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Semester 5 - Farmocology > Session 6 - Anti-Asthmatic drugs > Flashcards

Session 6 - Anti-Asthmatic drugs Flashcards

1
Q

What two main histopathological features is asthma characterised by?

A

Airway wall inflammation and remodelling (reversible airflow obstruction).

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2
Q

What are three possible causes of asthma?

A

Genetic
Pre/post-natal exposure to airborne allergens
Hygien Hypothesis

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3
Q

What is asthma defined as

A 
One or more of:
Wheeze
Cough 
Breathlessness
Chest tightness 
Variable airflow obstruction
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4
Q

Describe an asthmatic wheeze

A

High pitches expiratory sound which is of variable intensity and tone (polyphonic)

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5
Q

Describe an asthmatic cough

A

 Often worse at night (Lack of sleep, poor performance at school)
 Exercise induced (Decreased participation in activities)
 Dry cough

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6
Q

What do you look for in inspection of someone with asthma?

A 
o	Chest
	Scars, deformities
	Hyper-expansion (Barrel Chest)
o	General health
	Eczema, hay-fever
	Lethargy
	Can they speak?
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7
Q

What do you look for in percussion in asthma?

A

Hyper-resonant

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8
Q

What would you see in asthma spirometry

A

o Low PEFR
o Low FEV1/FVC Ratio
o >12% increase in FEV1 following salbutamol

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9
Q

How could you test the trigger of asthma allergens?

A

o Skin prick to aero-allergens, e.g. cat, dog, HDM

o Blood IgE levels to specific aero-allergens

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10
Q

What are chest x-rays for in asthma?

A

o Performed to exclude other diseases/inhalation of foreign body/pneumothorax

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11
Q

What is autonomic innervation of bronchial smooth muscle?

A

Sympathetic Activity -> Bronchodilation

Parasympathetic Activity -> Maintains airway smooth muscle tone

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12
Q

What do sympathetic nerves innervate in bronchioles?

A

Blood vessels and glands, NOT bronchial smooth muscle

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13
Q

What responds sympathetically and is attached to bronchial smooth muscle, epithelium, glands and mast cells?

A

B2 adrenoceptors

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14
Q

What does binding of noradrenaline to B2 adrenoceptors do?

A

bronchodilation, reduced histamine release and increased mucociliary clearance.

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15
Q

What does parasympathetic innervation of the airways do?

A

Parasympathetic activity is normally dominant in maintaining smooth muscle tone in the airways. Muscarinic Receptors are present on airway and vascular smooth muscle and glands. The M3 Receptor is pharmacologically the most important.

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16
Q

What are the three main categories of asthma pathophysiology in affected tissues

A

Smooth muscle dysfunction
Inflammation
Airway remodelling

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17
Q

What happens in smc dysfunction in asthma?

A

Increased contraction and mass of SMC

Increased cyto/chemokines

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18
Q

What are the immune cells involved in asthma?

A

Th2, mast cells

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19
Q

What are the five different remodelling factors which occur in Asthma

A 
	Mucus gland hyperplasia
	Airway wall thickening
	Increased smooth muscle mass
	Subepithelial fibrosis
	Epithelium desquamation
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20
Q

What is the early phase response in asthma?

A

In allergic asthma, initial response to allergen provocation is due to interaction with mast cell fixed IgE, resulting in histamine release and other potent spasmogens -> Bronchospasm

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21
Q

What occurs in the asthmatic late phase response?

A

Co-release of a range of mediators and chemotaxins activate a complex immune system response that brings leucocytes to the area. This sets off a further chain of event leading to exacerbated bronchospasm and congestion due to:
o Epithelial damage
 Increased exposure of the sensory irritant receptors, further exacerbating bronchial hyperactivity and sensitivity
o Thickening of the basement membrane
o Oedema
o Mucus production

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22
Q

Define bronchial hyperesponsiveness

A

exaggerated bronchoconstrictor response to direct pharmacological stimuli such as histamine, or indirect stimuli such as exercise

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23
Q

List the major drugs used to treat asthma

A

Short and long acting B2 agonists
Methylxanthines
Muscarinic receptor antagionists

24
Q

What is the mechanism of action of B2 agonists in the treatment of asthma (molecular mechanism plz, + both mechanisms)

A

β2 agonists act on the β2 receptors found on bronchial smooth muscle. The receptors are coupled to Gs Proteins, which cause an increase in cAMP and consequent decrease in intracellular [Ca2+]. This reduces the activity of myosin light chain kinase and thus muscle contraction.

Additionally, the decrease in intracellular Ca2+ will also and increase Ca2+ activated K+ currents, thus hyperpolarising muscle cells further and augmenting bronchodilation.

25
Q

How are B2 agonists administered?

A

β2 Agonists are administered by inhalation in aerosol, powder or nebulised form and can also be administered intravenously. Deposition within the pulmonary tract is related to particle size, with 1-5microns being optimal.

26
Q

What happens to the majority of drug in asthma?

A

However, the majority of the drug (up to 90% depending on the inhaler device) is deposited in the upper airway and/or swallowed before being removed by the liver.

27
Q

Name two fast acting B2 agonists

A

o Immediate Action
o Salbutamol – Duration of action 3-5hrs
o Terbutaline – Duration of action 3-5hrs

28
Q

Give two long acting B2 agonists

A

o Often given in adjunct with anti-inflammatories
o Formoterol – Duration of action 13hrs
o Salmeterol – Slower onset

29
Q

Give three adverse drug reactions of asthma

A
  • Inhaled high doses can cause skeletal muscle tremor

- B2 agonists can agonise cardicac B1 receptors and induce tachycardia and dysrhythmia

30
Q

What drug intercations are there with B2 agonists?

A

o β-blockers such as Propranolol, which bind to both β1 and β2 receptors

31
Q

Name the class of drugs which antagonise adenosine receptors

A

Methylxanthines

32
Q

Name two methylxanthines

A

 Theophylline

 Aminophylline

33
Q

What are the indications for methyxanthines?

A

 Status asthmaticus

 COPD

34
Q

What are the two adverse drug reactions to methylxanthines?

A

Psychomotor agitation

Tachycardia

35
Q

What does methylxanthines do?

A

Antagonise adenosine receptors

36
Q

When would methylxanthines be used?

A

As 3rd or 4th lines asthma treatments

37
Q

What is the mechanism of muscarininc receptor antagonists?

A

 Bind to and antagonise M3 cholinergic receptors on bronchial smooth muscle. This blocks the constricting effect of Ach and also inhibits mucus secretion.

38
Q

Give two examples of muscarininc receptor antagonists

A

 Ipratropium bromide

 Tiotropium bromide

39
Q

What are the indications for muscarinic receptor antagonist treatment?

A

 Ipratropium bromide

 Tiotropium bromide

40
Q

Why are there few adverse drug reactions involved in muscarinin receptor antagonists?

A

 Not well absorbed through the lungs, avoiding major systemic ADRs
 Dry mouth

41
Q

Outline the pharmacology of glucocorticoids

A

Like all steroid hormones, corticosteroids exert their effect via Nuclear Receptors. These receptors are found in the cytoplasm, complexed with heat shock proteins. Following the diffusion (or possibly transport) of their ligand into the cell and high-affinity binding, these receptors form a Homodimer with another ligand-receptor complex and translocate to the nucleus.

42
Q

What do glucocorticoids do in the nucleus

A

In the nucleus, the steroid-receptor complex homodimers can Transactivate or Transrepress genes by binding to Positive or Negative Hormone Response Elements. Large numbers of genes can be regulated in this way by a single ligand. Therapeutic effects of changes in gene expression may only be apparent some hours after administration.

43
Q

How do glucocorticoids express an anti-inflammatory effect?

A

Glucocorticoids have a profound generalised inhibitory effect on inflammatory response. This is mediated via reduced production of acute inflammatory mediators, especially eicosanoids (prostaglandins, leukotrienes), due to the production of Lipocortin, an enzyme that inhibits Phospholipase A2, preventing the formation of Arachidonic Acid and its metabolites.

Glucocorticoids also reduce the number of circulating immunocompetent cells (neutrophils and macrophages) and decrease the activity of cells involved in the chronic stages on inflammation (macrophages, fibroblasts), decreasing inflammation and decreasing healing.

44
Q

How are glucocorticoids used in asthma?

A

Glucocorticoids provide a cornerstone for the longer-term management of chronic asthma and can be administered by inhalation and in severe cases orally or intravenously. They have both an anti-inflammatory action and increase the expression of β2 Receptors. Optimal effects are seen after weeks/months of therapy.

Cases of acute asthma often require oral steroids (typically 40mg Prednisolone) for 1-2 weeks along with inhaled therapy. Asthma presenting to A&E may require intravenous hydrocortisone to be given.

45
Q

What are the pharmacokinetics of glucocorticoids in asthma?

A

10-50% of an inhaled dose is delivered to the lungs, depending on the inhaler device. A major proportion of the drug is deposited in the upper airway and/or swallowed and metabolised by the liver. Newer drugs are designed to undergo hepatic first pass metabolism to reduce ADR risk.

46
Q

What treatment is given in Mild Intermittent Asthma

A

Inhaled short acting β2 Agonist as required (E.g. Salbutamol)

47
Q

What treatment is given in step 2 (Introduction of regular preventer therapy)

A

Inhaled short acting β2 Agonist as required (E.g. Salbutamol)
Plus
Regular preventer therapy – corticosteroid (e.g. Beclometasone

48
Q

What treatment is given in Step 3 (Add on therapy)

A

Inhaled short acting β2 Agonist as required (E.g. Salbutamol)
Plus
Regular preventer therapy – corticosteroid (e.g. Beclometasone)
Plus
Regular long acting β2 Agonist (E.g. Salmeterol)

49
Q

What treatment is given in step 4 (trial additional therapy)

A

Inhaled short acting β2 Agonist as required (E.g. Salbutamol)
Plus
Regular preventer therapy – corticosteroid (e.g. Beclometasone)
Plus
Trial of additional therapy, such as Muscarinic Antagonist (e.g. Ipratropium Bromide), Leukotriene Receptor Antagonist, Methylxantine (e.g. Theophylline)

50
Q

What treatment is given in step 5 (oral steroids)

A

Continuous or frequent use of oral steroids (e.g. Prednisolone)

51
Q

Define severe acute asthma

A

Severe Acute Asthma is defined as any one of:
o Unable to complete sentences
o Pulse ≥ 110 bpm
o Respiration ≥ 25 per minute
o Peak expiratory flow 33-50% of best or predicted

52
Q

What are the life threatening features of severe acute asthma?

A 
o	Peak expiratory flow < 33%
o	PaO2 < 8kPa
o	PaCO2 > 4.5kPa
o	Silent chest
o	Cyanosis
o	Feeble respiratory effort
o	Hypotension, bradycardia, arrhythmia 
o	Exhaustion, confusion, coma
53
Q

When is severe acut asthma near fatal?

A

Severe, acute asthma is near fatal if PaCO2 is > 6kPa. Mechanical ventilation is required.

54
Q

How do you manage severe acute asthma?

A

o Oxygen – High flow, aim to keep O2 94-98% saturation
o Nebulised Salbutamol, continuous if necessary
o Intravenous Hydrocortisone
o Oral Prednisolone - ~40mg daily for 10-14 days

55
Q

How do you manage severe acute asthma if there is no response to primary treatment?

A

o Add nebulised Ipratropium Bromide
o Consider IV Magnesium Sulphate 1.2-2g over 20 minutes
o Consider IV Aminophylline if no improvement and life threatening features not responding to above treatment
 Beware if taking oral Theophylline

Semester 5 - Farmocology (27 decks)

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