pharmacology of asthma

Question 1

what is asthma?

Answer 1

a chronic inflammatory disease in which the cells and cellular components lead to airway hypertensiveness and variable, but widespread airflow obstruction in the lung

Question 2

how does moderate to severe asthma cause irreversible changes to the airway?

Answer 2

hypertrophy and hyperplasia of the smooth muscle. basement membrane and epithelium also thicken

Question 3

which cells contribute to an asthma attack?

Answer 3

mast cells and eosinophils

Question 4

how can respiratory difficulty during an asthma attack be quantified?

Answer 4

measuring FEV1 (forced expiratory volume in 1 second). response to a stimulus occurs within a few minutes

Question 5

how are mast cells responsible for early phase asthma?

Answer 5

stimulus -> mast cells -> spasmogens (Cys-Lys) + chemokines -> bronchospasm

Question 6

how are eosinophils responsible for early stage asthma?

Answer 6

cytokine releasing TH2 cells -> eosinophil activation -> mediators such as Cys-Lys cause airway inflammation + bronchospasm -> EMBP causes epithelial damage = airway hyper reactivity

Question 7

what prophylactic treatments are available for asthma?

Answer 7

• prevention or reduction of inflammation using corticosteroids e,g, beclomethasone
• fluticasone: less side effects than beclomethasone
• other non-steroidal anti-inflammatory drugs such as mast cell stabilisers

Question 8

what are the advantages of fluticasone over traditional corticosteroids?

Answer 8

direct delivery to lungs minimises side effects

favourable pharmacokinetics: poor systemic absorption from lungs, less gets into systemic circulation

Question 9

why are B2-adrenoceptor agonists used for symptomatic treatment of asthma?

Answer 9

lower alveoli have a lot of B-adrenoceptors
these drugs:
inhibit mucus secretion and stimulate mucus clearance
decrease tissue oedema
possess some anti-inflammatory properties

Question 10

how are acetylcholine, histamine and leukotrienes responsible for contraction of airway smooth muscle?

Answer 10

these agents interact with specific GPCRs in the smooth muscle to cause Ca2+ store mobilisation and Ca2+ influx -> Ca2+/calmodulin dependent activation of Myosin-light chain kinase and myosin phosphorylation

Question 11

what is the role of Rho kinase?

Answer 11

inhibition of myosin light chain phosphatase, prevents dephosphorylation and permits robust bronchoconstriction

Question 12

how do B2-adrenoceptors control smooth airway relaxation?

Answer 12

increased cAMP + PKA activity -> decrease in Ca due to efflux pathways -> inhibition of myosin phosphorylation by MLCK/promotion of myosin dephosphorylation

Question 13

what is the response when a B2-adrenoceptor agonist is delivered to the airways?

Answer 13

it will relax the airway smooth muscle and oppose or reverse the actions of contractile mediators

Question 14

what are spasmogens?

Answer 14

chemicals which elicit bronchospasm; cysteine-leukotrienes, Histamine

Question 15

list some B2-adrenoceptor agonists used for treatment of asthma

Answer 15

salbutamol, terbutaline, salmeterol

Question 16

explain the mechanism of salmeterol

Answer 16

used prophylactically for reversal of bronchoconstriction, binds at the B2-adrenoceptor, with a longer half life compared to salbutamol due to long, hydrophobic tail ‘leash’ which tethers it to the B-adrenoceptor