Elephant specific information, if available, is in blue.

Chemistry – Xanthine derivatives, aminophylline and theophylline are considered to be respiratory smooth muscle relaxants, but also have other pharmacologic actions. Aminophylline differs from theophylline only by the addition of ethylenediamine to its structure and may have different amounts 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 slight ammoniacal 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 point between 270-274°C. It is sparingly soluble in alcohol and only slightly soluble in water at a pH of 7, but solubility increases with increasing pH.

 

Storage/Stability/Compatibility – Aminophylline for injection should be stored in single-use containers in which carbon dioxide has been removed. It should also be stored at temperatures below 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 which can precipitate out of solution. Do not inject aminophylline solutions that contain a precipitate or visible crystals.

 

Aminophylline for injection is reportedly compatible when mixed with all commonly used IV solutions, but may be incompatible with 10% fructose or invert sugar solutions.

 

Aminophylline is reportedly compatible when mixed with the following drugs: amobarbital sodium, bretylium tosylate, calcium gluconate, chloramphenicol sodium succinate, dexamethasone sodium phosphate, dopamine HCl, erythromycin lactobionate, heparin sodium, hydrocortisone sodium succinate, lidocaine HCl, mephentermine sulfate, methicillin sodium, methyldopate HCl, metronidazole with sodium bicarbonate, pentobarbital sodium, phenobarbital sodium, potassium chloride, secobarbital sodium, sodium bicarbonate, sodium iodide, terbutaline sulfate, thiopental sodium, and verapamil HCl.

 

Aminophylline is reportedly incompatible (or data conflicts) with the following drugs: amikacin sulfate, 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, prochlorperazine edisylate 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 references for more specific information.

 

Pharmacology – The theophyllines competitively inhibit phosphodiesterase, thereby increasing amounts of cyclic AMP which increases the release of endogenous epinephrine. The increased levels 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 theophyllines posses may be a result of translocating intracellular ionized calcium.

 

The theophyllines directly relax smooth muscles in the bronchi and pulmonary vasculature, induce diuresis, increase gastric acid secretion and inhibit uterine contractions. They also have weak chronotropic 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 in patients with myocardial failure and/or pulmonary edema.

 

Pharmacokinetics – The pharmacokinetics of theophylline have been studied in several domestic species. After oral administration, the rate of absorption of the theophyllines is limited primarily by the dissolution of the dosage form in the gut. In studies in cats, dogs, and horses, bioavailabilities after oral administration are nearly 100% when non-sustained release products are used. One study in 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 the placenta 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 dogs has 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 low lipid 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 has weak bronchodilitory activity. Renal clearance contributes only about 10% to the overall plasma clearance 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 be expected that similar variability exists in veterinary patients, particularly those with concurrent illnesses.

 

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. Because it may cause or worsen preexisting arrhythmias, patients with cardiac arrhythmias should receive theophylline only with caution and enhanced monitoring. Neonatal and geriatric patients may have decreased clearances of theophylline and be more sensitive to its toxic effects. Patients with CHF may have prolonged serum half-lifes of theophylline.

 

Adverse Effects/Warnings – The theophyllines can produce CNS stimulation and gastrointestinal irritation after administration by any route. Most adverse effects are related to the serum level of the drug and may be symptomatic of toxic blood levels. Some mild CNS excitement and GI disturbances 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 acid secretion, diarrhea, polyphagia, polydipsia, and polyuria. Side effects in horses are generally dose related 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 20 micrograms/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 most life-threatening aspects of toxicity.

 

Treatment of theophylline toxicity is basically supportive. The gut should be emptied, charcoal and a cathartic administered after an oral ingestion, using the standardized methods and cautions associated with these practices. Patients suffering from seizures should have an adequate airway maintained and treated with IV diazepam. The patient should be constantly monitored for cardiac arrhythmias and tachycardia. Fluid and electrolytes should be monitored and corrected as necessary. Hyperthermia may be treated with phenothiazines and tachycardia treated with propranolol if either condition is considered life-threatening.

 

Drug Interactions – Phenobarbital or Phenytoin may decrease the effect of theophylline by increasing 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’s effect. Toxic synergism (arrhythmias) can occur if theophylline is used concurrently with sympath­omimetics (especially ephedrine) or possibly isoproterenol. Theophylline with halothane may cause 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 if measured by the Bittner or colorimetric methods. Values are not affected if using the uricase method. Theophylline serum levels can be falsely elevated by furosemide, phenylbutazone, probenecid, theobromine, caffeine, sulfathiazole, chocolate, or acetominophen if using a spectrophotometric method of assay.

 

Doses – Note: Theophyllines have a low therapeutic index; determine dosage carefully. Because of aminophylline/theophylline’s pharmacokinetic characteristics, it should be dosed on a lean body weight basis in obese patients. Dosage conversions between aminophylline and theophylline can be easily performed by using the information found in the Chemistry section above. Aminophylline causes intense local pain when administered IM and is rarely used or recommended via this route.

Horses:

Note:Intravenous aminophylline should be diluted in at least 100 ml of D5W or normal saline and administered slowly (not > than 25 mg/min).

a)   4 – 7 mg/kg PO tid (Robinson 1987)

b)   10 – 15 mg/kg PO theophylline bid; or up to 15 mg/kg given slowly IV. Monitor serum levels; do not exceed 15 micrograms/ml. (Beech 1987)

c)   Loading dose of 12 mg/kg PO (theophylline), followed by maintenance doses of 5 mg/kg PO bid (Button, Errecalde, and Mulders 1985)

 

 

Monitoring Parameters –

1)   Therapeutic efficacy and symptoms of toxicity

2)   Serum levels at steady state. The therapeutic serum levels of theophylline in humans are generally described to be between 10 – 20 micrograms/ml. Therapeutic and toxic levels have not been firmly established in veterinary species, so the human values should be used as a guide (Note: Some recommend not exceeding 15 micrograms/ml in horses).

 

Client Information – Give dosage as prescribed by veterinarian to maximize the drug’s benefit.

 

Dosage Forms/Preparations/FDA Approval Status/Withholding Times –

 

Veterinary-Approved Products: None

 

Human-Approved Products: The listing below is a sampling of products and sizes available; consult specialized references for a more complete listing.

 

Aminophylline Tablets 100 mg (78.9 mg theophylline), 200 mg (158 mg theophylline); (Rx); 225 mg (178 mg theophylline) controlled release tablets (Rx)

 

Aminophylline Injection 25 mg/ml (19.7 mg/ml theophylline) in 10 ml, & 20 ml vials amps and vials); (Rx)

 

Aminophylline oral liquid 105 mg/5 ml (90 mg theophylline); generic; (Rx)

 

Aminophylline suppositories 250mg (197.5 mg theophylline) & 500 mg (395 mg theo­phylline); (Rx)

 

Theophylline Time Released Capsules and Tablets; 50 mg, 60 mg, 65 mg, 75 mg, 100 mg, 125 mg, 130 mg, 200 mg, 250 mg, 260 mg, & 300 mg, 450 mg, 500 mg, 600 mg are avail­able (Note: Different products have different claimed release rates which may or may not correspond to actual times in veterinary patients; (Rx)

 

Theophylline Tablets and Capsules:  100 mg, 125 mg, 200 mg, 250 mg, 300 mg (Rx)

 

Theophylline Syrup; 80 mg/15 ml (26.7 mg/5 ml), 150 mg/15 ml (50 mg/5 ml) (Rx)

 

Theophylline Elixir/Solution 80 mg/15 ml (26.7 mg/5 ml) (Rx)