Xanthines
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 lesspreferred 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
Theophylline
Brand Names
Slo-phyllin, Theolair,
Formulations
Tablets, capsules,
Oxitriphylline
Aminophylline
Dyphylline
III.
Quibron-T, Dividose,
Bronkodyl, Elixophyllin,
Theo-Dur, Uni-Dur,
Uniphyl
Choledyl SA
syrup, elixir, extendedrelease tablets,
capsules
Tablets, syrup, elixir,
sustained-release
tablets
Aminophylline,
Tablets, oral liquid,
Phyllocontin, Truphylline injection, suppositories
Dilor, Lufyllin
Tablets, elixir, injection
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
<5 μg/ml
10-20 μg/ml
> 20 μg/ml
> 30 μg/ml
40-45 μg/ml
Therapeutic Effect
No effect
Therapeutic range
Nausea
Cardiac arrhythmias
Seizures
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
Central Nervous System
Gastrointestinal
Respiratory
Cardiovascular
Renal
Adverse Reaction
Headache, anxiety, restlessness,
insomnia, tremor, convulsions
Nausea, vomiting, anorexia,
abdominal pain, diarrhea,
hematemesis, G-E reflux
tachypnea
Palpitations,supraventricular
tachycardia, venricular
arrhythmias, hypotension
Diuresis
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