W5 Respiratory Pharmacology

Question 1

Innervation of the lung

Answer 1

Respiratory System: Control of
Bronchioles by ANS
* Parasympathetic nervous system
activation triggers
bronchoconstriction
* Predominantly VAGAL nerve
* Sympathetic nervous system
activation triggers bronchodilation
– Increased lung capacity
– Preparation for exercise
* CNS control: respiratory centre in medulla
* modulated by vagal afferents
* Affected by: PACO2 in arterial blood and
medulla and PAO2 in Carotid Bodies

Question 2

Respiratory physiology: other forms of innervation

Answer 2

Airways are also supplied with excitatory
and inhibitory non-adrenergic non-
cholinergic (NANC) nerves.
Neurotransmitters released include:
* Substance P – bronchoconstriction
* Nitric oxide – bronchodilation

Bronchial smooth muscle contains
receptors for other mediators
* Histamine – bronchoconstriction
* Leukotrienes (family of eicosanoid
inflammatory mediators produced
in leukocytes) -
bronchoconstriction

Question 3

What are the 2 Therapeutic aims? Particularly Asthma / COPD

Answer 3

1. Relief
   * Rescue patient from bronchospasm
   =Bronchodilators
2. Prophylaxis
   * Reduce the frequency of attacks
   * Reduce the severity of attacks
   * Limit structural remodelling
   =Anti-inflammatories

(There can overlap to different degrees)

Other:
* Mucolytics
* Cough
– Suppressants
– Other

Question 4

Bronchodilator classes

Answer 4

β-adrenoceptor agonists
 Xanthines
 Muscarinic receptor antagonists
 Leukotriene receptor antagonists
 Histamine receptor antagonists

Mechanisms involve inhibition of contraction

Question 5

What are some Anti-inflammatory classes? (4)

Answer 5

Mechanisms involve inhibition of inflammation:

• Glucocorticoids
• Cromoglicate and nedocromil (Cromones)
• Anti-IgE (immunotherapy)
• Phosphodiesterase (PDE) inhibitors (also bronchodilator effect) – cover in COPD

Question 6

β-adrenoceptor agonists: What are the steps in their MoA?

Answer 6

β2 receptor stimulation:
1. via Gs activates adenylyl cyclase that increases intracellular levels of cAMP - cAMP activates protein kinase A (PKA)

2. PKA phosphorylates numerous targets leading to bronchodilation (reduction of intracellular Ca2+):
   * Myosin light chain kinase (MLCK) activity reduced
   -Myosin not phosphorylated
   -Less smooth muscle contraction

• Activation of K+ channels leads to
  -hyperpolarisation that
  -reduces numbers of Ca2+ channels open
  -reduces rate of entry of extracellular Ca2+
  -Less intracellular Ca2+ means less contraction
  –Less intracellular Ca2+ released from sarcoplasmic reticulum.
  -Less contraction

Question 7

β-adrenoceptor agonists

Answer 7

• Generally inhalation of aerosol, powder or nebulised solution
  – Some may be given orally or by injection
• Why use inhaled therapy?
  – Lower doses leading to fewer side effects
  – Faster onset of action with inhaled bronchodilators than systemic
• The ideal MMAD for optimum penetration to the small
  airways - 5 μm or less.
  – The upper airway (nose and mouth) -100% deposition of particles
  greater than 10 and 15 μm
  – Particle sizes in the 5 to 10 μm range deposit in the first six airway
  generations
  mass median aerodynamic diameter - MMAD

Question 8

β-adrenoceptor agonists: Types

Answer 8

• Short acting β2-adrenoceptor agonists e.g. salbutamol, terbutaline
  – Hydrophilic in nature
  – Short duration of action (4-6 hours)
  – As needed, PRN
• Long acting β2-adrenoceptor agonists e.g. salmeterol, formoterol
  – Lipophilic in nature
  – Leech out of membrane prolonging duration of action (gen 8-12 hours)
  – NOT given as needed
• Adjunctive therapy
  – MUST NOT be given in the absence of a corticosteroid
  salbutamol
  salmeterol

Question 9

β-adrenoceptor agonists: Unwanted effects

Answer 9

• Result from Systemic absorption
  – Commonest
• Tremor
  – Other
• Nervous tension
• Headache
• Muscle cramps
• Peripheral vasodilatation
  – High doses
• Hypokalemia after high doses
• Tachycardia
• Cardiac dysrhythmias * Cardiac effects due to stimulation of beta2 receptors on the heart

– Enhance Th2 inflammatory pathway
– Downregulate β-adrenoceptors
– Regular use without corticosteroid not
recommended
* Partly clinical evidence based
* Evidence of Synergy between 2 systems
– Gene transcription