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Respiratory: Pharmacology > Bronchodilator and anti-inflammatory drugs in the treatment of asthma > Flashcards

Bronchodilator and anti-inflammatory drugs in the treatment of asthma Flashcards

1
Q

What are the 2 classes of drug used in the treatment of asthma?

A
  • Relievers

* Controllers/preventers

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2
Q

What are examples of relievers? (4)

A
  • SABAs
  • LABAs
  • CysLT1 receptor antagonists
  • Methylxanthines
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3
Q

What are relievers?

A

Act as bronchodilators

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4
Q

What are examples of controllers/preventers? (4)

A
  • Glucocorticoids
  • Cromoglicate
  • Monoclonal IgE antibodies
  • Methylxanthines
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5
Q

What class do methylxanthines fall under?

A

Both relievers and controllers/preventers

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6
Q

What are controllers/preventers?

A

Act as anti-inflammatory agents that reduce airway inflammation

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7
Q

Are controllers/preventers used in relief of an acute asthma attack?

A

No, they are used to prevent asthma attacks - very little effect when used acutely

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8
Q

When are relievers administered?

A

Treatment of acute bronchial spasms

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9
Q

What do methylxanthines do?

A

Treat bronchial spasms and inflammation

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10
Q

What are the advantages of aerosol therapy for asthma? (6)

A
  • 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
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11
Q

What are the disadvantages of aerosol therapy for asthma? (4)

A
  • 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
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12
Q

What are the advantages of oral therapy for asthma? (5)

A
  • 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
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13
Q

What are the disadvantages of oral therapy for asthma? (4)

A
  • 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
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14
Q

In what instances are oral and aerosol therapies for asthma used? (2)

A
  • Aerosol - mild to moderate disease

* Oral - severe disease

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15
Q

What are B2-Adrenoceptor agonists?

A

Physiological antagonists of all spasmogens

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16
Q

What are the classes of B-adrenoceptor agonists? (3)

A
  • Short-acting (SBA)
  • Long-acting (LABA)
  • Ultra long-acting (ultra-LABA)
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17
Q

What are examples of short-acting B2-adrenoceptor agonists? (3)

A
  • Salbutamol
  • Albuterol
  • Terbutaline
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18
Q

When are B2-adrenoceptor agonists taken for asthma?

A

First line treatment for mild, intermittent asthma

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19
Q

How are B2-adrenoceptors administered? (4)

A

Inhalation via

  • Metered dose
  • Dry powder devices

Or (less commonly)

  • Oral
  • IV
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20
Q

When are B2-adrenoceptors administered intravenously?

A

In an emergency

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21
Q

What is the dosage for B2-adrenoceptor agonists?

A

They are relievers taken as needed

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22
Q

How quickly do B2-adrenoceptors take effect?

A

Act rapidly (within 5 minutes when inhaled) - maximal effect within 30 minutes

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23
Q

How long does the effect of a short-acting B2-adrenoceptor last?

A

Relaxation persists for 3-5 hours

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24
Q

What additional effects of B2-adrenoceptors (other than relaxation of smooth muscle)?

A
  • Increase mucous clearance (via cilia)

* Decrease mediator release from mast cells and monocytes

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25
Q

What are side effects of B2-adrenoceptor agonists? (1 mild, 3 severe)

A

Very few adverse side effects as low systemic absorption
* Fine tremor

However, more severe side effects can occur: -

  • Tachycardia
  • Cardiac dysrhythmia
  • Hypokalaemia
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26
Q

What are examples of LABAs? (2)

A
  • Salmeterol

* Formoterol

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27
Q

Are LABAs used for acute relief of bronchospasm?

A

No, salmeterol too slow to act

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28
Q

Are salmeterol and formoterol slow-acting?

A

Salmeterol is, formoterol is not

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29
Q

What are LABAs useful for?

A

Treating nocturnal asthma (act for approximately 8 hours)

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30
Q

Should LABAs be used in mono therapy?

A

No, LABAs must always be co-administered with a glucocorticoid steroid class drug

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31
Q

Why is isoprenaline redundant in asthma treatment?

A

It is a non-selective B-agonist, so stimulates potentially harmful cardiac B1-adrenoceptors

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32
Q

Why are non-selective B-adrenoceptor antagonists contraindicated in the treatment of asthma?

A

Risk of bronchospasm

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33
Q

Why are LABAs always co-administered with corticosteroids?

A

LABAs alone may worsen asthma

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34
Q

What are glucocorticoids?

A

A class of corticosteroid

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35
Q

What are CysLT1 receptor. antagonists?

A

Bronchodilators

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36
Q

What are cysteinyl leukotrienes?

A
  • Produced by mast cells and inflammatory cells

* Cause smooth muscle contraction, mucous secretion and oedema

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37
Q

What are examples of CysLTs? (3)

A
  • LTC4
  • LTD4
  • LTE4
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38
Q

How do mast cells activate CysLT receptors?

A
  • 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
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39
Q

What does CysLT1 receptor activation cause?

A
  • Bronchoconstriction (early phase)

* Inflammation (late phase)

40
Q

What are examples of CysLT receptor antagonists? (2)

A
  • Montelukast

* Zafirlukast

41
Q

What are CysLT1 receptor antagonists effective in treating?

A
  • Effective against antigen-induced and exercise-induced bronchospasm
42
Q

What are CysLT1 receptor antagonists used in combination with in more severe conditions?

A

Inhaled corticosteroids

43
Q

How are CysLT1 receptor antagonists administered?

A

Oral route

44
Q

What are CysLT1 receptor antagonists not effective in the treatment of?

A

Acute severe asthma (bronchodilator activity is not as great as salbutamol)

45
Q

What are some side effects of CysLT1 receptor antagonists? (2)

A

Generally well-tolerated

  • Headache
  • Gastrointestinal upset
46
Q

What drugs have both a bronchodilator an anti-inflammatory effect?

A

Methylxanthines

47
Q

What are examples of methylxanthines? (2)

A
  • Theophylline

* Aminophylline

48
Q

What is the molecular mechanism of action of methylxanthines?

A

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)

49
Q

What are the effects of methylxanthines in the treatment of asthma? (4)

A
  • 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
50
Q

Are methylxanthines used in mono therapy?

A

No, they are second line drugs used in combination with B2-adrenoceptor agonists and glucocorticoids

51
Q

How are methylxanthines administered?

A

Oral route as sustained release preparations

52
Q

What are the disadvantages of methylxanthines? (2)

A
  • Have a very narrow therapeutic window

* Have adverse effects at supra-therapeutic conditions

53
Q

What are the side effects of methylxanthines at supra-therapeutic conditions? (3)

A

Result from actions involving the CNS, CVS, GI tract and kidneys

  • dysrhythmia
  • seizures
  • hypotension
54
Q

What are the side effects of methylxanthines at therapeutic concentrations? (4)

A
  • Nausea
  • Vomiting
  • Abdominal discomfort
  • Headache
55
Q

Why are methylxanthine problematic?

A

Due to drug interactions involving cytochrome P450 in the liver

56
Q

Where are corticosteroids synthesised in the body?

A

Adrenal cortex

57
Q

What are the 2 major classes of steroid hormone synthesised by adrenal cortex?

A
  • Glucocorticoids (zona fasiciculata)

* Mineralocorticoids (zona glomerulosa)

58
Q

Are glucocorticoids and mineralocorticoids pre-stored?

A

No, synthesised and released on demand

59
Q

Are glucocorticoids natural?

A

There are both natural (produced by adrenal medulla) and synthetic glucocorticoids

60
Q

What is the main hormone in glucocorticoids?

A

Cortisol

61
Q

What is medicated cortisol known as?

A

Hydrocortisone

62
Q

What is the effect on glucocorticoids (including hydrocortisone)? (2)

A
  • Decreases nflammatory responses

* Decreases immunological responses

63
Q

How are unwanted effects of corticosteroids in the liver avoided?

A

Delivery via airways

64
Q

What is an example of a mineralocorticoid?

A

Aldosterone

65
Q

What is the function of mineralocorticoids?

A

Regulate the retention of salt (and water) by the kidney

66
Q

What actions are unwanted in endogenous steroids in the treatment of inflammatory conditions?

A

Mineralocorticoid actions

67
Q

What are examples of synthetic derivatives of cortisol? (3)

A
  • Beclometasone
  • Budesonide
  • Fluticasone
68
Q

What are beclometasone, budesonide and fluticasone used for?

A

Anti-Inflammatory effect in the treatment of asthma

have no mineralocorticoid activity

69
Q

Are glucocorticoids not used to treat acute asthma attacks?

A

No, they have no direct bronchodilator action

70
Q

What are glucocorticoids used for in the treatment of asthma?

A

Used in prevention of asthma attacks

71
Q

Explain the molecular mechanism of action of glucocorticoids

A
  • 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
72
Q

What are the molecular effects of glucocorticoids? (4)

A
  • 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
73
Q

In what 2 ways are genes regulated?

A
  • By glucocorticoids acting at glucocorticoid response elements (GREs)
  • Modifying the structure of chromatin via the deacetylation of histones
74
Q

How are inflammatory genes expressed?

A

Histone acetyltransferases (HATs) - acetylation ‘unwinds’ DNA from histones allowing transcription

75
Q

How do glucocorticoids switch off gene transcription?

A

Glucocorticoids recruit histone deacetylases (HDACs) to activated genes and switch off gene transcription

76
Q

Why are glucocorticoids not effective in COPD?

A

In COPD, HDAC expression is lost, hence glucocorticoids cannot exert their suppressant effect on the transcirpiton of inflammatory genes

77
Q

What are glucocorticoid effects on inflammation in asthma? (6)

A
  • 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
78
Q

What are the 2 effects of glucocorticoids in asthma?

A
  • Prevent inflammation

* Resolve established inflammation

79
Q

How are unwanted systemic side effects prevented in glocucorticoids (beclometasone, budesonide, fluticasone)?

A

Administered by metered dose inhaler

80
Q

What are the most common adverse effects of glucocorticoids? (2)

A
  • Dysphonia (hoarse and weak voice)

* Oropharangeal candidiasis (thrush)

81
Q

What causes adverse effects of glucocorticoids?

A

Deposition of steroid in the oropharynx

82
Q

What are inhaled corticosteroids used to treat?

A

Mild ot moderate asthma

83
Q

What are oral steroids (prednisolone) used to treat?

A

Severe asthma

84
Q

How are unwanted systemic effects avoided in prednisolone?

A

Used in combination with an inhaled steroid to reduce the oral dose required

85
Q

Why is it important that patients take sufficient inhaled glucocorticoids?

A

To control symptoms and avoid disease progression, which may be irreversible

86
Q

What are cromones?

A

Second line drugs infrequently used prophylactically in the treatment of allergic asthma

87
Q

What are the effects of cromones in asthma? (2)

A
  • 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
88
Q

What is the potential mechanism of action of cromones e.g. cromoglicate?

A

A decrease in the sensitivity of irritant receptors associated with sensory C-fibres - triggers exaggerated reflexes and reduction of cytokine release

89
Q

What is a example of a cromone?

A

Sodium cromoglicate

90
Q

How are cromones administered?

A

Via inhalation

91
Q

In what patients are cromones most effective?

A

In children and young adults

92
Q

What is an example of an anti-IgE monoclonal antibody?

A

Omalizumab

93
Q

What are the mechanisms of action of anti-IgE monoclonal antibodies? (2)

A
  • 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
94
Q

What are the drawbacks of anti-IgE monoclonal antibodies? (2)

A
  • Requires intravenous administration

* Expensive treatment

95
Q

What is an example of an anti-IL5 monoclonal antibody?

A

Mepolizumab

96
Q

What are anti-IL5 monoclonal antibodies used to treat?

A

Asthma associated with severe eosinophilia

97
Q

What is the drawback of anti-IL5 monoclonal antibodies?

A

Very expensive

Respiratory: Pharmacology (4 decks)

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