Respiratory Disease (3) Drugs in Asthma

Question 1

Overview

Answer 1

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

Question 2

Definition of Asthma

Answer 2

> 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

Question 3

Asthma pathogenesis

Answer 3

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)

Question 4

Factors that influence asthma development and expression

Answer 4

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

Question 5

Airway obstruction after allergen challenge

Answer 5

> 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

Question 6

Typical spirometry tracings

Answer 6

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

Question 7

Inflammation in asthma

Answer 7

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

Question 8

Asthma Inflammation: Cells and Mediators (1)

Answer 8

Allergen
>Macrophage/dendritic cell >mast cell
»Th2 cell &raquo_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)

Question 9

Asthma Inflammation: Cells and Mediators (2)

Answer 9

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

Question 10

Airway mucosal oedema

Answer 10

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

Question 11

Mucus plugs in fatal asthma

Answer 11

Involuted epithelium to accomodate narrowing of the airways
>exacerbated by mucus plug
>different phenomena
»acute inflammation, repair, chronic inflammation

Question 12

Acute and Chronic Inflammation

Answer 12

Acute inflammation -> airway mucosal oedema

Chronic inflammation&raquo_space; eosinophils and desquamation
»airway remodelling

> > > > all lead to airway narrowing

Question 13

Key components of asthma pathogenesis

Answer 13

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)

Question 14

Treating Obstruction

Answer 14

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)

Question 15

Routes of drug administration

Answer 15

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)

Question 16

Therapeutic Outcomes

Answer 16

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

Question 17

Receptors on airway smooth muscle (ASM)

• Balance of relaxation and contraction

Answer 17

Functional antagonism

Constriction
>HIstamine
>leukotrienes
>ACh

Dilation
>Adrenaline (endogenous)
>PGE2
>Synthetic B2-adrenoceptor agonists

Question 18

Relievers: Short-acting B2-adrenoceptor Agonists

Answer 18

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

Question 19

Regulation of smooth muscle tone

Answer 19

(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

Question 20

B2-adrenoceptor agonists relax ASM

Answer 20

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

Question 21

Features of the B2-Adrenoceptor

Answer 21

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)

Question 22

Controllers: Long-acting B2-adrenoceptor agonists

Answer 22

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)

Question 23

Muscarininc receptor antagonists - Bronchodilators

Answer 23

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)

Question 24

Preventers: Glucocorticoids

Answer 24

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)

Question 25

Regulation of endogenous glucocorticoids

Answer 25

Inhaled route for steroids is particularly important
>targeting airway cells, dont want systemic effects

Cortisol levels - direct feedback mechanisms
>using oral steroids causes significant rise in systemic levels
>affects hypothalamus
>reduces pituitary action and causes adrenal activity
>Adrenal glands stop producing cortisol
>if drug is continuously consumed, no problem

> > if stop taking GCS, then we have a problem because we are no longer producing endogenous cortisol
no more growth hormones

Question 26

Glucocorticoids used to treat asthma

Answer 26

Inhaled GCS indicated if need B2-agonists > 3 times/week
>i.e. mild persistent asthma

Topical (inhaled GCS)
>budesonide
>fluticasone propinoate
(both available in combination with B2-agonist)

Start at effective dose - step down

Systemic (oral GCS)
>prednisolone (oral administration - several days, for acute exacerbations)

Question 27

Stepwise management - Pharmacotherapy

Answer 27

Outlines that treatment of increasingly severe disease involves increasing number of treatment combination

Question 28

Biologics in treatment of chronic allergic disease

• Asthma, atopic dermatitis, chronic sinusitis with nasal polyps

Answer 28

Nonspecific immunosuppression
>corticosteroids
»effective across all three diseases, but toxicity precludes widespread and long-term use

IL-5 specific blockers
>Mepolizumab (GSK)
»inhibit Th2 recruitment of eosinophils
»effective in asthma subgroups with high eosinophils
»also helps suppress steroid withdrawal exacerbations
(modest efficacy, expensive, large unmet need)
»>decreases total use of OCS, has been shown to facilitate complete weaning from chronic OCS (14%)
»>standard s.c. dosing has not been shown to decrease sputum eosinophilia, approved at higher dosing for EGPA

IgE-specific mAbs
>Omalizumab
»effective in allergic asthma