L 22 and 23 drugs used in asthma Flashcards
asthma
-Episodic bronchospasm resulting from an exaggerated bronchoconstrictor response
to various stimuli
-Bronchial hyperreactivity from chronic bronchial inflammation
-Episodic bronchospasm causes dyspnea, cough, and wheezing.
-Affects ~5% of adults and 7-10% of children.
-Over 3,000 fatality cases per year in US
types of asthma
-asthma is a heterogenous disease triggered by a variety of inciting agents
-extrinsic asthma (allergic asthma or classical asthma)
-intrinsic asthma
extrinsic asthma
-Hypersensitivity reaction induced by exposure to an extrinsic antigen (ex. dust mite, molds, and pollens)
-Commonly associated with other allergy in the patient as well as in other family members
-The onset is usually early in life.
-Elevated serum IgE levels and eosinophil count
-Driven by T H2 subset of CD4+ T cells
intrinsic asthma
-Nonimmune triggering mechanism (ex. aspirin, viral infection, cold, psychological stress, exercise)
-No personal or family history of allergy
-Serum IgE levels are normal.
extrinsic asthma attacks in two phases
-Acute bronchoconstriction (immediate asthmatic response) – 30-60 min after inhalation of
antigen
-Sustained bronchoconstriction (late asthmatic response) – 4-8 hours later after the immediate asthmatic response
acute bronchoconstriction
-immediate asthmatic response (IAR)
-Occurs after sensitization.
-Mediated by IgE, produced in response to exposure to foreign proteins
-IgE binds to FceR-1 on mast cells in the airway mucosa.
mast cells release ___
histamine, tryptase, leukotrienes (LTC 4 and LTD 4) and
prostaglandin D 2 (PGD 2)
Re-exposure to the allergen triggers the release of
mediators from the mast cells (mast cell degranulation).
Mediators cause the smooth muscle
contract and vascular leakage
direct stimulation of subepthelial vagal (parasympathetic receptors provoke
reflex bronchoconstriction
sustained bronchconstriction
-Late asthmatic response (LAR)
-3-6 hours after the early asthmatic response
sustained brochoconstriction is caused by the activation of TH2 cells and cytokine production
-ex. IL5, IL9, and IL13
-Attract and activate eosinophils.
-Stimulate mucus hypersecretion by bronchial epithelial cells.
-Stimulate IgE production by B lymphocytes
sustained bronchoconstriction activation of eosinophils
-Releases major basic protein (MBP), eosinophil cationic protein (ECP), peroxidase, which cause tissue damage.
-Amplifies and sustains the inflammation without additional exposure to the triggering antigen
airway remodeling in asthma: epithelium
Hyperplasia
Hypersecretion
airway remodeling in asthma: basement membrane
thickening
airway remodeling in asthma: smooth muscles
hypertropy
pharmacological treatment of asthma
-Sympathomimetics
-Inhaled corticosteroids (ICSs)
-Leukotriene pathway inhibitors
-Methylxanthine drugs
-Antimuscarinic agents
-Cromolyn and nedocromil
-Monoclonal antibodie
sympathomimetics
bronchodilators
“relievers”
inhaled corticosteroids (ICSs)
Anti-inflammatory steroids
“controllers”
leukotriene pathway inhibitors
5-lipoxygenase inhibitor
LTD 4 antagonists
mechanisms of sympathomimetics
-Binds to b 2 adrenergic receptors in the bronchial smooth muscle.
-Increases the cAMP concentration à relax the muscle cells
types of sympathomimetics
-nonselective
-beta selective
-beta 2 selective
nonselective sympathomimetics
Epinephrine (IV injection to relieve a severe attack)
beta selective sympathimimetics
-affects the heart, which has beta 1 adrenergic receptors
-isoproterenol: displaced by beta 2 selective drugs
beta 2 selective sympathomimetics
-most used for the treatment of asthma
-short-acting and long-acting beta 2 agonist
beta 2 selective agonist structure activity relationship
-Bulky N-substitutions à b 2 selective
-Substitutions in the phenyl ring (ex. resorcinol, salicyl alcohol) à b 2 selective and resistant to catechol-o-methyltransferase (COMT)
-Mostly racemic mixture (ex. levalbuterol); only R-isomer is active.
beta 2 selective agonist toxicities
-Tachycardia, arrhythmias – less of a concern for b 2 selective agonists
-Skeletal muscle tremors
-Induction of tachyphylaxis – reduction in the bronchodilator response upon regular uses
short acting beta 2 agonist (SABA)
-Albuterol, terbutaline, metaproterenol, pirbuterol
-PRN for acute attacks
long acting beta 2 agonist (LABA)
Salmeterol, formoterol
-Additional therapy for patients who is currently using inhaled glucocorticoids
-Not for acute attacks but for daily regular use
-No anti-inflammatory action; should not be used as monotherapy for asthma (black box warning).
-Commonly available as combination inhalers with corticosteroids
metaproternol
-Resorcinol analogue of isoproterenol
-Somewhat selective for β 2 receptor
-least potent β 2 agonist
-5-min onset and 4-hr duration when inhaled
-Good oral bioavailability
terbutaline
-N-t-butyl analogue of metaproterenol
-Greater b 2 selectivity
-3-fold greater potency than metaproterenol at b 2 receptors
-Good oral bioavailability
albuterol
-Most widely used
-Salicyl alcohol in the phenyl ring à resistant to COMT
-5-min onset and 4-8 hr duration of action when inhaled.
-Levalbuterol is R-isomer.
-Greater potency, but more expensive
pirbuterol
-Analogous to albuterol except the pyridine ring.
-Comparable duration of action as albuterol
-Less potent than albuterol
salmeterol
-Available as a powder
-Greater lipid solubility; dissolve in cellular membranes.
-20-minute onset and 12-hr duration of action
formoterol
-Available as a powder
-More rapid onset than salmeterol with a comparable duration of action
-Resistant to COMT and MAO
inhaled corticosteroids
-maintenace therapy for persistent asthma
-not curative
-systemic or oral cortcosteroids are reserved for severe cases
-inhaled corticosteroids are the most effective way to minimize the systemic adverse effects
inhaled corticosteroids adverse effects
-Candidiasis – can be treated with topical clotrimazole
-Can be reduced by having patients gargle water
and expectorate after each inhaled treatment
-Ciclesonide – 21-ester prodrug, associated with less candidiasis.
-Hoarseness – direct effect of corticosteroids on
the vocal cords
-Long term use may increase the risk of osteoporosis and cataracts
-In children, 1 cm reduction in their growth only
for the first year
leukotrienes
-Produced from arachidonic acid by 5-lipoxygenase.
-Involved in many inflammatory diseases and in
anaphylaxis
-LTB 4 – potent neutrophil chemoattractant
-LTC 4 and LTD 4 – responsible for many
symptoms of asthma, such as bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucus hypersecretion
leukotriene pathway inhibitors
-improve asthma control and reduce the frequency of asthma exacerbations.
-Not as effective as inhaled glucocorticoids.
-Effective when taken orally, easier than inhalation for children.
-Reduce significantly the response to aspirin in aspirin-induced asthma (5- y10% of asthma patients)
types of leukotriene pathway inhibitors
-5-lipoxygenase inhibitor – zileuton
-selective antagonists for the cysLT 1 receptor – zafirlukast, montelukast
zileuton
-5-lipoxygenase inhibitor
-Racemic mixture
-N-hydroxy group is essential for inhibitory activity.
-Good oral bioavailability
-Alternative to LABA in addition to inhaled corticosteroids
-Not for acute asthma attack
-Requires periodic monitoring of liver function.
monotelukast
-Blocks the binding of LTC 4, LTD 4, and LTE 4 to the receptor
-Once a day dosing
-Good oral bioavailability
-Reduces the frequency of asthma exacerbations
-Little toxicity
methylxanthine drugs
-Theophylline (most effective, more specific for smooth muscle), theobromine, and caffeine
-Once a mainstay of asthma treatment but have almost replaced by b 2 selective agonists
-Still used in some countries due to its low cost
mechanism of methylxanthine drugs
-inhibition of phosphodiesterase (PDE 3 and PDE 4) à increase in the cellular cAMP concentration –> bronchodilation and suppression of histamine release
-Block the action of adenosine, which causes bronchoconstriction and the release of histamine.
-Histone deacetylation, which suppresses inflammatory gene expression
toxicity of methylxanthine drugs
-Nausea, vomiting, tremulousness, arrhythmias
-Narrow therapeutic index
antimuscarinic agents
-anticholinergic agent
-Clinically valuable for patients who are intolerant of inhaled β agonists
mechanisms of antimuscarinic agents
-Stimulation of cholinergic (parasympathetic) nerves causes bronchoconstriction and mucus secretion.
-Antimuscarinic drugs competitively inhibit the action of acetylcholine at muscarinic receptors
ipratropium
-Bronchodilator
-Quaternary amine derivative of atropine
-Poorly absorbed into the circulation after inhaled.
-Minimal oral bioavailability
-Relatively free of systemic atropine-like effects
mast cells stabilizers
-Cromolyn and nedocromil
-Once widely used for asthma management, especially in children.
-Inhibit mast cell degranulation.
-No direct bronchodilator action; should be used prophylactically (daily dosing).
-poorly absorbed into the systemic circulation and have little toxicity, but not as potent or as predictably effective as glucocorticoids.
-The current indication is allergic rhinoconjunctivitis as eye drops
anti-IgE monoclonal antibody
Omalizumab
-Recognizes the portion of IgE that binds to its receptor (FceR-1 and FceR-2) on immune cells.
-Inhibits IgE binding to mast cells.
-Reserved for patients with severe asthma and allergic sensitization
anti-IL-5 therapy
-IL-5 released from T H-2 cells attracts and activates eosinophils.
-Anti-IL-5 monoclonal antibodies (Mepolizumab and Reslizumab)
-Anti-IL-5 receptor monoclonal antibody (Benralizumab)
-Used as a maintenance therapy of severe asthma in patients with an eosinophilic phenotype
short acting beta 2 agonist drugs
-Metaproterenol (Alupent ®)
-Terbutaline
-Albuterol
-Pirbuterol (Maxair ®)
long acting beta 2 agonist drugs
Salmeterol (Serevent ®)
Formoterol
inhaled corticosteroids drugs
-Triamcinolone acetonide (Azmacort ®)
-Beclomethasone dipropionate (Vanceril ®, Qvar ®)
-Flunisolide (Aerobid ®)
-Budesonide (Pulmicort ®)
-Mometasone furoate (Asmanex ®)
-Fluticasone propionate (Flovent ®)
-Ciclesonide (Alvesco ®)
leukotriene pathway inhibitors drugs
-Zileuton (Zyflo ®)
-Zafirlukast (Accolate ®)
-Montelukast (Singulair ®)
methylxanthine drugs to know
-Theophylline
-Theobromine
-Caffeine
antimuscarinic agents drugs
Ipratropium (Atrovent ®)
mast cells stabilizers drugs
Cromolyn (Gastrocrom ®)
Nedocromil (Tilade ®)
monoclonal antibodies drugs
-Omalizumab (Xolair ®)
-Mepolizumab (Nucala ®)
-Reslizumab (Cinqair ®)
-Benralizumab (Fasenra ®)
