A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

DRUGS USED TO TREAT ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE 237
Table 33.1: Comparative pharmacology of other β 2 -agonists
Drug Formulations Pharmacokinetics/ Other comments
available
pharmacodynamics
Terbutaline Metered-dose inhaler Plasma t 1/2 is 3–4 h Similar to salbutamol
Dry powder
Gastro-intestinal and
Nebulizer solution
hepatic metabolism
Tablets/syrup
Slow-release tablets
Salmeterol Metered-dose inhaler Onset slow; 12 h duration Prophylaxis and exerciseof
action. Hepatic metabolism induced asthma. Not
Dry powder
for treatment of acute
bronchospasm
Adenylyl
cyclase
Gi/Gs
ATP GDP GTP
2 -Agonist
2 -Receptor
cAMP
Protein kinase A
Ca 2
Myosin light↓
chain kinase
Phosphorylase
kinase↑
Bronchodilatation
↓ Mediator release
↓ Mucosal oedema
Figure 33.3: Membrane and intracellular events
triggered when β 2 -agonists stimulate β 2 -receptors.
Gi/Gs, inhibitory and stimulatory G-protein, GDP,
guanosine diphosphate; GTP, guanosine triphosphate;
cAMP, 3,5-cyclic adenosine monophosphate.
cascade of enzymes (see Figure 33.3). This causes a wide variety
of effects including:
1. relaxation of smooth muscle including bronchial, uterine
and vascular;
2. inhibition of release of inflammatory mediators;
3. increased mucociliary clearance;
4. increase in heart rate, force of myocardial contraction,
speed of impulse conduction and enhanced production of
ectopic foci in the myocardium and automaticity in
pacemaker tissue. This can cause dysrhythmias and
symptoms of palpitations;
5. muscle tremor;
6. vasodilatation in muscle, part of this effect is indirect, via
activation of endothelial NO biosynthesis;
7. metabolic effects:
• hypokalaemia (via redistribution of K into cells);
• raised free fatty acid concentrations;
• hyperglycaemia due to a greater increase in
glycogenolysis than in insulin secretion.
8. desensitization.
Pharmacokinetics
Salbutamol undergoes considerable presystemic metabolism
in the intestinal mucosa (sulphation) and hepatic conjugation
to form an inactive metabolite that is excreted in the urine.
Most (approximately 90%) of the dose administered by
aerosol is swallowed, but the 10–15% which is inhaled largely
remains as free drug in the airways. The plasma elimination
half-life (t 1/2 ) is two to four hours.
Salmeterol is long acting, with a duration of action of at
least 12 hours, allowing twice daily administration. The
lipophilic side-chain of salmeterol binds firmly to an exo-site
that is adjacent to, but distinct from, the β 2 -agonist binding
site. Consequently, salmeterol functions as an almost irreversible
agonist. The onset of bronchodilatation is slow (15–30
minutes). Salmeterol should not therefore be used to treat
acute attacks of bronchospasm. It is now advised as first-line
in prophylactic therapy, on a twice daily basis, with ‘top ups’
of short acting β 2 -agonists. Salmeterol should be used in conjunction
with inhaled glucocorticosteroids.
MUSCARINIC RECEPTOR ANTAGONISTS
Use
Osler recommended stramonium – which contains atropine –
in the form of cigarettes for asthmatics! In comparison to
atropine, modern agents, e.g. ipratropium, are quaternary
ammonium analogues and have reduced systemic absorption
due to their positive charge. Ipratropium is given three or four