drugs used in asthma Flashcards
is a heterogenous disease, usually characterized by chronic airway inflammation. it is defined by the history of respiratory symptoms such as wheeze, SOB, chest tightness, and cough that vary over time and in intensity, together with variable expiratory airflow limitation.
asthma
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in asthma patients there is a predominance of what cells that produces humoral response thereby stimulating plasma cells to produce IgE which attaches to Mast cells to produce a complex
TH2
____ secreted by plasma cells binds
the FcεRI receptor on submucosal mast cells and basophils and, when crosslinked by an antigen, induces the release of preformed mediators
such as histamine and leukotrienes, as well as the release of inflammatory cytokines.
Unbound IgE
These cells also migrate into the airway subepithelial mucosa, where they release inflammatory cytokines such as IL-5 and IL-13, which induce goblet cell metaplasia
and mucus production, and act as a chemokine for eosinophils, mast cells, and basophils
Th2
The histamine, tryptase, leukotrienes C4
and D4, and prostaglandin D2 released cause the smooth muscle contraction and vascular leakage responsible for the acute bronchoconstriction of the?
“early asthmatic response.”
“early asthmatic response” is
often followed in 3–6 hours by a second, more sustained phase of bronchoconstriction, the?
This late response is thought
to be due to cytokines characteristically produced by T2 lymphocytes, especially interleukins (IL) 5, 9, and 13.
“late asthmatic response,”
SYMPATHOMIMETIC AGENTS
Epinephrine, Ephedrine, Isoproterenol
Beta 2- selective drugs:
SABA:Albuterol, Terbutaline, Metaproterenol, Pirbuterol
LABA: Salmeterol, Formeterol
Ultra LABA: Indacaterol, Olodaterol, Vilanterol, Bambuterol
Methylxanthine drugs
Theophylline, Theobromine, Caffeine, Roflumilast (PDE4 inhibitor)
anti-muscarininc agents
SAMA: Ipatropium bromide
LAMA: Tiotropium, Aclidinium, Umeclidinium
CORTICOSTEROIDS
beclomethasone, budesonide, ciclesonide,
flunisolide, fluticasone, mometasone, and triamcinolone
LEUKOTRIENE PATHWAY INHIBITORS
zileuton, zafirlukast and montelukast
TARGETED (MONOCLONAL ANTIBODY)
THERAPY
Anti-IgE Monoclonal Antibodies: omalizumab
Anti-IL-5 Therapy:mepolizumab,reslizumab, benralizumab,Dupllumab
-are mainstays in the treatment of
asthma.
-Their binding to β-adrenergic receptors—abundant on
airway smooth muscle cells—stimulates adenylyl cyclase and increases the formation of intracellular cAMP thereby relaxing airway smooth muscle and inhibiting release
of bronchoconstricting mediators from mast cells
Adrenoceptor agonists/SYMPATHOMIMETIC AGENTS
is an effective, rapidly acting bronchodilator
when injected subcutaneously (0.4 mL of 1:1000 solution) or inhaled as a microaerosol from a pressurized canister (320 mcg per puff). Maximal bronchodilation is achieved within 15 minutes after inhalation and lasts 60–90 minutes.
Epinephrine
adverse effects of epinephrine
Because epinephrine
stimulates α and β1 as well as β2 receptors, tachycardia, arrhythmias, and worsening of angina pectoris are the serious adverse effects
used in China for more than 2000 years
before its introduction into Western medicine in 1924. Comparedwith epinephrine, ephedrine has a longer duration, oral activity, more pronounced central effects, and much lower potency.
Ephedrine
is a potent nonselective β1 and β2 bronchodilator.
When inhaled as a microaerosol from a pressurized canister,80–120 mcg isoproterenol causes maximal bronchodilationwithin 5 minutes and has a 60- to 90-minute duration of action.
Isoproterenol
They are effective after inhaled or oral administration
and have a longer duration of action than epinephrine
or isoproterenol.
Beta2-Selective Drugs
-Given by inhalation, these agents cause bronchodilation equivalent to that produced by isoproterenol. Bronchodilation is maximal within 15 minutes and persists for 3–4 hours.
-Nebulized therapy should
thus be reserved for patients unable to coordinate inhalation from a metered-dose inhaler
SABA: Albuterol, terbutaline, metaproterenol, and pirbuterol
are also available in oral form. One
tablet two or three times daily is the usual regimen; the principal adverse effects are skeletal muscle tremor, nervousness, and occasional weakness. This route of administration presents no advantage over inhaled treatment and produces more pronounced
adverse effects and is thus rarely prescribed
Albuterol and terbutaline
is available for subcutaneous
injection (0.25 mg).
The indications for this route are similar to those for subcutaneous epinephrine—severe asthma requiring emergency treatment when aerosolized therapy is not available or has been ineffective.
- it should be remembered that its longer duration of action means that cumulative effects
may be seen after repeated injections.
Terbutaline
with 12-hour durations
of action
- These drugs generally
achieve their long duration of bronchodilating action as a result of high lipid solubility. This permits them to dissolve in the smooth muscle cell membrane in high concentrations or, possibly, attach to “mooring” molecules in the vicinity of the adrenoceptor. - These drugs appear to interact with inhaled corticosteroids
- should not be used as monotherapy for asthma
Long-acting β2-selective agonists (LABA), salmeterol and formoterol
need to be taken only once a day, but because their prolonged bronchodilation masks symptoms of
bronchial inflammation, they should be used only in combination with an ICS for asthma.
-may be used as monotherapy for treatment of COPD
Ultra-long-acting β agonists: indacaterol, olodaterol,
vilanterol, and bambuterol
Their major source is beverages (tea,
cocoa, and coffee, respectively). The use of theophylline, once a mainstay of asthma treatment, has almost ceased with demonstration of the greater efficacy of inhaled adrenoceptor agonists for acute asthma and of inhaled anti-inflammatory agents for chronic asthma.
METHYLXANTHINES: theophylline, theobromine,
and caffeine.
ADVERSE EFFECTS: nausea, vomiting, tremulousness, arrhythmias) and
the requirement for monitoring serum levels because of its narrow therapeutic index
theophylline, theobromine,
and caffeine.
3 Mechanism of Action of Methylxanthines
1.At high concentrations, they can be shown to inhibit several members of the phosphodiesterase (PDE) enzyme family in vitro, thereby increasing concentrations of intracellular cAMP and, in some tissues, cGMP.
2.inhibition of cell surface receptors for
adenosine.
3.enhancement of histone deacetylation
inhibition of ___appears to be the most involved in relaxing airway smooth muscle and inhibition of ___ in inhibiting release of cytokines and chemokines,
thus decreasing immune cell migration and activation
PDE3,PDE4
PDE4 INHIBITOR?
roflumilast
-produces slight tachycardia, an increase in cardiac output, and an increase in peripheral resistance, potentially raising blood pressure slightly. In sensitive individuals, consumption of a few cups of coffee may result in arrhythmias. High doses of these agents relax vascular
smooth muscle except in cerebral blood vessels
-decrease blood viscosity and may improve
blood flow under certain conditions
methylxanthines :Cardiovascular Effects
these agents—in sufficient concentration—inhibit antigen-induced release of histamine from lung tissue.
- improve contractility of skeletal muscle
- reverse fatigue of the diaphragm in patients with COPD
methylxanthines
potent atropine analog that is poorly absorbed after aerosol administration and is therefore relatively free of systemic atropinelike effects.
SAMA:ipratropium
are approved for maintenance
therapy of COPD.
LAMA: A single dose of 18
mcg of tiotropium or 62.5 mcg of umeclidinium has a 24-hourduration of action,
- 400 mcg of aclidinium has a 12-hour duration
Greater bronchodilation, with less toxicity from systemic absorption,is achieved with a selective quaternary ammonium derivative of atropine,_____, which can be inhaled in high doses because of its poor absorption into the circulation and poor entry into the central nervous system
Ipatropium bromide
Afferent pathways in the vagus nerves travel to the central nervous system; efferent pathways from the central nervous system travel to efferent ganglia. Postganglionic fibers release acetylcholine (ACh), which binds to muscarinic receptors on airway smooth muscle. Inhaled materials may provoke bronchoconstriction by several possible mechanisms. First, they may trigger the release of chemical mediators from mast cells. Second, they may stimulate afferent receptors to initiate reflex bronchoconstriction or to release tachykinins (eg, substance P) that directly stimulate smooth muscle contraction.
Mechanisms of response to inhaled irritants
have long been used in the treatment of asthma and are presumed to act by their broad anti-inflammatory efficacy, mediated in part by inhibition of production of inflammatory cytokines
Corticosteroids (specifically, glucocorticoids)
They do not relax airway smooth muscle directly but reduce bronchial hyperreactivity and reduce the frequency of asthma exacerbations if taken regularly
Corticosteroids (specifically, glucocorticoids)
- effective in improving all indices of asthma control: severity of symptoms, tests of airway caliber and bronchial reactivity, frequency of exacerbations, and quality of life
- Inhalational treatment is the most effective way to avoid the systemic adverse effects
CORTICOSTEROIDS
adverse effects: oropharyngeal candidiasis, hoarseness
CORTICOSTEROIDS
- were once widely used for asthma management, especially in children,
- These drugs are thought to act by inhibiting mast cell degranulation and have no direct bronchodilator action.
- The main indication for current use for reducing symptoms of allergic rhinoconjunctivitis.
CROMOLYN & NEDOCROMIL
result from the action of 5-lipoxygenase on arachidonic
acid and are synthesized by a variety of inflammatory cells inthe airways, including eosinophils, mast cells, macrophages, and basophils.
Leukotrienes
is a potent neutrophil chemoattractant,
and LTC4 and LTD4 exert many effects known to occur
in asthma, including bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucus hypersecretion
Leukotriene B4 (LTB4)
Two approaches to interrupting the leukotriene pathway have been pursued:
- inhibition of 5-lipoxygenase, thereby preventing leukotriene synthesis
- inhibition of the binding of LTD4
to its receptor on target tissues, thereby preventing its action.
preferred by many patients, especially by the parents of asthmatic children, because of often exaggerated concerns over the toxicities of corticosteroids
LEUKOTRIENE PATHWAY INHIBITORS: zileuton, zafirlukast and montelukast,
inhibits the binding of IgE but does not activate IgE already bound to its receptor and thus does not provoke mast cell degranulation.
omalizumab
is restricted to patients with severe asthma
and evidence of allergic sensitization, and the dose administered is adjusted for total IgE level and body weight.
Administered by subcutaneous
injection every 2–4 weeks to asthmatic patients,
lowersfree plasma IgE to undetectable levels and significantly reduces the magnitude of both early and late bronchospastic responses to antigen challenge.
Omalizumab
Omalizumab’s most important clinical effect is?
reduction in the frequency and severity of asthma exacerbations, while enabling a reduction in corticosteroid requirements
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Two humanized monoclonal antibodies targeting IL-5, ___
and ___ , and another targeting the IL-5 receptor,____ , have recently been developed for the treatment of eosinophilic asthma
mepolizumab, reslizumab ,benralizumab
- T2 cells secrete ___ as a pro-eosinophilic cytokine that results in eosinophilic airway inflammation.
- Although not central to the mechanisms of asthma in all patients, a substantial proportion of patients with severe asthma have airway and peripheral eosinophilia driven by up-regulation of ___-secreting T2 lymphocytes.
IL-5
brand name:Nucala
generic name?
mepolizumab
a humanized monoclonal antibody targets IL5 and binds to it
Nucala/mepolizumab
Nucala blocks the IL5 binding to the ___ IL5 recpetor complex, inhibiting signal
Alpha chain
