FRCA Notes

β2-adrenoreceptor Agonists

  • Synthetic sympathomimetic amine with predominantly β2 receptor action

Presentation & uses

  • Presents as:
    • A metred-dose or dry powder inhaler for relief of acute symptoms in reversible lower airway obstruction, or as a tocolytic
    • A 2.5 - 5mg/ml solution for nebulisation
    • As a clear solution of 50 - 500μg/ml for IV infusion in the management of severe bronchospasm

Pharmacodynamics

  • Respiratory
    • Relaxation of bronchial smooth muscle, causing bronchodilation (increased dead space)
    • Reverses hypoxic pulmonary vasoconstriction and can increase shunt, causing hypoxaemia

  • Cardiovascular
    • High doses can cause stimulation of β1 receptors leading to tachycardia
    • Lower doses may cause β2-associated reductions in SVR and thus lower blood pressure
    • Can precipitate arrhythmias, especially in the presence of hypokalaemia

  • Metabolic
    • Stimulates the Na+/K+ ATPase causing a hypokalaemia
    • Raised blood sugar, which may be compounded by co-administered steroids

  • Relaxes the gravid uterus - a small amount crosses the placenta
  • Direct effect on skeletal muscle can cause tremor

Pharmacokinetics

  • Absorption
    • Incomplete GI absorption and significant 1st pass metabolism
    • Rapid onset following inhalational or IV use

  • Distribution
    • 10% protein bound
    • Half-life 4-6hrs

  • Metabolism & excretion
    • Hepatic metabolism to the inactive 4-O-sulphate metabolite
    • Excreted as both unchanged molecule and metabolite in the urine

  • Long-acting β2-agonist owing to the presence of a long, non-polar side chain that binds it to the β2 receptor
  • It has a long duration of action of 12hrs
  • It is 15x more potent than salbutamol at the β2 adrenoreceptor, but 4x less potent at the β1 adrenoreceptor
  • Its effects are similar to salbutamol, although also:
    • Prevents release of histamine, leukotrienes and PGD2 from mast cells
    • Has an anti-inflammatory effect via a different mechanism than steroids

Terbutaline

  • A β2 agonist with a similar action to salbutamol

Formoterol

  • A long-acting β2 agonist with a similar action to salmeterol

Ritodrine

  • A β2 agonist used primarily as a tocolytic
  • Has a β1 effect that can cause a tachycardia
  • Crosses the placenta and therefore can also cause foetal tachycardia
  • Use has been associated with:
    • Fatal maternal pulmonary oedema
    • Hypokalaemia
    • Hyperglycaemia
    • Restlessness and seizures

Ultra-long acting agents

  • Indacaterol and vilanterol are examples of ultra-long acting β2 agonists, both licensed for treatment of COPD in combination with anti-muscarinic agents
  • THeir duration of action is closer to 24hrs thus reducing dosing frequency to once daily