PHARMACOTHERAPY OF BRONCHIAL ASTHMA

Drug used in the treatment of bronchia asthma can be grouped into three main categories:

1. Bronchodilators
   a. β- Adrenergic agonists which include:
   ƒ Non selective β-agonists e.g. adrenaline
   ƒ Selective β-agonists e.g. salbutamol
   b. Methylxanthines; theophylline derivatives
   c. Muscranic receptor antagonists e.g. Ipratropium bromide
2. Mast cell stabilizers, e.g. cromolyn sodium, nedocromil, ketotifen
3. Antiinflammatory agents: corticosteroids

1. β- ADRENERGIC AGONISTS (SYMPATHOMIMETIC AGENTS)
   a) Non- selective- β-agonists

• Epinephrine, ephedrine, isoprotenerol
  b). Selective β-agonists
• Salbutamol, terbutaline, metaproterenol, salmeterol, formaterol and etc
  
  Mechanism of Action
  β-Agonists stimulate adenyl cyclase and increase formation of cAMP in the airway tissues.
  They have got several pharmacological actions important in the treatment of asthma
• Relax smooth muscles
• Inhibit release of inflammatory mediator or broncho constricting substances from mast
  cells.
• Inhibit microvasculature leakage
• Increase mucociliary transport
• 
  a. Non-selective β- agonists
• Cause more cardiac stimulation (mediated by a β1 receptor), they should be reserved for
  special situation.
• Epinephrine: very effective, rapidly acting bronchodilator especially preferable for the
  relief of acute attack of bronchial asthma.
• Administered by inhalation or subcutaneously.
  Side effects include arrhythmia and worsening of angina pectoris, increase blood pressure,
  tremors etc
  Contraindication: – hypertension, arrhythmia,
  Ephedrine: compared to epinephrine, it has longer duration of action but more pronounced
  central effect and lower potency. It can be given orally. The drug is currently infrequently used
  because of development of more efficacious and beta2-selective agents.
  b. Selective β2- selective agonists
  Largely replaced non – selective β2- agonists, are effective after inhaled or oral administration
  and have got longer duration of action. They are the most widely used sympathomimetics.
  Commonly used drugs both by oral and inhalation are Salbutamol, terbutaline, metaproterenol,
  pirbuterol and bitolterol.
  Salmeterol and formeterol are new generation, long acting β2- selective agonists (with duration
  of action 12 hrs or more). These drugs appear to interact with inhaled corticosteroids to improve
  asthma control.
  Delivery of adrenoreceptor agonists through inhalation results in the greatest local effect on
  airway smooth muscle with least systemic toxicity.
  
  Side effects
  Tremors, anxiety, insomnia, tachycardia, headache, hypertension and etc.
  Contraindications: Sympathomimetics are contraindicated in patients with known
  hypersensitivity to the drugs
  Precautions: They should be used cautiously in patients with hypertension, cardiac dysfunction,
  hyperthyroidism, glaucoma, diabetes, pregnancy.

1. METHYLXANTHINES

• The three important methylxanthines are theophylline, theobromine, and caffeine. The
  theophylline preparations most commonly used for therapeutic purposes is aminophylline
  (theophylline plus diethylamine).
  Mechanism of Action
  i. Competitively inhibit phosphodiesterase (PDE) enzyme leading to increased cAMP level.
  ii. They competitively inhibit the action of adenosine on adenosine (A1 and A2) receptors
  (adenosine has been shown to cause contraction of isolated airway smooth muscle and to
  provoke histamine release from airway mast cells.
  iii. Inhibit the release of histamines and leukotriens from the mast cells
  Of the three natural xanthines, agents theophylline is most selective in its smooth muscle
  effect, while caffeine has the most marked central effect.
• 
  Pharmacokinetics
• 
  Only slightly soluble in water so has been administered as several salts containing varying
  amounts of theophylline base. Most preparations are well absorbed from gastro intestinal tract
  and metabolized by liver. Doses should be decreased in cases of liver disease and heart failure.
• 
  Adverse Effects:
• 
  Anorexia, nausea vomiting, abdominal discomfort, headache, anxiety, insomnia, seizures,
  arrhythmias
  Theophylline is now largely reserved for patients in whom symptoms remain poorly controlled
  despite the combination of regular treatment with an inhaled anti- inflammatory agent and as
  needed use of a ß2 agonist.
  80

1. MUSCRANIC RECEPTOR ANTAGONISTS
   Mechanism of Action
   Muscarinic antagonist competitively inhibit effect of acetylcholine at muscarinic receptors –
   hence block the contraction of air way smooth muscle and the increase in secretion of mucus
   that occurs in response to vagal activity e.g atropine sulfate
   Systemic adverse effects as a result of rapid absorption include urinary retention, tachycardia,
   loss of accommodation and agitation and local effects like excessive dryness of mouth limits the
   quantity of atropine used. Ipratropium bromide is poorly absorbed and does not readily enter the
   central nervous system thus permits the delivery of high doses to muscarinic receptor in the
   airways; hence, it can safely be used for bronchial asthma.
   Antimuscranic antagonist drugs appear to be slightly less effective than β- agonists agents in
   reversing asthmatic bronchospasm, The addition of ipratropium enhances the bronchodilation
   produced by nebulized albuterol in acute sever asthma. The antimuscarinic agents appear to
   be of significant value in chronic obstructive pulmonary diseases – perhaps more than asthma.
   They are useful as alternative therapies for patients intolerant of β – agonists
2. ANTI-INFLAMMATORY AGENTS: CORTICOSTEROIDS
   Used both for treatment and prophylactic purposes
   Mechanism of action
   They are presumed to act by their broad anti inflammatory efficacy mediated in part by inhibition
   of production of inflammatory mediators. They also potentiate the effects of β- receptor agonists
   and inhibit the lymphocytic-eosinophilic airway mucosal inflammation
   Effects on airway

• decreases bronchial reactivity
• increases airway caliber
• decreases frequency of asthma exacerbation and severity of symptoms
  The corticosteroids commonly used are hydrocortisone, predinisolone, beclomethasone,
  triamcinolone and etc.
  The drugs can be taken by inhalation as aerosol, oral, or an IV administration
  Because of severe adverse effects when given chronically, oral and parenteral corticosteroids
  are reserved for patient who need urgent treatment and those who have not improved with.
  bronchodilator. Aerosol treatment is the most effective way to decrease the systemic adverse
  effect of corticosteroid therapy. Abrupt discontinuation should be discouraged because of the
  fear of adrenal insufficiency. Doses should be decreased after improvement. Regular or
  controlled therapy is better maintained with aerosol corticosteroids.
  Clinical uses in bronchial asthma
• Urgent treatment of severe asthma not improved with bronchodilator
  o IV, inhalation or oral.
• Nocturnal asthma prevention
  o oral or inhalation
• Chronic asthma
  o Regular aerosol corticosteroids
  Side effects:
• Suppression of the hypothalamic-pituitary-adrenal axis
• Osteoporosis
• Sodium retention and hypertension
• Cataract
• Impairment of growth in children
• Susceptibility to infection like oral candidiasis, tuberculosis