A Textbook of Clinical Pharmacology and Therapeutics

cascade of enzymes (see Figure 33.3). This causes a wide var-
iety 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;


2. metabolic effects:
   
   
   • hypokalaemia (via redistribution of Kinto cells);
   
   
   • raised free fatty acid concentrations;
   
   
   • hyperglycaemia due to a greater increase in
     glycogenolysis than in insulin secretion.
     8.desensitization.
   
   
   
   

Pharmacokinetics

Salbutamolundergoes 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 (t1/2) is two to four hours.

Salmeterolis long acting, with a duration of action of at

least 12 hours, allowing twice daily administration. The

lipophilic side-chain of salmeterolbinds firmly to an exo-site

that is adjacent to, but distinct from, the β 2 -agonist binding

site. Consequently, salmeterolfunctions as an almost irre-

versible agonist. The onset of bronchodilatation is slow (15–30

minutes).Salmeterolshould 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.Salmeterolshould be used in con-

junction 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. Ipratropiumis given three or four

DRUGSUSED TOTREATASTHMA ANDCHRONICOBSTRUCTIVEPULMONARYDISEASE 237

Table 33.1:Comparative pharmacology of other β 2 -agonists

Drug Formulations Pharmacokinetics/ Other comments

available pharmacodynamics

Terbutaline Metered-dose inhaler Plasma t1/2is 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 exercise-

of action. Hepatic metabolism induced asthma. Not

Dry powder for treatment of acute

bronchospasm

ATP GDP GTP

Myosin light↓

chain kinase

Phosphorylase

kinase↑

Adenylyl

cyclase

Protein kinase A

cAMP

Ca^2 

 2 -Agonist

 2 -Receptor

Bronchodilatation

↓ Mediator release

↓ Mucosal oedema

Gi/Gs

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.