Bronchodilators and Anti-Inflammatory Drugs in the Treatment of Asthma Flashcards
Three types drugs used in asthma treatment?
Relievers
Controllers/preventors
Methylxanthines have properties of both (brochodilator and anti-inflammatory)
Describe reliever drugs and the three types
Act as bronchodilators but have little influence on underlying condition
Three types:
Short acting β2-adrenoceptor agonists (SABAs)
Long acting β2-adrenoceptor agonists (LABAs)
CysLT1 receptor antagonists
Describe controller drugs and the two types
Act as anti-inflammatory agents that reduce airway inflammation
Glucocorticoids mainly (for all of the most mild forms of asthma), like inhaled corticosteroid (ICS)
Cromoglicate
Humanised monoclonal IgE antibodies
Step 1 of pharmacological management of asthma?
SABA for very mild intermittent asthma
Step 2 of pharmacological management of asthma?
If SABA is needed more than once a day, add a regular, inhaled glucocorticoid
Step 3 of pharmacological management of asthma?
If control is inadequate, add a LABA and monitor
If of benefit, continue
If inadequate, increase ICS dose
If no response to LABA, stop administration and increase ICS dose
If still inadequate, institute trials of other therapies, like CysLT1 receptor antagonist or theophylline
Step 4 of pharmacological management of asthma?
If there is perisistent asthma and it is poorly controlled, increase ICS dose and add a fourth drug, like CysLT1 receptor antagonist, theophylline or oral β2 agonists
Step 5 of pharmacological management of asthma?
If control is still inadequate, give oral glucocorticoid and refer to specialist care
Pharmacokinetic differences between aerosol and oral therapy for asthma?
Aerosol - slow absorption from lung surface so rapid system clearance as there is a low conc. in systemic circulation
Oral - good oral absorption (with exceptions) and slow systemic clearance
Dose differences between aerosol and oral therapy for asthma?
Aerosol - low does delivered rapidly to target
Oral - high systemic dose necessary to achieve an appropriate conc. in lung
Systemic conc. of drug with aerosol and oral therapy for asthma?
Aerosol - low
Oral - high
Incidence of adverse effects with aerosol and oral therapy for asthma?
Aerosol - low
Oral - high (but depends on drug)
Distribution of drug with aerosol and oral therapy for asthma?
Aerosol - reduced in severe airway disease
Oral - unaffected by airway disease
Compliance with aerosol and oral therapy for asthma?
Aerosol - good with bronchodilators (taken as needed); less so with anti-inflammatory drugs
Oral - good
Ease of administration of aerosol and oral therapy for asthma?
Aerosol - difficult for small children and infirm people
Oral - good
Effectiveness of aerosol and oral therapy for asthma?
Aerosol - good in mild to moderate disease
Oral - good even in severe disease
Describe action and brief mechanism of β2-adrenoceptor agonists
Act as PHYSIOLOGICAL antagonists of all spasmogens, like ACh and histamine
Cause airway smooth muscle relaxation but do not block effect of parasympathetic stimulation; block consequences of stimulation
Mechanism of β2-adrenoceptor agonist action?
Binds to β2-adrenoceptor, activating Gs which activates adenylyl cyclase
Adenyyl cyclase degrades ATP to cAMP (cyclic adenosine monophosphate)
cAMP activates PKA (protein kinase A) which causes phosphorylation of MLCK and myosin phosphatase
Relaxation
cAMP can be inhibited by PDE (phosphodiesterase), so PDE can be blocked to increase PKA conc.
Mechanism involves decrease in intracellular Ca2+ conc. and activation of conductance K+ channels
Classes of β2-adrenoceptor agonists?
Short-acting (SABA)
Long-acting (LABA)
Ultra-long acting
Give examples of SABAs?
Salbutamol, AKA albuterol
Terbutaline
When are SABAs used?
First line treatment for mild, intermittent asthma that are “relievers” taken as needed
Administrations of SABAs?
Usually by inhalation via metered dose/dry powder devices (lessens systemic effects)
Or orally for children/infants
Or i.v in emergency
Action time for SABAs?
Act rapidly, often within 5 mins when inhaled, to relax bronchial smooth muscle
Maximal effect within 30 mins
Relaxation persists for 3-5 hrs
What changes go SABAs cause?
Increase mucous clearance
Decrease mediator release from mast cells and monocytes
Adverse effects of SABAs?
Few due to unwanted systemic absorption when administered by inhalation:
Fine tremor (most common due to skeletal muscles expressing β2-adrenoceptors)
Tachycardia (β2-adrenoceptors are targets but agonist can bind to β1-adrenoceptor in heart)
Cardiac dysrhythmia
Hypokalaemia (effect on Na+/K+ ATPase increases K+ conc. in muscle cells and decreases it in plasma) - sometimes, β2-adrenoceptors used to treat hyperkalaemia
Examples of LABAs?
Salmeterol and formoterol
When are LABAs used?
NOT recommended for acute relief of bronchospasm (salmeterol, not formeterol, is slow to act)
Useful for nocturnal asthma as act for ~8 hrs
Cautions of LABAs?
DO NOT USE LABAs ALONE - used as add-on therapy in asthma inadequately controlled by other drugs
They must always be co-administered with a GLUCOCORTICOID
In the US, there are combination inhalers, like symbicort (budesonide and formoterol) and seratide (fluticasone and salmeterol)
Why are selective β2-adrenoceptor agonists used?
Reduce potentially harmful stimulation of cardiac β1-adrenoceptors
Non-selective agonists, like isoprenaline, are redundant and no longer used
Risks of non-selective β-adrenoceptor antagonists?
In asthmatic patients, there is a risk of bronchospasm, e.g: with propranolol (a β-blocker)
Caution with non-selective β-adrenoceptor antagonists?
Never use non-selective β1, β2-adrenoceptor antagonists with asthmatics, like propranolol
Risks with LABAs?
May worsen asthma by several mechanisms
Cause increased incidence of asthmatic deaths
Long-term use of LABA consequences and reason for this?
Persistent activation of β2-adrenoceptors causes receptor desensitisation and endocytosis, resulting in loss of function
Enzymes involved with desensitisation of β2-adrenoceptors?
Protein Kinase A (PKA)
G protein receptor kinases (GRKs), specifically β-adrenoceptor kinases
What does endocytosis in LABA long-term use entail?
β-arrestin binds to phosphorylated β2-adrenoceptor (by GRK) forming β-arrestin/receptor complex
β-arrestin acts as a scaffold protein, linking desensitised β-adrenoceptors to “endocytotic machinery” that INTERNALISES THE RECEPTOR
Receptors are internalised in clathrin-coated pits and vesicles; then trafficked to either endosome for recycling OR lysosome for degradation
Explain why LABAs are often used in combination with glucocorticoids
Suppress pathways that result in internalisation of β2-adrenoceptors and so maintain function
Describe what CysLT1 receptor antagonists do, examples and how they arise
Act COMPETITIVELY at CysLT1 receptor
LTC4, LTD4, LTE4 derived from mast cells, and infiltrating inflammatory cells, cause smooth muscle contraction, mucous secretion and oedema
Mechanism of CysLT1 receptor activation?
Mast cell activates and intracellular release of arachidonic acid is stimulated by phospholipase A2
Arachidonic acid metabolised to 5-lipoxygenate by FLAP1
Formation of LTA4 - metabolised to LTB4 and LTC4 which leave the mast cell
LTB4 acts as a chemokine and and attracts inflammatory cells into airways (infiltrate and release CysLTs)
LTC4 is metabolised to LTD4 and LTE4
LTC4, LTD4, LTE4 and the cysLTs work on cysLT1 receptor (antagonist will competitively block to suppress bronchoconstriction and inflammation)
Examples of CysLT1 receptor antagonists?
Any drug with suffix ukast
Motelukast
Zafirlukast
How are CysLT1 receptor antagonists effective?
As ADD ON therapy (SHOULD NOT USE ALONE) against early and late bronchospasm in mild, persistent asthma and in combination with other medication, like inhaled corticosteroids, in more severe conditions
Effective against antigen-induced and exercise-induced (cold, dry air) brochospasm
Outcome of CysLT1 receptor antagonist use?
Relax bronchial smooth muscle in response to CysLTs and are administered via ORAL route
When are CysLT1 receptor antagonists not used?
Not recommended for relief of acute severe asthma, as bronchodilator activity is less than salbutamol
Side effects of CysLT1 receptor antagonists?
Generally well tolerated but headaches and GI upset have been reported
Examples of methylxanthines?
Theophylline
Aminophylline
(Present in coffee, tea and chocolate-containing beverages)
Methylxanthine activity?
Combine bronchodilator (at high doses) and anti-inflammatory actions, inhibit mediator release from mast cells and increase mucous clearance
Mechanism of methylxanthine action?
Uncertain - may involve inhibition of isoforms of phosphodiesterases, specifically PDE III AND IV) that inactivate cAMP and cGMP (second messengers that relax smooth muscle and may exert an anti-inflammatory effect)
AT HIGH DOSES (not encountered therapeutically), theophylline inhibits PDE3 from breaking cAMP down to 5’AMP
cAMP accumulates and this facilitates relaxation
Other methods with which methylxanthines may act?
Increase diaphragmatic contractility and reduce fatigue which may improve lung ventilation
Theophylline activates histone deacetylase (HDAC) which may potentiate anti-inflammatory action of glucocorticoids
How are methylxanthines used?
Second line drugs used in combination with β2-adrenoceptor agonists and glucocorticoids
Administered orally as sustained release preparations
Why are methylxanthines so dangerous?
Have a very narrow therapeutic window and exert adverse effects at supra-therapeutic concentrations
Side effects of methylxanthines?
Have effects on CNS, CVS, GI tract and kidneys:
Dysrhythmia
Seizures
Hypotension
At therapeutic conc., frequently cause nausea, vomiting, abdominal discomfort and headache
Cautions with methylxanthines?
Problematic due to numerous drug interactions
Mathylxanthines are metabolised in liver by CYP450s (also metabolise some antibiotics) - interact with erythromycin
Antibiotics are metabolised but methylxanthines are not, leading to accumulation
Location of corticosteroid production?
Adrenal cortex
Not pre-stored, but synthesised and released on demand
Two major classes of corticosteroids and specific site of synthesis?
Glucocorticoids (synthesised in the zona fasiciculata) - main hormone in man is cortisol, a type of glucocorticoid (hydrocortisone)
Mineralocorticoids (synthesised in zona glomerulosa)
What does cortisol do?
Regulates numerous processes:
Main ones - inflammatory and immunological responses
There are others and oral glucocorticoids can cause all these effects so try to avoid use
Uses of cortisol derivatives?
Synthetic derivatives, like beclometasone, budesonise and fluticasone, with little/no mineralocorticoid activity are used for anti-inflamamtory effect in asthma
Structural differences between cortisol and beclometasone?
In beclometasone, -OH group with a larger group to retain gluco but not mineralocorticoid activity
Why are glucocorticoids not used for acute bronchospasm? What are they used for?
Have no direct bronchodilator action
Used as mainstay treatment in prophalaxis of asthma and are preferably delivered by inhalational route to minimise adverse effects
Main mineralocorticoid and briefly what it does?
Aldosterone regulates retention of salt (and water) by kidney
Endogenous steroids?
May posses both gluco and mineralocorticoid actions
Latter are unwanted in treatment of inflammatory conditions
Mechanism of glucocorticoid action?
Signal via NUCLEAR RECEPTORS, specifically GRα
Glucocorticoids are lipophilic molecules - diffuse into cell
Within cytoplasm, combine with GRα causing dissociation of inhibitory heat shock proteins
Activated receptor translocated to nucleus aided by “importins”
Within nucleus, activated receptor monomers assemble into homodimers and bind to glucocorticoid response elements (GREs) in promotor region of specific genes
Transcription of specific genes is either “switched-on” (transactivated) or “switched off” (transpressed) to alter mRNA levels and rate of synthesis of mediator proteins
What genes do glucocorticoids switch on and off?
Those encoding for inflammatory proteins
Activate genes that encode anti-inflammatory mediators
How else are genes regulated?
Modifying chromatin structure (via deacetylation of histones)
How does acetylation and deacetylation of histones work? Mechanism of glucocorticoids in relation to this?
Expression of inflammatory genes is associated with acetylation of histones by histone acetyltransferases (HATs) - acetylation unwinds DNA from histones allowing transcription of genes
GLUCOCORTICOIDS RECRUIT HDACs (histone deacetylases) to activated genes and switch off gene transcription
Chromatin definition?
Histones + DNA
Mechanism of glucocorticoid suppression of inflammation?
Decrease formation of TH2 cytokines (IL-4, IL-5) and cause apoptosis
IL-4 cannot activate TH2 to plasma cells and so IgE production is prevented
IL-5 cannot stimulate eosinophils (prevent allergen-induced influx of them into lungs - cause apoptosis)
IL-13 reduces no. of mast cells and Fcε expression
Effects of glucocorticoids on inflammatory cells in asthma?
Decreased inflammatory cell numbers via apoptosis (eosinophils, T-lymphocytes, mast cells, macrophages and dendritic cells)
Decreased cytokine release
Effects of glucocorticoids on structural cells in asthma?
Epithelial cell production of cytokines and mediatiors decreases
Endothelial leakage decreases
ASM increases β2-receptors and decreases cytokine production
Mucous glands decrease secretion
Reasons why glucocorticoids are used in asthma?
Prevent inflammation and resolve established inflammation
Short-term - do not alleviate early stage bronchospasm but long-term treatment (in combination with LABAs is)
Common adverse affects of glucocorticoid use?
Due to deposition of the steroid in oropharynx are:
Dysphonia (hoarse, weak voice)
Oropharyngeal candidiasis (thrush)
Severe, chronic or rapidly deteriorating asthma treatment with glucocorticoids?
Oral prednisolone may be used in combination with inhaled steroid to reduce oral dose and minimise side effects
Broncodilator drugs co-administered
How are patients instructed to use glucocorticoids?
Encouraged to take sufficient inhaled glucocorticoids to control symptoms and avoid disease progression (perhaps irreversible)
When and why are cromones used?
Second-line drugs now rarely used PROPHYLACTICALLY to treat allergic asthma (particularly children)
Mechanism of cromone action?
Uncertain but includes a weak anti-inflammatory effet
Decrease in irritant receptor sensitivity associated with sensory C-fibres (trigger exagerated reflexe)
Reduce cytokine release
Problem with inhalation of cromones?
Inhalation means little systematic absorption
Effectiveness of cromones?
Reduce both phases of asthma attach but a while to develop and block late-phase reaction - frequent dosing needed
More effective in children/young adults than older
Mechanism of monoclonal antibodies in asthma treatment?
Binds IgE via Dv to prevent attachment to Fcε receptors - suppresses mast cell degranulation and response
Reduced Fcε receptor expression on inflammatory cells
When are monoclonal antibodies used?
Asthma associated with severe eosinophilia (dramatic increase in eosinophils)
Very expensive
Administration of monoclonal antibodies?
Requires intravenous administration
Examples of monoclonal antibodies and where they are directed?
Omalizumab - directed against IgE
Mepolizumab - IL-5
