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PBL SEM 2 > PBL 2 - drug treatment for asthma > Flashcards

PBL 2 - drug treatment for asthma Flashcards

1
Q

what are the 2 types of asthma drugs?

A

preventers and relievers

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2
Q

what are the main 1st line drugs?

A
  • B2-adrenergic agonists

- glucocorticoids (steroids)

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3
Q

what are some additional drugs given when the 1st line drugs fail to provide adequate control?

A
  • theophylline
  • muscarinic receptor antagonists
  • leukotriene antagonists
  • cromoglicate
  • biologics (eg. anti-IgE)
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4
Q

name 4 types of broncodilators

A
  1. B2-adrenergic receptor agonists
  2. theophylline
  3. muscarinic receptor antagonists
  4. leukotriene receptor antagonists
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5
Q

name a B2-adrenergic receptor agonist

A

salbutamol

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6
Q

what do B2-adrenergic receptor agonists do?

A

bind to and activate the B2 subtype of adrenoreceptor

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7
Q

where do B2 agonists have their effects?

A
  • main effect on B2-adrenoreceptors in bronchiole smooth muscle cells
  • also on receptors on mucous glands in the bronchiole wall and on cilitaed epithelial cells that line the lumen of the bronchiole
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8
Q

what are the main effects of B2 agonsits?

A
  • stimulate signalling pathways that evoke muscle relaxation and bronchodilation in bronchiole smooth muscle cells
  • stimulate mucus secretion and increase the beat frequency of cilia, which together increase mucociliary clearance
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9
Q

what are the non-muscle actions of B2-agonsits?

A
  • evidence that they activate B2 adrenoreceptors on mast cells — reduce mediator release
  • activate receptors on parasympathetic nerve endings in the bronchiole wall — inhibits the release of the neurotransmitter acetylcholine = a bronchoconstrictor
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10
Q

what kind of receptors are B2-adrenergic receptors?

A

G protein coupled receptors — Gs

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11
Q

what are the natural agonists of the beta 2 receptor?

A

noradrenaline (released from sympathetic nerve terminals) and adrenaline

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12
Q

describe the steps of how the beta 2 receptor works when an endogenous or synthetic agonist binds to the receptor

A
  1. the endogenous or synthetic agonist binds to a high affinity site on the receptor
  2. causes a conformational change in the receptor protein
  3. receptor now has an increased affinity for the Gs protein so that when the Gs and adenylate cyclase proteins bump into each other they interact and the Gs protein becomes activated
  4. therefore when adenylate cyclase next bumps into Gs, the G protein stimulates its activity
  5. adenylate cyclase: ATP —> cAMP
  6. cAMP then binds to an inactive enzyme known as protein kinase A, causing it to become activated
  7. protein kinase A phosphorylates several proteins that promote the relaxation of smooth muscle
  8. the proteins phosphorylate regulate contractile proteins interactions or the conc of calcium ions in the cell
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13
Q

what is the result of a reduction of intracellular calcium?

A

bronchodilation

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14
Q

why can cAMP levels be controlled?

A

because the molecule is constantly synthesised and degraded

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15
Q

what is the role of phosphodiesterase?

A

inactivates cAMP

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16
Q

what drug is an example of a beta receptor antagonist (beta blocker)?

A

propranolol

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17
Q

how can the beta blocker bind to the beta receptor?

A

the antagonist has similar homology to the beta agonist

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18
Q

how is the beta antagonist different from a beta agonist?

A
  • the antagonist competes with the agonist for binding to the receptor site
  • the antagonist does not interact with the Gs protein and stimulate a signalling cascade
  • it simply blocks the agonist from binding and having an effect
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19
Q

tolerance to beta agonists?

A

prolonged activation of the receptor can cause it to become less sensitive to an agonist

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20
Q

what drugs prevent B2 receptors from developing a tolerance?

A

corticosteroids

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21
Q

what are the different types of B2-adrenergic agonists?

A
  1. SABA
  2. LABA
  3. Ultra-LABA
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22
Q

how is the tolerance avoided?

A

LABAs (and especially U-LABAs) are given with a corticosteroid

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23
Q

name 2 SABAs

A
  • salbutamol

- terbutaline

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24
Q

describe SABAs

A
  • max effect achieved within 30mins. lasts 3-5 hours
  • used “as needed” to control symptoms
  • the mainstay of acute asthma treatment
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25
Q

name 2 LABAs

A
  • salmeterol

- formoterol

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26
Q

describe LABAs

A
  • duration of action 8-12 hours
  • given 2x daily
  • used daily as adjunctive therapy, not “as needed”
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27
Q

name 2 ultra-LABAs

A
  • vilanterol

- indacaterol

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28
Q

describe U-LABAs

A
  • duration of action roughly 24 hours
  • given 1x daily
  • used in same way as LABAs
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29
Q

how are beta agonists administered and why?

A

inhalation — minimise side effects and get to lungs — delivers enough drug to the airways to cause bronchodilation, while minimising the conc reaching the circulation

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30
Q

why are there and what are the side effects of beta agonists?

A

—> result from absorption into systemic circulation and activation of B2-receptors in other parts of the body

  • tremor (activation in skeletal muscles)
  • muscle cramps
  • headaches (due to dilation of cerebral blood vessels)
  • tachycardia (due to drop in BP due to peripheral vasodilation)
  • cardiac dysrhythmia = rare but serious (involves agonist-induced hypolakaemia = excessive uptake of K+ by cells)
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31
Q

what does theophylline do?

A

inhibits phosphodiesterase — therefore stops cAMP from being inactivated — results in muscle relaxation and subsequent bronchodilation

also adenosine receptor antagonist

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32
Q

describe adenosine receptors. theophylline?

A
  • present on airways smooth muscle
  • evoke bronchoconstriction
  • regulate degranulation on most inflammatory cells
  • theophylline competes with adenosine for binding to its reception, thereby promoting bronchodilation and reducing the release of inflammatory mediators
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33
Q

is theophylline a 1st line asthma treatment?

A

no — it can be added to therapy when patients fail to respond adequately to 1st line treatment with a B2 receptor agonist and corticosteroid

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34
Q

what are the unwanted side effects of theophylline?

A
  • CNS stimulation — tremors, sleep disturbance
  • vasodilation — drop in BP
  • cardiac stimulation — arrhythmias
  • GI tract stimulation — anorexia, nausea, vomiting
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35
Q

are adverse effects of theophylline common and why?

A

yes

theophylline has a narrow therapeutic window meaning that adverse effects occur at a plasma conc close to that required for the therapeutic effect. adverse effects are therefore common, but the plasma conc of theophylline can be monitored to optimise dosing

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36
Q

name a muscarinic receptor antagonist

A

ipratropium

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37
Q

how do muscarinic receptor antagonists work?

A

bind to muscarinic receptors on bronchiole smooth muscle and prevent binding of acetylcholine

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38
Q

what are bronchioles innervated by? neurotransmitter?

A

postganglionic parasympathetic neurones which employ Ach as the neurotransmitter

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39
Q

what does Ach do when it is released from a nerve terminal in bronchiole wall?

A

binds to and activates muscarinic receptors on smooth muscle cells in the bronchiole wall

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40
Q

what type of receptors are muscarinic receptors?

A

G protein coupled receptors — therefore agonist binding to the receptor activates signalling cascades

41
Q

what is the result of Ach binding to muscarinic receptors in bronchiole wall smooth muscle cells?

A

results in a rise in intracellular Ca2+ — trigger for contraction — constriction of bronchioles

42
Q

how does nerve activity change in asthmatic airways?

A

nerve activity raised — Ach release is high — smooth muscle contracted — airways narrowed

43
Q

how does an increase in parasympathetic nerve activity result in bronchoconstriction?

A
  1. rise in PS activity
  2. increased signals to nerve terminal
  3. increased Ach release
  4. more Ach binds to muscarinic receptors
  5. rise in intracellular Ca2+
  6. more tension by muscle cells
  7. excessive bronchoconstriction
44
Q

in some types of asthma, what happens to the PS nerves supplying the bronchioles?

A

they are hyperactive — more Ach released — hypercontractility — narrow bronchioles

45
Q

how can this hyperactivity of PS nerves be reduced?

A

by muscarinic antagonists

46
Q

what do muscarinic antagonists do?

A

suppress the effect of Ach released from overactive PS nerves by competing with Ach for binding to the receptor

47
Q

why is ipratropium (a muscarinic receptor) a main drug used in asthma?

A

it is hydrophilic and poorly absorbed from the airways into the systemic circulation — therefore when given by inflation its effects are localised to the lung and has few unwanted effects

48
Q

what else may muscarinic receptor antagonists do?

A

reduce elevated mucus secretion in asthma and increase clearance of bronchial secretions

49
Q

where are leukotriene receptors located? what do they do?

A

on airways smooth muscle and epithelial cells where they promote bronchoconstriction, as well as on mast cells and other inflammatory cells where they cause the release of inflammatory mediators

50
Q

what do leukotriene antagonists do?

A

compete with endogenous leukotrienes for the receptor — drugs prevent the receptors from being activated

51
Q

what cytotoxic enzyme is vital for the formation of leukotrienes?

A

phospholipase A2

52
Q

when phospholipase A2 is phosphorylated, what does it do?

A

it translocates to the membrane where it cuts out part of the phospholipid to release the free fatty acid, arachidonic acid = a precursor to a myriad of signalling molecules

53
Q

what 2 different signalling intermediates are made from arachidonic acid?

A
  1. cycle-oxygenate (COX)

2. lipoxygenase

54
Q

describe the COX pathway

A

COX generates cyclin endoperoxides, which are converted by additional enzymes to a series of prostaglandins, some of which contribute to inflammation

55
Q

where is lipoxygenase mainly found?

A

mainly in leukocytes, including mast cells

56
Q

what does lipoxygenase mediate responses to?

A

immunological stimuli

57
Q

describe the lipoxygenase pathway

A
58
Q

what is phospholipase A2 regulated by?

A

calcium and phosphorylation

59
Q

what are the cysteine leukotrienes (cysLT)?

A

leukotriene C4, D4 and E4

60
Q

where do the cysteinyl leukotrienes act on? what are the effects?

A
  • cysteinyl leukotriene receptors found on inflammatory cells and bronchiole smooth muscle
  • promote bronchoconstriction, airway oedema, mucus secretion and the recruitment of inflammatory cells
  • all contribute to the pathology of asthma
61
Q

what type of receptors are leukotriene receptors?

A

G protein coupled receptors

62
Q

aspirin and other non-steroidal anti-inflammatory drugs are inhibitors of what?

A

cyclooxygenase

63
Q

why is there greater production of leukotrienes with aspirin and other non-steroidal anti-inflammatory drugs?

A

COX is inhibited so there is more arachidonic acid available fro the lipoxygenase pathway — greater production of leukotrienes

64
Q

how can aspirin provoke an asthma attack in some asthmatics?

A

increase the availability of cysteinyl leukotrienes — greater stimulation of their receptors

65
Q

what are leukotriene receptor antagonists prescribed with? are they a first line treatment?

A

not a 1st line treatment — prescribed with an anti-inflammatory corticosteroid

66
Q

in what asthmas are leukotriene antagonists most effective?

A

exercise-induced or aspirin-sensitive asthma

67
Q

any adverse effects of leukotriene antagonists?

A

generally well tolerated — adverse effects are mainly headache and GI disturbance via cysteinyl leukotriene receptors on smooth muscle

68
Q

name 2 leukotriene antagonists

A
  • montelucast - taken 1x daily

- zafirlucast - taken 2x daily

69
Q

what are the main anti-inflammatory drugs used to treat asthma?

A

glucocorticoids

70
Q

what do glucocorticoids mimic the actions of?

A

cortisol = an endogenous steroid hormone produced in the adrenal cortex and released at elevated levels in response to stress and low blood glucose concentrations

71
Q

what do glucocorticoids reduce the production of? effect?

A
  • cytokines
  • spasmogens (leukotrienes C4 and D4)
  • leukocyte chemotaxis

therefore reduce bronchospasm, recruitment and activation of inflammatory cells

72
Q

how are glucocorticoid receptors normally kept in an inactive state?

A

by heat shock proteins — dissociate from the receptor when it is bound to glucocorticoid

73
Q

what does the receptor-glucocorticoid complex do when it crosses the nuclear membrane?

A

binds to a glucocorticoid response element within the DNA to influence DNA transcription

74
Q

how does the glucocorticoid-receptor complex influence transcription?

A

increase transcription of anti-inflammatory proteins (lipocortin) and decreases transcription of pro-inflammatory proteins

75
Q

what is the target of lipocortin?

A

phospholipase A2 — inhibits it, stopping cleavage of phospholipid to generate arachidonic acid — inhibits COX + lipoxygenase pathways

76
Q

how quickly do glucocorticoids act to reduce the symptoms of asthma?

A

can take several days — requires changes in protein synthesis

77
Q

what are the main glucocorticoids for treating asthma and how often are they inhaled?

A
  • beclometasone = 2x daily
  • fluticasone = 2x daily
  • budesonide = 1x daily
  • mometasone = 1x daily
  • cidesonide = 1x daily
78
Q

which glucocorticoid are patients usually started on and why?

A

beclometasone as it is less potent

79
Q

when are nebulisers used?

A

to treat an acute axacerbation of asthma symptoms

80
Q

what glucocorticoid may be given orally?

A

prednisolone

81
Q

unwanted effects of glucocorticoids?

A
  • adverse effects are rare with inhaled steroids

- adrenal suppression can occur with oral or high doses of glucocorticoids taken regularly

82
Q

why can cromoglicate and nedocromil not prevent bronchoconstriction during an asthma attack?

A

they do mot effect bronchiole smooth muscle

83
Q

what do cromoglicate and nedocromil do?

A

reduce inflammation and hypersensitivity in asthmatic airways (although their anti-inflammatory effects are weak compared to glucocorticoids)

  • mast cell stabilisation
  • reduction of neuronal reflexes (desensitised to irritants)
  • inhibition of cytokine release from T cells
  • inhibition of inflammatory cells and mediators
84
Q

clinical use of cromoglicate and nedocromil

A
  • not used much now to treat asthma but when they are they:
  • are used prophylactically to prevent both the early (bronchoconstriction) and late (inflammation) phases of an asthma attack
  • are slow to act — effects may take weeks to develop
  • are given by inhalation (aerosol, nebuliser solution or powder)
  • are most effective in children
  • have few unwanted effects — mainly irritation of the URT. hypersensitivity reactions have been reported but are rare)
85
Q

what are biologic drugs created from?

A

natural sources using recombinant DNA technology

86
Q

what biologic drug is used to treat asthma and why?

A

humanised IgGI monoclonal antibodies — have a very high affinity and specificity for their targets

87
Q

what biologic drugs are used and what do they target?

A
  • omalizumab — target IgE
  • mepolizumab — target Il-5
  • reslizumab — target Il-5
  • benralizumab — target Il-5 receptor
88
Q

what does omalizumab bind to?

A

binds to circulating IgE and prevents it from interacting with the FCe receptor on mast cells and other inflammatory cells — prevents the allergen from cross-linking and activating the receptor to trigger degranulation

89
Q

biologic drugs are only effective against what type of asthma?

A

allergen-induced asthma

90
Q

unwanted effects of biologic drugs?

A

generally safe due to their high specificity

  • headache and increase risk of infection
  • rare = anaphylaxis
91
Q

usual delivery of biologic drugs?

A

subcutaneous injection, but may be given by i.v. infusion

— drug is released slowly into circulation to reach a peak plasma conc after a few days — injections to maintain plasma levels are required every few weeks

92
Q

what would be prescribed for a mild asthmatic with rare attacks?

A

inhaled B2-agonist when required

93
Q

what would be prescribed for mild asthma with more frequent attacks?

A
  • glucocorticoid for prophylaxis

- B2-agonist when needed for acute attack

94
Q

what would be prescribed for moderate to severe asthma?

A

drug combination preferred, usually:

  • LABA with glucocorticoid
  • in combined inhaler
95
Q

when are other drugs added?

A

when this previous approach fails to provide adequate control

96
Q

asthma medications are given in metered dose inhales, if the patient uses the inhaler correctly, approx how much of the drug dose will be deposited in the lungs?

A

10%

97
Q

why could an asthma attack be caused by a beta blocker when used to reduce BP?

A

because beta adrenorecpetors relax smooth muscle when activated

98
Q

what are blue inhalers?

A

relievers — beta 2 agonists = bronchodilators (main are salbutamol and terbutaline)

99
Q

what are brown inhalers?

A

preventers = corticosteroids (eg. beclomethasone dipropionate) — anti-inflammatory glucocorticoids — reduce production of cytokines/spasmogens/leukocyte chemotaxis — therefore reduce bronchospasm and recruitment and activation of inflammatory cells

PBL SEM 2 (44 decks)

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