Respiratory Disease (3) Drugs in Asthma Flashcards
- Know the mechanism of action of anti-asthma agents - Appreciate the rationale for drug combinations in asthma
Overview
Focus on Beta-agonists and Glucocorticoids
>how GCs are indicated in asthma, what dose to use, why, and what combination
> Need to know MOA of these 2 classes of drugs
> Need to know rationale for their combinations, and other combinations of drugs used to treat asthma
Definition of Asthma
> Chronic inflammatory disorder of airways
> Many cells and cellular elements play a role
> Chronic inflammation associated with airway hyperresponsiveness
(narrow too easily and too much)
>leads to recurrent episodes of wheezing, breathlessness, chest tightness, coughing
> Widespread, variable, often reversible airflow limitation
Asthma pathogenesis
APC (Predisposition to overproduce IgE)
>antigen
»Lymphocyte clonal expansion
> B Cell (directed by IL-4 to class switch to IgE, IgE binds to mast cells with high affinity)
Chronic re-exposure to antigen
Mast cell activation
> Th2
Pro-inflammatory cytokines
Eosinophil recruitment and activation (out of circulation and into airway wall, mast cells there already, recruited cells cause airways to constrict)
> > > Bronchospasm, mucous, hyperaemia (increase in blood flow), vascular leak, cellular proliferation, fibrosis (remodelling occurs over weeks to months)
AIRWAY OBSTRUCTION
(many mediators that are spasmodic for airway muscle are dilatory for blood vessels)
Factors that influence asthma development and expression
Host factors >Genetic >>atopy (predisposition to produce IgE), airway hyperresponsiveness (genetic factors that predispose sensitivity to spasmodic mediators) >Gender >obesity
Environmental factors >indoor/outdoor allergens >occupational sensitizers >Tobacco smoke >respiratory infection >Diet
Airway obstruction after allergen challenge
> encounter allergen
release histamine and leukotriene
Cause muscles to shorten and close off airways
> Leukotriene production goes on for some time but histamine is rapidly metabolised
> > Histamine is not a satisfactory clinical target in asthma even if its role in asthma is compelling
It is there, released, has actions, but blocking its effects does not have enough therapeutic effects to resolve asthma
Typical spirometry tracings
Much of disease involves narrowing of airways and increased airway resistance
>tested with spirometry
Volume and flow
>FEV1
>decreased in asthma but rescued by bronchodilators
Inflammation in asthma
Beta-agonists little to no effect on the inflammation
Glucocorticoids suppress the inflammation strongly
>thats why we combine the drugs
Asthma PT airways have eosinophils already present, but more recruited by mast cells during inflammation
>very little to no eosinophils in the smooth muscle, all seem to congregate in the epithelium
>release cytotoxins which cause desquamation (shedding)
>Subepithelial region also shows eosinophils that have migrated in
Asthma Inflammation: Cells and Mediators (1)
Allergen
>Macrophage/dendritic cell >mast cell
»Th2 cell »_space;Neutrophil
»>Eosinophils
Result in
>Mucus hypersecretion (hyperplasia)
>Vasodilation (new vessels - angiogenesis)
>Plasma leak (oedema)
>Epithelial shedding (subepithelial fibrosis)
>Sensory nerve activation
>Cholinergic reflex
>Bronchoconstriction (hypertrophy/hyperplasia of the ASM)
Asthma Inflammation: Cells and Mediators (2)
Think of: Cells > Mediators > Effects
Inflammatory cells
>Mast cells, eosinophils, Th2 cells, basophils, neutrophils, platelets
Structural cells
>Epithelial cells, SM cells, Endothelial cells, Fibroblasts, Nerves
Mediators
>Histamine, Leukotriene, Prostanoids, PAF, Kinins, Nitric Oxide, Cytokines, Chemokines, Growth Factors
Effects >Bronchospasm >Plasma exudation >Mucus secretion >AHR >Structural changes
Airway mucosal oedema
30 mins after allergen challenge
>Narrowed airways has changed surface appearance
>Red: Hyperaemic (increase in blood flow)
>Glistening: Increased mucus secretion in airways
Beta agonist may not be able to reverse response after 30 mins of allergen challenge
>this action has to be prevented rather than reversed
>Hence the combination of an inhibitor and a reliever
Mucus plugs in fatal asthma
Involuted epithelium to accomodate narrowing of the airways
>exacerbated by mucus plug
>different phenomena
»acute inflammation, repair, chronic inflammation
Acute and Chronic Inflammation
Acute inflammation -> airway mucosal oedema
Chronic inflammation»_space; eosinophils and desquamation
»airway remodelling
> > > > all lead to airway narrowing
Key components of asthma pathogenesis
Induction Phase
>poorly understood, related to acquisition of allergy
Smooth muscle shortening
>well understood, most important chemical mediators identified
>Histamine, ACh, Cys-LTs
»>treated with Beta-agonists
Inflammation
>not completely understood, some key chemical mediators known
>Histamine, kinins, neurokinins, endothelin, Cys-LTs, IL-4/13, IL-5, granulocyte-macrophage colony-stimulating factor GM-CSF)
»>treated with anti-inflammatory drugs (Glucocortocoids)
Treating Obstruction
Airway smooth muscle shortening (narrowing of lumen)
>Relievers (short acting B-agonists)
>Controllers (Long acting B-agonists)
>Preventers (GCs)
Bronchial wall oedema (swelling, encorachment on lumen)
>Preventers (GCs)
Mucus hypersecretion (occlusion of lumen) >Preventers (GCs)
Routes of drug administration
Oral once daily is ideal
>compliance decreases with increasing frequency of dose
(also decreases with inhalational use compared to oral)
Site of disease allows topical treatment
>metered dose inhaler
>localisation of adverse effects, systemic absorption
(delivered inhalants also expose airway cells to initial high concentration of drug, needs to be taken into consideration when dosing)
Parenteral treatment
>more severe disease (acute and chronic)
Therapeutic Outcomes
Symptom control >improve quality of life >short acting bronchodilator usage >reduce number of exacerbations (Oral GCs courses) >hospital admissions
Airway function
>FEV1
>Peak expiratory flow rate (PEFR) - level and variability
>AHR
Inflammation >experimental rater than routine >Biopsy >induced sputum >>cellular and mediator content >exhaled nitric oxide as an indicator of Th2 mediated asthma
Surrogate markers may be valuable for disease assessment and appropriate pre-crisis therapeutic adjustments
Receptors on airway smooth muscle (ASM)
- Balance of relaxation and contraction
Functional antagonism
Constriction
>HIstamine
>leukotrienes
>ACh
Dilation
>Adrenaline (endogenous)
>PGE2
>Synthetic B2-adrenoceptor agonists
Relievers: Short-acting B2-adrenoceptor Agonists
Short-acting
>salbutamol, terbutaline (RELIEVERS)
> mainstay of acute bronchodilator therapy
Short acting agents have rapid (2-5 min) onset of action
duration of 2-4h (diffusion, not metabolism)
Selectivity
>for B2-AR is very important
>Significant adverse effects can occur from B1-AR action
(Tachycardia if beta-agonist rapidly absorbed and accumulates in system)
(Individuals with cor-morbid cardiovascular disease - increase risk of cardiac event)
Adverse effects
>B1-receptor activation produces tachycardia
>B2-action causes tremor
USED only as required, i.e. upon perception of bronchospasm
Regulation of smooth muscle tone
(Contractile agonists work through their own receptors - commonly GPCR-Gq coupled, that activate PLC/IP3 and increase PKC, also simultaneously activates Rho Kinase)
>remember PKC and Rho Kinase inhibits Myosin Light Chain Phosphatase
Beta agonists are indifferent to cause of contraction, i.e. will work in asthma that has different causes and different mediators
B2-agonists > B2-ARs (GPCR-Gs)
>AC > increase cAMP
>Stimulate increase in PKA
>Inhibit Ca2+ oscillations
>Inhibit Myosin Light Chain Kinase (so MLC not phosphorylated, no crossbridge cycling)
>Activates Myosin Light Chain Phosphatase (removes phosphate from MLC-P, inactivating it)
> > overall reduction in ASM contraction
B2-adrenoceptor agonists relax ASM
PKA alters calcium dynamics
1) reduces activity of inositol triphosphate (IP3) receptor
>less Ca2+ released upon Gq coupled GPCR activation
2) Ca2+ that is released is stored again in SR more rapidly because SERCA can respond to increase in PKA by increasing pump activity
Features of the B2-Adrenoceptor
Low degree of tachyphylaxis (desensitisation leading to downregulation) on ASM
High degree of tachyphylaxis on inflammatory cells
>mast cell action relatively unimportant
Tachyphylaxis caused by >induction of PDEs >reduced receptor number >reduced coupling to adenylate cyclase (beta-adrenergic receptor kinase activity higher in mast cells than ASM, thats why mast cells desensitise so quickly)
Controllers: Long-acting B2-adrenoceptor agonists
Long-acting (CONTROLLERS)
>Salmeterol (slow onset, 12h duration)
>Formoterol (rapid onset, 12h duration)
Concern
>equivalent to regular short-acting B2-agonists?
(100x more selectivity is preferred for B2 because of cardiovascular effects of B1)
Reduce number of exacerbations
>benefit of chronic bronchodilation
>some tolerance develops to bronchoprotective effects
Combined with inhaled GCS in single actuator
(Because if asthma is severe enough to warrant LABA, ten it is significant enough to warrant preventer therapy with GCS)
Muscarininc receptor antagonists - Bronchodilators
Ipratropium bromide Tiotropium bromide >non-selective for Muscarinic receptors (M1/2/3) >May not be optimal as blocks >Auto-inhibition (M2)
> given once daily
Less bronchodilation than B2-agonists
Used prophalacticly
USED IN COPD (discussed in COPD lecture)
Preventers: Glucocorticoids
Anti-inflammatory
>Multiplicity of beneficial targets - GCS regulate vast number of cells, 20% of genome in different cell types can be increased or decreased by GCS
Suppress:
>inducible enzymes of inflammation (e.g. PLA2)
>Inflammatory cytokines (e.g. TNFalpha)
>Adhesion molecule expression (e.g. ICAM-1)
Induce
>Annexin-1 (inflammation-resolving mediator)
>B2-AR (can induce or preserve B2-AR receptor population)
- Decrease inflammatory cell number and activation
- Decrease probability and severity of episode of asthma
- Slow onset of action and maximum benefit
(too late to administer GCS once phenomena has occurred, MOA of this class takes relatively long to change gene/protein expression which changes presence of cell types or their activities, takes a while to manifest)
