TOpic 15, selective b2 stimulants and other bronchodialators

Question 1

goals of therapy

Answer 1

1. reduce intensity and frequency of symptoms. 2. Relief of acute asthma symptoms. 3. Long term therapy: prevention of inflammation

Question 2

how to treat asthmatic patients

Answer 2

1. Asses the severity of asthma and start the treatment according to the guidelines 2. increase Intensity of treatment stepwise, until the asthma is well controlled 3. reduce dose of anti-inflammatory agents gradually (if possible), to minimize the side effects

Question 3

drugs used in asthma treatment

Answer 3

are:

Question 4

Short-acting b__₂ agonists (SABA):

• Rapid onset (5-30min)
• Duration: 4-6 hours
• Symptomatic treatment of acute bronchospasm – inhaler
  
  • Used as relievers
• b₂ agonists aren’t anti-inflammatory so never use alone
  
  • Although it may be used as a monotherapy for patients with intermittent asthma or exercise-induced asthma

Action:

• Bronchodilation
• ­ mucociliary transport
• ¯ release of inflammatory mediators

Adverse effects:

• Cardiovascular disturbances (Tachycardia, palpitation, angina)
  
  • Direct cardiac effect (b₁, b₂)
  • Vasodilation (b₂)
  • Presnaptic norepinephrine release (b₂)
• Hypokalemia
• Metabolic effects: Hyperglycemia, hyperlipidemia
• Hypomagnesemia
• Skeletal muscle tremors
• ¯ PaO₂
• Mild loss of appetite, disturbed sleep
• Development of tolerance

Drugs:

• Albuterol (salbutamol)
• Levalbuterol
• Terbutaline
• Fenoterol

Answer 4

Short-acting b__₂ agonists (SABA):

• Rapid onset (5-30min)
• Duration: 4-6 hours
• Symptomatic treatment of acute bronchospasm – inhaler
  
  • Used as relievers
• b₂ agonists aren’t anti-inflammatory so never use alone
  
  • Although it may be used as a monotherapy for patients with intermittent asthma or exercise-induced asthma

Action:

• Bronchodilation
• ­ mucociliary transport
• ¯ release of inflammatory mediators

Adverse effects:

• Cardiovascular disturbances (Tachycardia, palpitation, angina)
  
  • Direct cardiac effect (b₁, b₂)
  • Vasodilation (b₂)
  • Presnaptic norepinephrine release (b₂)
• Hypokalemia
• Metabolic effects: Hyperglycemia, hyperlipidemia
• Hypomagnesemia
• Skeletal muscle tremors
• ¯ PaO₂
• Mild loss of appetite, disturbed sleep
• Development of tolerance

Drugs:

• Albuterol (salbutamol)
• Levalbuterol
• Terbutaline
• Fenoterol

Question 5

what are the LABA drugs

Answer 5

Albuterol (salbutamol)

Levalbuterol

Terbutaline

Fenoterol

Question 6

Long-acting b__₂ agonists (LABA):

Answer 6

Long-acting b__₂ agonists (LABA):

• Slower onset of action
• Duration: 12 hours
  
  • Higher lipophilicity è accumulation in membranes
• Not used for quick relief of an acute asthma attack, but rather as controllers in patients with moderat/severe asthma and COPD
• Never used as a monotherapy.
  
  • Only used in a combination with asthma controlling-medication
    
    • Inhaled corticosteroids (main choice)
    • Synergistic effect: Small dose of steroid + LABA is stronger than a high dose of steroid

Action:

• Bronchodilation

Adverse effects:

• Same as SABA

Drugs:

• Salmeterol (=albuterol)
  
  • Partial agonist
• Formoterol
  
  • Faster onset of action
• Clenbuterol
  
  • Oral agent
• Bambuterol (® Terbutaline)
  
  • Oral agent
• Indacaterol, olodaterol, vilanterol
  
  • Duration > 24h (VLABA)

Question 7

what are the LABA drugs

Answer 7

Drugs:

• Salmeterol (=albuterol)
  
  • Partial agonist
• Formoterol
  
  • Faster onset of action
• Clenbuterol
  
  • Oral agent
• Bambuterol (® Terbutaline)
  
  • Oral agent
• Indacaterol, olodaterol, vilanterol
  
  • Duration > 24h (VLABA)

Question 8

Theophylline (xanthine)

Answer 8

Other bronchodilators:

Xanthines:

• Other xanthines with no bronchodilator effect: caffeine, theobromine
• Theophylline:
  
  • It gives rise to aminophylline
  • Therapeutic effect:
    
    • Bronchodilation
      
      • decrease a₁ receptor
      • decrease PDE₃ [phosphodiesterase] è ­ cAMP
    • decrease Release of inflammatory mediators
      
      • ¯decrease PDE₄
      • decrease a₁ receptor
      • ­ HDAC2
    • increase­ Ciliary activity
  • Side effects:
    
    • ­ CNS
      
      • Anxiety
      • Insomnia
      • Tremor
      • Seizures
    • Cardiovascular:
      
      • At low doses, mild elevation of BP (a receptor decrease)
      • At higher doses, “inodilator” effect (­ cAMP)
    • Diuretic effect
      
      • increase­ GFR
      • decrease Tubular sodium resorption
    • ­ Gastrointestinal secretions increase
      
      • Gastric acid
      • Digestive enzyme
• Pharmacokinetics:
  
  • Good oral absorption
  • Narrow therapeutic index

• Clinical use:
  
  • Prevention of asthmatic attack (oral, extended-release tablets)
  • Reliever in acute asthma (aminophylline IV)

Question 9

MaChR antagonists?

Answer 9

mAChR antagonists:

• Mechanism of action:
  
  • M₃ is present in bronchial smooth muscle cells (they normally cause contraction)
  • We use only drugs having a quaternary nitrogen nowadays because:
    
    • Plasma concentration stays low
    • The drugs don’t enter CNS
• Therapeutic effects:
  
  • Bronchodilation
  • decrease Bronchial secretions
  • Block vagally-mediated contraction of airway smooth muscle and mucus secretion
• Clinical use:
  
  • Relievers (ipratropium) or controllers in asthma and COPD
    
    • Used adjacent to b₂ agonists
    • Instead of b₂ agonists, if those are contraindicated or not tolerated
    • If cholinergic tone is elevated (e.g. nocturnal asthma)
    • Patients with concomitant COPD
    • Asthmatic attack – alternative or add-on drugs for SABA
    • • Adverse effects:
  • Dry mouth
  • Cough
• Drugs:
  
  • Atropine
  • Ipratropium
    
    • Non-selective muscarinic receptor antagonist
    • Onset: < 15min
    • Duration: 4-6h
    • Administration: 3x/day
  • Tiotropium, glycopyrronium, aclidinium, umeclidinium
    
    • Selective for M₃ receptors (slower dissociation)
    • Longer effect: T_1/2 = 11h - 6 days (except aclidinium)
    • Administration: 1x/day