Drugs Affecting the Kallikrein-Kinin System

DRUGS AFFECTING THE KALLIKREIN-KININ SYSTEM

Drugs that modify the activity of the kallikrein-kinin system are available, though none are in wide clinical use. Considerable effort has been directed toward developing kinin receptor antagonists, since such drugs have considerable therapeutic potential as anti-inflammatory and antinociceptive agents. Competitive antago-nists of both B₁ and B₂ receptors are available for research use. Examples of B₁ receptor antagonists are the peptides [Leu₈-des-Arg₉]bradykinin and Lys[Leu₈-des-Arg₉]bradykinin. The first B₂ receptor antagonists to be discovered were also peptide derivatives of bradykinin. These first-generation antagonists were used exten-sively in animal studies of kinin receptor pharmacology. However, their half-life is short, and they are almost inactive on the human B₂ receptor.

Icatibant is a second-generation B₂receptor antagonist. It is adecapeptide with an affinity for the B₂ receptor similar to that of bradykinin and is absorbed rapidly after subcutaneous administra-tion. Icatibant has been shown to be effective in the treatment of hereditary angioedema, an autosomal dominant disorder character-ized by recurrent episodes of bradykinin-mediated angioedema of the airways, gastrointestinal tract, extremities, and genitalia. It may also be useful in other conditions including drug-induced angio-edema, airway disease, thermal injury, ascites, and pancreatitis.

Recently, a third generation of B₂-receptor antagonists was developed; examples are FR 173657, FR 172357, and NPC 18884. These antagonists block both human and animal B₂ recep-tors and are orally active. They have been reported to inhibit bradykinin-induced bronchoconstriction in guinea pigs, carra-geenin-induced inflammation in rats, and capsaicin-induced nociception in mice. These antagonists have promise for the treat-ment of inflammatory pain in humans.SSR240612 is a new, potent, and orally active selective antago-nist of B₁ receptors in humans and several animal species. It exhib-its analgesic and anti-inflammatory activities in mice and rats and is currently in preclinical development for the treatment of inflammatory and neurogenic pain.

The synthesis of kinins can be inhibited with the kallikrein inhibitor aprotinin. Kinin synthesis can also be blocked with ecallantide, a newly developed recombinant plasma kallikreininhibitor which, like the B₂-receptor antagonist icatibant, is effective in the treatment of hereditary angioedema. Actions of kinins mediated by prostaglandin generation can be blocked nonspecifically with inhibitors of prostaglandin synthesis such as aspirin. Conversely, the actions of kinins can be enhanced with ACE inhibitors, which block the degradation of the peptides. Indeed, as noted above, inhibition of bradykinin metabolism by ACE inhibitors contributes significantly to their antihyperten-sive action.

Selective B₂ agonists are under study and have been shown to be effective in some animal models of human cardiovascular dis-ease. These drugs have potential for the treatment of hyperten-sion, myocardial hypertrophy, and other diseases.