L15 Clinical Pharmacology of Asthma

Ventilation occurs by contraction and relaxation of respiratory muscles, and the elastic [blank_start]recoil[blank_end] of connective tissue in lungs. Any disease that [blank_start]inhibits[blank_end] elastic recoil can cause ventilation issues. Obstructive diseases affect inspiratory rate (e.g. [blank_start]asthma, COPD[blank_end]), whereas restrictive diseases affect inspiratory capacity (e.g. [blank_start]pulmonary fibrosis[blank_end]).

Selectivity is defined as a 10 fold (2 log order) difference in affinity between receptor subtypes.

Choosing a selective drug helps to reduce on-target [blank_start]side effects[blank_end]. E.g. a Beta-2 agonist will have less effect on the heart than a [blank_start]non-selective[blank_end] Beta agonist. If excessive doses are used then selectivity will be [blank_start]overcome[blank_end] and the drug will act on other receptor subtypes. E.g. the usual inhaled dose of [blank_start]salbutamol[blank_end] for acute asthma is 100 mcg, the dose used for severe asthma is 5 mg, 50 times more, and [blank_start]tachycardia[blank_end] is expected.

Long acting beta agonists have a long half life because of their long duration of activity.

Because the off-rate of binding is slow, long acting M-antagonists will be more potent (the dose will be lower than for short acting).

Drugs for bronchodilation: - Short acting beta agonists — [blank_start]salbutamol, terbutaline[blank_end] - Long acting beta agonists — [blank_start]salmeterol, formoterol, vilanterol[blank_end] - Short acting muscarinic antagonists — [blank_start]ipratropium[blank_end] - Long acting muscarinic antagonists — [blank_start]glycopyrronium, tiotropium, umeclidinium[blank_end]

Side effects of bronchodilators for low dose beta agonists are an increased [blank_start]heart[blank_end] rate. Effects of high doses can include an increased heart rate, tremor, nervousness, peripheral [blank_start]vasodilation[blank_end], sleep [blank_start]disturbances[blank_end], and decreased plasma [blank_start]potassium[blank_end]. Side effects of muscarinic antagonists are an increased heart rate and a [blank_start]dry[blank_end] mouth.

Corticosteroid (anti-inflammatory) side effects: — Inhaled low dose < [blank_start]500[blank_end] mcg/day (budesonide equivalents) - [blank_start]oral candidiasis[blank_end] — Inhaled high dose < [blank_start]1200[blank_end] mcg/day (budesonide equivalents) - oral candidiasis, growth [blank_start]delays[blank_end] (not certain, and minor, reversible), occasional HPA axis [blank_start]suppression[blank_end] — Prednisone 5 mg/day, long term (>2 weeks) - [blank_start]oedema, dyspepsia, cushingoid[blank_end] symptoms.

Lung delivery from MDI: ≈ [blank_start]20%[blank_end] gets to the active locations in the lungs (bronchioles) ≈ [blank_start]50%[blank_end] deposits onto the oropharynx and can then reach the stomach and is absorbed ≈ [blank_start]30%[blank_end] either deposits to other areas or is exhaled

Systemic availability from lung delivery is clinically irrelevant.