1 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Reminder:  QUIZ NEXT WEEK ON:  Anti-infectives, Xanthines, Surfactants

Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Chapter 8 Xanthines

3 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Clinical Uses of Xanthines  Asthma  COPD  Apnea of prematurity

4 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Clinical Indications for the Use of Xanthines  Use in asthma  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

5 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Clinical Indications for the Use of Xanthines (cont’d)  Use in COPD  Theophylline: recommended by GOLD as alternative to β 2 -agonist and anticholinergics  Not used in acute exacerbations  Use in apnea of prematurity  First-line treatment  Theophylline most extensively used, but caffeine citrate may be a better choice (safer, higher therapeutic index)

6 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Specific Xanthine Agents  Also known as methylxanthines  Found as alkaloids in plant species  Theophylline  Tea leaves  Theobromine  Cocoa seeds or beans  Caffeine  Coffee beans and kola nuts  Cocoa seeds or beans  Tea leaves

7 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. General Pharmacological Properties  Effects on humans  CNS stimulation  Cardiac muscle stimulation  Diuresis  Bronchial, uterine, and vascular smooth muscle relaxation Theophylline is generally classified as a bronchodilator Theophylline is generally classified as a bronchodilator  Peripheral and coronary vasodilation  Cerebral vasoconstriction Used in headache remedies Used in headache remedies

8 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. General Pharmacological Properties (cont’d)  Structure-activity relations  Theophylline Methyl attachments at N-1 and N-3 enhance bronchodilation/increase side effects Methyl attachments at N-1 and N-3 enhance bronchodilation/increase side effects  Caffeine Additional methyl group at N-7 decreases bronchodilation Additional methyl group at N-7 decreases bronchodilation  Dyphylline Derivative of theophylline with methyl attachment at N-7 that weakens bronchodilation Derivative of theophylline with methyl attachment at N-7 that weakens bronchodilation  Enprofylline Not available in the United States Not available in the United States Potent bronchodilator Potent bronchodilator Large substitution at the N-3 position Large substitution at the N-3 position

9 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. General Pharmacological Properties (cont’d)  Proposed theories of activity  Exact mechanism of action is unknown Smooth muscle relaxation via inhibition of phosphodiesterase (?) Smooth muscle relaxation via inhibition of phosphodiesterase (?) Antagonism of adenosine (?) Antagonism of adenosine (?) Catecholamine release (?) Catecholamine release (?)

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

11 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Titrating Theophylline Doses  Individuals metabolize theophylline at different rates  Equivalent doses of theophylline salts  Anhydrous theophylline = 100% theophylline  Salts of theophylline not pure by weight

12 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Titrating Theophylline Doses (cont’d)  Serum levels of theophylline  <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  Asthma  5 to 15 μg/mL  COPD  5 to 10 μg/mL

13 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc.  Dosage schedules  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) 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 Each 0.5 mg/kg = 1 μg/mL serum level  Slow titration: 16 mg/kg/24 hr or 400 mg/24 hr (whichever is less) 16 mg/kg/24 hr or 400 mg/24 hr (whichever is less) Titrating Theophylline Doses (cont’d)

14 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc.  Methods of titration:  Clinical reaction of patient  Serum drug levels  1–2 hours after administration (immediate release)  5–9 hours after administration (sustained release) Titrating Theophylline Doses (cont’d)

15 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Theophylline Toxicity and Side Effects  Narrow therapeutic margin  Distressing side effects may occur at therapeutic levels  Inhaled theophylline is being studied  Common side effects:  Gastric upset Not recommended in patients with peptic ulcer or acute gastritis Not recommended in patients with peptic ulcer or acute gastritis  Headache  Anxiety  Diuresis

16 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Factors Affecting Theophylline Activity  Conditions affecting liver/kidneys  Interactions with other drugs (see Box 8-2 in the textbook)  Conditions that increase theophylline levels:  Viral hepatitis  Left ventricular failure  Condition that decreases theophylline levels:  Smoking  Additive effect:  β-Agonists

17 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Clinical Uses  Asthma  Use debated  Only after other relievers and controllers have failed  COPD  If ipratropium bromide and β 2 -agonist fail to provide control

18 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Nonbronchodilating Effects of Theophylline  Increase in force of respiratory muscle contractility  Increase in respiratory muscle endurance  Increase in ventilatory drive  Cardiovascular effects  Increased cardiac output  Decreased pulmonary vascular resistance  Antiinflammatory effects

19 Copyright © 2012, 2008, 2002, 1998, 1994, 1989, 1984, 1978 by Mosby, Inc., an affiliate of Elsevier Inc. Use in Apnea of Prematurity  Xanthines are the first-line choice when nonpharmacological methods are unsuccessful  Caffeine citrate is preferred over theophylline  Loading dose of caffeine citrate is 20 mg/kg  Daily maintenance dose of 5 mg/kg