Respiratory Pharmacology

• Anti-inflammatory agents- Anti-IgE:

  e.g. Omalizumab

  
  

  What is the mechanism of action of Omalizumab?


  - binds to free IGE, decreasing cell-bound IGE

  - decreases expression of high affinity receptors

  - decreases mediator release

  - decreases allergic inflammation

  - prevents exacerbation of asthma and reduced symptoms

  
• Anti-inflammatory agents- Anti-IgE:

  e.g. Omalizumab

  
  

  what do Omalizumabs do?


  Binds to free IgE and stops mast cells and other immune cells from being activated by IGE
• Anti-inflammatory agents- Anti-IgE:

  e.g. Omalizumab

  
  

  What is different about using Omalizumab as treatment for asthma?


  It's the first biological agent for the treatment of asthma

  
  

  - Must be given as a subcutaneous injection

  - Is very costly

  - It's only used in moderate to severe asthmatics whose asthma is not controlled by glucocorticosteroids
• Anti-inflammatory agents- cromones

  
  

  What is an example of a cromone?

  - Sodium Cromoglicate
• Anti-inflammatory agents- cromones

  
  

  What do cromones do?

  They're known as mast cell stabilisers

  
  

  - Their mechanism of action is unknown.

  - They reduce inflammatory cell activation & recruitment

  - Aren't as effective as glucocorticosteroids (they have a short half life)
• Anti-inflammatory agents- xanthines

  
  

  What can decrease the effectiveness of xanthines?


  Smoking, as it promotes plasma clearance
• Anti-inflammatory agents- xanthines

  
  

  What do the side effects of xanthine include?

  Nausea, vomiting, arrythmias, hypokalaemia, hypotension, seizures
• Anti-inflammatory agents- xanthines

  
  

  Do xanthines have a narrow therapeutic window?

  Yes, they are given approx. 10-20 micrograms/ml
• Anti-inflammatory agents- xanthines

  
  

  what is an example of a xanthine?

  - theophylline
• Anti-inflammatory agents- xanthines

  
  

  What do xanthines (e.g. theophylline) do?

  Inhibit phosphodiesterase (PDE) so the metabolism of cAMP is impaired so there is an increased activity of the pathway that leads to airway smooth muscle relaxation

  
• Anti-inflammatory agents- leukotrienes antagonists

  
  

  What are the side effects of anti-leukotriene drugs?

  (rare)

  -> but can include headaches and GI disturbance
• Anti-inflammatory agents- leukotrienes antagonists

  
  

  How effective are the anti-leukotriene drugs?

  - relatively long acting

  - have the greatest benefit in severe asthma (combination with GCS) so quite effective

  - Useful for aspirin-sensitive & exercise-induced asthma

  - has oral bioavailability
• Anti-inflammatory agents- leukotrienes antagonists

  
  

  What are some anti-leukotriene drugs?

  • 5-lipoxygenase (LO) inhibitors

  e.g. Zileuton

  • Leukotriene receptor antagonists

  e.g. Montelukast
• Anti-inflammatory agents- leukotrienes antagonists

  
  

  how do anti-leukotriene drugs work?

  They prevent:

  -bronchoconstriction

  - oedema

  - cellular infiltration

  - mucus production
• Anti-inflammatory agents- leukotrienes antagonists

  
  

  How are leukotrienes synthesised?

  Membrane phospholipids are modified in order to obtain arachidonic acid, which then undergoes the lipoxygenase pathway in order to form leukotrienes

  
• Anti-inflammatory agents- Glucocorticosteroids

  
  

  what are the size effects of Glucocorticosteroids taken via the oral or prolonged high dose route (e.g. prednisolone)?

  • Growth retardation, bruising

  • Immunosuppression

  • Suppression of hypothalamic-pituitary axis

  • Osteoporosis (serum osteocalcin), water retention (also

  binds to mineral corticosteroid receptor), diabetes

  • Hypertension, weight gain, ocular hypertension
• Anti-inflammatory agents- Glucocorticosteroids

  
  

  what are the size effects of Glucocorticosteroids taken via the inhaled route (e.g. fluticasone proprionate)?


  • oral candidiasis (fungal infection)

  • hoarseness, cough, voice problems
• Anti-inflammatory agents- Glucocorticosteroids

  
  

  Describe the role of ICS (inhaled corticosteroids) in asthma therapy.

  
• Anti-inflammatory agents- Glucocorticosteroids

  
  

  what are the actions of glucocorticosteroids in asthma?

  - Inhibition of leukotriene & cytokine synthesis/release

  - Inhibits recruitment of inflammatory cells (T cells, eosinophils, mast cells)

  - Anti-oedema

  - Increases beta-adrenoreceptor function (enhances bronchodilator effect of beta2-agonists)
• Anti-inflammatory agents- Glucocorticosteroids

  
  

  what are the affects of Glucocorticosteroids?


  - causes activation of proteins that prevent inflammation

  (e.g. annexin (lipocortin))

  - causes repression of proinflammatory genes that express inflammatory proteins

  (e.g. cytokines, chemokines, adhesion molecules and inflammatory enzymes)

  
  

  -> THIS PREVENTS INFLAMMATION

  
• Anti-inflammatory agents- Glucocorticosteroids

  
  

  How do glucocorticosteroids work in asthma?

  - Glucocorticosteroids moves through the lipid bilayer of cell & associates with a receptor complex in cytosol.

  - This complex is normally associated with a regulatory protein called HSP90: When the steroid docks to the receptor, this negative regulator will disperse into cytosol, allowing receptor complex to translocate to nucleus.

  - At the nucleus, the receptor complex leads to trans-repression of transcription factors normally associated with pro-inflammatory protein synthesis. They can also activate anti-inflammatory pathways.

  
• Anti-inflammatory agents- Glucocorticosteroids

  
  

  
  

  what is an example of a Glucocorticosteroid?


  fluticasone propionate
• Anti-inflammatory agents- Glucocorticosteroids

  
  

  how many rings structures do Glucocorticosteroids have?

  4
• Anti-inflammatory agents

  
  

  Give some examples of anti-inflammatory agents.

  first line drug:

  - Glucocorticosteroids (inhaled & oral)

  
  

  second line drug:

  (when patient does not respond to Glucocorticosteroids)

  - Leukotriene antagonists: montelukast (given orally)

  - Xanthines: theophylline, aminophylline

  - Cromones: sodium cromoglicate

  - Anti-IgE: Omalizumab (given subcutaneously)
• Bronchodilators- Muscarinic antagonists

  
  

  what are the side effects of Muscarinic antagonists?

  dry mouth

  -> this means less saliva excretion which can lead to ulcers that result in the inability to swallow and eat properly

  
  

  (less rare: urinary retention, constipation, acute angle glaucoma)
• Bronchodilators- Muscarinic antagonists

  
  

  
  

  how long does Tiotropium bromide inhibit bronchoconstriction?

  24 hours
• Bronchodilators- Muscarinic antagonists

  
  

  how long does Ipratropium Bromide inhibit bronchoconstriction?

  6 hours
• Bronchodilators- Muscarinic antagonists

  
  

  what do Muscarinic antagonists do?

  - Prevents smooth muscle contraction

  - Prevents mucus secretion induced by activation of parasympathetic nerves

  - Inhibits bronchoconstriction

  - mainly used in treatment of COPD

  
• Bronchodilators- Muscarinic antagonists

  
  

  what are some example of Muscarinic antagonists?

  - Ipratropium Bromide

  - Tiotropium bromide
• Bronchodilators- Beta2-agonists

  
  

  what are the side effects of beta2 agonists?

  tremor, increased heart rate, hypokalemia (targeting beta-receptors at extra-pulmonary sites)
• Bronchodilators- Beta2-agonists

  
  

  How are beta2 agonists administered?

  via the inhaled route

  (metered dose inhaler, dry powder and nebulizer)
• Bronchodilators- Beta2-agonists

  
  

  What is the mechanism of action of beta2 agonists?

  - It activates beta2 adrenoreceptor on surface of airway smooth muscle cells

  - This induces adenylyl cyclase to convert ATP to cAMP.

  - That drives protein kinase A activity downstream that can then convert MLCK to its phosphorylated form, which causes smooth muscle relaxation

  
• Bronchodilators- Beta2-agonists

  
  

  what do beta2 agonists do?

  - relaxes smooth muscles (bronchodilator)

  - inhibits mast cell degranulation
• Bronchodilators- Beta2-agonists

  
  

  how can you tell between long acting and short acting beta2 agonists by looking at their structure?

  long acting ones are longer and bigger
• Bronchodilators- Beta2-agonists

  
  

  what do beta2 agonists have a similar structure to?

  adrenaline and isoprenaline
• Bronchodilators- Beta2-agonists

  
  

  what are the two types of beta2-agonists?

  - Short acting beta2 agonists (SABA):

  e.g. salbutamol

  
  

  - Long acting beta2 agonists (LABA):

  for Asthma/COPD- salmeterol

  for COPD- indacaterol
• Bronchodilators

  
  

  Give some examples of bronchodilators.

  - Beta2-agonists (direct)

  - Muscarinic antagonists (indirect; used in COPD)
• diseases:

  asthma allergen exposure:

  
  

  what happens during the AHR phase?

  - bronchospasm on an inflamed oedematous airway that is very sensitive/twitchy to any inhaled irritant

  
  

  -> lasts days
• diseases: asthma

  
  

  What are the 2 types of drugs used in pharmacological treatment of asthma?

  1. Bronchodilators

  2. Anti-inflammatory agents
• diseases:

  asthma allergen exposure:

  
  

  what happens during the delayed phase?

  - airways narrow due to mucosal swelling/oedema as a result of mediators released from inflammatory cells recruited into airways initiated b event of the immediate phase

  - small component of broncospasm

  
  

  -> lasts hours