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Pharmacology > Bronchodilators and Anti-Inflammatory Drugs in the Treatment of Asthma > Flashcards

Bronchodilators and Anti-Inflammatory Drugs in the Treatment of Asthma Flashcards

1
Q

Three types drugs used in asthma treatment?

A

Relievers
Controllers/preventors

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

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2
Q

Describe reliever drugs and the three types

A

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

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3
Q

Describe controller drugs and the two types

A

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

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4
Q

Step 1 of pharmacological management of asthma?

A

SABA for very mild intermittent asthma

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5
Q

Step 2 of pharmacological management of asthma?

A

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

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6
Q

Step 3 of pharmacological management of asthma?

A

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

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7
Q

Step 4 of pharmacological management of asthma?

A

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

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8
Q

Step 5 of pharmacological management of asthma?

A

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

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9
Q

Pharmacokinetic differences between aerosol and oral therapy for asthma?

A

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

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10
Q

Dose differences between aerosol and oral therapy for asthma?

A

Aerosol - low does delivered rapidly to target

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

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11
Q

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

A

Aerosol - low

Oral - high

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12
Q

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

A

Aerosol - low

Oral - high (but depends on drug)

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13
Q

Distribution of drug with aerosol and oral therapy for asthma?

A

Aerosol - reduced in severe airway disease

Oral - unaffected by airway disease

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14
Q

Compliance with aerosol and oral therapy for asthma?

A

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

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15
Q

Ease of administration of aerosol and oral therapy for asthma?

A

Aerosol - difficult for small children and infirm people

Oral - good

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16
Q

Effectiveness of aerosol and oral therapy for asthma?

A

Aerosol - good in mild to moderate disease

Oral - good even in severe disease

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17
Q

Describe action and brief mechanism of β2-adrenoceptor agonists

A

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

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18
Q

Mechanism of β2-adrenoceptor agonist action?

A

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

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19
Q

Classes of β2-adrenoceptor agonists?

A

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

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20
Q

Give examples of SABAs?

A

Salbutamol, AKA albuterol

Terbutaline

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21
Q

When are SABAs used?

A

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

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22
Q

Administrations of SABAs?

A

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

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23
Q

Action time for SABAs?

A

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

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24
Q

What changes go SABAs cause?

A

Increase mucous clearance

Decrease mediator release from mast cells and monocytes

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25
Q

Adverse effects of SABAs?

A

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

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26
Q

Examples of LABAs?

A

Salmeterol and formoterol

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27
Q

When are LABAs used?

A

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

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28
Q

Cautions of LABAs?

A

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)

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29
Q

Why are selective β2-adrenoceptor agonists used?

A

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

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30
Q

Risks of non-selective β-adrenoceptor antagonists?

A

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

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31
Q

Caution with non-selective β-adrenoceptor antagonists?

A

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

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32
Q

Risks with LABAs?

A

May worsen asthma by several mechanisms

Cause increased incidence of asthmatic deaths

33
Q

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

A

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

34
Q

Enzymes involved with desensitisation of β2-adrenoceptors?

A

Protein Kinase A (PKA)

G protein receptor kinases (GRKs), specifically β-adrenoceptor kinases

35
Q

What does endocytosis in LABA long-term use entail?

A

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

36
Q

Explain why LABAs are often used in combination with glucocorticoids

A

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

37
Q

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

A

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

38
Q

Mechanism of CysLT1 receptor activation?

A

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)

39
Q

Examples of CysLT1 receptor antagonists?

A

Any drug with suffix ukast
Motelukast
Zafirlukast

40
Q

How are CysLT1 receptor antagonists effective?

A

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

41
Q

Outcome of CysLT1 receptor antagonist use?

A

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

42
Q

When are CysLT1 receptor antagonists not used?

A

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

43
Q

Side effects of CysLT1 receptor antagonists?

A

Generally well tolerated but headaches and GI upset have been reported

44
Q

Examples of methylxanthines?

A

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

45
Q

Methylxanthine activity?

A

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

46
Q

Mechanism of methylxanthine action?

A

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

47
Q

Other methods with which methylxanthines may act?

A

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

48
Q

How are methylxanthines used?

A

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

49
Q

Why are methylxanthines so dangerous?

A

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

50
Q

Side effects of methylxanthines?

A

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

51
Q

Cautions with methylxanthines?

A

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

52
Q

Location of corticosteroid production?

A

Adrenal cortex

Not pre-stored, but synthesised and released on demand

53
Q

Two major classes of corticosteroids and specific site of synthesis?

A

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

54
Q

What does cortisol do?

A

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

55
Q

Uses of cortisol derivatives?

A

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

56
Q

Structural differences between cortisol and beclometasone?

A

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

57
Q

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

A

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

58
Q

Main mineralocorticoid and briefly what it does?

A

Aldosterone regulates retention of salt (and water) by kidney

59
Q

Endogenous steroids?

A

May posses both gluco and mineralocorticoid actions

Latter are unwanted in treatment of inflammatory conditions

60
Q

Mechanism of glucocorticoid action?

A

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

61
Q

What genes do glucocorticoids switch on and off?

A

Those encoding for inflammatory proteins

Activate genes that encode anti-inflammatory mediators

62
Q

How else are genes regulated?

A

Modifying chromatin structure (via deacetylation of histones)

63
Q

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

A

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

64
Q

Chromatin definition?

A

Histones + DNA

65
Q

Mechanism of glucocorticoid suppression of inflammation?

A

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

66
Q

Effects of glucocorticoids on inflammatory cells in asthma?

A

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

67
Q

Effects of glucocorticoids on structural cells in asthma?

A

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

68
Q

Reasons why glucocorticoids are used in asthma?

A

Prevent inflammation and resolve established inflammation

Short-term - do not alleviate early stage bronchospasm but long-term treatment (in combination with LABAs is)

69
Q

Common adverse affects of glucocorticoid use?

A

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

70
Q

Severe, chronic or rapidly deteriorating asthma treatment with glucocorticoids?

A

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

71
Q

How are patients instructed to use glucocorticoids?

A

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

72
Q

When and why are cromones used?

A

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

73
Q

Mechanism of cromone action?

A

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

74
Q

Problem with inhalation of cromones?

A

Inhalation means little systematic absorption

75
Q

Effectiveness of cromones?

A

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

76
Q

Mechanism of monoclonal antibodies in asthma treatment?

A

Binds IgE via Dv to prevent attachment to Fcε receptors - suppresses mast cell degranulation and response

Reduced Fcε receptor expression on inflammatory cells

77
Q

When are monoclonal antibodies used?

A

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

78
Q

Administration of monoclonal antibodies?

A

Requires intravenous administration

79
Q

Examples of monoclonal antibodies and where they are directed?

A

Omalizumab - directed against IgE

Mepolizumab - IL-5

Pharmacology (17 decks)

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