Bronchodilators and Anti-Inflammatory Drugs in the Treatment of Asthma

Question 1

Three types drugs used in asthma treatment?

Answer 1

Relievers
Controllers/preventors

Methylxanthines have properties of both (brochodilator and anti-inflammatory)

Question 2

Describe reliever drugs and the three types

Answer 2

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

Question 3

Describe controller drugs and the two types

Answer 3

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

Question 4

Step 1 of pharmacological management of asthma?

Answer 4

SABA for very mild intermittent asthma

Question 5

Step 2 of pharmacological management of asthma?

Answer 5

If SABA is needed more than once a day, add a regular, inhaled glucocorticoid

Question 6

Step 3 of pharmacological management of asthma?

Answer 6

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

Question 7

Step 4 of pharmacological management of asthma?

Answer 7

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

Question 8

Step 5 of pharmacological management of asthma?

Answer 8

If control is still inadequate, give oral glucocorticoid and refer to specialist care

Question 9

Pharmacokinetic differences between aerosol and oral therapy for asthma?

Answer 9

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

Question 10

Dose differences between aerosol and oral therapy for asthma?

Answer 10

Aerosol - low does delivered rapidly to target

Oral - high systemic dose necessary to achieve an appropriate conc. in lung

Question 11

Systemic conc. of drug with aerosol and oral therapy for asthma?

Answer 11

Aerosol - low

Oral - high

Question 12

Incidence of adverse effects with aerosol and oral therapy for asthma?

Answer 12

Aerosol - low

Oral - high (but depends on drug)

Question 13

Distribution of drug with aerosol and oral therapy for asthma?

Answer 13

Aerosol - reduced in severe airway disease

Oral - unaffected by airway disease

Question 14

Compliance with aerosol and oral therapy for asthma?

Answer 14

Aerosol - good with bronchodilators (taken as needed); less so with anti-inflammatory drugs
Oral - good

Question 15

Ease of administration of aerosol and oral therapy for asthma?

Answer 15

Aerosol - difficult for small children and infirm people

Oral - good

Question 16

Effectiveness of aerosol and oral therapy for asthma?

Answer 16

Aerosol - good in mild to moderate disease

Oral - good even in severe disease

Question 17

Describe action and brief mechanism of β2-adrenoceptor agonists

Answer 17

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

Question 18

Mechanism of β2-adrenoceptor agonist action?

Answer 18

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

Question 19

Classes of β2-adrenoceptor agonists?

Answer 19

Short-acting (SABA)
Long-acting (LABA)
Ultra-long acting

Question 20

Give examples of SABAs?

Answer 20

Salbutamol, AKA albuterol

Terbutaline

Question 21

When are SABAs used?

Answer 21

First line treatment for mild, intermittent asthma that are “relievers” taken as needed

Question 22

Administrations of SABAs?

Answer 22

Usually by inhalation via metered dose/dry powder devices (lessens systemic effects)
Or orally for children/infants
Or i.v in emergency

Question 23

Action time for SABAs?

Answer 23

Act rapidly, often within 5 mins when inhaled, to relax bronchial smooth muscle
Maximal effect within 30 mins
Relaxation persists for 3-5 hrs

Question 24

What changes go SABAs cause?

Answer 24

Increase mucous clearance

Decrease mediator release from mast cells and monocytes

Question 25

Adverse effects of SABAs?

Answer 25

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

Question 26

Examples of LABAs?

Answer 26

Salmeterol and formoterol

Question 27

When are LABAs used?

Answer 27

NOT recommended for acute relief of bronchospasm (salmeterol, not formeterol, is slow to act) Useful for nocturnal asthma as act for ~8 hrs

Question 28

Cautions of LABAs?

Answer 28

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)

Question 29

Why are selective β2-adrenoceptor agonists used?

Answer 29

Reduce potentially harmful stimulation of cardiac β1-adrenoceptors Non-selective agonists, like isoprenaline, are redundant and no longer used

Question 30

Risks of non-selective β-adrenoceptor antagonists?

Answer 30

In asthmatic patients, there is a risk of bronchospasm, e.g: with propranolol (a β-blocker)

Question 31

Caution with non-selective β-adrenoceptor antagonists?

Answer 31

Never use non-selective β1, β2-adrenoceptor antagonists with asthmatics, like propranolol

Question 32

Risks with LABAs?

Answer 32

May worsen asthma by several mechanisms | Cause increased incidence of asthmatic deaths

Question 33

Long-term use of LABA consequences and reason for this?

Answer 33

Persistent activation of β2-adrenoceptors causes receptor desensitisation and endocytosis, resulting in loss of function

Question 34

Enzymes involved with desensitisation of β2-adrenoceptors?

Answer 34

Protein Kinase A (PKA) | G protein receptor kinases (GRKs), specifically β-adrenoceptor kinases

Question 35

What does endocytosis in LABA long-term use entail?

Answer 35

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

Question 36

Explain why LABAs are often used in combination with glucocorticoids

Answer 36

Suppress pathways that result in internalisation of β2-adrenoceptors and so maintain function

Question 37

Describe what CysLT1 receptor antagonists do, examples and how they arise

Answer 37

Act COMPETITIVELY at CysLT1 receptor LTC4, LTD4, LTE4 derived from mast cells, and infiltrating inflammatory cells, cause smooth muscle contraction, mucous secretion and oedema

Question 38

Mechanism of CysLT1 receptor activation?

Answer 38

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)

Question 39

Examples of CysLT1 receptor antagonists?

Answer 39

Any drug with suffix ukast Motelukast Zafirlukast

Question 40

How are CysLT1 receptor antagonists effective?

Answer 40

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

Question 41

Outcome of CysLT1 receptor antagonist use?

Answer 41

Relax bronchial smooth muscle in response to CysLTs and are administered via ORAL route

Question 42

When are CysLT1 receptor antagonists not used?

Answer 42

Not recommended for relief of acute severe asthma, as bronchodilator activity is less than salbutamol

Question 43

Side effects of CysLT1 receptor antagonists?

Answer 43

Generally well tolerated but headaches and GI upset have been reported

Question 44

Examples of methylxanthines?

Answer 44

Theophylline Aminophylline (Present in coffee, tea and chocolate-containing beverages)

Question 45

Methylxanthine activity?

Answer 45

Combine bronchodilator (at high doses) and anti-inflammatory actions, inhibit mediator release from mast cells and increase mucous clearance

Question 46

Mechanism of methylxanthine action?

Answer 46

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

Question 47

Other methods with which methylxanthines may act?

Answer 47

Increase diaphragmatic contractility and reduce fatigue which may improve lung ventilation Theophylline activates histone deacetylase (HDAC) which may potentiate anti-inflammatory action of glucocorticoids

Question 48

How are methylxanthines used?

Answer 48

Second line drugs used in combination with β2-adrenoceptor agonists and glucocorticoids Administered orally as sustained release preparations

Question 49

Why are methylxanthines so dangerous?

Answer 49

Have a very narrow therapeutic window and exert adverse effects at supra-therapeutic concentrations

Question 50

Side effects of methylxanthines?

Answer 50

Have effects on CNS, CVS, GI tract and kidneys: Dysrhythmia Seizures Hypotension At therapeutic conc., frequently cause nausea, vomiting, abdominal discomfort and headache

Question 51

Cautions with methylxanthines?

Answer 51

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

Question 52

Location of corticosteroid production?

Answer 52

Adrenal cortex | Not pre-stored, but synthesised and released on demand

Question 53

Two major classes of corticosteroids and specific site of synthesis?

Answer 53

Glucocorticoids (synthesised in the zona fasiciculata) - main hormone in man is cortisol, a type of glucocorticoid (hydrocortisone) Mineralocorticoids (synthesised in zona glomerulosa)

Question 54

What does cortisol do?

Answer 54

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

Question 55

Uses of cortisol derivatives?

Answer 55

Synthetic derivatives, like beclometasone, budesonise and fluticasone, with little/no mineralocorticoid activity are used for anti-inflamamtory effect in asthma

Question 56

Structural differences between cortisol and beclometasone?

Answer 56

In beclometasone, -OH group with a larger group to retain gluco but not mineralocorticoid activity

Question 57

Why are glucocorticoids not used for acute bronchospasm? What are they used for?

Answer 57

Have no direct bronchodilator action Used as mainstay treatment in prophalaxis of asthma and are preferably delivered by inhalational route to minimise adverse effects

Question 58

Main mineralocorticoid and briefly what it does?

Answer 58

Aldosterone regulates retention of salt (and water) by kidney

Question 59

Endogenous steroids?

Answer 59

May posses both gluco and mineralocorticoid actions | Latter are unwanted in treatment of inflammatory conditions

Question 60

Mechanism of glucocorticoid action?

Answer 60

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

Question 61

What genes do glucocorticoids switch on and off?

Answer 61

Those encoding for inflammatory proteins | Activate genes that encode anti-inflammatory mediators

Question 62

How else are genes regulated?

Answer 62

Modifying chromatin structure (via deacetylation of histones)

Question 63

How does acetylation and deacetylation of histones work? Mechanism of glucocorticoids in relation to this?

Answer 63

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

Question 64

Chromatin definition?

Answer 64

Histones + DNA

Question 65

Mechanism of glucocorticoid suppression of inflammation?

Answer 65

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

Question 66

Effects of glucocorticoids on inflammatory cells in asthma?

Answer 66

Decreased inflammatory cell numbers via apoptosis (eosinophils, T-lymphocytes, mast cells, macrophages and dendritic cells) Decreased cytokine release

Question 67

Effects of glucocorticoids on structural cells in asthma?

Answer 67

Epithelial cell production of cytokines and mediatiors decreases Endothelial leakage decreases ASM increases β2-receptors and decreases cytokine production Mucous glands decrease secretion

Question 68

Reasons why glucocorticoids are used in asthma?

Answer 68

Prevent inflammation and resolve established inflammation | Short-term - do not alleviate early stage bronchospasm but long-term treatment (in combination with LABAs is)

Question 69

Common adverse affects of glucocorticoid use?

Answer 69

Due to deposition of the steroid in oropharynx are: Dysphonia (hoarse, weak voice) Oropharyngeal candidiasis (thrush)

Question 70

Severe, chronic or rapidly deteriorating asthma treatment with glucocorticoids?

Answer 70

Oral prednisolone may be used in combination with inhaled steroid to reduce oral dose and minimise side effects Broncodilator drugs co-administered

Question 71

How are patients instructed to use glucocorticoids?

Answer 71

Encouraged to take sufficient inhaled glucocorticoids to control symptoms and avoid disease progression (perhaps irreversible)

Question 72

When and why are cromones used?

Answer 72

Second-line drugs now rarely used PROPHYLACTICALLY to treat allergic asthma (particularly children)

Question 73

Mechanism of cromone action?

Answer 73

Uncertain but includes a weak anti-inflammatory effet Decrease in irritant receptor sensitivity associated with sensory C-fibres (trigger exagerated reflexe) Reduce cytokine release

Question 74

Problem with inhalation of cromones?

Answer 74

Inhalation means little systematic absorption

Question 75

Effectiveness of cromones?

Answer 75

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

Question 76

Mechanism of monoclonal antibodies in asthma treatment?

Answer 76

Binds IgE via Dv to prevent attachment to Fcε receptors - suppresses mast cell degranulation and response Reduced Fcε receptor expression on inflammatory cells

Question 77

When are monoclonal antibodies used?

Answer 77

Asthma associated with severe eosinophilia (dramatic increase in eosinophils) Very expensive

Question 78

Administration of monoclonal antibodies?

Answer 78

Requires intravenous administration

Question 79

Examples of monoclonal antibodies and where they are directed?

Answer 79

Omalizumab - directed against IgE | Mepolizumab - IL-5