Page 346 - Basic _ Clinical Pharmacology ( PDFDrive )

332 SECTION IV Drugs with Important Actions on Smooth Muscle

LTB may cause vasoconstriction as well as smooth muscle cell luteinizing hormone (LH) and LH-releasing hormone release
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migration and proliferation, possibly contributing to athero- from isolated rat anterior pituitary cells.
sclerosis and injury-induced neointimal proliferation. LTC and
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LTD reduce myocardial contractility and coronary blood flow,
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leading to depression of cardiac output. Lipoxin A and lipoxin B INHIBITION OF EICOSANOID
exert coronary vasoconstrictor effects in vitro. In addition to their SYNTHESIS
vasodilatory action, EETs may reduce cardiac hypertrophy as well
as systemic and pulmonary vascular smooth muscle proliferation Corticosteroids block all the known pathways of eicosanoid
and migration. synthesis, perhaps in part by stimulating the synthesis of several
inhibitory proteins collectively called annexins or lipocortins.
2. Gastrointestinal—Human colonic epithelial cells synthesize They inhibit phospholipase A activity, probably by interfering
2
LTB , a chemoattractant for neutrophils. The colonic mucosa of with phospholipid binding, thus preventing the release of arachi-
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patients with inflammatory bowel disease contains substantially donic acid.
increased amounts of LTB . It appears that activation of the BLT The NSAIDs (eg, indomethacin, ibuprofen; see Chapter 36)
2
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receptor, possibly by agonists other than LTB , is protective in block both prostaglandin and thromboxane formation by revers-
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colonic epithelium and contributes to maintenance of barrier ibly inhibiting COX activity. The traditional NSAIDs are not
function. selective for COX-1 or COX-2. The more recent, purposefully
designed selective COX-2 inhibitors vary—as do the older
3. Airways—The cysteinyl leukotrienes, particularly LTC and drugs—in their degree of selectivity. Indeed, there is consider-
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LTD , are potent bronchoconstrictors and cause increased micro- able variability between (and within) individuals in the selectivity
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vascular permeability, plasma exudation, and mucus secretion attained by the same dose of the same NSAID. Aspirin is an
in the airways. Controversies exist over whether the pattern and irreversible COX inhibitor. In platelets, which lack nuclei, COX-1
specificity of the leukotriene receptors differ in animal models and (the only isoform expressed in mature platelets) cannot be restored
humans. LTC -specific receptors have not been found in human via protein biosynthesis, resulting in extended inhibition of TXA
2
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lung tissue, whereas both high- and low-affinity LTD receptors biosynthesis.
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are present. EP-receptor agonists and antagonists are under evaluation
in the treatment of bone fracture and osteoporosis, whereas
C. Renal System TP-receptor antagonists are being investigated for usefulness in
There is substantial evidence for a role of the epoxygenase prod- the treatment of cardiovascular syndromes. Direct inhibition of
PGE biosynthesis through selective inhibition of the inducible
2
ucts in regulating renal function, although their exact role in the mPGES-1 isoform is also under examination for potential thera-
human kidney remains unclear. Both 20-HETE and the EETs peutic efficacy in pain and inflammation, cardiovascular disease,
are generated in renal tissue. 20-HETE, which potently blocks and chemoprevention of cancer.
+
2+
the smooth muscle cell Ca -activated K channel and leads to Although they remain less effective than inhaled corticosteroids,
vasoconstriction of the renal arteries, has been implicated in the a 5-LOX inhibitor (zileuton) and selective antagonists of the
pathogenesis of hypertension. In contrast, studies support an CysLT receptor for leukotrienes (zafirlukast, montelukast, and
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antihypertensive effect of the EETs because of their vasodilating pranlukast; see Chapter 20) are used clinically in mild to moderate
and natriuretic actions. EETs increase renal blood flow and may asthma. Growing evidence for a role of the leukotrienes in cardio-
protect against inflammatory renal damage by limiting glomerular vascular disease has expanded the potential clinical applications of
macrophage infiltration. Inhibitors of soluble epoxide hydrolase, leukotriene modifiers. Conflicting data have been reported in ani-
which prolong the biologic activities of the EETs, are being devel- mal studies depending on the disease model used and the molecular
oped as potential new antihypertensive drugs. In vitro studies, target (5-LOX versus FLAP). Human genetic studies demonstrate
and work in animal models, support targeting soluble epoxide a link between cardiovascular disease and polymorphisms in the
hydrolase for blood pressure control, although the potential for leukotriene biosynthetic enzymes, and indicate an interaction
pulmonary vasoconstriction and tumor promotion through anti- between the 5-LOX and COX-2 pathways, in some populations.
apoptotic actions require careful investigation.
NSAIDs usually do not inhibit lipoxygenase activity at con-
centrations attained clinically that inhibit COX activity. In fact,
D. Miscellaneous by preventing arachidonic acid conversion via the COX pathway,
The effects of these products on the reproductive organs have not NSAIDs may cause more substrate to be metabolized through
been elucidated. the lipoxygenase pathways, leading to an increased formation of
Similarly, actions on the nervous system have been suggested the inflammatory and proliferative leukotrienes. Even among the
but not confirmed. 12-HETE stimulates the release of aldosterone COX-dependent pathways, inhibiting the synthesis of one deriva-
from the adrenal cortex and mediates a portion of the aldosterone tive may increase the synthesis of an enzymatically related prod-
release stimulated by angiotensin II but not that by adrenocorti- uct. Therefore, drugs that inhibit both COX and lipoxygenase are
cotropic hormone. Very low concentrations of LTC increase and being developed. One such drug, the COX-2/5-LOX inhibitor
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higher concentrations of arachidonate-derived epoxides augment darbufelone, has shown promise in studies of cancer cells and in