Flashcards in Pharmacology of Asthma and COPD: bronchodilators Deck (43):
In what locations of the respiratory system do asthma, bronchitis and COPD occur?
Asthma & bronchitis are a disease of the larger (>2mm) conducting airways: trachea, bronchi and bronchioles
COPD is a disease of the smaller airways (<2mm): respiratory bronchioles, alveolar ducts and alveolar sacs
COPD is characterised by airflow obstruction that is not fully reversible.
The airflow obstruction does not change markedly over several months and is usually progressive in the long term.
COPD is predominantly caused by smoking
Characteristic features of asthma?
- reversible obstruction (to a degree) of airways
- response to stimuli (temperature & pollution) that are not themselves noxious and do not affect non- asthmatic subjects
- increased broncuial hyper-responsivness to wide variety of stimuli
- mucus secretion
- oedema due to increased vascular permeability
What is bronchial hyperresonsiveness?
An increased sensitivity to a wide variety of airway narrowing stimuli.
What happens when an asthmatic inhales an antigen?
- House dust mice produce small circular pellets which can be inhaled from the air and respond to a an antigen expressed on the mast cells
- Cross-linking occurs resulting in degranulation of mast cells
- Mediators are released: histamine. prostaglandins, leukotrienes and cytokines e.g. interleukin
Effects of which include
- oedema due to increased vascular permeability in blood vessels
- increased mucus secretion
- increased cell recruitment e.g. eosionphils and T lymphocytes
- cilia in airways become damaged- can no longer clear out mucus- exposed to sensory nerves underneath- more stimulation of sensory nerves resulting in more bronchoconstriciton
Difference between healthy and asthmatic lungs viewed down a bronchoscope
A bronchoscope allows us to see down into the bifurcations of the airways.
-wide, clear conducting airways
- lumen full of air allowing for clear access to alveoli
- clear visualisations of the bifurcations
- bifurcations are more obscured
- conducting airways are full of mucus
- red, inflamed airway walls
- oedema and vascular leakeage further compressing the airway
Describe the biology of the asthma cell
- damage to epithelial layer exposing sensory nerves underneath
- plasma exudation resulting in oedema
- inflammatory cell infiltration
- mucus plug in airway lumen containing inflammatory cells and plasma exudate
- thickened basement membrane
How can lung function overtime in hospitals?
Can measure there forced expiratory volume in 1 second.
- can extract protein from house dust mice that cause the response and expose it in hospital conditions
- first exposure induces a sharp decrease in FEV1 as a result of histamine release causing airway contraction
- accounted mast cell surface IgE cross reacting with HDM antigen triggering histamine and leukotriene release- AIRWAY SMOOTH MUSCLE CONTRACTION
- recovers within the first hour
- 6 hours later, a secondary spontaenous fall in FEV1
- this is due to an increase in inflammatory cell recruitment (20%)
- in asthma this is predominantly eosinophils
what happens to the basement membrane of asthmatics?
The thickened reticular basement membrane is made up of myofibroblasts secreting collagen.
if the tissue is continously damaged, the tissue tried to repiar itself producing scar tissue- airway wall remodelling
disrupted epithelium, thicken reticular basement membrane, inflammatory cell infiltrate & eosinophils
Difference between asthmatic and healthy cilia?
In healthy lungs, the epithelial layer is covered in cilia and goblet cells. when mucus is secreted from goblet cells, the cilia sweep it up the airway to remove inflammatory cells, foreign material.
- epithelium is continously damaged by exposure to allergen
- constant disruption of mucus results in thickening of the mucus triggered by materials secreted from degranulated eosinophils
- dagaed epothelium exposes sensory nerves underneath which respond to temperature,, humidity and irritants in the air
- exposure and stimulation of the nerves triggers mucus secretion and muscle contraction- HYPERRESPONSIVENESS
- constantlyl get degranulation of mast cells resulting in degradation of protective cilia layer
Medicinal plants used in the pharmacological treatment of asthma
- deadly nightshage (atropa belladonna)
- thorn apple (datura stramonium)
active ingrediant- anticholinergic alkaloids atropine, hyoscyamine and scopolamine
What is COPD?
- vast majority of COPD is caused by cigarette smoke- although polution is another culprit
- alveolar macropgaes make up 95% of resident inflammatory cells in the lungs. Normally, there to phagocytose infectious, toxic particles.
- cigarette smoke activates these cells and tries to phagocytose them. once acgivated, they secrete large amounts of cytokines and inflammatory mediators.
- unlike in asthma, IL-8 is secreted which specifically recruits neutrophils
- neutrophils secrete enzymes e.g. neutrophil elastase to degrade bacteria
- in smokers this is overwhelmed and these enzymes are secreted into the lung tissue resulting in lung tissue degradation
- overtime the alveoli structure becomes completely destroyed leading to empysema
- UNLIKE ASTHMA THIS IS DESTRUCTION OF THE PERIPHERAL AIRWAYS NOT THE CONDUCTING AIRWAYS
- outcome for the measurement of COPD in the clinic is the 6 minute walk test
Describe the pathology of COPD
In normal lung parenchyma, alveolar in terminal airways adjacent to pulmonary endothelial cells provide a minimal barrier for air/blood exchange
In chronic bronchitis, in the early stages, significant neutrophil recruiment inflaming the airways and secreting elastases.
in emphysema, continual secretion of proteases causes tissue destruction bringing about emphysema. Can no longer absrob oxygen which is why patients are given supplemental oxygen.
What is the effect of smoking on annual decline in FEV1?
All of us have a decline in lung function with increasing age
• When you smoke, you accelerate this decline in lung function.
• If you stop smoking (shown by the dotted line) the decline in lung function returns to the normal rate of decline
• Whilst stopping smoking can arrest the increased rate of decline, you cannot recover what has been lost as this is due to irreversible peripheral airway destruction
• Eventually this decline in lung function is incompatible with life triggering disability and ultimately premature death!
• All treatments we have for COPD are at best symptomatic, we cannot alter disease outcome
Drug pharmacological treatment of asthma
First step is to induce bronchodilation
- Beta 2 adrenergic receptor agonists (short acting and long acting)
- muscarinic antagonists (indirect)
- xanthines (but not used acutely)
- glucocorticosteroids (inhaled)
- cromones (sodium cromoglicate, nedocromil sodium)
- leukotriene antagonists
- Anti- IL-5
How do inflammatory mediators such as histamine cause smooth muscle contraction?
- Histamine released from allergen stimulated mast cells stimulate H1- histamine receptors
- H1 receptor activation mobilises calcium from the SR, increasing intracellular concentration of calcium
- Ca2+ binds to calmodulin (CaM)
- The Ca2+ bound CaM activates myosin light chain kinase (MLCK)
- MLCK phosphorylates light chains in the myosin heads and increases activation of myosin ATPase
- Active myosin crossbridges slide along actin filaments creating muscle tension INCREASING MUSCLE CONTRACTION
- histamine signalling also inactivates myosin light chain phosphatase (also increases contraction)
How do beta-2 agonists function as bronchodilators?
1) inhibit calcium release/ increase uptake into the SR
2) inhibits MLCK (via phosphorylation)
3) activates MLCP (disinhibition via phsophorylation of RhoA, phosphorylation MYPT1)
Describe beta 2 adrenergic receptors
- G-protein coupled 7 transmembrane receptor
- intracellular carboxyl group
- agonist into 30-40% into the lipid bilayer
- coupled to Gs
How do activation of B2 adrenergic receptors cause bronchodilation?
-B2 adrenergic receptors are found in the airway smooth muscle
-stimulation increases adenylyl cyclase (AC) activity increasing the production of cAMP from ATP
-increased cAMP increases the activity of protein kinase A, inducing relaxation through 3 mechanisms
1) inhibiting Ca2+ release
2) inhibiting myosin light chain kinase
3) increasing activity of myosin light chain phosphatase
What are the current, short-acting, long- acting and ultra long-acting bronchodilators?
Oral vs inhalation
-metered dose inhaler produces more bronchodilation at lower doses whereas the oral route requires larger doses to be effective
- less systemic side effects with inhalation
- more rapid onset of action with inhalation
positives and negatives of the compressor-driven nebuliser
- no portability
- bacterial contamination
- delivers constant doses
terbutaline can be injected subcutaneously without the need for patient cooperation, for example in astham
only 10% of the inhaled dose reaches the airways, the rest is swallowed.
How do muscarinic antagonists work as bronchodilators?
By inhibiting parasympathetic innervation of the airway smooth muscle.
- under normal conditions, ACh is released at the junction between the post ganglionic parasympathetic nerves and the airway smooth muscle
- ACh stimulates M3 muscarinic ACh receptors on the airway smooth muscle triggering bronchoconstriciton
- blockade of M3 muscarinic receptor antagonists block parasympathetic innervation inhibiting bronchoconstriction
Give examples of short acting and long acting muscarinic antagonists used as bronchodilators
what is the effectiveness of combination therapy (sympathomimetic and anticholinergic)
- B2 agonists amplifies the smooth relaxation induced by antimuscarinics
- the addition of a muscarinic antagonist can amplify the bronchodilation elicited by the B2 agonist
-due to reduction of PLC activation which in turn reduces the eterologus densitisation of beta2 receptors
- the combination should help to overcome inter and intra patient variability
e.g. carmoterol + tiotropium
olodaterol + tiotropium
What is the interaction between glycopyrronium and indacaterol?
demonstrates synergism on efficacy of bronchidlation
increased observed relaxant response
What are MABA molecules?
Combination treatments are advancing from co-treatment with beta 2 agonists and muscarinic antagonists in a single inhaler to having them combind in a SINGLE MOLECULE
- introduces diversity
- modulates physical properties
- modulates potency, selectivity and metabolism
How do xanthines function in airway disease?
- theophylline & doxophylline
- are structurally related to caffeine and caninduce bronchodilation
- have to be taken orall as tablets so are associated with systemic side effects similar to high caffeien usage: stimulation of heart rate, force of contraction and cardiac arrythmias
- therefore, are not used extensively for mainstream therapy
- sometimes given to children early on who are not capable of using inhalers
- get some antiinflammatory effects due to effects of phosphodiesterases
How do glucocorticosteroids work in the treatment of asthma?
involved in trans-activation and trans- repression
- annexin (lipcortin)
- B2 adrenoceptors
- mitogen kinase phosphate-1
- adhesion molecules
- inflammatory enzymes (COX2, NOS)
what are the 6 cellular actions of glucocorticoids?
-Inhibition of leukotriene and cyctokine synthesis/release
• Inhibit lymphocyte proliferation and pulmonary recruitment
• Inhibit activation, chemotaxis, adhesion of eosinophils and also promotes eosinophil apoptosis
• Inhibits mast cell proliferation
• Increases β2-adrenoceptor function
what are the 6 roles of glucocorticoids in asthma?
- Prevents infiltration and activation of inflammatory cells
• Reduces mucosal oedema
• Improves airflow and lung function
• Decreases airway hyperresponsiveness • Decreases frequency and severity of exacerbations
• Improves quality of life
Side effects of oral or prolonged high dosages of glucocorticoids?
- Growth retardation, bruising
• Suppresion of hypothalamic-pituitary axis
• Osteoporosis (Serum osteocalcin), water retention, diabetes
• Hypertension, weight gain, ocular hypertension
Side effects of inhaled route of glucocorticoids?
-Oral candiadiasis (fungal infection)
• Hoarseness, cough, voice problems
• No sign or bronchial atropy, metaplasia or malignant transformation
Give examples of fixed dose triple therapies
DPI: fluticasone fuorate, umeclidinium, vilanterol
pMDI- beclometasone, formoterol fumarate
HFA pMDI- budesonide/ glycopyrronium bromide/ formoterol fumarate
How do cromones work?
- When mast cells are activated by cross-linking with allergens (i.e.HDM), They degranulate releasing many different pro inflammatory mediators including IL-5, histamine, LTs, reactive oxygen species and prostaglandins.
• Cromones eg. Cromolyn and nedocromil, inhibit mast cell degranulation preventing the release of these mediators from mast cells in response to allergen exposure.
• Cromones have an incredibly short half life, and require 6-8 times daily treatment, so has major compliance issues
How do anti-leukotrienes work?
When mast cells are activated by cross-linking with allergens (i.e.HDM), Leukotrienes are released from internal stores
• Induce Bronchoconstriction
• Increase vascular permeability
• Mucus secretion
• Bronchial hyperresponsiveness
• They are however not the same as steroids and have been shown in the clinic to be less effective than steroids (limited effects on eosinophil recruitment)
How does IL-5 work?
Il-5 is a cytokine released by mast cells that is critical for eosinophil recruitment
• Development of IL-5 monoclonal antibodies (mepolizumab) to ‘mop up’ have shown efficacy in clinical trials in inhibiting eosinophil recruitment
• Only used in severe asthma in hospitals due to the cost and given by injection once every 4 weeks.
• 3 more in the pipeline currently
How do anti IgE antibodies work?
IgE expressed on mast cells cross-links with antigens on allergens in allergic asthma initiating the asthmatic response
• Inhibit IgE interaction with allergen via anti-IgE antibodies blocks the response. However, these are again very expensive (year long treatment ~ $10,000)
What is the effect of glucocorticoids in the treatment of COPD?
Unlike Asthma, steroids have no effect on lung function decline in COPD
• 5 independent studies have now shown no difference between placebo and steroids
• Chronic treatment of COPD patients with steroids increases risk of pneumonia and infection
IN THE PAST, BIG PHARMACEUTICAL COMPANIES HAVE AGGRESIVELY MARKETED STEROIDS FOR TREATEMENT OF BOTH COPD AND ASTHMA BASED ON INFLAMMATION. THIS GRAPH CHALLENGES THIS AND DEMONSTRATES NO BENEFITS OF STEROIDS IN COPD TREATMENT
What is an alternative that can be used for COPD instead of glucocorticoids?
PDE4 inhibition: roflumilast
PDE4 belongs to a family of enzymes (PDE1-11).
• PDE4 is the predominant enzyme in inflammatory cells (i.e. neutrophils) which can be inhibited via treatment to reduce inflammation
• PDE4 hydrolyses cAMP upregulating the inflammatory response: • Increases in protease release from cells, increasing tissue damage
• Roflumilast has been approved for COPD treatment as an inhibitor of PDE4 activity
- shown a decrease in neutrophil recruitment
- shown a decrease in the release of pro-inflammatory mediators causing tissue damage and degradation
Drugs for asthma
• Anticholinergic agents
- Anti IgE Anti-IL5