DRUGS AFFECTING THE
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
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.
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.
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
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.