Clinical Indications for Use of Xanthines


I.                  Use in Asthma

a.    Sustained-release theophylline is indicated as a long term controller drug, for maintenance therapy of mild, persistent (Step2) asthma or greater

b.    Sustained-release theophylline is considered as a less-preferred alternative to low-dose inhaled corticosteroids or cromolyn-like agents as second-line maintenance drug therapy in stable asthma


II.              Use in Chronic Obstructive Pulmonary Disease

a.    Xanthines would be considered for moderate (Stage II) and severe (Stage III) COPD

b.    Recommended as an alternative to ß2 agonists or anticholinergic agents

c.     Intravenous theophylline may be used in severe exacerbations of COPD when aggressive inhaled bronchodilator therapy is inadequate


III.           Use in Apnea of Prematurity

a.    Xanthines are first-line agents of choice to stimulate breathing in apnea of prematurity


Specific Xanthine Agents



I.                  Natural Sources of Methylxanthines

a.    Theophylline

                                                 i.      tea leaves

b.    Caffeine

                                                 i.      tea leaves

                                               ii.      coffee beans

                                             iii.      kola nuts

                                            iv.      cocoa seeds

c.     theobromine

                                                 i.      cocoa seeds and beans


II.              Xanthine Derivatives


Xanthine Derivative

Brand Names



Slo-phyllin, Theolair, Quibron-T, Dividose, Bronkodyl, Elixophyllin, Theo-Dur, Uni-Dur, Uniphyl

Tablets, capsules, syrup, elixir, extended-release tablets, capsules


Choledyl SA

Tablets, syrup, elixir, sustained-release tablets


Aminophylline, Phyllocontin, Truphylline

Tablets, oral liquid, injection, suppositories


Dilor, Lufyllin

Tablets, elixir, injection


III.    Examples of Xanthine Derivatives


     Slo-Bid                  Theo-Dur                      Uniphyl


General Pharmacologic Properties


I.                  Physiologic Effects of Xanthines

a.    CNS stimulation

b.    Cardiac muscle stimulation

c.     Diuresis

d.    Bronchial, uterine, and vascular smooth muscle relaxation

e.    Peripheral and coronary vasodilation

f.      Cerebral vasoconstriction


II.              In clinical use, theophylline is classified as a bronchodilator because it causes relaxation of bronchial smooth muscle


Mode of Action


I.                  Theories of Activity

a.    Previously known as phosphodiesterase inhibitors

                                                 i.      It was thought that xanthines caused smooth muscle relaxation by inhibiting phosphodiesterase, leading to an increased level of cyclic AMP

                                               ii.      This theory has been questioned

b.    Other theories

                                                 i.      Antagonism of Adenosine

1.    may block smooth muscle constriction and mast cell degranulation

                                               ii.      Catecholamine Release (epinephrine)

1.    xanthines may cause the production and release of endogenous catecholamines leading to bronchial relaxation


II.              Conclusion

a.    There is no accepted definitive explanation for the action of xanthines to date

b.    There may be multiple mechanisms involved



Titrating Theophylline Doses


I.                  Equivalent Doses of Theophylline Salts

a.    The standard with which salts of theophylline are compared is anhydrous theophylline (100% theophylline)

b.    Salts of theophylline are not pure and have different potencies

                                                             i.      For example, a 200 mg dose of Choledyl will not give the same amount of theophylline as a 200 mg dose of Theo-Dur

                                                           ii.      This will affect the dose needed to achieve the desired response


II.              Serum Levels of Theophylline

a.    Individuals metabolize xanthines at different rates

b.    Serum levels must be monitored

                                                             i.      immediate release forms

1.    1-2 hr. after administration

                                                           ii.      sustained release forms

1.    5-9 hr. after administration


Serum Level

Therapeutic Effect

<5 μg/ml

No effect

10-20 μg/ml

Therapeutic range

> 20 μg/ml


> 30 μg/ml

Cardiac arrhythmias

40-45 μg/ml



c.     Recommended serum levels

                                                             i.      Asthma

1.    5-15 μg/ml

                                                           ii.      COPD

1.    10-12 μg/ml


III.           Dosage Schedules

a.    Acute therapy: 

                                                             i.      Oral loading dose of 5 mg/kg

b.    Chronic therapy

                                                             i.      16 mg/kg/24 hr or 400 mg/24 hr which ever is less

                                                           ii.      Dosages may need to be adjusted for age, heart disease and liver disease



Theophylline Toxicity and Side Effects


I.                  Theophylline has a narrow therapeutic margin (low therapeutic index)

a.    Very little difference between the dose and serum level that give therapeutic benefit and those that cause toxic side effects


II.              Most common side effects

a.    gastric upset

b.    headache

c.     anxiety

d.    nervousness


III.           Other Side Effects


Organ System

Adverse Reaction

Central Nervous System

Headache, anxiety, restlessness, insomnia, tremor, convulsions


Nausea, vomiting, anorexia, abdominal pain, diarrhea, hematemesis, G-E reflux




Palpitations,supraventricular tachycardia, venricular arrhythmias, hypotension





Factors Affecting Theophylline Activity


I.                  Theophylline is metabolized by the liver and eliminated by the kidneys

a.    Any condition that affects these organs can affect theophylline levels in the

b.    See text, page 161, Box 8-2


Clinical Application


I.                  Recent guidelines for the pharmacological management of asthma and COPD do not indicate theophylline as first-line therapy


II.              Disadvantages of theophylline use

a.    Narrow therapeutic margin

b.    Toxic effects

c.     Unpredictable blood levels

d.    Many drug-drug and drug-condition interactions


III.           Use in Asthma

a.    Theophylline is suggested after ß agonists, inhaled corticosteroids and mediator antagonists target the underlying inflammation

b.    Still used as first-line treatment for severe asthma (IV or oral)


IV.            Use in COPD

a.    Used as a maintenance agent if ipratropium bromide and a ß agonist fail to provide adequate contro

b.    Used in acute exacerbations unresponsive to other treatment


V.                Non-bronchodilating Effects of Theophylline

a.    increased respiratory muscle strength (diaphragm)

                                                             i.      inhibit or reverse muscle fatigue and ventilatory failure

b.    increased respiratory muscle endurance

c.     increased central ventilatory drive

d.    cardiovascular effects

                                                             i.      increased cardiac output

                                                           ii.      decreased pulmonary vascular resistance

                                                         iii.      improved myocardial muscle perfusion

e.    anti-inflammatory effects


VI.            Use In Apnea of Prematurity

a.    Theophylline and caffeine are the first-line choice for treatment

b.    Theophylline is converted to caffeine in the neonate

c.     Caffeine is the preferred choice

                                                             i.      Penetrates more readily into the cerebrospinal fluid

                                                           ii.      More potent stimulant of the CNS and respiratory system

                                                         iii.      Dosing regimens are simpler and give more predictable results

                                                        iv.      Wider therapeutic margin, with fewer side effects

d.    Caffeine citrate (Cafcit) administration

                                                             i.      oral or IV

                                                           ii.      loading dose:  20 mg/kg

                                                         iii.      maintenance: 5 mg/kg qd

                                                        iv.      serum concentration of 5-20 mg/L is effective

                                                          v.      approved by the FDA for apnea of prematurity



VII.         Conclusion

a.    The non-bronchodilating effects (increased respiratory muscle strength and ventilatory drive) may be as important as the bronchodilating effects of xanthines  

b.    These effects are complementary to the bronchodilating action of ß agonists and anticholinergic bronchodilators in managing asthma and COPD