Page 322 - Basic _ Clinical Pharmacology ( PDFDrive )

308 SECTION IV Drugs with Important Actions on Smooth Muscle

including drug-induced angioedema, airway disease, thermal VASOPRESSIN RECEPTORS, AGONISTS,
injury, ascites, and pancreatitis. & ANTAGONISTS
A third generation of B -receptor antagonists has been devel-
2
oped; examples are FR 173657, FR 172357, and NPC 18884. Three subtypes of AVP receptors have been identified; all are
These antagonists block both human and animal B receptors and G protein-coupled. V receptors mediate the vasoconstric-
2
1a
are orally active. They have been reported to inhibit bradykinin- tor action of AVP; V receptors mediate release of ACTH by
1b
induced bronchoconstriction in guinea pigs, carrageenan-induced pituitary corticotropes; and V receptors mediate the antidiuretic
2
inflammation in rats, and capsaicin-induced nociception in mice. action. V effects are mediated by G activation of phospholipase
1a
q
These antagonists have promise for the treatment of inflammatory C, formation of inositol trisphosphate, and increased intracellular
pain in humans. calcium concentration. V effects are mediated by G activation of
SSR240612 is a new, potent, and orally active selective antago- adenylyl cyclase. 2 s
nist of B receptors in humans and several animal species. It reduces AVP analogs selective for vasoconstrictor or antidiuretic activ-
1
obesity in diabetic rats, has analgesic and anti-inflammatory activi- ity have been synthesized. The first specific V vasoconstrictor
1
ties in mice and rats, and is currently in preclinical development for agonist to be synthesized was [Phe , Ile , Orn ]vasotocin. [Phe ,
2
2
8
3
the treatment of inflammatory and neurogenic pain. Ile , Hgn , Orn(i-Pr) ]vasopressin, or selepressin, is a newer
8
4
8
The synthesis of kinins can be inhibited with the kallikrein short-acting selective V receptor agonist. Selective V antidiuretic
2
1a
inhibitor aprotinin. Kinin synthesis can also be inhibited by two analogs include 1-deamino[D-Arg ]arginine vasopressin (dDAVP)
8
preparations of human plasma C1-INH, cinryze and berinert, and 1-deamino[Val , D-Arg ]arginine vasopressin (dVDAVP).
4
8
and these are used for the intravenous prophylaxis or treatment AVP, often in combination with norepinephrine, has proved
of hereditary angioedema. Ecallantide, a more recently developed beneficial in the treatment of septic and other vasodilatory shock
recombinant plasma kallikrein inhibitor, is also effective. It is states, at least in part by virtue of its V agonist activity. Terlip-
1a
more potent and selective than C1-INH and can be administered ressin (triglycyl lysine vasopressin), a synthetic vasopressin analog
by subcutaneous injection. that is converted to lysine vasopressin in the body, is also effective.
Actions of kinins mediated by prostaglandin generation can be However, AVP and terlipressin also stimulate renal V receptors,
2
blocked nonspecifically with inhibitors of prostaglandin synthesis and this may have undesirable effects. Therefore, interest has
such as aspirin. Conversely, the actions of kinins can be enhanced focused on the use of selepressin in septic shock. Two phase 2 trials
with ACE inhibitors, which block the degradation of the peptides. are in progress, and preliminary results are positive.
Indeed, as noted above, inhibition of bradykinin metabolism by Antagonists of the vasoconstrictor action of AVP are also
ACE inhibitors contributes significantly to their antihypertensive available. The peptide antagonist d(CH2) [Tyr(Me) ]AVP also
2
5
action. has antioxytocic activity but does not antagonize the antidiuretic
Selective B agonists are under study and have been shown action of AVP. A related antagonist d(CH2) [Tyr(Me) Dab ]AVP
5
2
2
5
to be effective in some animal models of human cardiovascular lacks oxytocin antagonism but has less anti-V activity. Nonpep-
1
disease. These drugs have potential for the treatment of hyperten- tide, orally active V -receptor antagonists have been developed,
1a
sion, myocardial hypertrophy, and other diseases. examples being relcovaptan and SRX251.
The V antagonists have been particularly useful in revealing the
1a
■ VASOPRESSIN important role that AVP plays in blood pressure regulation in situ-
ations such as dehydration and hemorrhage. They have potential
as therapeutic agents for the treatment of such diverse conditions
Vasopressin (arginine vasopressin, AVP; antidiuretic hormone, as Raynaud’s disease, hypertension, heart failure, brain edema,
ADH) plays an important role in the long-term control of blood motion sickness, cancer, preterm labor, and anger management. To
pressure through its action on the kidney to increase water reab- date, most studies have focused on heart failure; promising results
sorption. This and other aspects of the physiology of AVP are have been obtained with V antagonists such as tolvaptan, which
2
discussed in Chapters 15 and 37 and will not be reviewed here. is, however, currently approved only for use in hyponatremia. V
1a
AVP also plays an important role in the regulation of arterial antagonists also have potential, and conivaptan (YM087), a drug
pressure by its vasoconstrictor action. Mutant mice lacking the with both V and V antagonist activity, has also been approved for
receptor (see below) show significantly lower 1a 2
gene for the V 1a treatment of hyponatremia (see Chapter 15).
blood pressure compared with control mice. AVP increases
total peripheral resistance when infused in doses less than those
required to produce maximum urine concentration. Such doses ■ NATRIURETIC PEPTIDES
do not normally increase arterial pressure because the vasopressor
activity of the peptide is buffered by a reflex decrease in cardiac
output. When the influence of this reflex is removed, eg, in shock, Synthesis & Structure
pressor sensitivity to AVP is greatly increased. Pressor sensitivity The atria and other tissues of mammals contain a family of peptides
to AVP is also enhanced in patients with idiopathic orthostatic with natriuretic, diuretic, vasorelaxant, and other properties. The
hypotension. Higher doses of AVP increase blood pressure even family includes atrial natriuretic peptide (ANP), brain natriuretic
when baroreceptor reflexes are intact. peptide (BNP), and C-type natriuretic peptide (CNP). The peptides