Ketotifen fumarate is a noncompetitive H1 antagonist commercially available in oral and ophthalmic forms; ketotifen acts as an antihistamine, mast cell stabilizer, and beta-2 adrenergic receptor expression modulator. Ketotifen is approved for allergic conjunctivitis (as ophthalmic preparation), allergic rhinitis (as oral preparation), and prevention of asthma attacks in susceptible individuals (as oral preparation). Ketotifen has also been shown to act synergistically with B2-agonist asthma medications through upregulation of beta-2 adrenergic receptors, particularly in extended co-administration.
The H1 antagonism effects of ketotifen, while central to its mechanism of action in allergic rhinitis and allergic conjunctivitis, do not appear relevant to the effects of ketotifen in treating asthma. Asthma and hypersensitivity has been correlated with abnormal levels of key cellular enzymes, which ketotifen in turn modulates and helps to normalize:
asthmatics had less methyltransferase activity and greater phosphodiesterase activity than healthy individuals. These enzymatic activities were nearer to values obtained in healthy individuals when we preincubated cells with ketotifen. The modulator effect of this drug on these two enzymes permits, on the one hand, to re-establish the beta-receptor numbers expressed on the membrane, and on the other hand, to inhibit mediator secretion provoked by antigenic stimulus. With its action on adenylate cyclase and phosphodiesterase activities, it allows cAMP intracellular accumulation and hinders the secretory process. Through its action on methyltransferase activity, it is responsible for the normalization of beta-receptor expression observed in asthmatic patients treated with ketotifen.
The two pathways through which ketotifen appears to exert a therapeutic benefit in asthma are mast cell stabilization (preventing the release of mediators) and beta-receptor expression modulation.
Raajimaker et al (1984) find that the inhibition of phosphodiesterase also contributes to the “[modulating] action on beta-2 adrenergic receptors”.
Ketotifen not only increases beta-receptor density, but when co-administered with beta-adrenergic receptor agonists, maintains it, leading Koshino et al (1988) to conclude that “ketotifen might be valuable when beta-agonists are administered for long term treatment in asthmatic patients”.
As discussed by Klooker et al (2010), the stabilization of mast cells may also be the mechanism behind a therapeutic effect observed in some patients with irritable bowel syndrome (IBS):
ketotifen [but not placebo] increases the threshold for discomfort in patients with IBS with visceral hypersensitivity, reduces IBS symptoms and improves health-related quality of life. Whether this effect is secondary to the mast cell stabilising properties of ketotifen or H(1) receptor antagonism remains to be further investigated.
Ketotifen also exerts an inhibitory effect on release of prostaglandin D2 (PGD2), an pro-inflammatory fatty signaling molecule, and interferes with receptor binding of leukotrienes, thought to be involved in both bronchial asthma and allergic rhinitis.
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 Klooker TK, Braak B, Koopman KE, Welting O, Wouters MM, van der Heide S, Schemann M, Bischoff SC, van den Wijngaard RM, Boeckxstaens GE. The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut. 2010 Sep;59(9):1213-21.