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22 Cards in this Set
- Front
- Back
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Medications for obstructive lung disease overview
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General inflammation, eosinophils, lymphocytes, mast cells, basophils – inhaled (or oral) corticosteroids
Leukotrienes – leukotriene modifiers (5-lipo-oxygenase inhibitors or LTD4 receptor antagonists) IgE (immunoglobulin E) - omalizumab, a monoclonal anti-IgE antibody Parasympathetic motor tone – anti-cholinergic drugs Sympathetic motor tone – beta2-adrenergic receptor – beta-agonists (short and long-acting drugs) |
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Medications for obstructive lung diseases: overview
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Inhaled Medications are the preferred route of administration
These are “topical” medications -Promote “local” treatment effect (efficacy) -Prevent “systemic” effects (toxicity) Drug Delivery is key to this balance -Ideal Particle size -Different Inhaler Devices -Propellant (gas or patient inspiratory flow) |
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Particle size and airway deposition
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>5 microns
-No clinical benefit -Systemic absorption and degradation by liver if swallowed 2-5 microns -Optimal size for clinical benefit <2 microns -Clinical benefit uncertain -Systemic absorption Propellant also plays an important factor |
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CFC, HFA, and DPI propellants
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CFC
-Chlorofluorocarbon -Banned in 2008 HFA -Hydrofluoroalkane DPI -Dry powder inhaler -No gas |
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Inside a pressurized metered dose inhaler (pMDI)
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Hardware
Valve: - Elastomers - Seals - Gasket Actuator Formulation -Propellant (CFC or HFA) -Co-solvent (alcohols) -Surfactant -ICS in solution or suspension HFA-pMDI=slower softer warmer plumes |
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Inside a dry powder inhaler
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Propellant is patient’s inspiratory flow
Drug is in powder form in “unit doses” Unit dose is “loaded” by patient at time of dosing |
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Drug delivery: Key points
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The drug needs to get to the target tissue (the lung) to work
-Particle size is key -Determined by drug + delivery device (and the propellant) -Transition from older CFC-pMDI has improved lung delivery for most inhalers Once the drug is in the lung, then the pharmacologic properties of that drug become important |
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Beta2 adrenergic agonists
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Beta2-adrenergic receptors (B2AR) are present on bronchial smooth muscle cells and mast cells (much less)
Activation of the B2AR by B2-agonists leads to smooth muscle relaxation, bronchodilation Traditional G-coupled protein receptors Pharmacologic properties determine onset and duration of action of B2-agonists (BA) -Short-acting (SABA) vs Long-acting (LABA) G coupled receptor -Increases cAMP (airway relaxation) |
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Chemical structure of beta agonists
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Short side chains
-Hydrophilic -Short duration -Rapid onset -Albuterol Medium side chains -Intermediate lipophilicity -Long duration -Rapid onset -Formoterol Long side chains -Lipophilic -Long duration -Slow onset -Salmeterol (never use long term as monotherapy) |
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Glucocorticoids: formulation, mechanism, efficiacy, systemic toxicity
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Inhaled preferred over oral steroids (ICS)
Mechanism of action the same Efficacy of inhaled drug dependent on: -Delivery to the lung -Residency time in the lung -Potency of the steroid Systemic toxicity of inhaled drug is due to: -Delivery to non-lung areas with absorption -Metabolism of the drug |
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Intracellular inhaled corticosteroid (ICS) mechanism of action
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ICS binds to GR
Heat-shock protein disassociation (hsp 90) Conformational change in GR and activation of GR Translocates to nucleus GR binds to DNA through glucocorticoid response elements (GRE) Increased anti-inflammatory activity |
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ICS topical efficacy vs systemic effects
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Particle size plays a large role
-Too small, its absorbed at end of airway -Too big, its absorbed via swallowing 10-60% deposited in lungs -Anti-inflammatory effects 40-90% swallowed -GI absorption -Inactivated by liver but can get into systemic circulation and have systemic side effects |
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Ideal steroid potency/efficacy, negligible oropharyngeal effects, negligible systemic effects
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Potency/Efficacy:
-High respirable fraction -High receptor binding -Lipophilicity -Lipid conjugation -BDP/BMP, Fluticasone, Budesonide, Ciclesonide Negligible oropharyngeal effects -Small particle size -Prodrug moiety -Ciclesonide Negligible systemic effects -Low oral bioavailability -High systemic clearance -High plasma protein binding |
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ICS/LABA (long acting beta2 agonist) combination products
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Ideal marriage of two drug classes with complementary actions in one inhaler
Advantage for three ICS -Fluticasone/salmeterol -Budesonide/formoterol -Mometasone/formoterol Strengths and Weaknesses of combination drugs are those of the individual components |
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Complementary mechanism of action of ICS/LABA
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Steroid sparing drugs
-Beta agonists prime steroid receptors so they require less steroid stimulation for activation - Steroid receptor complexes also increase beta2 receptor synthesis |
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Leukotrieine modifier drugs: formulation, mechanism, classes
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Oral medications
Mechanism of action involves disruption of the arachidonic acid pathway important in inflammatory cells Two main classes of modifiers (LTMs) -5-lipoxygenase inhibitors (Zileuton) -Leukotriene (LTD4) receptor antagonists (Montelukast, Zafirlukast) |
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Cysteinyl leukotrienes in asthma
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Increase mucus secretion
Decrease mucus transport Cationic proteins (epithelial cell damage Increase release of tachykinins |
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Anticholinergic drugs: Overview
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Quaternary Ammonium Compounds which are poorly absorbed
Antagonize underlying increased vagal tone of the airways, thus relaxing bronchial smooth muscles reduce bronchospasm and mucus secretion Used most often in COPD, but recent articles suggest good efficacy in asthma also |
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Methylxanthines
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Theophyllines
Oral medication Bronchodilation by inhibiting phosphodiesterases via adenosine receptors Very narrow therapeutic index -Many drug interactions, especially with antibiotics -Toxicity can be severe New more selective PDE4 inhibitor just FDA approved (roflumilast) – less toxicity |
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Mast cell stabilizers
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Nedocromil
Cromolyn Both inhaled medications by DPI Not used much anymore Were used for exercise induced asthma and in children as “steroid-sparing” anti-inflammatory drugs Weak drugs |
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Immunomodulators: overview
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Biologic medications
Typically monoclonal antibodies to known inflammatory mediators Subcutaneous or intravenous administration (every 2 weeks or monthly) Anti-IgE, omalizumab (Xolair™) -Recombinant humanized IgG -First to market |
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Allergic cascade
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B lymphocyte
E switch Plasma cell releases IgE Mast cells and basophils degranulate when encountering allergens releasing mediators Allergic inflammation: eosinophils and lymphocytes Exacerbation IgG anti IgE antibodies bind to free IgE, reducing cell bound IgE. Reduces high-affinity receptors (on mast cells and basophils). Reduces mediator release. Reduces asthma exacerbations and symptoms. |
