Pharmacology of asthma Flashcards
What is chronic asthma
a common chronic inflammatory condition of the airways, associated with airflow hyperresponsiveness and variable airflow obstruction
what is acute asthma
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.
most frequent symptoms of asthma
- cough
- wheeze
- chest tightness
- breathlessness
pharmacological treatment options for asthma
- SABA short acting beta2 agonists e.g., salbutamol
- LABA “ e.g., formoterol
- LTRA leukotriene receptor antagonist e.g., monteleukast
- ICS inhaled corticosteroids e.g. budesonide
- Oral corticosteroids e.g., prednisolone
- Biologics e.g., mepolizumab
- Others e.g., theophylline, tiotropium
What happens to FEV1 when a B2 agonist is used
Increases as airways dilate
In mild asthma what structural changes are seen in airways
Goblet cell hyperplasia
Sub-basement membrane thickening
Collagen deposition + cellular infiltrate in the submucosal area
Bronchioles do not have adrenergic fibres they only have ____ fibres
Parasympathetic firbes. The only way to activate B2 receptors is with adrenaline.
How do glucocorticoids prevent asthmatic symptoms (general)
inhibit the action of cytokines (e.g., Il-4, Il-13)
Which group of drugs are bronchodilators- providing symptomatic relief?
B2 agonists
Theophylline
LTRA (leukotrine receptor agonists)
Anti-muscarinics
Which group of drugs are anti-inflammatory in asthma
glucocorticoids
targeted biologics
Salbutamol
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
Signalling in cardiac cells
- Gas activates adenylyl cyclase
- Adenylyl cyclase converts ATP to cAMP and PPi
- cAMP activates protein kinase A (PKA)
- PKA phosphorylates voltage gated ion channels in the heart, making them more responsive
- 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
Signalling in smooth muscle cells
- Gas activates adenylyl cyclase
- Adenylyl cyclase converts ATP to cAMP and PPi
- cAMP activates protein kinase A (PKA)
- PKA phosphorylates the MLCK (myosin light chain kinase), turning it off
- Results in decreased muscle contraction
- M3 and A1 receptors are coupled to Gaq subunits
- They activate phospholipase B
- This activates IP3 and DAG
- Release of internal stores of clacium
- Aids in muscle contraction
M2 and a2 receptors turn adenylyl cyclase off
Budesonide
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
Montelukast
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
Arachidonic acid metabolism
- Membrane phospholipids are converted to arachidonic acid by PLA2
- Arachidonic acid is then converted to leukotriene 4 by thr 5-lipooxygenase enzyme
- Leukotriene 4 is then conjugated with glutathione
Aspirin and asthma
- Arachidonic metabolism can go into one of two pathways.
- Aspirin and other NSAIDs may divert AA into the LOX pathway as the COX is inhibited
- The LOX pathway results in formation of leukotrienes and therefore bronchoconstriction
Targeted biologics in asthma
Not first line treatment
Extremely expensive
Used as a prophylaxis
- Omalizumab
- Mepolizumab and reslizumab
- Benralizumab
Omalizumab
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
Mepolizumab and reslizumab
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
Benralizumab
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
Theophylline
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
tiotropium
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
COPD general
Disease of smokers
Impairs normal lung defences allowing frequent airway infection (bronchitis) and alveoli (pneumonia)
Inflammatory reaction→ tissue destruction (emphysema)
Pathopshyiolgy of COPD
- Cigarette smoke
- Activatrion of alveolar macrophages and neutrophils (release chemtactic factors, cytokines like Il-8 and ,mediators like LTB
- Macrophages and neutrophils release proteases
- mucous hypersecretion and alveolar wall destruction
Therapeutic goals of asthma
Relief
reverse bronchospasm
Reduce mucous secretion and suppress airway oedema in severe
Prophylaxis
prevent bronchospasm
decrease chronic inflammation
decrease airway remodelling
therapeutic goals of COPD
relief
increase airway patency
control recurrent infection
prophylaxis
decrease chronic inflammation
control mucous secretion
COPD therapy
SABA- salbutamol
LABA- formoterol
SAMA- ipratropium
LAMA- tiotropium
ICS- budesonide
differences between astha and COPD
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
