Drugs used to treat asthma Flashcards
Regulation of respiration
Spontaneous rhythmic discharge. Voluntary control. (Cortex to motor neurones, Diaphragm) Autonomic regulation (Respiratory centre modulated by a variety of factors - PCO2, PO2, afferents from lungs. Regulation of bronchial smooth muscle (efferent pathways to lungs)
Autonomic regulation of lungs: Parasympathetic innervation
Bronchial and vascular smooth muscle and glands.
Ach
M3 cholinergic receptors (increase IP3)
Stimulation results in bronchoconstriction and increased mucus secretions.
Autonomic regulation of lungs: Sympathetic innervation.
Bronchial smooth muscle.
Circulating adrenaline (from adrenal medulla) acts on β2-receptors (increase cAMP) on bronchial smooth muscle.
Smooth muscle relaxation and bronchodilation.
Third neuronal pathway
NANC innervation (nonadrenergic noncholinergic), variety of peptides and other mediators. Inhibitory: NO on bronchial smooth muscle. Smooth muscle relaxation and bronchodilator. Excitatory: Substance P, neurokinin A. Smooth muscle contraction, bronchoconstriction.
Other factors regulating respiration
Sensory receptors in airways regulate afferent pathways.
Exogenous chemical - Ammonia, Sulfur dioxide.
Endogenous stimuli - Inflammatory mediators.
Physical stimuli - Cold air.
Regulation of airways smooth muscle
Ach (Parasympathetic system) - Bronchoconstriction, mucus secretion (M3).
Circulating adrenaline (sympathetic system) - Bronchodilation (β2)
NANC - Inhibitory, stimulatory peptides regulation.
Sensory receptor - sensitive to chemical or physical stimuli.
What is asthma?
Recurrent reversible obstruction of the airways in response to stimuli that are not themselves noxious and do not cause the syndrome in non-asthmatic.
Asthma: Pathology
Acute airway obstruction caused by contraction of the airway smooth muscle.
Mucus hypersecretion and thickening/plugging.
Airway inflammation.
Asthma - Symptoms
Dyspnoea (particularly breathing out)
Wheezing
Coughing
Disease process - 2 phases
Immediate phase
Late/delayed phase
Immediate phase
Bronchoconstriction on exposure to stimuli/allergen.
Bronchospasm.
Allergens, irritant chemicals, cold air.
Interaction with mast cells:
Release of spasmogens - Histamine, leukotrienes (LTC4LTD4). Bronchospasm/mucus secretion. Release chemotoxins, LTB4 attraction of leucocytes.
Late/delayed phase
Inflammation/damage in response to inflammatory mediators.
Progressing of inflammatory response initiated during immediate phase.
Vasodilation, oedema and mucus secretion.
Influx of cytokine releasing lymphocytes and eosinophils.
Normally associated with immune response.
Long lasting damage to epithelium of bronchial tissue.
Hyoper-reactivity of bronchial tissue (perhaps exposing sensory receptors)
Therapeutic approaches
- Glucocorticoids
- Cysteinyl-leukotriene (CysLT1) receptor antagonist.
- β2 agonists, M antagonists (muscarinic), xanthines.
- Chromolyn
Bronchodilators
β2 agonists Mainly
Muscarinic antagonists
Xanthines
β2 adrenergic agonists
Dilate the bronchi
Direct action on the β2 receptors on bronchial smooth muscle (mimic circulating adrenaline).
Also inhibits mediator release from mast cells.
Given by inhalation (short-acting - Salbutamol, 4-6 hours, long acting Salmeterol 12 hours)
Side effects - Tolerance and tremor
Action of Salbutamol and Salmeterol on β2 adrenoreceptor.
G-protein coupled receptor
Stimulation of β2 receptor results in activation of adenalyl cyclase and an increase in the secondary messenger cAMP, leading to smooth muscle relaxation.
Muscarinic antagonists
Dilate bronchi Block the M3 mediated bronchostriction Block parasympathetic tone Decrease mucus secretion Blocks M3 mediated smooth muscle contraction. EG Ipratropium - Given by inhalation
Xanthines
Derivatives of caffine and theobromine.
Bronchodilation - Proposed to block phosphodiesterase family of enzymes.
Blocking phosphodiesterase III and IV increase cAMP leading to bronchodilator.
Anti-inflammatory properties - Phosphodiesterases also associated with inflammatory processes
Example of Xanthines
Theophylline
Well absorbed orally
Narrow therapeutic window
Side effects include chronotropic and ionotropic stimulation, CNS stimulation and GI disturbances.
Glucocorticoids
Suppress the inflammatory response and bronchospasm.
Induce synthesis of polypeptide lipocortin which inhibits phospholipase A2 so decreases production of inflammatory mediators.
LTC4LTD4 - Spasmogens
LTB4 - Chemotaxins
PGE2PGI2 - Vasodilators, cytokines (stimulate lymphocytes)
Example of Glucocorticoids
Beclomethasone by inhalation
Prednisolone orally (short term)
Hydrocortisone injection
Side effects of Glucocorticoids
Opportunistic infections
EG Oral candidates (if inhaled)
Cushing like syndrome when taken systemically
Sodium Cromolyn
Originally proposed to be a mast cell stabiliser.
Prevents release of histamine and inflammatory mediators.
Appears to also inhibit hyper-responsitivity.
By depressing neuronal reflexes triggered by irritant receptors.
Cysteinyl-leukotriene (CysLT1) receptor antagonist
Supposed to target both phases
Effective for mild persistent asthma
Not as effective as glucocorticoids
Side effects of β2 receptor agonist
May cause tremor (maybe β3 mediated) and tolerance.
Side effects of Xanthines
Cause tremor, tachycardia, short half-life, narrow therapeutic window
Coughing
Reflex triggered by mechanical or chemical stimulation of upper respiratory tract.
Serves to expel foreign bodies and unwanted materials from airway.
Cough centre in brain stem.
Intercostal and phrenic nerves regulation respiratory muscle.
