RESP - E. RESP PHARMACOLOGY ASTHMA AND COPD-COVERED

Question 1

Asthma

Answer 1

• 10% population have it
• reversible increases in airway resistance - bronchoconstriction and inflammation (increasing mucus production)
• decreases in FEV1 in attack but if give bronchodilator, FEV1 will increase
• <70% of normal and FEV1:FVC ratio decreased = increased airway resistance
• reverse by a B2-AR agonist - bronchodilator

Question 2

COPD

Answer 2

• chronic bronchitis and emphysema
• gradual loss of lung function
• irreversible
• 80% deaths related to smoking
• late onset
• high energy demand and difficulty eating

mild = FEV1 80% of normal: smoker cough and little breathlessness
moderate = 50-79%: breathless on moderate exertion
severe = 30-49%: breathless at rest, wheeze, cough
very severe = <30%: on oxygen

Question 3

how does asthma affect lungs

Answer 3

• airway inflammation: mast cells and neutrophils (histamine released)
• increased vascular permeability so more fluid in tissue (oedema)
• thinning (desquamation) of epithelial layer
• mucus build up due to goblet cells
• remodelling off airways: increase growth of smooth muscle, thickening of luminal BM which impairs communication between the 2 cells

Question 4

what is remodelling of the airways

Answer 4

more smooth muscle so next time exposed to something which causes airway constriction, you get increased constriction = hyper responsiveness of airways

Question 5

cytokines

Answer 5

• Interleukins (1-25)
  IL-1-pro-inflammatory and stimulates T-cells
  IL-8-chemokine for attracting neutrophils to area of inflammation
• Cysteinyl leukotrienes
  Contract smooth muscle
  Increase vascular permeability
  Increase mucus
  Attract leukocytes
• TNF-alpha
  Pro-inflammatory
  Chemotactic - attract immune cells to area of inflam
  Increase smooth muscle proliferation (remodelling)

Question 6

chemokines

Answer 6

• chemotactic cytokines
• guide cells (neutrophils, eosinophils, mast cells etc)
• C chemokines, CC chemokines, CXC chemokines, CX3C chemokines
• which bind to chemokine receptors

Question 7

2 categories for asthma therapy

Answer 7

1. bronchodilators (SABA)
   - relief of symptoms - PRN
   - block early phase of asthma attack caused by bronchoconstriction
2. anti-inflam agents (LABAs)
   - prevent attack - daily basis
   - prevent late phase caused by release of cytokines

Question 8

bronchodilators

Answer 8

• B2-AR agonists - salbutamol (SABA) in Ventolin inhaler: PRN
• 1st choice
• increase FEV1
• bronchodilation due to relaxation go smooth muscle
• B-ARs on mast cells, increase in cAMP prevents release of mediators (eg - histamine) and also inhibition of mucus production
• inhalation
• longer acting agent (salmeterol) for long term prevention - everyday

Question 9

what is desensitisation

Answer 9

• long-term use of B-AR agonists = tolerance/desensitisation ie: loss of activity of receptor
• due to internalisation of receptor
• prevented by steroids

Question 10

LABAs

Answer 10

• salmeterol, formoterol (2x daily)
• Indacaterol (1x daily)
  but salbutamol is 4x daily
• absorbed into lipid bilayer of cells ie: can activate receptor for longer period of time as stays next to receptor once used
• slowly released over time to activate receptor

Question 11

adverse effects of B2-AR agonists

Answer 11

• tremor (B2-AR on SkM)
• palpitations (B1-AR on heart)
• hypokalaemia (B2-AR on kidney)
  *due to high doses (nebulisers) as more drug gets into sys circulation and effects B-ARs elswhere

Question 12

what does phosphodiesterases do

Answer 12

• break down cAMP and cGMP
• switch off signal
• bronchoconstriction

PDE3 and PDE4 in airways which regulate cAMP

Question 13

phosphodiesterase inhibitors

Answer 13

• Roflumilast (PDE4) inhibitor (Daxas) for COPD
• reduces inflammation
• enhances B-AR effects as B2-AR increases cAMP

Question 14

muscarinic M-receptor antagonists

Answer 14

• block parasympathetic bronchoconstriction (ACh acts at muscarinic receptors)
• Ipratropium (SAMA): non-selective antagonist so prevents ACh induced constriction of airways
• side effects due to other M-receptors affected
• inhalation
• inhibits mucus secretion
• Tiotropium (LAMA) - slow dissociation from receptor

Question 15

side effects of muscarinic M-receptor antagonists

Answer 15

• non-selective so block muscarinic receptors around body (inhaled is more selective than oral)
• dry mouth
• nausea/headache (CNS)
• atrial fibrillation and tachycardia and palpitation (cardiac)
• constipation (GI)
• urinary retention
• blurred vision (accomadation)

Question 16

Xanthines (eg Theophylline)

Answer 16

• bronchodilators, not as good at B-AR agonists
• 2nd line use
• oral (or IV aminophylline in emergency)
• anti-inflame effects
• add on in life-threatening asthma and tried everything else
• PDE inhibitors but not at clinically relevant concs
• Adenosine receptor antagonist?

Aminophylline
- mix of theophylline and ethylenediamine (2:1)
- improves solubility
- measure plasma theophylline after 4-6 hours after start of IV infusion due to toxicity

Question 17

side effects of Xanthines

Answer 17

• tremor, palpitations, nausea
• CNS stimulation: sleep disturbance, over-activity
• inhibition of metabolism increases risk of toxicity
  eg - cimetidine, verapamil
• induction of metabolism reduces plasma levels
  eg - smoking, need to give higher doses and when stop smoking, decrease dose