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Unit 13 Week 1 (Sam) > Pharmacology of asthma > Flashcards

Pharmacology of asthma Flashcards

1
Q

What is chronic asthma

A

a common chronic inflammatory condition of the airways, associated with airflow hyperresponsiveness and variable airflow obstruction

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2
Q

what is acute asthma

A

the progressive worsening of asthma symptoms, including breathlessness etc.

An acute exacerbation is marked by a reduction in baseline objective measures of pulmonary function, such as peak expiratory flow rate and FEV1.

Arguably More serious. Degeneration of these symptoms.

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3
Q

most frequent symptoms of asthma

A
  • cough
  • wheeze
  • chest tightness
  • breathlessness
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4
Q

pharmacological treatment options for asthma

A
  1. SABA short acting beta2 agonists e.g., salbutamol
  2. LABA “ e.g., formoterol
  3. LTRA leukotriene receptor antagonist e.g., monteleukast
  4. ICS inhaled corticosteroids e.g. budesonide
  5. Oral corticosteroids e.g., prednisolone
  6. Biologics e.g., mepolizumab
  7. Others e.g., theophylline, tiotropium
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5
Q

What happens to FEV1 when a B2 agonist is used

A

Increases as airways dilate

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6
Q

In mild asthma what structural changes are seen in airways

A

Goblet cell hyperplasia

Sub-basement membrane thickening

Collagen deposition + cellular infiltrate in the submucosal area

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7
Q

Bronchioles do not have adrenergic fibres they only have ____ fibres

A

Parasympathetic firbes. The only way to activate B2 receptors is with adrenaline.

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8
Q

How do glucocorticoids prevent asthmatic symptoms (general)

A

inhibit the action of cytokines (e.g., Il-4, Il-13)

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9
Q

Which group of drugs are bronchodilators- providing symptomatic relief?

A

B2 agonists

Theophylline

LTRA (leukotrine receptor agonists)

Anti-muscarinics

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10
Q

Which group of drugs are anti-inflammatory in asthma

A

glucocorticoids

targeted biologics

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11
Q

Salbutamol

A

CLASS: Short-Acting B2 agonist (SABA)

CHEMSITRY: small molecule, analogue of adrenaline

PHARMACOLOGY: 1* target- B2 adrenoceptor (GPCR)

Activity- partial agonist

Selectivity- B2>B1 not massively tho. targets lungs → into blood→ heart has B1 receptors → increased HR

PHYSIOLOGY: B2 receptors present on smooth muscle cells (and mast cells)

GS –> ↑adenylyl cyclase –> cAMP –> ↑cAMP –> ↑PKA and decreased Ca2+ in cells –>deactivate MLC kinase and activate MLC phosphatase–> s.m. relaxation

Bronchodilation, tocolytic (stops labor) and casuses vasodilation in cap beds

Increased cAMP caused decreased degranulation of mast cells

CLINICAL: obstructive airway disease, premature labor, performance enhancement

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12
Q

Signalling in cardiac cells

A
  1. Gas activates adenylyl cyclase
  2. Adenylyl cyclase converts ATP to cAMP and PPi
  3. cAMP activates protein kinase A (PKA)
  4. PKA phosphorylates voltage gated ion channels in the heart, making them more responsive
  5. Increased AP generation and force of contraction

cAMP also binds to HCN channels making their threshold voltage for opening lower, incresing the rate of AP firing

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13
Q

Signalling in smooth muscle cells

A
  1. Gas activates adenylyl cyclase
  2. Adenylyl cyclase converts ATP to cAMP and PPi
  3. cAMP activates protein kinase A (PKA)
  4. PKA phosphorylates the MLCK (myosin light chain kinase), turning it off
  5. Results in decreased muscle contraction
  6. M3 and A1 receptors are coupled to Gaq subunits
  7. They activate phospholipase B
  8. This activates IP3 and DAG
  9. Release of internal stores of clacium
  10. Aids in muscle contraction

M2 and a2 receptors turn adenylyl cyclase off

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14
Q

Budesonide

A

CLASS: inhaled corticosteroid (ICS)

CHEMISTRY: synthetic glucocorticoid

PHARMACOLOGY: 1* target: glucocorticoid receptor (nuclear hormone receptor)

Activity: agonist

PHYSIOLOGY: transrepression: decreases pro-inflammatory mediators

transactivation: increases anti-inflammatory mediators

CLINICAL: Anti-inflammatory

Immunosuppressive

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15
Q

Montelukast

A

CLASS: LeukoTriene Receptor Antagonist (LTRA)

CHEMISTRY: synthetic analogue of leukotriene

PHARMACOLOGY: 1* target: CysLT1 (GPCR)

Activity: Competitive antagonist

PHYSIOLOGY: LT’s are inflammatory mediators derived from arachidonic acid. They result in smooth muscle contraction, vascular permeability and leukocyte activation

CLINICAL: prophylaxis of asthma

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16
Q

Arachidonic acid metabolism

A
  1. Membrane phospholipids are converted to arachidonic acid by PLA2
  2. Arachidonic acid is then converted to leukotriene 4 by thr 5-lipooxygenase enzyme
  3. Leukotriene 4 is then conjugated with glutathione
17
Q

Aspirin and asthma

A
  1. Arachidonic metabolism can go into one of two pathways.
  2. Aspirin and other NSAIDs may divert AA into the LOX pathway as the COX is inhibited
  3. The LOX pathway results in formation of leukotrienes and therefore bronchoconstriction
18
Q

Targeted biologics in asthma

A

Not first line treatment

Extremely expensive

Used as a prophylaxis

  • Omalizumab
  • Mepolizumab and reslizumab
  • Benralizumab
19
Q

Omalizumab

A

CHEMISYRY: humanised monoclonal igG1

PHARMACOLOGY: target: unbound IgE heavy chain constant

Activity: neutralising/ blocking

PHYSIOLOGY:

Decreases binding of IgE to FCσR1 receptor on mast cells/ basophils therefore decreased allergen inducing mediator release

CLINICAL: prophylaxis for severe allergic asthma

20
Q

Mepolizumab and reslizumab

A

CHEMISTRY: Humanised monoclonal IgG

PHARMACOLOGY: target: Il-5

Activity: neutralise/ block

PHYSIOLOGY: Il-5 is important in growth, differentiation, recruitment, activation and survival of eosinophils.

CLINICAL: severe eosinophilic asthma

21
Q

Benralizumab

A

CHEMSITRY: humanised monoclonal IgG

PHYSIOLOGY: Target: Il-5 receptor on eosino/basophils

Action: Fc region also binds to immune cells- tagrteing the eosino/basophil for destruction

CLINICAL: severe eosoinophilic asthma

22
Q

Theophylline

A

CLASS: methylxanthine

CHEMISTRY: analogue of purine

PHARMACOLOGY: Target: adenosine receptors Activity: competitive antagonist

Target: Phsophodiesterases Activity: Non-selective Competitive inhibitor

PHYSIOLOGY: A2 receptor→Gas→increase cAMP …→bronchodilation

decresase phosphodiesterase→increased cAMP→ bronchodilation

Increaes HR and force of contraction

23
Q

tiotropium

A

CLASS: long acting muscarinic antagonist (LAMA)

CHEMISTRY: synthetic nalgoue of atropine

PHARMACOLOGY: 1* target: m3 receptor Activity: non selective competitive antagonist

PHYSIOLOGY: Ach→M3→Gaq… increase in cytosolic Ca2+→ contraction and mucous secretion

antagonism causes bronchodilation and decreased secretion

Target symmpathetic action of sm.muscle

24
Q

COPD general

A

Disease of smokers

Impairs normal lung defences allowing frequent airway infection (bronchitis) and alveoli (pneumonia)

Inflammatory reaction→ tissue destruction (emphysema)

25
Q

Pathopshyiolgy of COPD

A
  1. Cigarette smoke
  2. Activatrion of alveolar macrophages and neutrophils (release chemtactic factors, cytokines like Il-8 and ,mediators like LTB
  3. Macrophages and neutrophils release proteases
  4. mucous hypersecretion and alveolar wall destruction
26
Q

Therapeutic goals of asthma

A

Relief

reverse bronchospasm

Reduce mucous secretion and suppress airway oedema in severe

Prophylaxis

prevent bronchospasm

decrease chronic inflammation

decrease airway remodelling

27
Q

therapeutic goals of COPD

A

relief

increase airway patency

control recurrent infection

prophylaxis

decrease chronic inflammation

control mucous secretion

28
Q

COPD therapy

A

SABA- salbutamol

LABA- formoterol

SAMA- ipratropium

LAMA- tiotropium

ICS- budesonide

29
Q

differences between astha and COPD

A

both are chornic inflam conditions that produce airway obstruction

asthma

bronchospasm AND inflammation

intermittent periods of worsening

drug treatment may address

for symptoms use bronchodilators

COPD

Alveolar breakdown (emphysema) and bronchitis (inflammation)

gradual deterioration

smoking prevention is essential in long term public health

Unit 13 Week 1 (Sam) (6 decks)

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