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)
Most potent anti-inflammatory drug
Inhaled corticosteroids
When are anti-IgE monoclonal antibodies used
Omalizumab; used in severe persistent allergic asthma . Given as an injection every 2-4 weeks.
When are anti-IL5 injections given to patients every 4 weeks
Mepolizumab, reslizumab; severe refractory eosinophilic asthma despite max therapy
What medication has little effect on pulmonary function but reduces exacerbations and oral steroid sparring effect
Anti-IgE and anti-IL5. Both given as injection and very expensive.
What is severe refractory eosinophilic asthma
Severe asthma that can’t be adequately controlled despite available treatment possibilites
Physiological effects of B2 agonists
Mast cell stabilization, increased muco-ciliary clearance, decreased extravasation of proteins, smooth muscle relaxation,
Examples of long acting B2 agonists
BID - Salmeterol/formoterol
OD - Indacaterol/ vilanterol/olodaterol
What is in a SMART combination inhaler
Beclamethasone (ICS) + Formoterol (LABA)
B2 agonists in asthma and COPD
ICS + LABA dual in asthma
ICS + LABA or LAMA/LAMA dual or ICS/LABA/LAMA triple in COPD
What do M1 cholinergic receptors do
Enhance cholinergic reflex
What do M2 cholinergic receptors do
Inhibit acetylcholine release
What do M3 cholinergic receptors do
Mediate bronchoconstriction and mucus secretion
What do muscarinic antagonist drugs work on
Post junctional end plate M3 receptors
Short acting muscarinic antagonist
Ipatropium QID - Inhaled 4 times daily
Long acting muscarinic antagonist
Tiotropium (OD), Umeclidinium (OD), Aclidinium (BID) and Glycopyrronium (OD/BID)
Muscarinic antagonists in COPD
LAMA/LABA dual - Glycopyrronium + Indacaterol or Tiotropium + Olodaterol
ICS/LAMA/LABA triple - Beclometasone + Formoterol + Glycopyrronium
Muscarinic antagonist in asthma
Triple therapy with Tiotropium only
ICS/LABA/LAMA
What is used with inhaled corticosteroids as non steroidal anti-inflammatory
Methylxanthines
Theophylline (Oral) for maintenance therapy
Aminophylline (IV) for acute attacks
What are used in addition to LABA/LAMA in COPD to reduce exacerbations
PDE4 inhibitors such as Roflumilast (oral tablet OD)
What can be used to reduce sputum viscosity and aide sputum expectoration in COPD
Mucolytics such as carbocisteine and erdosteine (oral)
Are respiratory stimulants such as doxapram hydrochloride indicated for acute asthma
Doxapram stimulates increase in tidal volume and respiratory rate. These are NOT indicated acute asthma
Pathology of COPD
Irritants cause stimulation of resident alveolar macrophage. Cytokine production activates neutrophils and CD8+ T cells that increase macrophage numbers. They release matrix metalloproteinase that cause chronic bronchitis and emphysema
What receptors cause bronchoconstriction
M3 muscarinic receptors via parasympathetic efferents
Where are M1 muscarinic acetylcholine receptors present
Ganglia, facilitate fast neurotransmission mediated by ACh acting on nicotine receptors.
Where are M2 muscarinic acetylcholine receptors present
Postganglionic neurone terminals where they act as inhibitory autoreceptors reducing release of ACh
Where are M3 muscarinic acetylcholine receptors present
Airway smooth muscle that mediate contraction to ACh
Also on mucus secreting cells mediating mucus secretion
Why prefer selective muscarinic acetylcholien receptor antagonist over Atropine (not selective)
Reduces systemic exposure avoiding multiple potential adverse effects of generalised parasympathetic block
Why do muscarinic receptor antagonists have little systemic absorption
Due to quarternary ammonium group
Do muscarinic receptor antagonists have an effect of COPD progression
No, use is mainly palliative to reduce bronchospasms and decrease mucus secretion
What does Ipratropium block
M1, M2 and M3 receptors
What drugs block M3 receptors
Tiotropium, glycopyrronium, aclidinium, umeclidinium
What is block of M2 receptors in COPD not wanted
M2 is an inhibitory autoreceptor present on post-ganglionic neurones. Antagonism of this will increase amount of ACh released from post-ganglionic neurone
Examples of ultra-LABA
Indacaterol and olodaterol, not recommended for acute relief of bronchospasms. Once daily dosing
Is LABA or SAMA more effective in increased FEV1
Combination of both, B2 agonists and M antagonists
How do PDE4 drugs work
Phosphodiesterase-4 (PDE4) is the prominent PDE present on macrophage, neutrophils and T cells. Inhibition of PDE4 may have inhibitory effects of inflammation and immune cells
Example of PDE4 drug
Rofumilast. Oral treatment for severe COPD but limiting adverse GI effects
Are COPD patients generally responsive to glucocorticoids
No due to oxidative/nitrative stress associated with chronic inhalation of tobacco smoke
When are glucocorticoids generally administered to COPD patients
Patients with frequent and severe exacerbations when given with a LABA
