Neurohypophyseal Hormones Oxytocin Vasopressin

The posterior pituitary (neurohypophysis) is the source of vasopressin, oxytocin, a- and jS-MSH, and coherin. The synthesis, transport, and release of these hormones have been reviewed by Brownstein.32 Vasopressin and oxytocin are synthesized and released by neurons of the hypothalamic-neurohypophyseal system. These peptide hormones, and their respective neurophysin carrier proteins, are synthesized as structural components of separate precursor proteins, and these proteins appear to be partially degraded into smaller bioactive peptides in the course of transport along the axon.

The structures of vasopressin and oxytocin have been elucidated, and these peptides have been synthesized. Actually, three closely related nonapeptides have been isolated from mammalian posterior pituitary: oxytocin and arginine vasopressin from most mammals and lysine vasopressin from pigs. The vasopressins differ from one another in the nature of the eighth amino acid residue: arginine and lysine, respectively. Oxytocin has leucine at position 8, and its third amino acid is isoleucine instead of phenylalanine. Several analog of vasopressin have been synthesized and their antidiuretic activity evaluated. Desmopressin, 1-desamino-8-arginine-vasopressin, is a synthetic derivative of vasopressin. It is a longer-acting and more potent antidiuretic than vasopressin, with much less pressor activity. Desmopressin is much more resistant to the actions of peptidases because of the deamina-tion at position 1, which accounts for its longer duration of action. The substitution of d- for l-arginine in position 8 accounts for its sharply lower vasoconstrictive effects.

Vasopressin also is known as the pituitary antidiuretic hormone (ADH). This hormone can effect graded changes in the permeability of the distal portion of the mammalian nephron to water, resulting in either conservation or excretion of water; thus, it modulates the renal tubular reabsorption of water. ADH has been shown to increase cAMP production in several tissues. Theophylline, which promotes cAMP by inhibiting the enzyme (phosphodi-esterase) that catalyzes its hydrolysis, causes permeability changes similar to those caused by ADH. Cyclic AMP also effects similar permeability changes; hence, it is suggested that cAMP is involved in the mechanism of action of ADH.

The nonrenal actions of vasopressin include its vasoconstrictor effects and neurotransmitter actions in the central nervous system, such as regulation of ACTH secretion, circulation, and body temperature.

ADH is therapeutically useful in the treatment of diabetes insipidus of pituitary origin. It also has been used to relieve intestinal paresis and distention.

Oxytocin is appropriately named because of its oxytocic action. Oxytocin exerts stimulant effects on the smooth muscle of the uterus and mammary gland and has a relaxing ef fect on vascular smooth muscle when administered in high doses. It is considered the drug of choice to induce labor, particularly in cases of intrapartum hypotonic inertia. Oxytocin also is used in inevitable or incomplete abortion after the 20th week of gestation. It also may be used to prevent or control hemorrhage and to correct uterine hypotonicity. In some cases, oxytocin is used to promote milk ejection; it acts by contracting the myoepithelium of the mammary glands. Oxytocin is usually administered parenterally by intravenous infusion, intravenous injection, or intramuscular injection. Oxytocin citrate buccal tablets are also available, but the rate of absorption is unpredictable, and buccal administration is less precise. Topical administration (nasal spray) 2 or 3 minutes before nursing to promote milk ejection is sometimes recommended.33 See Table 27.5 for product listing.

Oxytocin Injection, USP. Oxytocin injection is a sterile solution in water for injection of oxytocic principle prepared by synthesis, or obtained from the posterior lobe of the pituitary of healthy, domestic animals used for food by humans. The pH is 2.5 to 4.5; expiration date, 3 years.

Oxytocin preparations are widely used with or without amniotomy to induce and stimulate labor. Although injection is the usual route of administration, the sublingual route is extremely effective. Sublingual and intranasal spray (Oxytocin Nasal Solution, USP) routes of administration also will stimulate milk letdown.

Vasopressin Injection, USP. Vasopressin injection (Pitressin) is a sterile solution of the water-soluble pressor principle of the posterior lobe of the pituitary of healthy, domestic animals used for food by humans; it also may be prepared by synthesis. Each milliliter possesses a pressor activity equal to 20 USP posterior pituitary units; expiration date, 3 years.

Vasopressin Tannate. Vasopressin tannate (Pitressin Tannate) is a water-insoluble tannate of vasopressin ad ministered intramuscularly (1.5-5.0 pressor units daily) for its prolonged duration of action by the slow release of vasopressin. It is particularly useful for patients who have diabetes insipidus, but it should never be used intravenously.

Felypressin. Felypressin, 2-l-phenylalanine-8-l-lysine vasopressin, has relatively low antidiuretic activity and little oxytocic activity. It has considerable pressor (i.e., vasoconstrictor) activity, which differs from that of epinephrine (i.e., following capillary constriction in the intestine it lowers the pressure in the vena portae, whereas epinephrine raises the portal pressure). Felypressin also causes increased renal blood flow in the cat, whereas epinephrine brings about a fall in renal blood flow. Felypressin is five times more effective as a vasopressor than is lysine vasopressin and is recommended in surgery to minimize blood flow, especially in obstetrics and gynecology.

Lypressin. Lypressin is synthetic 8-l-lysine vasopressin, a polypeptide similar to ADH. The lysine analog is considered more stable, and it is absorbed rapidly from the nasal mucosa. Lypressin (Diapid) is pharmaceutically available as a topical solution, spray, 50 pressor units (185 /ug)/mL in 5-mL containers. Usual dosage, topical (intranasal), one or more sprays applied to one or both nostrils one or more times daily.

Desmopressin Acetate. Desmopressin acetate (DDAVP, Stimate) is synthetic 1-desamino-8-d-arginine vasopressin. Its efficacy, ease of administration (intranasal), long duration of action, and lack of side effects make it the drug of choice for the treatment of central diabetes insipidus. It may also be administered intramuscularly or intravenously. It is preferred to vasopressin injection and oral antidiuretics for use in children. It is indicated in the management of temporary polydipsia and polyuria associated with trauma to, or surgery in, the pituitary region.

TABLE 27.5 Neurohypophyseal Hormones: Pharmaceutical Products

Preparation

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