Page 326 - Basic _ Clinical Pharmacology ( PDFDrive )

312 SECTION IV Drugs with Important Actions on Smooth Muscle

ETs exert widespread actions in the body. In particular, they vasodilation in humans. These observations provide evidence
cause potent dose-dependent vasoconstriction in most vascular that the ET system participates in the regulation of vascular tone
beds. Intravenous administration of ET-1 causes a rapid and tran- under resting conditions. The activity of the system is higher in
sient decrease in arterial blood pressure followed by a sustained males than in females. It increases with age, an effect that can be
increase. The depressor response results from release of prostacy- counteracted by regular aerobic exercise.
clin and nitric oxide from the vascular endothelium, whereas the Increased production of ET-1 has been implicated in a variety
pressor response is due to direct contraction of vascular smooth of diseases, including pulmonary and arterial hypertension, renal
muscle. ETs also exert direct positive inotropic and chronotropic disease, diabetes, cancer, heart failure, and atherosclerosis. Indeed,
actions on the heart and are potent coronary vasoconstrictors. endothelin antagonism with bosentan, ambrisentan, and maci-
They act on the kidneys to cause vasoconstriction and decrease tentan has proved to be an effective and generally well-tolerated
glomerular filtration rate and sodium and water excretion. In the treatment for patients with pulmonary arterial hypertension,
respiratory system, they cause potent contraction of tracheal and an important condition with few effective treatments (see Box:
bronchial smooth muscle. ETs interact with several endocrine The Treatment of Pulmonary Hypertension). Hepatotoxicity is a
systems, increasing the secretion of renin, aldosterone, AVP, and known side effect of endothelin antagonists but is generally dose-
ANP. They exert a variety of actions on the central and periph- related and reversible. Cases of idiosyncratic hepatitis resulting
eral nervous systems, the gastrointestinal system, the liver, the in acute liver failure leading to death have been reported with
urinary tract, the reproductive system, eye, skeleton, and skin. sitaxsentan, and it was withdrawn in 2010. Other promising
ET-1 is a potent mitogen for vascular smooth muscle cells, cardiac targets for these drugs are resistant hypertension, chronic renal
myocytes, and glomerular mesangial cells. disease, connective tissue disease, and subarachnoid hemorrhage.
The signal transduction mechanisms triggered by binding of On the other hand, clinical trials of the drugs in the treatment
ET-1 to its vascular receptors include stimulation of phospholi- of heart failure have been disappointing. Thus, at present, pul-
pase C, formation of inositol trisphosphate, and release of calcium monary arterial hypertension remains the only clinical condition
from the endoplasmic reticulum, which results in vasoconstric- approved for endothelin receptor antagonists.
tion. Conversely, stimulation of PGI and nitric oxide synthesis Endothelin antagonists occasionally cause systemic hypotension,
2
results in decreased intracellular calcium concentration and increased heart rate, facial flushing or edema, and headaches. Poten-
vasodilation. tial gastrointestinal effects include nausea, vomiting, and constipa-
tion. Because of their teratogenic effects, endothelin antagonists
are contraindicated in pregnancy. Bosentan has been associated
INHIBITORS OF ENDOTHELIN with fatal hepatotoxicity, and patients taking this drug must have
SYNTHESIS & ACTION monthly liver function tests. Negative pregnancy test results are
required before prescribing this drug for women of child-bearing
The ET system can be blocked with receptor antagonists and age.
by drugs that block endothelin-converting enzyme. ET or ET
A
B
receptors can be blocked selectively, or both can be blocked with B. Dual Inhibitors of Endothelin-Converting Enzyme and
nonselective ET -ET antagonists. Neprilysin
B
A
Bosentan is a nonselective ET receptor blocker. It is active A newer strategy now being widely tested in clinical trials uses
orally and blocks both the initial transient depressor (ET ) and combined inhibition of endothelin-converting enzyme and nepri-
B
the prolonged pressor (ET ) responses to intravenous ET. A newer lysin. Daglutril (SLV306) is a prodrug that is converted to the
A
dual endothelin receptor antagonist, macitentan, was developed active metabolite KC-12625, a mixed inhibitor of endothelin-
by modifying the structure of bosentan. Additional ET receptor converting enzyme and neprilysin. Thus, it simultaneously inhib-
antagonists with increased selectivity include the ET antagonists its the formation of ET and the breakdown of natriuretic peptides.
A
ambrisentan, with some ET A selectivity, and sitaxsentan, the Daglutril appears to be well tolerated with few or none of the side
antagonist.
most selective ET A effects on liver function and edema observed with endothelin
The formation of ETs can be blocked by inhibiting endothelin- antagonists. It has been shown to have beneficial effects in heart
converting enzyme with phosphoramidon. Phosphoramidon is failure and to lower blood pressure in patients with type 2 diabetes
not specific for endothelin-converting enzyme, but more selective and nephropathy.
inhibitors including CGS35066 are available.
Physiologic & Pathologic Roles of ■ VASOACTIVE INTESTINAL
Endothelin PEPTIDE
A. Effects of Endothelin Antagonists
Systemic administration of ET receptor antagonists or endothelin- Vasoactive intestinal peptide (VIP) is a 28-amino-acid peptide that
converting enzyme inhibitors causes vasodilation and decreases belongs to the glucagon-secretin family of peptides. VIP is widely
arterial pressure in humans and experimental animals. Intra- distributed in the central and peripheral nervous systems, where it
arterial administration of the drugs also causes slow-onset functions as one of the major peptide neurotransmitters. It is present