1 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of...

11Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc.Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc.

Reminder:Reminder:

QUIZ NEXT WEEK ON:QUIZ NEXT WEEK ON: Anti-infectives, Xanthines, SurfactantsAnti-infectives, Xanthines, Surfactants

Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc.Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc.

Chapter 8Chapter 8

XanthinesXanthines


Clinical Uses of XanthinesClinical Uses of Xanthines

AsthmaAsthma COPDCOPD Apnea of prematurityApnea of prematurity


Clinical Indications for Clinical Indications for the Use of Xanthinesthe Use of Xanthines

Use in asthmaUse in asthma Theophylline: maintenance therapy (step 2 or Theophylline: maintenance therapy (step 2 or

alternative in step 3 with ICS) of mild, persistent alternative in step 3 with ICS) of mild, persistent asthmaasthma

Patients older than 5 years of agePatients older than 5 years of age Side effects and narrow therapeutic index may Side effects and narrow therapeutic index may

make it a poor choice vs. other agentsmake it a poor choice vs. other agents


Clinical Indications for Clinical Indications for the Use of Xanthines the Use of Xanthines (cont’d)(cont’d)

Use in COPDUse in COPD Theophylline: recommended by GOLD as Theophylline: recommended by GOLD as

alternative to βalternative to β22-agonist and anticholinergics-agonist and anticholinergics

Not used in acute exacerbationsNot used in acute exacerbations Use in apnea of prematurityUse in apnea of prematurity

First-line treatmentFirst-line treatment Theophylline most extensively used, but caffeine Theophylline most extensively used, but caffeine

citrate may be a better choice (safer, higher citrate may be a better choice (safer, higher therapeutic index)therapeutic index)


Specific Xanthine AgentsSpecific Xanthine Agents

Also known as Also known as methylxanthinesmethylxanthines Found as alkaloids in plant speciesFound as alkaloids in plant species TheophyllineTheophylline

Tea leavesTea leaves TheobromineTheobromine

Cocoa seeds or beansCocoa seeds or beans CaffeineCaffeine

Coffee beans and kola nutsCoffee beans and kola nuts Cocoa seeds or beansCocoa seeds or beans Tea leavesTea leaves


General Pharmacological PropertiesGeneral Pharmacological Properties

Effects on humansEffects on humans CNS stimulationCNS stimulation Cardiac muscle stimulationCardiac muscle stimulation DiuresisDiuresis Bronchial, uterine, and vascular smooth muscle Bronchial, uterine, and vascular smooth muscle

relaxationrelaxation• Theophylline is generally classified as a bronchodilatorTheophylline is generally classified as a bronchodilator

Peripheral and coronary vasodilationPeripheral and coronary vasodilation Cerebral vasoconstriction Cerebral vasoconstriction

• Used in headache remediesUsed in headache remedies


General Pharmacological General Pharmacological Properties (cont’d)Properties (cont’d)

Structure-activity relationsStructure-activity relations TheophyllineTheophylline

• Methyl attachments at N-1 and N-3 enhance Methyl attachments at N-1 and N-3 enhance bronchodilation/increase side effectsbronchodilation/increase side effects

CaffeineCaffeine• Additional methyl group at N-7 decreases bronchodilationAdditional methyl group at N-7 decreases bronchodilation

DyphyllineDyphylline• Derivative of theophylline with methyl attachment at N-7 that Derivative of theophylline with methyl attachment at N-7 that

weakens bronchodilationweakens bronchodilation Enprofylline Enprofylline

• Not available in the United StatesNot available in the United States

• Potent bronchodilatorPotent bronchodilator

• Large substitution at the N-3 positionLarge substitution at the N-3 position


General Pharmacological General Pharmacological Properties (cont’d)Properties (cont’d)

Proposed theories of activityProposed theories of activity Exact mechanism of action is unknownExact mechanism of action is unknown

• Smooth muscle relaxation via inhibition of Smooth muscle relaxation via inhibition of phosphodiesterase (?)phosphodiesterase (?)

• Antagonism of adenosine (?)Antagonism of adenosine (?)

• Catecholamine release (?)Catecholamine release (?)


Proposed Mechanism of ActionProposed Mechanism of Action

Figure 8-3 Figure 8-3 Two proposed mechanisms of action by which theophylline and xanthines Two proposed mechanisms of action by which theophylline and xanthines reverse airway obstruction. reverse airway obstruction. A,A, Inhibition of phosphodiesterase. Inhibition of phosphodiesterase. B,B, Blockade of adenosine Blockade of adenosine receptors. receptors. AMP,AMP, Adenosine monophosphate; Adenosine monophosphate; ATP,ATP, adenosine triphosphate. adenosine triphosphate.


Titrating Theophylline DosesTitrating Theophylline Doses

Individuals metabolize theophylline at Individuals metabolize theophylline at different ratesdifferent rates

Equivalent doses of theophylline saltsEquivalent doses of theophylline salts Anhydrous theophyllineAnhydrous theophylline = 100% theophylline = 100% theophylline Salts of theophyllineSalts of theophylline not pure by weight not pure by weight


Titrating Theophylline Doses Titrating Theophylline Doses (cont’d)(cont’d)

Serum levels of theophyllineSerum levels of theophylline <5 <5 μμg/mL: No effects seeng/mL: No effects seen 10 to 20 10 to 20 μμg/mL: Therapeutic rangeg/mL: Therapeutic range >20 >20 μμg/mL: Nauseag/mL: Nausea >30 >30 μμg/mL: Cardiac arrhythmiasg/mL: Cardiac arrhythmias 40 to 45 40 to 45 μμg/mL: Seizuresg/mL: Seizures

AsthmaAsthma 5 to 15 5 to 15 μμg/mL g/mL

COPDCOPD 5 to 10 5 to 10 μμg/mLg/mL


Dosage schedulesDosage schedules Used to titrate drug levelsUsed to titrate drug levels Rapid theophyllization:Rapid theophyllization:

• 5 mg/kg 5 mg/kg lean body weightlean body weight oral loading dose of oral loading dose of anhydrous theophylline (if patient was not previously anhydrous theophylline (if patient was not previously receiving theophylline)receiving theophylline)

• Each 0.5 mg/kg = 1 Each 0.5 mg/kg = 1 μμg/mL serum levelg/mL serum level

Slow titration:Slow titration:• 16 mg/kg/24 hr or 400 mg/24 hr 16 mg/kg/24 hr or 400 mg/24 hr (whichever is less)(whichever is less)



Methods of titration:Methods of titration: Clinical reaction of patientClinical reaction of patient Serum drug levelsSerum drug levels

1–2 hours after administration (immediate release)1–2 hours after administration (immediate release) 5–9 hours after administration (sustained release)5–9 hours after administration (sustained release)



Theophylline Toxicity Theophylline Toxicity and Side Effectsand Side Effects

Narrow therapeutic marginNarrow therapeutic margin Distressing side effects may occur at therapeutic Distressing side effects may occur at therapeutic

levelslevels Inhaled theophylline is being studiedInhaled theophylline is being studied

Common side effects:Common side effects: Gastric upsetGastric upset

• Not recommended in patients with peptic ulcer or acute Not recommended in patients with peptic ulcer or acute gastritisgastritis

HeadacheHeadache AnxietyAnxiety DiuresisDiuresis


Factors Affecting Factors Affecting Theophylline ActivityTheophylline Activity

Conditions affecting liver/kidneysConditions affecting liver/kidneys Interactions with other drugs (see Box 8-2 in Interactions with other drugs (see Box 8-2 in

the textbook)the textbook) Conditions that increase theophylline levels:Conditions that increase theophylline levels:

Viral hepatitisViral hepatitis Left ventricular failureLeft ventricular failure

Condition that decreases theophylline levels:Condition that decreases theophylline levels: SmokingSmoking

Additive effect:Additive effect: β-Agonistsβ-Agonists


Clinical UsesClinical Uses

AsthmaAsthma Use debatedUse debated Only after other relievers and controllers have Only after other relievers and controllers have

failedfailed COPDCOPD

If ipratropium bromide and βIf ipratropium bromide and β22-agonist fail to -agonist fail to

provide controlprovide control


Nonbronchodilating Effects Nonbronchodilating Effects of Theophyllineof Theophylline

Increase in force of respiratory muscle Increase in force of respiratory muscle contractilitycontractility

Increase in respiratory muscle enduranceIncrease in respiratory muscle endurance Increase in ventilatory driveIncrease in ventilatory drive Cardiovascular effectsCardiovascular effects

Increased cardiac outputIncreased cardiac output Decreased pulmonary vascular resistanceDecreased pulmonary vascular resistance

Antiinflammatory effectsAntiinflammatory effects


Use in Apnea of PrematurityUse in Apnea of Prematurity

Xanthines are the first-line choice when Xanthines are the first-line choice when nonpharmacological methods are nonpharmacological methods are unsuccessfulunsuccessful

Caffeine citrate is preferred over theophyllineCaffeine citrate is preferred over theophylline Loading dose of caffeine citrate is 20 mg/kgLoading dose of caffeine citrate is 20 mg/kg Daily maintenance dose of 5 mg/kgDaily maintenance dose of 5 mg/kg

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