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Respiratory (Charlotte) > Asthma- pharmacology > Flashcards

Asthma- pharmacology Flashcards

1
Q

What can cause asthma?

A

Allergens (in atopic individuals)
Exercise (cold, dry air)
Respiratory infections
Dust, environmental pollutants, smoke

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2
Q

What are characteristic symptoms of asthma?

A

Cough
Wheeze
Shortness of breath

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3
Q

In asthma, there are pathological changes to the bronchioles. What causes this?

A

Long-standing inflammation.

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4
Q

What are the pathological changes in the bronchioles that occur in asthma?

A

Increased smooth muscle mass (hyperplasia and hypertrophy)
Accumulation of interstitial fluid
Increased number of goblet cells and increased mucous secretion
Epithelial damage exposing sensory nerve endings

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5
Q

What causes the wheeze heard in asthma?

A

The sound of air moving through occluded airways, as caused by mucous in the airways.

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6
Q

a) Name the two components which contribute to hyper-responsiveness in asthma.
b) define these

A

a)Hyper-reactivity
Hyper-sensitivity
b) Hyper-sensitivity is increased sensitivity to bronchoconstrictor influences.
Hyper-reactivity is an increased response to the influences.
Together, they make hyper-responsiveness.

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7
Q

What contributes to the hyper-sensitivity in asthma? (I.e. the increased sensitivity to bronchoconstrictor influences)

A

Epithelial damage exposes sensory nerve endings.
These are C fibres and irritant receptors.
These set up a reflex which makes the patient cough, narrowing the airways.
Also release peptides causing neurogenic inflammation.

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8
Q

What are the two phases of an asthma attack, and what causes them?

A

The immediate and delayed phase.
The immediate phase is caused by bronchoconstriction and the late phase is caused by inflammation.
When bronchoconstriction is occurring, the airways are being primed for the inflammatory response which will occur later.

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9
Q

Describe the difference in response to an allergen shown by an atopic, asthmatic individual, and a non-atopic individual.

A

A non-atopic individual: the allergen would be phagocytosed by an antigen-presenting cell (dendritic cell) and this presents the antigen to T cells. This produces a low-level TH-1 immune response, i.e. a cell-mediated immune response, involving IgG and macrophages.
Atopic individual: Antigen presentation results in a strong TH-2 response i.e. an antibody-mediated immune response involving IgE.

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10
Q

Describe in detail the immune response of an atopic individual to the initial exposure to an allergen.

A

Induction phase: The allergen is phagocytosed by a dendritic cell. It is processed and its antigen is presented to T CD4+ cells via MHC II (major histocompatability complex II). These will engage Th0 cells, which have the option of maturing into Th1 cells (as in non-atopic individuals) or Th2 cells (in atopic individuals). These pathways are mutually exclusive.
Th2 cells produce interleukins, including IL-4. This helps them bind to B cells. The B cells proliferate and mature into plasma cells which can produce a specific IgE.

There has been no attack at this stage- is simply priming the system for a response to a subsequent exposure to that same antigen.

Effector phase: TH2 cells also produce IL-5. This acts on eosinophils in the bone marrow, causing them to proliferate, leave the bone marrow, and enter the lung tissue. The eospinophils express receptors for the IgE.
TH2 cells also produce IL-4 and IL-13. This causes tissue-resident mast cells to express IgE receptors. The IgE starts to bind to these receptors.

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11
Q

Describe what happens when an atopic individual is subsequently exposed to the same antigen which caused the induction and effector phase.

A

The antigen binds to the IgE which is bound to mast cells and eosinophils.
Effect on mast cells: Mast cell is activated, causing Ca2+ entry from the extracellular environment, and Ca2+ release from intracellular stores (i.e. increase in intracellular Ca2+). This causes degranulation of the mast cell.
Spasmogens released: Preformed histamine, and
LTC4 and LTD4 (these are not preformed- have to be produced.)
Chemotaxins and chemokines also released: PGD2, LTB4 and PAF (platelet activating factor). These attract mono-nucleated cells and eosinophils, which set up an inflammatory response.

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12
Q

What are the key immune events in the immediate phase of an asthma attack and what is the outcome?

A

Activation of mast cells and mononuclear cells by the antigen (which binds to the IgE on the mast cell).
This causes release of spasmogens from the mast cells (histamine and cysLTs) resulting in bronchospasm.
Also, release of chemotaxins and chemokines, although these do not exert an effect until the late phase.

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13
Q

What are the key immune events in the late/delayed phase of an asthma attack and what is the outcome?

A

The chemotaxins and chemokines released in the inital phase cause infiltration of TH2 cells and monocytes, and activation of eosinophils.
TH2 and monocytes release inflammatory mediators such as cysLTs. These cause airway inflammation and hyper-reactivity.
Activated eosinophils release eosinophil major basic protein and eosinophil cationic proteins. These cause epithelial damage and expose nerve endings, resulting in hyper-sensitivity.
Collectively, these events result in bronchospasm, cough and wheeze.

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14
Q

a) What is the effect of reliever drugs on the airways?

b) Name these drugs

A

a) These act as bronchodilators.
b) Short acting Beta-2 adrenoceptors agonists. long acting beta-2 adrenoceptor agonists, cysLT antagonists, methylxanthines.

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15
Q

a) What is the effect of controller/preventer drugs?

b) Name these drugs.

A

a) These act as anti-inflammatory agents which reduce airway inflammation.
b) Glucocorticoids, chromoglicate, Humanised monoclonal IgE antibodies, methylxanthines.

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16
Q

Describe the events that occur when a beta-2 adrenoceptor agonist binds to the receptor.

A

The beta 2 agonist binds. The receptor is a G-protein coupled receptor, and is coupled to Gs protein. Activation of Gs causes increased adenylyl cyclase activity, which causes increased conversion of ATP to cAMP (i.e. increased concentration of cAMP).
cAMP causes activation of PKA, which phosphorylates myosin light chain kinase (MLCK). When this is activated, there is smooth muscle relaxation.

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17
Q

Describe the pathways leading to desensitisation of beta-2 adrenoceptors.

A

One pathway involves PKA. When it is activated, it phosphorylates the B2 adrenoceptor as well as MLCK (this can occur even when the agonist is unbound). This means that there is reduced G protein coupling.
2nd pathway: Involves G protein receptor kinases. When the B2 adrenoceptor is activated and the agonist is still bound, GRK can phosphorylate it on intracellular domains. It is then recognised by Beta arrestin which “arrests” the adrenoceptor signalling.
There is endocytosis of the receptor from the cell membrane.

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18
Q

How does beta arrestin cause the endocytosis of the beta-2 adrenoceptor?

A

Beta-arrestin acts as a scaffold protein, which links the desensitised beta-2 adrenoceptor to endocytotic machinery which internalises the receptor.
There is a morphological change in the membrane in which the receptor is bound, and a clathrin-coated pit develops. Eventually it becomes pinched off internally as an endosomal vesicle. The beta arrestin unbinds, and the receptor is transferred to an acidic vesicle. The agonist also unbinds now, and the intracellular domain of the receptor is dephosphorylated. The receptor is trafficked to endosomes for recycling to the surface, or to lysosomes for degradation.

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19
Q

Name a SABA

A

Salbutamol

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20
Q

How is salbutamol delivered?

A

Usually inhaled.
It can be given orally in children
Can also be given IV in an emergency.

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21
Q

How long does salbutamol take to work, and how long does the effect last for?

A

It can act in 5 minutes, and reaches maximal effect in 30 minutes.
Relaxation can last for 4-6 hours.

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22
Q

How can SABAs be taken prophylactically?

A

By taking the drug shortly before undertaking an acitivity which is likely to induce an asthma attack.

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23
Q

How can there be systemic absorption of SABAs when they are inhaled?

A

Most systemic absorption comes from accidentally swallowing the drug.
Some drug will be absorbed across airway epithelium.

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24
Q

What are systemic side effects of SABAs?

A

Fine tremor

Occasional tachycardia.

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25
Q

Name a LABA

A

Salmeterol

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26
Q

What should LABAs not be used for?

Why?

A

They should not be used for acute relief of bronchospasm.

This is because they can be relatively slow to act.

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27
Q

What should LABAs not be given in the absence of?

Why?

A

Glucocorticoids.

This is because LABAs provide symptomatic relief but do not treat the underlying inflammation.

28
Q

a) Which CysLTs are released from mast cells and infiltrating inflammatory cells?
b) What effect do they have?

A

a) LTC4, LTD4, LTE4

b) They cause smooth muscle contraction, mucous secretion and oedema.

29
Q

Which cysteine leukotrienes activate the cysLT1 receptor?

A

LTD4, LTE4 and others.

30
Q

What does activation of the cysLT1 receptor cause?

A

Early phase: bronchoconstriction

Delayed phase: inflammation.

31
Q

Name 2 cysLT1 receptor antagonists?

A

Montelukast, Zafirlukast

32
Q

When are cysLT1 receptor antagonists used?

A

In mild persistend asthma as add on therapy

In severe asthma in combination with other medications.

33
Q

When are cstLT1 receptor antagonists effective?

A

In the treatment of antigen-induced and exercise-induced asthma.

34
Q

How are cysLT1 receptor antagonists delivered?

A

By the oral route

35
Q

What should cysLT1 receptor antagonists not be used for?

A

Relief of acute severe asthma.

Their bronchodilator activity is less than that of salbutamol.

36
Q

Name two xanthines.

A

Theophylline and aminophylline.

37
Q

What are xanthines present in?

A

Coffee, tea, and chocolate containing beverages.

38
Q

What actions do xanthines have?

A

A combination of bronchodilator and anti-inflammatory actions.

39
Q

How are xanthines delivered?

A

By the oral route

40
Q

What are some side effects of xanthines?

A

Nausea, vomiting, abdominal discomfort, headache.

At higher concentrations: seizures and cardiac arrhythmias.

41
Q

a) What are the two classes of corticosteroids that are released from the adrenal cortex and where in the adrenal cortex are they made?
b) What type of hormones are these?

A

a) Glucocorticoids (zona fasciculata) and mineralocorticoids (zona glomerulosa)
b) Steroid hormones

42
Q

a) What is the main glucocorticoid in man?

b) What is its synthetic equivalent?

A

a) Cortisol

b) hydrocortisone

43
Q

a) What is the main mineralocorticoid?

b) What is its function?

A

a) aldosterone

b) It regulates the retention of salt and water by the kidney

44
Q

Which type of corticosteroid is unwanted in the treatment of inflammatory conditions?

A

Mineralocorticoids.

45
Q

Do glucocorticoids have bronchodilator action?

A

No.They are ineffective in relieving bronchospasm when given acutely.

46
Q

How are glucocorticoids preferentially delivered?

Why?

A

Via the inhalation route.

To limit systemic effects

47
Q

Describe how glucocorticoids bring about changes in the transcription of a gene.

A

The glucocorticoid passes through the membrane (as it is lipophilic) and enters the cell.
It binds to glucocorticoid receptor alpha (GR alpha). This causes dissociation of an inhibitory heat shock protein, previously bound to the GR alpha (e.g. HSP90).
The activated receptor moves into the nucleus, aided by importins.
Here it binds to another bound receptor, and this newly formed dimer binds to glucocorticoid response elements (GREs) at the promoter region of a specific gene.
This causes either transactivation or transrespression of the gene.

48
Q

What is the most common effect of glucocorticoids on a)genes which code for anti-inflammatory proteins and b)genes which code for inflammatory proteins?

A

a) Transactivation

b) Transrepression

49
Q

How do glucocorticoids cause transrepression of genes which code for anti-inflammatory protiens?

A

Expression of these genes is associated with acetylation of histone proteins, by histone acetyltransferases (HATs).
This neutralises the charge on the DNA, allowing it to unwind and be transcripted.
Glucocorticoids recruit histone deacetylases (HDACs) to activated genes, which switches off transcription.

50
Q

What effects do glucocorticoids have on the inflammatory cells and proteins involved in an asthma attack?

A

TH2 and cytokines: Glucocorticoids reduce the production of TH2 produced cytokines and increase apoptosis.
Eosinophils: Glucocorticoids prevent the allergen-induced influx of eosinophils into the lung and also induce apoptosis.
Mast cells: Glucocorticoids reduce the number of cells and decrease the expression of the Fc receptor for the IgE.
IgE antibodies: Glucocorticoids prevent the production of these.

51
Q

What effects do glucocorticoids have on structural cells involved in an asthma attack?

A

Endothelial cells: Glucocorticoids reduce the cytokines and inflammatory mediators released by endothelial cells.
They also decrease the leakage of fluid between endothelial cells (reducing oedema).
Airway smooth muscle cells: Increased expression of beta 2 receptors (increases response to adrenaline and bronchodilators). Decreased release of cytokines.
Mucous glands: Decreased mucous secretion.

52
Q

How can glucocorticoids be used effectively?

A

In long term treatment (not for short term relief), particularly in combination with a LABA.

53
Q

What is a commonly used, inhaled glucocorticoid?

A

Beclametasone

54
Q

How soon does efficacy of inhaled glucocorticoids develop?

A

Over a few days

55
Q

Side effects of inhaled glucocorticoids

A

The side effects are due to deposition of the steroid in the oropharynx. They include dysphonia, and oral candidiasis.

56
Q

a) Which glucocorticoid is used in chronic, severe, or rapidly deteriorating asthma?
b) How is it delivered?
c) What is it co-administered with?

A

a) Prednisolone
b) Orally
c) Inhaled steroids (can reduce the oral dose required and minimise unwanted systemic side effects) and inhaled bronchodilators.

57
Q

a) Are cromolins used frequently?

b) What are they used for?

A

a) No- they are second line drugs and used infrequently.

b) The treatment of allergic asthma (particularly in children).

58
Q

Do cromolins have a direct effect on bronchial smooth muscle?

A

No

59
Q

What are proposed mechanisms of action for cromolins?

A

They exert a weak anti-inflammatory effect.
Thought to involve a decrease in sensitivity of irritant receptors associated with C fibres which trigger exaggerated reflexes
And a reduction in the release of cytokines.

60
Q

a) Name a cromolin
b) How is it delivered?
c) Which patients is it used in?
d) How long does it take for efficacy to develop?

A

a) Sodium cromoglicate
b) Inhalation
c) More effective in children and young adults than in older patients
d) Several weeks

61
Q

a) Name a monoclonal antibody treatment, directed against IgE?
b) How does this work?
c) Who is this treatment used in? Why is it not more commonly used?

A

a) omalizumab
b) It binds to the Fc part of the IgE, preventing it from binding to its receptor in inflammatory cells. This reduces the response of these cells, e.g. mast cells, to the allergens. It also reduces the expression of the FcE receptor on various inflammatory cells.
c) It is reserved for patients with very severe asthma that does not respond to other treatments.
It is expensive and requires IV administration every few weeks.

62
Q

Outline the different asthma steps/severities and the drugs used in each case.

A 
Step 1 (intermittent): SABA prn
Step 2 (mild persistent): Add on inhaled steroid
Step 3 and 4 (moderate persistent and severe persistent): Add on LABA and theophylline if needed
63
Q

Why are spacer devices used?

A

To reduce problems with coordination
To reduce oropharyngeal and laryngeal side effects
To reduce systemic absorption from swallowed fraction of drug
Acts as a holding chamber for aerosol
Reduces particle size and velocity
Improves lung deposition

64
Q

Describe the use of antihistamines in asthma

A

They are H1 receptor antagonists
They are delivered via the oral route
They are only of value when there is a known allergenic trigger, i.e. in atopic asthma
More effective in allergic rhinitis than in asthma
Additive effects when given together with leukotriene receptor antagonists.

65
Q

What is the treatment of acute astshma attack?

A

OSHITMAN
O-100% oxygen through a non-rebreather mask
S- nebulised salbutamol back to back
H- Hydrocortisone (IV) or predinisolone (oral)
I- ipratropium bromide nebulised hourly
T- theophylline (IV) or aminophylline (IV)
M- magnesium
An- Call an anaesthetist.

Respiratory (Charlotte) (12 decks)

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