Chapter 8

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Transcript Chapter 8

Reminder:
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QUIZ NEXT WEEK ON:
Anti-infectives, Xanthines, Surfactants
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Chapter 8
Xanthines
Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc.
Clinical Uses of Xanthines
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Asthma
COPD
Apnea of prematurity
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Clinical Indications for
the Use of Xanthines
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Use in asthma
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Theophylline: maintenance therapy (step 2 or
alternative in step 3 with ICS) of mild, persistent
asthma
Patients older than 5 years of age
Side effects and narrow therapeutic index may
make it a poor choice vs. other agents
Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc.
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Clinical Indications for
the Use of Xanthines (cont’d)
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Use in COPD
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Theophylline: recommended by GOLD as
alternative to β2-agonist and anticholinergics
Not used in acute exacerbations
Use in apnea of prematurity
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First-line treatment
 Theophylline most extensively used, but caffeine
citrate may be a better choice (safer, higher
therapeutic index)
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Specific Xanthine Agents
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Also known as methylxanthines
Found as alkaloids in plant species
Theophylline
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Theobromine
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Tea leaves
Cocoa seeds or beans
Caffeine
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Coffee beans and kola nuts
Cocoa seeds or beans
Tea leaves
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General Pharmacological Properties
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Effects on humans
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CNS stimulation
Cardiac muscle stimulation
Diuresis
Bronchial, uterine, and vascular smooth muscle
relaxation
• Theophylline is generally classified as a bronchodilator
Peripheral and coronary vasodilation
Cerebral vasoconstriction
• Used in headache remedies
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General Pharmacological
Properties (cont’d)
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Structure-activity relations
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Theophylline
• Methyl attachments at N-1 and N-3 enhance
bronchodilation/increase side effects
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Caffeine
• Additional methyl group at N-7 decreases bronchodilation
Dyphylline
• Derivative of theophylline with methyl attachment at N-7 that
weakens bronchodilation
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Enprofylline
• Not available in the United States
• Potent bronchodilator
• Large substitution at the N-3 position
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General Pharmacological
Properties (cont’d)
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Proposed theories of activity
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Exact mechanism of action is unknown
• Smooth muscle relaxation via inhibition of
phosphodiesterase (?)
• Antagonism of adenosine (?)
• Catecholamine release (?)
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Proposed Mechanism of Action
Figure 8-3 Two proposed mechanisms of action by which theophylline and xanthines
reverse airway obstruction. A, Inhibition of phosphodiesterase. B, Blockade of adenosine
receptors. AMP, Adenosine monophosphate; ATP, adenosine triphosphate.
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Titrating Theophylline Doses
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Individuals metabolize theophylline at
different rates
Equivalent doses of theophylline salts
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Anhydrous theophylline = 100% theophylline
Salts of theophylline not pure by weight
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Titrating Theophylline Doses
(cont’d)
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Serum levels of theophylline
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Asthma
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<5 μg/mL: No effects seen
10 to 20 μg/mL: Therapeutic range
>20 μg/mL: Nausea
>30 μg/mL: Cardiac arrhythmias
40 to 45 μg/mL: Seizures
5 to 15 μg/mL
COPD
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5 to 10 μg/mL
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Titrating Theophylline Doses (cont’d)
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Dosage schedules
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Used to titrate drug levels
Rapid theophyllization:
• 5 mg/kg lean body weight oral loading dose of
anhydrous theophylline (if patient was not previously
receiving theophylline)
• Each 0.5 mg/kg = 1 μg/mL serum level
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Slow titration:
• 16 mg/kg/24 hr or 400 mg/24 hr (whichever is less)
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Titrating Theophylline Doses (cont’d)
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Methods of titration:
Clinical reaction of patient
Serum drug levels
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1–2 hours after administration (immediate release)
5–9 hours after administration (sustained release)
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Theophylline Toxicity
and Side Effects
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Narrow therapeutic margin
Distressing side effects may occur at
therapeutic levels
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Inhaled theophylline is being studied
Common side effects:
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Gastric upset
• Not recommended in patients with peptic ulcer or acute
gastritis
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Headache
Anxiety
Diuresis
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Factors Affecting
Theophylline Activity
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Conditions affecting liver/kidneys
Interactions with other drugs (see Box 8-2 in
the textbook)
Conditions that increase theophylline levels:
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Condition that decreases theophylline levels:
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Viral hepatitis
Left ventricular failure
Smoking
Additive effect:
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β-Agonists
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Clinical Uses
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Asthma
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Use debated
Only after other relievers and controllers have
failed
COPD
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If ipratropium bromide and β2-agonist fail to
provide control
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Nonbronchodilating Effects
of Theophylline
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Increase in force of respiratory muscle
contractility
Increase in respiratory muscle endurance
Increase in ventilatory drive
Cardiovascular effects
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Increased cardiac output
Decreased pulmonary vascular resistance
Antiinflammatory effects
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Use in Apnea of Prematurity
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Xanthines are the first-line choice when
nonpharmacological methods are
unsuccessful
Caffeine citrate is preferred over theophylline
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Loading dose of caffeine citrate is 20 mg/kg
Daily maintenance dose of 5 mg/kg
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