theophylline for dogshas been reported to be 0.82 L/kg. The volume of distribution in cats is reported to be 0.46 L/kg, and in horses, 0.85 - 1.02 L/kg. Because of the low volumes of distribution and theophylline's lowlipid solubility, obese patients should be dosed on a lean body weight basis.
Theophylline is metabolized primarily in the liver (in humans) to 3-methylxanthine, which hasweak bronchodilitory activity. Renal clearance contributes only about 10% to the overall plasmaclearance of theophylline. The reported elimination half-lives (mean values) in various species are:dogs » 5.7 hours; cats » 7.8 hours, pigs » 11 hours; and horses » 11.9 to 17 hours. In humans, there are very wide interpatient variations in serum half lives and resultant serum levels. It could beexpected that similar variability exists in veterinary patients, particularly those with concurrentillnesses.
Contraindications/Precautions - The theophyllines are contraindicated in patients who are hypersensitive to any of the xanthines, including theobromine or caffeine. Patients who are hypersensitive to ethylenediamine should not take aminophylline.
The theophyllines should be administered with caution in patients with severe cardiac disease, gastric ulcers, hyperthyroidism, renal or hepatic disease, severe hypoxia, or severe hypertension.
Becuase it may cause or worsen preexisting arrhythmias, patients with cardiac arrhythmias shouldreceive theophylline only with caution and enhanced monitoring. Neonatal and geriatric patientsmay have decreased clearances of theophylline and be more sensitive to its toxic effects. Patientswith CHF may have prolonged serum half-lifes of theophylline.
Adverse Effects, Warnings
The theophyllines can produce CNS stimulation and gastrointestinalirritation after administration by any route. Most adverse effects are related to the serum level of thedrug and may be symptomatic of toxic blood levels. Some mild CNS excitement and GIdisturbances are not uncommon when starting therapy and generally resolve with chronic administration in conjunction with monitoring and dosage adjustments.Dogs and cats can exhibit symptoms of nausea and vomiting, insomnia, increased gastric acidsecretion, diarrhea, polyphagia, polydipsia, and polyuria. Side effects in horses are generally doserelated and may include: nervousness, excitability (auditory, tactile, and visual), tremors, diaphoresis, tachycardia, and ataxia. Seizures or cardiac dysrhythmias may occur in severe intoxications.
Overdosage - Symptoms of toxicity (see above) are usually associated with levels greater than 20micrograms/ml in humans and become more severe as the serum level exceeds that value.
Tachycardias, arrhythmias, and CNS effects (seizures, hyperthermia) are considered to be the mostlife-threatening aspects of toxicity.
Treatment of theophylline toxicity is basically supportive. The gut should be emptied, charcoal anda cathartic administered after an oral ingestion, using the standardized methods and cautionsassociated with these practices. Patients suffering from seizures should have an adequate airwaymaintained and treated with IV diazepam. The patient should be constantly monitored for cardiacarrhythmias and tachycardia. Fluid and electrolytes should be monitored and corrected as necessary. Hyperthermia may be treated with phenothiazines and tachycardia treated with propranolol ifeither condition is considered life-threatening.
Drug Interactions
Phenobarbital or Phenytoin may decrease the effect of theophylline byincreasing its clearance.Agents which may increase theophylline effects, include cimetidine, erythromycin, allopurinol, thiabendazole, clindamycin, lincomycin.
Theophylline may decrease the effects of phenytoin, lithium carbonate, or pancuronium.
Theophylline and beta-adrenergic blockers (propranolol, etc.) may antagonize each other'seffect.
Toxic synergism (arrhythmias) can occur if theophylline is used concurrently with sympathomimetics (especially ephedrine) or possibly isoproterenol. Theophylline with halothane maycause increased incidence of cardiac dysrhythmias.
Theophylline with ketamine can cause an increased incidence of seizures.
Laboratory Interactions - Theophylline can cause falsely elevated values of serum uric acid ifmeasured by the Bittner or colorimetric methods. Values are not affected if using the uricasemethod.
Theophylline serum levels can be falsely elevated by furosemide, phenylbutazone, probenecid, theobromine, caffeine, sulfathiazole, chocolate, or acetominophen if using aspectrophotometric method of assay.