Bronchodilator and anti-inflammatory drugs in the treatment of asthma Flashcards
What are the 2 classes of drug used in the treatment of asthma?
- Relievers
* Controllers/preventers
What are examples of relievers? (4)
- SABAs
- LABAs
- CysLT1 receptor antagonists
- Methylxanthines
What are relievers?
Act as bronchodilators
What are examples of controllers/preventers? (4)
- Glucocorticoids
- Cromoglicate
- Monoclonal IgE antibodies
- Methylxanthines
What class do methylxanthines fall under?
Both relievers and controllers/preventers
What are controllers/preventers?
Act as anti-inflammatory agents that reduce airway inflammation
Are controllers/preventers used in relief of an acute asthma attack?
No, they are used to prevent asthma attacks - very little effect when used acutely
When are relievers administered?
Treatment of acute bronchial spasms
What do methylxanthines do?
Treat bronchial spasms and inflammation
What are the advantages of aerosol therapy for asthma? (6)
- Slow absorption from lung surface and rapid systemic clearance
- Only low dose required
- Delivered directly to target
- Low systemic concentration
- Reduced side effects
- Good with bronchodilators
What are the disadvantages of aerosol therapy for asthma? (4)
- Distribution of drug reduced in severe airway disease
- Difficult administration for small children and elderly
- Only effective in mild to moderate disease
- Not good with anti-inflammatory drugs
What are the advantages of oral therapy for asthma? (5)
- Good oral absorption
- Distribution of drug unaffected by airway disease
- Can be used in addition to bronchodilators and anti-inflammatory drugs
- Ease of administration
- Effective in even severe disease
What are the disadvantages of oral therapy for asthma? (4)
- Slow systemic clearance
- High systemic dose necessary to achieve an appropriate concentration in the lung
- High systemic concentration of drug
- High incidence of adverse effects
In what instances are oral and aerosol therapies for asthma used? (2)
- Aerosol - mild to moderate disease
* Oral - severe disease
What are B2-Adrenoceptor agonists?
Physiological antagonists of all spasmogens
What are the classes of B-adrenoceptor agonists? (3)
- Short-acting (SBA)
- Long-acting (LABA)
- Ultra long-acting (ultra-LABA)
What are examples of short-acting B2-adrenoceptor agonists? (3)
- Salbutamol
- Albuterol
- Terbutaline
When are B2-adrenoceptor agonists taken for asthma?
First line treatment for mild, intermittent asthma
How are B2-adrenoceptors administered? (4)
Inhalation via
- Metered dose
- Dry powder devices
Or (less commonly)
- Oral
- IV
When are B2-adrenoceptors administered intravenously?
In an emergency
What is the dosage for B2-adrenoceptor agonists?
They are relievers taken as needed
How quickly do B2-adrenoceptors take effect?
Act rapidly (within 5 minutes when inhaled) - maximal effect within 30 minutes
How long does the effect of a short-acting B2-adrenoceptor last?
Relaxation persists for 3-5 hours
What additional effects of B2-adrenoceptors (other than relaxation of smooth muscle)?
- Increase mucous clearance (via cilia)
* Decrease mediator release from mast cells and monocytes
What are side effects of B2-adrenoceptor agonists? (1 mild, 3 severe)
Very few adverse side effects as low systemic absorption
* Fine tremor
However, more severe side effects can occur: -
- Tachycardia
- Cardiac dysrhythmia
- Hypokalaemia
What are examples of LABAs? (2)
- Salmeterol
* Formoterol
Are LABAs used for acute relief of bronchospasm?
No, salmeterol too slow to act
Are salmeterol and formoterol slow-acting?
Salmeterol is, formoterol is not
What are LABAs useful for?
Treating nocturnal asthma (act for approximately 8 hours)
Should LABAs be used in mono therapy?
No, LABAs must always be co-administered with a glucocorticoid steroid class drug
Why is isoprenaline redundant in asthma treatment?
It is a non-selective B-agonist, so stimulates potentially harmful cardiac B1-adrenoceptors
Why are non-selective B-adrenoceptor antagonists contraindicated in the treatment of asthma?
Risk of bronchospasm
Why are LABAs always co-administered with corticosteroids?
LABAs alone may worsen asthma
What are glucocorticoids?
A class of corticosteroid
What are CysLT1 receptor. antagonists?
Bronchodilators
What are cysteinyl leukotrienes?
- Produced by mast cells and inflammatory cells
* Cause smooth muscle contraction, mucous secretion and oedema
What are examples of CysLTs? (3)
- LTC4
- LTD4
- LTE4
How do mast cells activate CysLT receptors?
- Mast cell activated
- Intracellular release of arachidonic acid by phophsolipiase A2
- Archidonic acid stimulates release of LTA4
- LTA4 becomes LTB4 and LTC4, which pass via transporters through cell membrane
- LTC4 becomes LTD4 and LTE4 which stimulate CysLT1 receptors
- LTB4 causes infiltration of more inflammatory cells that release CysLTs
What does CysLT1 receptor activation cause?
- Bronchoconstriction (early phase)
* Inflammation (late phase)
What are examples of CysLT receptor antagonists? (2)
- Montelukast
* Zafirlukast
What are CysLT1 receptor antagonists effective in treating?
- Effective against antigen-induced and exercise-induced bronchospasm
What are CysLT1 receptor antagonists used in combination with in more severe conditions?
Inhaled corticosteroids
How are CysLT1 receptor antagonists administered?
Oral route
What are CysLT1 receptor antagonists not effective in the treatment of?
Acute severe asthma (bronchodilator activity is not as great as salbutamol)
What are some side effects of CysLT1 receptor antagonists? (2)
Generally well-tolerated
- Headache
- Gastrointestinal upset
What drugs have both a bronchodilator an anti-inflammatory effect?
Methylxanthines
What are examples of methylxanthines? (2)
- Theophylline
* Aminophylline
What is the molecular mechanism of action of methylxanthines?
Uncertain molecular mechanism of action
* May inhibit phosphodiesterses (PDE3 and PDE4) that inactivate cAMP and cGMP (secondary messengers that relax smooth muscle and perhaps exert and anti-inflammatory effect)
What are the effects of methylxanthines in the treatment of asthma? (4)
- Inhibit mediator release from mast cells
- Increase mucus clearance
- Increase diaphragmatic contractility and reduce fatigue (improve lung ventilation)
- Theophilline activates histone deacetylase (HDAC) which helps the anti-inflammatory action of glucocorticoids
Are methylxanthines used in mono therapy?
No, they are second line drugs used in combination with B2-adrenoceptor agonists and glucocorticoids
How are methylxanthines administered?
Oral route as sustained release preparations
What are the disadvantages of methylxanthines? (2)
- Have a very narrow therapeutic window
* Have adverse effects at supra-therapeutic conditions
What are the side effects of methylxanthines at supra-therapeutic conditions? (3)
Result from actions involving the CNS, CVS, GI tract and kidneys
- dysrhythmia
- seizures
- hypotension
What are the side effects of methylxanthines at therapeutic concentrations? (4)
- Nausea
- Vomiting
- Abdominal discomfort
- Headache
Why are methylxanthine problematic?
Due to drug interactions involving cytochrome P450 in the liver
Where are corticosteroids synthesised in the body?
Adrenal cortex
What are the 2 major classes of steroid hormone synthesised by adrenal cortex?
- Glucocorticoids (zona fasiciculata)
* Mineralocorticoids (zona glomerulosa)
Are glucocorticoids and mineralocorticoids pre-stored?
No, synthesised and released on demand
Are glucocorticoids natural?
There are both natural (produced by adrenal medulla) and synthetic glucocorticoids
What is the main hormone in glucocorticoids?
Cortisol
What is medicated cortisol known as?
Hydrocortisone
What is the effect on glucocorticoids (including hydrocortisone)? (2)
- Decreases nflammatory responses
* Decreases immunological responses
How are unwanted effects of corticosteroids in the liver avoided?
Delivery via airways
What is an example of a mineralocorticoid?
Aldosterone
What is the function of mineralocorticoids?
Regulate the retention of salt (and water) by the kidney
What actions are unwanted in endogenous steroids in the treatment of inflammatory conditions?
Mineralocorticoid actions
What are examples of synthetic derivatives of cortisol? (3)
- Beclometasone
- Budesonide
- Fluticasone
What are beclometasone, budesonide and fluticasone used for?
Anti-Inflammatory effect in the treatment of asthma
have no mineralocorticoid activity
Are glucocorticoids not used to treat acute asthma attacks?
No, they have no direct bronchodilator action
What are glucocorticoids used for in the treatment of asthma?
Used in prevention of asthma attacks
Explain the molecular mechanism of action of glucocorticoids
- Glucocorticoids are lipophilic - enter cells by diffusion across the plasma membrane
- Within the cytoplasm, they combine with GRa causing dissociation of inhibitory heat shock proteins (e.g. HSP90)
- The activated receptor translocates to the nucleus aided by ‘importins’
- Within the nucleus activated receptors form homodimers and bind to glucocorticoid response elements (GRE) in the promotor region of specific genes
- The transcription of specific genes is either ‘switched-on’ (transactivated) or ‘switched off’ (transrepressed) to alter the rate of synthesis of mediator proteins
What are the molecular effects of glucocorticoids? (4)
- Suppress the activation of inflammatory genes
- Increase the translation of anti-infamamtory genes
- Increase cellular concentration of anti-inflammatory proteins
- Decrease intracellular concentration of inflammatory proteins
In what 2 ways are genes regulated?
- By glucocorticoids acting at glucocorticoid response elements (GREs)
- Modifying the structure of chromatin via the deacetylation of histones
How are inflammatory genes expressed?
Histone acetyltransferases (HATs) - acetylation ‘unwinds’ DNA from histones allowing transcription
How do glucocorticoids switch off gene transcription?
Glucocorticoids recruit histone deacetylases (HDACs) to activated genes and switch off gene transcription
Why are glucocorticoids not effective in COPD?
In COPD, HDAC expression is lost, hence glucocorticoids cannot exert their suppressant effect on the transcirpiton of inflammatory genes
What are glucocorticoid effects on inflammation in asthma? (6)
- Decrease the formation of TH2 cytokines and cause apoptosis
- Suppress production of IgE from plasma cells
- Decrease number of eosinophils, macrophages, mast cells and dendritic cells
- Decrease vascular permeability
- Increase expression of B2-receptors on smooth muscle
- Decrease mucous secretion
What are the 2 effects of glucocorticoids in asthma?
- Prevent inflammation
* Resolve established inflammation
How are unwanted systemic side effects prevented in glocucorticoids (beclometasone, budesonide, fluticasone)?
Administered by metered dose inhaler
What are the most common adverse effects of glucocorticoids? (2)
- Dysphonia (hoarse and weak voice)
* Oropharangeal candidiasis (thrush)
What causes adverse effects of glucocorticoids?
Deposition of steroid in the oropharynx
What are inhaled corticosteroids used to treat?
Mild ot moderate asthma
What are oral steroids (prednisolone) used to treat?
Severe asthma
How are unwanted systemic effects avoided in prednisolone?
Used in combination with an inhaled steroid to reduce the oral dose required
Why is it important that patients take sufficient inhaled glucocorticoids?
To control symptoms and avoid disease progression, which may be irreversible
What are cromones?
Second line drugs infrequently used prophylactically in the treatment of allergic asthma
What are the effects of cromones in asthma? (2)
- Mast cell stabilizers - agents that supress histamine release from mast cells (but this is not the basis of their action in asthma)
- Have no direct effect on bronchial smooth muscle
What is the potential mechanism of action of cromones e.g. cromoglicate?
A decrease in the sensitivity of irritant receptors associated with sensory C-fibres - triggers exaggerated reflexes and reduction of cytokine release
What is a example of a cromone?
Sodium cromoglicate
How are cromones administered?
Via inhalation
In what patients are cromones most effective?
In children and young adults
What is an example of an anti-IgE monoclonal antibody?
Omalizumab
What are the mechanisms of action of anti-IgE monoclonal antibodies? (2)
- Binds to IgE via Fc to prevent attachment to FcE receptors – suppresses mast cell response to allergens
- Reduces expression of Fc receptors on various inflammatory cells
What are the drawbacks of anti-IgE monoclonal antibodies? (2)
- Requires intravenous administration
* Expensive treatment
What is an example of an anti-IL5 monoclonal antibody?
Mepolizumab
What are anti-IL5 monoclonal antibodies used to treat?
Asthma associated with severe eosinophilia
What is the drawback of anti-IL5 monoclonal antibodies?
Very expensive
