|
The Paradox of Beta Blockade
In the recent past, β blockers were contraindicated in heart failure because acute doses produced a deterioration in myocardial contractility and hence the possibility of tipping a patient into an acute heart failure. Paradoxically, chronic dosing with select β blockers (know as beta inverse agonists) was subsequently shown to produce beneficial effects and reduce deaths in heart failure, and is now standard drug management for treating heart failure.
Recently, several leading research centers have shown a similar paradoxical effect in obstructive lung diseases, i.e. that acute dosing with beta-blockers produces bronchoconstriction, whereas chronic dosing produced bronchoprotection against challenges which induce airway hyperresponsiveness. The beneficial effects of the use of select β blockers with chronic dosing (versus the negative effects with acute dosing) are attributed to the known upregulation of β2 adrenoceptors with chronic dosing and chronic exposure to selective β blockers such as INV102 (nadolol). This observation has now led to a fundamental shift in thinking and to the proposition of use of β blockers for obstructive lung diseases such as COPD and asthma.
Not all Beta Blockers are Inverse Agonists
Receptor agonists, antagonists and inverse agonists bind to the same receptor types. An inverse agonist is an agent that binds to the receptor binding-site and reverses intrinsic activity of the receptors (also referred to as 'constitutive activity'). Inverse agonists exert the opposite pharmacological effect of a receptor agonist and are effective against certain types of receptors. Beta adrenoceptor inverse agonists are a subset of β-blockers that, like all β-blockers, can inhibit agonist-induced signaling, except that inverse agonists can also inhibit signaling produced by constitutively active receptors. INV102 (nadolol) is one such inverse agonist agent. In recent studies, several investigators have demonstrated the reciprocal effects of INV102 and its extended effect on cell signaling. Specifically, that chronic agonist exposure can produce desensitization and inhibit signaling, while chronic treatment with inverse agonists may produce sensitization and enhance signaling. These data indicate the important role that duration of drug therapy can have on the observed physiologic and clinical response. In summary, certain β blockers that are initially detrimental when used short term are now considered beneficial in the treatment of disease when used chronically.
Evidence to Support Inverse Agonism and Use of Beta Blockers for Obstructive Lung Diseases
1. Regulatory Precedence: Reversal of contraindication to indication for inverse β agonists in the
treatment of chronic (congestive) heart failure (CHF)
- Once contraindicated, carvedilol and metoprolol received approval for CHF
- Inverse agonists are now standard of care
- β-blockers without inverse agonist activity failed
- Pattern of early adverse effect and long-term benefit with inverse
agonists seen in heart failure and hypothesized for obstructive lung disease
2. MOA: Basic mechanism of inverse agonism supports use in
obstructive lung diseases
- Mucous cell metaplasia is present in animal models of obstructive lung disorders
- IL-13 and other cytokines (IL-5, IL-10) are regulated by intrinsic
activation of β-2 receptors
- Prevents mucus cell metaplasia administered prior to insult
- Treats (reverses) mucus cell metaplasia
- Decreases IL-10 and IL-5 secretion
- Acts additively or synergistically with corticosteroids
- Further studies ongoing
3. Clinical Trials: Studies of steady state dosing with a selective β-blocker INV102 (nadolol) in subjects with asthma
- Two clinical trials have been completed in subjects with asthma
- No deaths, hospitalizations, serious adverse events
- No acute bronchoconstriction
- Limited by dose titration
- Reversible with albuterol/ salbutamol
- Clinically relevant and statistically significant improvement
in PC20 methacholine, a validated measurement of hyper-
responsiveness (shown below)
4. Decreased exacerbation rate in COPD patients receiving inverse agonists
|
