Asthma

• CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

  • Chronic conditions:

  1. narrowing of airways
  2. predominantly inflammatory
  3. combination of bronchitis and emphysema
  4. poorly reversible

  • CHRONIC BRONCHITIS = persistent cough with mucous production
  • EMPHYSEMA = destruction of tissues around alveoli
• BRONCHIAL ASTHMA

  • Chronic condition:

  1. narrowing of airways
  2. occurs in attacks
  3. predominantly inflammatory
  4. obstruction largely reversible, remodelling so
• CAUSES OF ASTHMA

  • background tendency

  1. genetic factors- allergy + atopy genes
  2. environmental influences in early life (maternal smoking, dietary, environmental allergies)

  • specific triggers

  1. exercise or emotion
  2. cold air
  3. fungal spores
  4. drugs
  5. pollens
  6. excrta of house dust mites
  7. respiratory tract infections
  8. animal fur, dander, saliva
  9. environmental pollutants
  10. occupational factors
• AIRWAYS IN ASTHMA

  1. Trachea and primary bronchi
  2. Bronchioles + alveoli

  ATHMA: pathological changes in the airway wall

  
• IMMUNE SYSTEM IN ASTHMA

  
• MAST CELLS

  • Granules containing pre-formed (early) mediators (e.g. histamine, proteases, proteoglycans chemotactic factors)
  • other mediators (synthesised de novo) are often derived from membrane lipids

  
• DEGRANULATING EOSINOPHIL

  
• EFFECTS OF MEDIATORS OF BRONCHIAL ASTHMA

  EARLY MEDIATORS

  • Acetylcholine, Leukotrienes C4, D4, E4 (Prostaglandin D2, Histamine)

  1. contraction of airways smooth muscle
  2. increased vascular permeability
  3. increased bronchial secretions

  • Chemotatic factors

  1. infiltration of lung tissue by neutrophils and eosinophils
• EFFECTS OF MEDIATORS OF BRONCHIAL ASTHMA

  LATER MEDIATORS

  • Leukotrienes C4, D4, E4, Interleukins, Growth factors

  1. contraction of airways smooth muscle
  2. increased vascular permeability
  3. increased bronchial secretions
  4. remodelling

  • Major basic protein from eosinophils

  1. epithelial desquamation
  2. cell death
• ANTI-ASTHMA DRUGS: β2 ADRENOCEPTOR AGONISTS

  • RELIEVERS = short acting beta agonists (can be fast onset long acting beta agonists when combined with a steroid)
  • PREVENTERS = mostly glucocortoids, but may use oral theophyline, leukotriene antagonists and long acting beta agonists alongside steroids

  
• RELATIVE ORDER OF DRUG POTENCY AT THE β-ADRENOCEPTOR

  • Non-selective agonists

  1. Isoprenaline > adrenaline > noradrenaline

  • Agonists selective for subtypes of the β-adrenoceptor

  1. β1- dobutamine
  2. β2- salbutamol

  • Selective antagonist

  1. β1 Atenolol

  • Non-selective antagonist

  1. β1 + β2- Propranolol
• EFFECTS MEDIATED BY β-ADRENOCEPTORS

  
• USES OF SHORT-ACTING DRUGS

  • All asthmatics should have a reliever inhaler
  • if asthma occurs twice a week, or less, may be a sole drug
  • in many people, used in edition to preventers
  • most commonly inhaled, but available as tablets, oral solutions, injectable solutions and infusions
• β-AGONIST BRONCHODILATORS

  • long acting drugs such as salmeterol are given twice a day to prevent symptoms

  1. ring of salmeterol repetitively activates the receptor
  2. the terminal portion of the alkyl amine chain anchors the molecule to the receptor

  • its lipophilicity also means that it dissolves into membranes and slowly leaks out, thus remaining in the tissues for longer
• UNWANTED EFFECTS OF β-AGONIST BRONCHODILATORS

  • tremor

  1. peripheral effect involving interference with muscle spindle function

  • tachycardia, palpitations

  1. activation of cardiac β-adrenoceptors

  • nervous tension

  1. effect on CNS

  • hypokalaemia

  1. stimulation of Na+/ K+ ATPase in skeletal muscle

  • headaches
  • muscle cramps

  *these may be minimised by inhalation rather than oral administration
• ROUTES OF ADMINISTRATION

  • MDIs get a drug into the lungs and reduce the amount that enters the systemic circulation

  1. 10% of drug says in MDI
  2. 80% of drug impacts in the mouth
  3. 10% of drug enters lungs
  4. 90% of drug entering body is swallowed

  • unintended oral dose doesn't have enough of a bronchodilator effect to treat asthma
• GLUCOCORTICOIDS IN ASTHMA

  • Cortisol and Hydrocortisone are chemically the same

  1. administrated- hormone: cortisol/ drug: hydrocortisone

  • Glucocorticoid receptor action anti-inflammatory effects:

  1. decreased activation, proliferation and migration of immune system cells
  2. Decreased expression of pro-inflammatory cytokines and cyclo-oxygenase 2 (therefore decreased prostaglandin production)
  3. increased expression of anti- inflammatory mediators
  4. **effects are slow; effective as preventers of asthma attacks

  • common drugs used in inhaler formulation:

  1. beclometasone + budesonide + fluticasone
• SIDE EFFECTS OF GLUCOCORTICOIDS: Cushing's syndrome

  • Actions of adrenal steroids

  1. Glucocortoids (metabolic effects, anti-inflammatory, immunosuppressive)
  2. Mineralocorticoids (water + electrolyte balance)
  3. **mediated by different NHRs

  • Actions of natural steroids:

  1. cortisol (hydrocortisone) --> act on both MCRs and GCRs
  2. aldosterone (mineralcorticoid effects only)

  • CUSHING'S DISEASE: due to pituitary tumour

  1. excess glucocorticoids due to treatment with GC or another type of tumour
• REDUCING GLUCOCORTOID SIDE EFFECTS

  1. Drug delivery must be as efficient as possible (inhalation)
  2. Change the duration of action by changing its structure

  • gives better control of effects and side effects
  • SHORT (hydrocortisone, fludrocortisone), MODERATE (prednisolone), LONG (dexamethasone)
• TRANSACTIVATION PATHWAY

  • some anti-inflammatory effects
  • metabolic effects
  • skin thinning

  TRANSREPRESSION PATHWAY

  • some anti-inflammatory effects
  • selective glucocorticoid receptor agonist/ modulators favour the trans repression pathway (better side effects)
• GLUCOCORTICOID FEEDBACK MECHANISMS

  • Hydrocortisone increases availability of glucose and suppresses the immune system

  1. prepares for fight/ flight
  2. cortisol does this as well

  
• LEUKOTRIENE RECEPTOR ANTAGONISTS

  • Leukotrienes:

  1. produced by mast cells, eosinophils, basophils and macrophages
  2. agonists at cysteine-leukotriene (CysLT) receptors (GPCRs)
  3. contract bronchial smooth muscle
  4. stimulates mucus secretion
  5. increases microvascular permeability

  • 'Lukast' drugs act on leukotriene receptors

  1. used for exercise-induced and aspirin-induced asthma
  2. used as add-on preventers

  • unwanted side effects

  1. abdominal pain and GI tract upsets
  2. Headaches
  3. rarely produce psychiatric side effects (depression + hallucinations)
• MUSCARINIC RECEPTOR ANTAGONIST

  • Parasympathetic neurone increase their release of acetylcholine, leading to both bronchoconstriction and increased mucus production

  1. therefore antagonising muscarinic receptors is a good intervention

  • Atropine and hyoscine are non-selective muscarinic antagonists and readily pass into the systemic circulation (as they are tertiary amines)

  1. cause a lot of side effects in the parasympathetic nervous system
  2. **no longer used to treat asthma: however, structurally related compounds, Ipratropium and tiotropium are still used
• ITRATROPIUM BROMIDE

  • short acting muscarinic antagonists (SAMA) used as an add-on in severe asthma; also used in COPD
  • administerated via inhaler or nebuliser
  • does not select between mACh receptor subtypes
  • quaternary amine with a permanent positive charge: its not easily absorbed into the systemic circulation
• TIOTROPIUM BROMIDE

  • long acting muscarinic antagonist (LAMA)
  • administrated via inhalation
  • quaternary amine, minimising its systemic effects
  • used in severe asthma, and in COPD
• MUSCARINIC ANTAGONIST UNWANTED EFFECTS:

  1. dry mouth
  2. constipation
  3. headache
  4. nausea
  5. dizziness
  6. cardiac arrhythmias
• THEOPHYLLINE

  • member of the alkyllxanthine class of drugs
  • administrated orally in sustained release capsules or IV for a life-threatening acute asthma attack
  • when injected, its often complexed with ethylenediamine to improve its solubility

  MECHANISM:

  1. acts as a non-selective inhibitor of phosphodiesterase (enzymes that breakdown cAMP/ the increase in cAMP that theophylline causes may promote bronchodilator and reduce inflammation)
  2. Antagonist of adenosine receptors (helps promote bronchodilaton/ causes some of the cardiac side effects of theophylline)
• UNWANTED EFFECTS FROM HIGH DOSAGE THEOPHYLLINE:

  1. nausea/ vommiting
  2. anxiety
  3. headache
  4. sleep disturbances
  5. tachycardia/ dysrhymias
  6. convulsions
• OMALIZUMB

  • Humanised monoclonal antibody against immunoglobulin E (IgE)
  • once bound by omalizumb. IgE is rapidly removed from the circulation

  1. therefore omalizumb can act as a preventer drug in severe allergic asthma