Drugs used to treat asthma L12 Flashcards
How can respiration be regulated
- spontaneous rhythmic discharge from respiratory centre in medulla
- involuntary - voluntary control
- involves cortex to motor neurones and 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)
how does parasympathetic NS control respiratory system
ACH released and binds to muscarinic 3 receptors stimulating bronchoconstriction and increased mucus secretions
how does sympathetic NS control respiratory system
adrenaline from adrenal medulla or noradrenaline acts on B2 receptors on bronchial smooth muscle
- smooth muscle relaxation and bronchodilation
how does NANC (nonadrenergic noncholinergic) affect respiratory system
- Variety of peptides, and other mediatiors
- Inhibitory: NO on bronchial smooth muscle
Smooth muscle relaxation & bronchodilation - Excitatory: substance P, neurokinin A
Smooth muscle contraction, bronchoconstriction
what do sensory receptors in airways do
regulate afferent pathways
1. Exogenous chemical
- Ammonia, sulphur dioxide,
2. Endogenous stimuli
- Inflammatory mediators
3. Physical stimuli
- Cold air
what is asthma
Recurrent reversible obstruction of the airways in response to stimuli which are not themselves noxious and do not cause the syndrome in non-asthmatic
what is the pathology of asthma
- Acute airway obstruction caused by contraction of the airway smooth muscle
- Mucus hypersecretion and thickening /plugging
- Airway inflammation
what are the symptoms of asthma
Dyspnoea (particularly breathing out)
Wheezing
Coughing
what are the two phases of asthma
- immediate phase
- Bronchoconstriction on exposure to stimuli/allergen - late/delayed phase
- Inflammation/damage in response to inflammatory mediators
what is Bronchospasm
part of the immediate phase
the initial response to allergins/irritants
these things interact with mast cells causing bronchospasm
what happens when allergins interact with mast cells
Release of spasmogens-Histamine, leukotrienes (LTC4 LTD4)
BRONCHOSPASM/MUCUS SECRETION
Release Chemotaxins, LTB4 attraction of leucocytes
- these are inflammatory mediators
what happens in delayed phase
Vasodilation, oedema and mucus secretion
there is an influx of cytokine releasing lymphocytes (Th2) and eosinophils
- they normally work in immune response
- but in asthma, they cause damage to epithelium of bronchi tissue and causes it to become hyper-reactive as it exposes sensory receptors
what drug can effect mast cells, bronchospasm and inflamation
MC: chromolyn
BS: Bronchodilators
- B2 agonists, M antagonists, Xanthines
- target immediate phase
I: glucocorticoids
how do B2 adrenergic agonists treat asthma
Dilate the bronchi
Direct action on the β2 receptors on bronchial smooth muscle (mimic circulating adrenaline)
Also inhibits mediator release from mast cells
how are B2 adrenergic agonists given and what are their side effects
Given by inhalation
- Short acting-Salbutamol 4-6 hr
- Long acting Salmeterol 12 hr
Side effects
- Tolerance
- Tremor
how do Salbutamol and Salmeterol activate B2 receptors
G-protein coupled receptor
Stimulation of β2 receptor results in activation of adenalyl cyclase and an increase in the second messenger cAMP, leading to smooth muscle relaxation and bronchodilation
why does Salmeterol have a longer half life
it has a long carbon chain with lipophilic end
- Lipophilic end anchors its self into membrane – not metabolised as quickly, can react on receptor
what are the effects of muscarinic antagonists
bronchodilation
- Block the M3 stopping bronchoconstriction
Decrease mucus secretion
- Blocks M3 stops smooth muscle contraction
give an example of muscarinic antagonist
- how is it given
Ipratropium
Given by inhalation
Relatively non selective but not well absorbed so doesn’t get into circulation and cause many side effects
what would happen if Ipratropium did get into systemic circulation
normal effects of muscarinic antagonist
- dilating pupils and bronchi
- increased cardiac output
- decreased GI motility
- decreased gland secretion
what are Xanthines
derivatives of caffeine and theobromine
what do Xanthines cause
Bronchodilation
Proposed to block phosphodiesterase family of enzymes
Blocking phosphodiesterase III and IV increases cAMP leading to bronchodilation
Anti-inflammatory properties
Phosphodiesterases also associated with inflammatory processes
give an example of Xanthines
- how is it given
- what are the side effects
Theophylline
well absorbed orally
Narrow therapeutic window
Side effects include, chronotropic and inotropic stimulation, CNS stimulation, GI disturbances
what do glucocorticoids do
Suppress the inflammatory response and bronchospasm
Induce synthesis of polypeptide lipocortin which inhibits phospholipaseA2 so decreases production of inflammatory mediators
LTC4 LTD4 – spasmogens
LTB4 – chemotaxins
PGE2, PGI2 vasodilators, cytokines (stimulate lymphocytes
effective in both phases
give 3 examples of glucocorticoids
Beclomethasone
- by inhalation
Prednisolone
- orally (short term)
Hydrocortisone
- injection
what are the side effects of glucocorticoids
Opportunistic Infections e.g. oral candidiasis (if inhaled)
Typical glucocorticoid side effects (Cushing like syndrome) when taken systemically.
what does Sodium Cromolyn do
first thought to be a mast cell stabiliser
now though to to also inhibit hyper-responsivity
by depressing neuronal reflexes triggered by irritant receptors
what does Cysteinyl-leukotriene (CysLT1) receptor antagonists do
Supposed to target both phases
Effective for mild persistent asthma
Not as effective as glucocorticoids
