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XANTHINES

Chapter 8
Introduction
• Theophylline has been traditionally used to
treat asthma and chronic obstructive
pulmonary disease patients in both stable and
acute phases
• Mechanism of action of xantines is unclear
• Their clinical use has been relegated to that of
second or third-line agents
IDENTIFICATION
• Theophylline is related
chemically to the natural
metabolite xanthine,
which is a precursor of
uric acid
• Theophylline and
caffeine, because of their
methyl attachments,
these agents are often
referred to as
metylxanthines
Specific Xanthine Agents
• Natural Sources of Methylxanthines
– Theophylline
• tea leaves
– Caffeine
• tea leaves
• coffee beans
• kola nuts
• cocoa seeds
– theobromine
• cocoa seeds and beans
General Pharmacologic Properties
• Physiologic Effects of Xanthines
– CNS stimulation
– Cardiac muscle stimulation
– Diuresis
– Bronchial, uterine, and vascular smooth muscle
relaxation
– Peripheral and coronary vasodilation
– Cerebral vasoconstriction
• In clinical use, theophylline is classified as a
bronchodilator because it causes relaxation of
bronchial smooth muscle
Clinical Indications for Use of Xanthines
• Use in Asthma
– Sustained-release theophylline is indicated
as a long term controller drug, for
maintenance therapy of mild, persistent
(Step2) asthma or greater
– 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
• Use in Chronic Obstructive Pulmonary Disease
– Xanthines would be considered for moderate
(Stage II) and severe (Stage III) COPD
– Recommended as an alternative to ß2 agonists or
anticholinergic agents
– Intravenous theophylline may be used in severe
exacerbations of COPD when aggressive inhaled
bronchodilator therapy is inadequate
• Use in Apnea of Prematurity
– Xanthines are first-line agents of choice to
stimulate breathing in apnea of prematurity
Mode of Action
• Theories of Activity
–Previously known as
phosphodiesterase inhibitors
• It was thought that xanthines caused
smooth muscle relaxation by inhibiting
phosphodiesterase, leading to an
increased level of cyclic AMP
• This theory has been questioned
– Other theories
• Antagonism of Adenosine
– may block smooth muscle constriction and mast
cell degranulation
• Catecholamine Release (epinephrine)
– xanthines may cause the production and release of
endogenous catecholamines leading to bronchial
relaxation
• Conclusion
– There is no accepted definitive explanation for the
action of xanthines to date
• There may be multiple mechanisms involved
Xanthine Derivatives
Xanthine Brand Names Formulations
Derivative
Theophylline Slo-phyllin, Theolair, Tablets, capsules,
Anhydrous Quibron-T, Dividose, syrup, elixir,
(100% Bronkodyl, extended-release
theophylline) Elixophyllin, Theo- tablets, capsules
Dur, Uni-Dur,
Uniphyl
Oxitriphylline Choledyl SA Tablets, syrup,
(64% theophylline) elixir, sustained-
release tablets

Aminophylline Aminophylline, Tablets, oral liquid,


(79% theophylline) Phyllocontin, injection,
Truphylline suppositories
Dyphylline Dilor, Lufyllin Tablets, elixir,
injection
Examples of Xanthine Derivatives

Slo-Bid Theo-Dur Uniphyl


Titrating Theophylline Doses
• Equivalent Doses of Theophylline Salts
– The standard with which salts of theophylline are
compared is anhydrous theophylline (100%
theophylline)
– Salts of theophylline (oxytriphylline) are not pure
and have different potencies
• For example, a 200 mg dose of Choledyl will not give
the same amount of theophylline as a 200 mg dose of
Theo-Dur
• This will affect the dose needed to achieve the desired
response
• Serum Levels of Theophylline
– Individuals metabolize xanthines at
different rates
– Serum levels must be monitored
• immediate release forms
– 1-2 hr. after administration
• sustained release forms
– 5-9 hr. after administration
Serum Level Therapeutic Effect
<5 μg/ml No effect
10-20 μg/ml Therapeutic range
> 20 μg/ml Nausea
> 30 μg/ml Cardiac arrhythmias
40-45 μg/ml Seizures
– Recommended serum levels
• Asthma - 5-15 μg/ml
• COPD - 10-12 μg/ml
• Dosage Schedules
– Acute therapy:
• Oral loading dose of 5 mg/kg
– Chronic therapy
• 16 mg/kg/24 hr or 400 mg/24 hr which ever is
less
• Dosages may need to be adjusted for age,
heart disease and liver disease
Theophylline Toxicity and Side Effects
• Theophylline has a narrow therapeutic
margin (low therapeutic index)
– Very little difference between the dose and
serum level that give therapeutic benefit and
those that cause toxic side effects
• Most common side effects
– gastric upset
– headache
– anxiety
– nervousness
Other Side Effects
Organ System Adverse Reaction
Central Nervous Headache, anxiety,
System restlessness, insomnia,
tremor, convulsions
Gastrointestinal Nausea, vomiting,
anorexia, abdominal pain,
diarrhea, hematemesis,
G-E reflux
Respiratory tachypnea
Cardiovascular Palpitations,supraventricu
lar tachycardia, venricular
arrhythmias, hypotension
Renal Diuresis
Factors Affecting Theophylline Activity
• Theophylline is metabolized by the liver and
eliminated by the kidneys
– Any condition that affects these organs can affect
theophylline levels in the body
– Drugs and condition that affect theophylline
• Increase serum levels
– Beta blocking agents, corticosteroids, influenza
vaccine, alcohol, pneumonia, CHF…
• Decrease serum levels
– Rifampin, cigarette smoking, beta agonist,
barbiturates…
Clinical Application
• Recent guidelines for the pharmacological
management of asthma and COPD do not
indicate theophylline as first-line therapy
• Disadvantages of theophylline use
– Narrow therapeutic margin
– Toxic effects
– Unpredictable blood levels
– Many drug-drug and drug-condition
interactions
• Use in Asthma
– Theophylline is suggested after ß agonists, inhaled
corticosteroids and mediator antagonists target
the underlying inflammation
– Still used as first-line treatment for severe asthma
(IV or oral)
• Use in COPD
– Used as a maintenance agent if ipratropium
bromide and a ß agonist fail to provide adequate
control
– Used in acute exacerbations unresponsive to
other treatment
• Non-bronchodilating Effects of Theophylline
– increased respiratory muscle strength
(diaphragm)
• inhibit or reverse muscle fatigue and ventilatory
failure
– increased respiratory muscle endurance
– increased central ventilatory drive
– cardiovascular effects
• increased cardiac output
• decreased pulmonary vascular resistance
• improved myocardial muscle perfusion
– anti-inflammatory effects
• Use In Apnea of Prematurity
– Theophylline and caffeine are the first-line
choice for treatment
– Theophylline is converted to caffeine in the
neonate
– Caffeine is the preferred choice
• Penetrates more readily into the cerebrospinal
fluid
• More potent stimulant of the CNS and respiratory
system
• Dosing regimens are simpler and give more
predictable results
• Wider therapeutic margin, with fewer side effects
– Caffeine citrate (Cafcit) administration
• oral or IV
• loading dose: 20 mg/kg
• maintenance: 5 mg/kg qd
• serum concentration of 5-20 mg/L is
effective
• approved by the FDA for apnea of
prematurity
Conclusion
• The non-bronchodilating effects (increased
respiratory muscle strength and ventilatory
drive) may be as important as the
bronchodilating effects of xanthines
• These effects are complementary to the
bronchodilating action of ß agonists and
anticholinergic bronchodilators in
managing asthma and COPD

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