Drugs used to treat asthma

Question 1

Regulation of respiration

Answer 1

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)

Question 2

Autonomic regulation of lungs: Parasympathetic innervation

Answer 2

Bronchial and vascular smooth muscle and glands.
Ach
M3 cholinergic receptors (increase IP3)
Stimulation results in bronchoconstriction and increased mucus secretions.

Question 3

Autonomic regulation of lungs: Sympathetic innervation.

Answer 3

Bronchial smooth muscle.
Circulating adrenaline (from adrenal medulla) acts on β2-receptors (increase cAMP) on bronchial smooth muscle.
Smooth muscle relaxation and bronchodilation.

Question 4

Third neuronal pathway

Answer 4

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.

Question 5

Other factors regulating respiration

Answer 5

Sensory receptors in airways regulate afferent pathways.
Exogenous chemical - Ammonia, Sulfur dioxide.
Endogenous stimuli - Inflammatory mediators.
Physical stimuli - Cold air.

Question 6

Regulation of airways smooth muscle

Answer 6

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.

Question 7

What is asthma?

Answer 7

Recurrent reversible obstruction of the airways in response to stimuli that are not themselves noxious and do not cause the syndrome in non-asthmatic.

Question 8

Asthma: Pathology

Answer 8

Acute airway obstruction caused by contraction of the airway smooth muscle.
Mucus hypersecretion and thickening/plugging.
Airway inflammation.

Question 9

Asthma - Symptoms

Answer 9

Dyspnoea (particularly breathing out)
Wheezing
Coughing

Question 10

Disease process - 2 phases

Answer 10

Immediate phase

Late/delayed phase

Question 11

Immediate phase

Answer 11

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.

Question 12

Late/delayed phase

Answer 12

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)

Question 13

Therapeutic approaches

Answer 13

1. Glucocorticoids
2. Cysteinyl-leukotriene (CysLT1) receptor antagonist.
3. β2 agonists, M antagonists (muscarinic), xanthines.
4. Chromolyn

Question 14

Bronchodilators

Answer 14

β2 agonists Mainly
Muscarinic antagonists
Xanthines

Question 15

β2 adrenergic agonists

Answer 15

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

Question 16

Action of Salbutamol and Salmeterol on β2 adrenoreceptor.

Answer 16

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.

Question 17

Muscarinic antagonists

Answer 17

Dilate bronchi
Block the M3 mediated bronchostriction
Block parasympathetic tone
Decrease mucus secretion
Blocks M3 mediated smooth muscle contraction.
EG Ipratropium - Given by inhalation

Question 18

Xanthines

Answer 18

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

Question 19

Example of Xanthines

Answer 19

Theophylline
Well absorbed orally
Narrow therapeutic window
Side effects include chronotropic and ionotropic stimulation, CNS stimulation and GI disturbances.

Question 20

Glucocorticoids

Answer 20

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)

Question 21

Example of Glucocorticoids

Answer 21

Beclomethasone by inhalation
Prednisolone orally (short term)
Hydrocortisone injection

Question 22

Side effects of Glucocorticoids

Answer 22

Opportunistic infections
EG Oral candidates (if inhaled)
Cushing like syndrome when taken systemically

Question 23

Sodium Cromolyn

Answer 23

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.

Question 24

Cysteinyl-leukotriene (CysLT1) receptor antagonist

Answer 24

Supposed to target both phases
Effective for mild persistent asthma
Not as effective as glucocorticoids

Question 25

Side effects of β2 receptor agonist

Answer 25

May cause tremor (maybe β3 mediated) and tolerance.

Question 26

Side effects of Xanthines

Answer 26

Cause tremor, tachycardia, short half-life, narrow therapeutic window

Question 27

Coughing

Answer 27

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.