Genomic Effects of CS
The mechanisms of action of CS on the inflammatory process are complex. The classic antiinflamma-tory effects implicate the activation or repression of multiple genes involved in the inflammatory process. Thus, CS produce their effects on cells by activating glucocorticoid receptors that alter transcription through direct DNA binding or transcription factor inactivation. As a consequence, CS increase the synthesis of antiinflammatory proteins, or inhibit the synthesis of many inflammatory proteins through suppression of the genes that encode them. This
effect is also denominated genomic because it implies the participation of cellular genome. The length of time between CS entry into the cell and the production of new proteins is in order of hours or still days.
This fact is in concordance with clinical evidence that shows a 4 to 12 h delay to be able to detect beneficial
effects of SCS.
Rapid Nongenomic Effects of CS
Although the major part of the investigation has been performed in the last decade, already in 1942 Hans Selye13 observed that some CS-induced effects (anesthesia) only minutes after their application, constituting the first notification of a nongenomic effect of CS. Two decades later, acute cardiovascular effects of aldosterone (after 5 min of its administration) were reported in humans.
Lately, CS have also been shown to acutely decrease nasal itching in allergic rhinitis patients.15 These rapid effects are initiated by specific interactions with membrane-bound or cytoplasmic CS receptors, or nonspecific interactions with the cell membrane, and the responses are much more rapid (seconds or minutes).
Membrane receptor inactivation has been shown to induce rapid effects on a variety of second messenger systems.
In addition, CS could bind other receptors, ion channels, enzymes, or transporters.
More recently, research has been focused in the nongenomic effects of ICS on airway smooth-muscle tone, and particularly in the study of the mucosal blood flow of asthmatic and healthy people. Thus, membrane binding sites for CS have been demonstrated in smooth-muscle cells isolated from human airway blood vessels. Studies also show that asthmatics present a significant increase in airway mucosal blood flow in comparison with healthy subjects (24 to 77% higher in asthmatics), and that inhalation of fluticasone (880 g) or budes-onide (400 g) decreases blood flow in both groups. This effect is transient, reaching a maximum approximately 30 min after inhalation, and returning to basal values at 60 to 90 min.
This blood flow decrease is dose dependent, with a greater effect in asthmatics than in healthy subjects. Finally, it was not specific for fluticasone or budesonide, and also it was demonstrated for beclomethasone. However, fluticasone and budesonide cause greater effect than beclomethasone.18 Evidence suggests that CS decrease airway blood flow by modulating sympathetic control of vascular tone, potentiating noradrenergic neurotransmission in the airway vasculature.
After release from sympathetic terminals, norepineph-rine must be taken up by postsynaptic cells from CS-induced vasoconstriction. Furthermore, this decrease of airway blood flow is likely to enhance the action of inhaled bronchodilators by diminishing their clearance from the airway Thus, simultaneous administration of ICS and bronchodilators could be of clinical significance.
In summary, CS can show two different effects on acute asthma patients :
(1) the classic antiinflammatory or genomic action, involving the modification of gene expression, that occurs with a time lag of hours or days; and (2) the nongenomic action, with has a rapid onset (minutes), is reversible (short duration), and is dose dependent.
Finally, a direct relationship was observed between the ICS-induced airway blood flow decrease and predrug airway blood flow.
These vascular effects of ICS on airway blood can be expected to have therapeutic implications in the management of acute asthma, and its characteristics are fundamental to establish the optimum dose and timing of administration in the emergency department (ED) setting.
Accordingly, ICS would have to be administered simultaneously with bronchodilators in high and repeated or sequential doses as a way to obtain and maintain the effect throughout the time. Since ICS induce vaso-constriction peaks between 30 and 60 min after drug administration, their use in intervals not 30 min seems adequate. The objective of this review was the analysis of the best evidence available on the early clinical impact of ICS for acute asthma patients.
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