Asthma: Therapeutic Overview

Goals:

1. reverse acute attacks (use a beta-2 receptor agonist; direct acting bronchodilator).
2. Control recurrent attacks (use inhaled or oral steroids)
3. Reduce bronchial inflammation and the associated hyper-reactivity (use anti-inflammatory)

Treatments:

Cromolyn, for controlling mediator release from mast-cells and other cells; generalized membrane-stabilizing effects; most effective in prophylactic treatment of exercise induced asthma.

Corticosteroids, local or systemic, for controlling edema, mucus production, and eosinophil infiltration (also controlling transcription of genes for mediators); controversial because if used chronically, steroids may have other metabolic effects – the latest evidence suggests that inhaled steroids have no other effects than local, desired anti-inflammatory action (doesn’t apply to all steroids).

Beta-2 adrenergic agonists, for relaxing bronchial smooth muscle and decreasing microvascular permeability. Long acting agents are now prevalent.

Theophylline (xanthines), for reducing frequency of recurrent attacks of bronchospasm (adenosine antagonist, phosphodiesterase inhibitor?); narrow therapeutic window as far as blood concentration, must monitor blood levels.

Ipatropium bromide, for inhibiting muscarinic effects of acetylcholine on bronchial smooth muscle

Uses:

Beta-2 adrenergic agonists and ipratropium bromide, for short-term control of airway obstruction.

Theophylline, steroids and cromolyn, for regular use to control attacks (given by mouth)

Avoidance of causative factors (i.e., allergens and triggers); cromolyn sodium and inhaled steroids, for controlling inflammation in bronchi.


The theophylline class is closely related to caffeine. In fact a student several years ago had an acute asthma attack and self-medicated by quickly drinking several cups of coffee and her asthma attack was ceased. The mechanism of action probably involves the adenosine receptor and inhibition of phosphodiesterase on the smooth muscle, which raises cAMP to relax the smooth muscle.



When the insult occurs on the cell membrane, various pathways are triggered. One is the formation of arachidonic acid from precursors. It can go two ways: if it goes by the cyclo-oxygenase pathway (COX-1, COX-2), you get the classic prostaglandins that cause pain fever and inflammation. There’s another enzyme that converts arachidonic acid to leukotrienes, lipoxygenase. So there are 2 enzymes acting on arachidonic acid… the ones that are important here are the leukotrienes, which are very powerful bronchoconstrictors. So if you inhibit the cyclooxygenase via aspirin or another NSAID, you shunt the arachidonic acid through the other pathway (the lipoxygenase pathway). So in many asthmatics, the leukotriene pathway is turned on by inhibition of the cyclooxygenase pathway (See the case at the beginning of the lecture).



Here we see a list of several drugs that influence blood concentrations of Theophylline. Erythromycin, ciprofloxacin, propranolol, phenytoin, rifampin, etc. elevate the blood levels of theophylline. What we know of theophylline is that its very highly metabolized by the p450 enzyme system. Any drug that inhibits that system (erythromycin is a prototype) means that theophylline concentration is increased in the blood into a toxic range. The downside of theophylline is drug interactions. Theophylline toxicity is like drinking 10-12 cups of coffee – palpitations, nervousness, tachycardia, sweating, etc.



What about Atrovent (Ipatropium bromide)? It is structurally similar to atropine, but doesn’t cross the blood:brain barrier, and has little if any effect on muscarinic receptor in the heart. It turns off the cholinergic pathway. This is a non-systemic agent. Most likely, you’ll see a combo of a beta-2 agonist and ipatropium for a combined effect of a bronchodilator and blocking the muscarinic receptor (drug= combivent).



Epinephrine is available as an emergency drug in response to an acute bronchospasm that is life-threatening; you must be able to inject this subcutaneously or intramuscularly. It is the drug of choice. Epi will also effect beta-1 in heart, alpha receptors in the arteries, and you’ll get systemic effects. When the pt is taking a selective beta-2 agonist these drugs cause a degree of tachycardia. Beta-2 agonists are not purely broncho-specific.



Corticosteroids probably affect the migration of the eosinophils, and there appears to be NO EFFECT on bone marrow density with the inhaled form of corticosteroids. They are very effective in decreasing vascular permeability, and clearly the actions are complementary, you don’t use a steroid as a bronchodilator; steroids are anti-inflammatory drugs. Many of the leukotriene blockers have a role not as monotherapy but as ‘steroid sparing’ agents.


Trade Names

There are many names, most of these are available as generic drugs now. They all have the same mechanism of action but differ in potency and duration of action. Inhaled steroids include Aerobid (flunisolide), Asmacort (triamcinolone acetonide), Beclovent and Vanceril (beclomethasone dipropionate= very popular), Flovent (fluticasone), Pulmicort (budesonide)…

When we talk about beta-2 adrenergic receptor agonists, we must talk about selectivity. Epinephrine has no selectivity, metaproterenol is very selective for beta-2. Albuterol, Terbutaline, and Salmeterol are more selective for beta-2. There isn’t much difference with regard to selectivity, physicians typically choose between meds based on tolerability. Terbutaline is associated with a slight tremor, pts don’t like this too much.



Asthma in children is almost epidemic now. Long-term use of any of these drugs, particularly the steroids, is worrisome because these drugs were previously thought to affect growth – although the evidence now is that the inhaled corticosteroids do not affect growth and bone density. In pregnancy, the issue is risk vs. benefit. Generally, a beta-adrenergic agonist can be given in normal adults; its important to maintain the mother’s health and safety. The benefit to the mother is greater than the risk of teratogenic effects. COPD is a group of bronchial inflammatory conditions including bronchitis. You’ll see COPD most in smokers. Bronchitis will respond well to a beta-2 agonist. There are no drugs for the treatment of emphysema (loss of lung elasticity).


Anything that raises cAMP will probably cause bronchodilation. The role of antihistamines is marginal.

Category: Pharmacology Notes