Pharmacology Flashcards
How does the parasympathetic division control bronchial smooth muscles
Postganglionic cholinergic fibres cause bronchial smooth muscle contraction mediated my M3 muscarinic ACh receptors on airway smooth muscle cells and increase mucus production via M3 muscarinic ACh receptors on goblet cells
Postganglionic noncholinergic fibres cause bronchial smooth muscle relaxation by Nitric Oxide (NO) and Vasoactive Intestinal Peptide (VIP)
Is there sympathetic innervation of bronchial smooth muscle in humans
No but post-ganglionic fibres supply submucosal glands and smooth muscle of blood vessels
How does sympathetic nervous system cause bronchodilation
Sympathetic innervation of vascular smooth muscle. Adrenaline from Chromaffin cells of adrenal medulla cause bronchodilation via B2-adrenoceptors
What cause contraction in smooth muscle cells
Depolarization opens Ca channels causing an inflow of Calcium. Hormones activates GPCR which eventually leads to the opening of IP3 receptor causing Ca influx. Increased intracellular Ca leads to contraction
How does increase Ca cause contraction
Ca binds to Calmodulin which forms a Ca-Calmodulin complex. This combines myosin light chain kinase (MLCK) to activate it. This kinase phosphorylates inactive myosin cross bridge to phosphorylated myosin cross bridge (binds actin). This allows sliding of Actin and Myosin filaments.
What brings about relaxation in smooth muscle
Dephosphorylation of myosin light chain by myosin phosphatase. This requires return of intracellular Ca concentration to basal level
How does protein kinase A inhibit contraction or facilitate relaxation
Adrenaline from sympathetic nervous system activates GPCR which activates protein kinase A. This inhibits contraction by inhibiting myosin light chain kinase. It also facilitates relaxation by stimulating myosin phosphatase
What is Asthma
Intermittent attacks of bronchoconstriction causing tight chest, wheezing, difficulty in breathing and cough
What can chronic asthma cause
Increase mass of smooth muscle
Accumulation of interstitial fluid (oedema)
Increased secretion of mucus
Epithelial damage (exposing nerve fibres)
Sub-epithelial fibrosis
What causes bronchial hyper-responsiveness in asthma
Exposure of sensory nerve endings contributes to increased sensitivity of the airways by bronchoconstrictor influences
Hypersensitivity vs hyperreactivity
Hypersensitivity is how much concentration of bronchoconstrictor is needed to induce a fall in FEV1 whereas hyperreactivity is the opposite
Phases of asthma attack
In two phases, immediate phase (bronchospasm) and delayed phase (inflammatory reaction)
Response to allergens in nonatopic individuals
Low level Th1 response, cell-mediated involving IgG and macrophage
Strong Th2 response, antibody-mediated involving IgE
How does allergic asthma develop
Induction phase - Antigen presenting cells present to CD4+ T cells which cause preferential differentiation into Th2 cells that activate B cells via IL-4. These B cells mature to IgE secreting plasma cells.
Effector phase - Th2 also secrete IL-5 and activate Eosinophils. IL-3 and IL-4 from Th2 cells cause expression of Fc receptors for IgE on mast cells
What happens on subsequent encounter to antigen in allergic asthma
Antigen cross links with IgE receptors. This stimulates Ca2+ entry into mast cells and release of Ca2+ from intracellular stores. This causes release of preformed Histamine from mast cells and production and release of other agents such as leukotrienes that cause airway smooth muscle contraction. They also release pro-inflammatory factors: platelet-activating factor, prostaglandins that attract cells: macrophage and eosinophils causing local inflammation
Why can corticosteroids cause pneumonia
Due to immune suppression and impaired ciliary clearance. Especially with fluticasone, retainted in lung for long periods
Why are oral steroids used for acute exacerbations and not maintenance
Ex: Prednisolone, has a low therapeutic ratio. Inhaled steroids such as Beclomethasone have a high therapeutic ratio and is used as maintenance monotherapy in asthma
Combination therapy for COPD
Inhaled corticosteroid (ICS) + LABA
How can lung delivery be optimised
Using extra fine solution inhaler with a spacer
Function of spacer device
Acts as a holding chamber for the aerosol, improve lung deposition, reduce particle size and velocity
When are cromones such as cromoglycate used
In asthma only. They are mast cell stabilizers. Not used much due to poor efficacy
How can leukotrienes cause asthma
Leukotrienes cause oedema in blood vessels, increase mucus secretion, decrease mucus transport, eosinophillic influx, contraction and proliferation of airway smooth muscle
How can eosinophil influx cause cause epithelial cell damage
Increase numbers of eosinophils in the airway causes release of inflammatory mediators such as cationic proteins. These damage epithelial cells and expose sensory fibres. This stimulates cough and other bronchial reflexes
Leukotriene receptor antagonists can be used in?
Asthma only, exercise induced asthma and allergic rhinitis (with histamine)
