In healthy people, innate and adaptive immune responses are triggered by various immune cells (notably neutrophils, resident alveolar macrophages and dendritic cells) drawn to the site of infection by numerous inflammatory cytokines and neutrophilic attractants (such as CXCR2 receptor ligands). In this situation, mucociliary clearance is initiated and spores are successfully phagocytosed, clearing the infection from the host.In people with predisposing lung diseases—such as persistent asthma or cystic fibrosis (or rarer diseases such as chronic granulomatous disease or Hyper-IgE syndrome)—several factors lead to an increased risk of ABPA. These include immune factors (such as atopy or immunogenic HLA-restricted phenotypes), as well as genetic factors (such as CFTR gene mutations in both asthmatics and cystic fibrosis patients and a ZNF77 mutation resulting in a premature stop codon in asthmatics and ABPA patients). By allowing Aspergillus spores to persist in pulmonary tissues, it permits successful germination which leads to hyphae growing in mucus plugs. There are hypersensitivity responses, both a type I response (atopic, with formation of immunoglobulin E, or IgE) and a type III hypersensitivity response (with formation of immunoglobulin G, or IgG). The reaction of IgE with Aspergillus antigens results in mast cell degranulation with bronchoconstriction and increased capillary permeability. Immune complexes (a type III reaction) and inflammatory cells are deposited within the mucous membranes of the airways, leading to necrosis (tissue death) and eosinophilic infiltration. Type 2 T helper cells appear to play an important role in ABPA due to an increased sensitivity to interleukin (IL) 4 and IL-5.
It cleaves angiotensinogen to angiotensin I, which is in turn converted by angiotensin-converting enzyme (ACE) to angiotensin II. Angiotensin II has both direct and indirect effects on blood pressure. It directly causes arterial smooth muscle to contract, leading to vasoconstriction and increased blood pressure. Angiotensin II also stimulates the production of aldosterone from the adrenal cortex, which causes the tubules of the kidneys to increase reabsorption of sodium, with water following, thereby increasing plasma volume, and thus blood pressure. Aliskiren binds to the S3bp binding site of renin, essential for its activity. Binding to this pocket prevents the conversion of angiotensinogen to angiotensin I.
Aliskiren is also available as combination therapy with hydrochlorothiazide. Chemistry
The chemical name for aliskiren is (2 S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2-methylpropyl)-4-hydroxy-2-isopropyl-7-[ 4-methoxy-3-(3-methoxypropoxy)benzyl]-8-methylnonanamide. Rationale for design
Many drugs control blood pressure by interfering with angiotensin or aldosterone. However, when these drugs are used chronically, the body increases renin production, which drives blood pressure up again. Therefore, pharmacologists have been looking for a drug to inhibit renin directly. Aliskiren is the first drug to do so. References
External links
"Aliskiren". Drug Information Portal. U.S. National Library of Medicine. Aliskiren at the US National Library of Medicine Medical Subject Headings (MeSH)