Asthma (Bio)

Asthma

Symptoms
- Coughing
- Wheezing
- SOB
- Chest Tightness
Tests
- FHx
- Physical Exam
- Spirometry (Breath test)
- Allergy Tests
- In more severe cases
  - Xray/CT scan/Bronchoscopy

Inflammation of the air passages results in a temporary narrowing of the airways which carry oxygen to lung
Airway Obstruction in asthma is due to;
- Pulmonary inflammation
- Bronchospasm - bronchial smooth muscle hyperactivity
- Increased mucus secretion
- Cholinergic nerve over-activity

Initial Phase
- Minutes
  - Interaction of allergen w/ Mast cell IgE → release of histamine and PGD2 → Bronchoconstriction
Intermediate Phase
- Hours
  - Release of chemokines (IL-4,5,13) stimulating leukocyte release
Late Phase
- Days
  - Influx of Th2 lymphocytes, activating neutrophils and eosinophils that release toxic proteins which cause damage to the lung epithelium

Parasympathetic
- Predominant innervation of airway smooth muscle
  - Vagus Nerve
- Occupation of M3 receptors by Ach (released from Vagus)
  - Causes bronchoconstriction
Sympathetic
- No direct sympathetic supply of smooth muscle
- Innervate blood vessels
- When circulating adrenaline acts at B2 adrenoceptors on airway smooth muscle, it inhibits bronchoconstriction

Bronchodilators
- B2 adrenoreceptor agonists
- Muscarinic Antagonits
- Xanthines
Anti-inflammatory Drugs
- Glucocorticoids
- Leukotriene synthesis inhibitors and receptor antagonists

Mechanism of Action
- Bind Beta 2 Adrenoreceptors
- Causes relaxation of bronchial smooth muscle (bronchodilation) by increasing cAMP via G-protein-linked activation of adenylate cyclase
Examples
- Short Acting (T1/2 2-3 Hrs.)
  - - SABA Salbutamol (Ventolin)
- Long Acting
  - Salmeterol / Formterol / Indacaterol / Vilanterol
  - Long-acting compounds bind to an exo-site on the B2 receptor causing repeated prolonged activation
Administration
- Inhaled as power or aerosol
- Rarely given orally i/v
Systemic Side Effects
- Tremor
- Arrhythmias
- Hypokalaemia
- Muscle cramps

Mechanism of Action
- Ipratropium
  - Inhibition of the action of acetylcholine at M1, M2, and M3 muscarinic receptors, thus producing bronchodilation and reducing mucous secretion
  - Slower acting than B2 agonists
- Tiotropium
  - Selective inhibition of M1 and M3 receptors
Example
- Ipratropium Bromide
- Tiotropium Bromide
- Umeclidinium Bromide
- Glycopyrronium Bromide
Administration
- Given via inhalation
  - Not well absorbed - little systemic effects
Side effects
- Well tolerated
- The most common side effects are dry mouth and urinary retention

Mechanism of Action
- Relax bronchial smooth muscle (Bronchodilation) by inhibiting phosphodiesterase resulting in increased cAMP and cGMP.
- Also inflammatory actions (inhibit late phase)
Example
- Caffeine
- Theophylline
  - Taken Orally
  - Short half-life
  - Sustained release preparations available
- Aminophylline
  - IV
Side Effects
- Narrow therapeutic range
- Side effects likely w/ contractions > 110 μmol/i
  - Gastrointestinal: nausea / anorexia
  - Cardiovascular: Arrhythmias can be fatal
  - CNS: nervousness, tremor, seizures
Pharmacokinetics
- Metabolised in the liver
- Cytochrome P450 (CYP1A2) is the main isoform responsible for the metabolism (and inactivation) of theophylline

Many drugs interact w/ theophylline by inhibiting or potentiating its metabolism by cytochrome P450 isoenzyme (CYP1A2)
Rifampicin (an anti-tuberculosis drug) can increase Theophylline clearance by increasing Cytochrome P450 activity
Erythromycin and clarithromycin inhibit cytochrome P450 activity, metabolism of theophylline, increasing theophylline toxicity
Both smoking and excessive caffeine consumption can alter the blood lvls of theophylline, which may affect the dosing.

Mechanism of Action
- Overall inhibition of Transcription of Genes Coding Cytokines Involved in Inflammation
- Bind cytosolic glucocorticoid receptor (GR) in the cytosol, translocate to the nucleus, and transactivate responsive genes via glucocorticoid response elements (GRE)
  - Lipocortin-1 which inhibits Phospholipase A2, reducing inflammatory prostaglandins
- Regulating pro-inflammatory transcription factors such as AP-1 and NF-kappa B preventing their binding to their gene target (transrepression)
  - COX2, inflammatory and cytokine expression is inhibited
- End result decreased inflammation
Examples
- Inhaled (P mode of admin)
  - Beclomethasone
  - Budesonide (extensive 1st pass metabolism in liver)
  - Fluticasone (poor gut absorption)
- Oral
  - Prednisolone
- IV
  - Hydrocortisone

Side Effects

Important Systemic SE	Important SE from inhaled Therapy
Adrenal Suppression
Infections	Oral Candidiasis (Thrush)
Mineralocorticoid Effects Hypertension Fluid Retention Electrolyte Imbalance
Structural Effects Osteoporosis Myopathy Growth Delay Central Obesity	Dysphonia - myopathy of laryngeal muscles
Metabolic Effects Glucose intolerance

Prevent & Tx
- Risk of systemic SE if using long-term or frequent courses
  - Monitor BP
  - Check urine or BS and cholesterol for signs of diabetes mellitus and hyperlipidemia
  - Monitor bone mineral density
    - If significant reduction, consider bisphosphonate TX (adults)
  - Monitor growth in children
  - Screen for cataracts and glaucoma

Administration
- Oral
Benefit seen in ~ 50% pf px.
- Most effective in
  - Exercise-induced bronchoconstriction (EIB)
  - Cold-induced bronchoconstriction
  - Asprin and NSAID-induced bronchoconstriction
  - Not for acute asthma attacks
Low Side Effect Profile
- Headaches
- Gastrointestinal upset
- Rarely Churg Strauss Syndrome (Inflammation of BV)

Anti-IgE (Omalizumab) a monoclonal antibody used in px w/ elevated serum of IgE
Anti-inflammatory drugs
- Methotrexate
- Gold (salts used in arthritis)
- Cycolsporin (natural fungal immunosuppressant-psoriasis)
Anti-TNF-alpha agents (monoclonal antibodies)
Allergen-Specific Immunotherapy

Quick Relief of Bronchospasm (Px initiated)
- 2-4 puffs of inhaled short-acting B2 agonists as required for symptoms
- If more severe - up to 3 treatments at 20 min intervals, or single nebulizer tx
- Course of oral prednisolone may be needed
Accident and Emergency Management of an Acute Severe Attack
- Ensure adequate hydration
- 40-60% oxygen via face mask
- Nebulized B2 agonists (salbutamol)
- Nebulized ipratropium
- Oral prednisolone or IV hydrocortisone
If life-threatening consider
- Magnesium sulphate 2gm IV over 20mins (Bronchodilator)
- IV aminophylline or salbutamol

Px education/counselling should be provided gradually
- Dont overwhelm px
- Each session should add to the content of the previous session and reinforce existing knowledge