Hypothalamic and Pituitary Drugs



Hypothalamic and Pituitary Drugs



Classification of Hypothalamic and Pituitary Drugs




aAlso goserelin (ZOLADEX), nafarelin (SYNAREL), triptorelin (TRELSTAR), and histrelin (SUPPRELIN).


bAlso cetrorelix (CETROTIDE) and degarelix (FIRMAGON).


cAlso bromocriptine (PARLODEL).




Overview


The hypothalamus and pituitary gland constitute an important neuroendocrine system that regulates growth, reproduction, metabolic rates, and other critical body functions. The pituitary gland (hypophysis) is divided into two major lobes: the adenohypophysis (anterior lobe) and the neurohypophysis (posterior lobe). Various hormones are secreted by each of these lobes and by the hypothalamus.



Adenohypophysis and Hypothalamus


The adenohypophysis secretes six hormones: (1) corticotropin (adrenocorticotropic hormone [ACTH]); (2) somatotropin (growth hormone); (3) follicle-stimulating hormone (FSH); (4) luteinizing hormone (LH); (5) thyrotropin (thyroid-stimulating hormone [TSH]); and (6) prolactin. The actions of these anterior pituitary hormones are summarized in Figure 31-1.


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FIGURE 31-1 Relationships among hypothalamic hormones, pituitary hormones, and target organs. Numerous hormone-releasing and hormone-inhibiting factors formed in the arcuate and other hypothalamic nuclei are transported to the anterior pituitary by hypophysioportal vessels. In response to hypothalamic hormones, the anterior pituitary secretes the following: corticotropin, which evokes corticosteroid secretion by the adrenal cortex; growth hormone (GH), which elicits production of insulin-like growth factors by the liver; follicle-stimulating hormone (FSH), which stimulates spermatogenesis and facilitates ovarian follicle development; luteinizing hormone (LH), which elicits testosterone secretion by the testes, facilitates ovarian follicle development, and induces ovulation; thyroid-stimulating hormone (TSH), which stimulates thyroxin secretion by the thyroid gland; and prolactin, which induces breast tissue growth and lactation. The posterior pituitary hormones, which are formed in the supraoptic and paraventricular nuclei, are transported by nerve axons to the posterior lobe, where they are released by physiologic stimuli. Oxytocin induces milk ejection by the breast and stimulates uterine contractions during labor. Vasopressin increases water and sodium reabsorption by the kidneys.

The secretion of anterior pituitary hormones is controlled by several hormone-releasing and hormone-inhibiting factors that are formed in the hypothalamus. These hypothalamic hormones include the following: (1) corticotropin-releasing hormone; (2) growth hormone–releasing hormone (GHRH); (3) somatostatin (growth hormone–inhibiting hormone); (4) gonadotropin-releasing hormone (GnRH); (5) thyrotropin-releasing hormone (TRH); and (6) dopamine (prolactin-inhibiting hormone [PIH]). Evidence also suggests the presence of one or more prolactin-releasing factors. The various hypothalamic hormones are secreted by the arcuate and other hypothalamic nuclei, and they are transported to the anterior pituitary via the hypophysioportal circulation.


The anterior pituitary hormones are transported to their target organs via the systemic circulation. In the target organs, they stimulate growth, development, and the secretion of other hormones, which both activate specific functions in various organs and exert negative feedback inhibition of the corresponding hypothalamic and pituitary hormones.




Uses of Hypothalamic and Pituitary Hormones


Hypothalamic and pituitary hormones are used for both diagnostic and therapeutic purposes. Hypothalamic hormone-releasing factors are helpful in assessing the functional capacity of the anterior pituitary to secrete particular pituitary hormones. Anterior pituitary hormones are used to evaluate the functional capacity of their target organs, to stimulate hypofunctional target organs, and to provide replacement therapy in hormone-deficiency states. Posterior pituitary hormones are used therapeutically to regulate specific physiologic functions.


All of the hypothalamic and pituitary hormones are peptides or small proteins that are extensively degraded in the gut after oral administration. For this reason, most of these hormones are administered parenterally. A few of them are available as a spray for intranasal administration.



Anterior Pituitary Hormones


Corticotropin and Related Drugs


Corticotropin is a 39–amino-acid peptide that is released from the anterior pituitary in response to corticotropin-releasing hormone stimulation. Corticotropin then stimulates the adrenal cortex to produce cortisol, aldosterone, and adrenal androgens by increasing the activity of the enzyme that converts cholesterol to pregnenolone (cholesterol side-chain cleavage enzyme) and is the rate-limiting enzyme in corticosteroid production.



Corticotropin Preparations


Two corticotropin preparations are available for clinical use: porcine corticotropin and a synthetic form of human corticotropin called cosyntropin. Cosyntropin contains the first 24 amino acids of human corticotropin, which are the ones necessary for its biologic activity. Cosyntropin is preferable for clinical use because it produces fewer allergic reactions.


Cosyntropin is used in two diagnostic tests. First, it is used to distinguish congenital adrenal hyperplasia from ovarian hyperandrogenism. Second, and more commonly, it is used to diagnose adrenal insufficiency in a test that measures plasma cortisol levels before and after a cosyntropin injection. Cosyntropin increases cortisol levels in healthy individuals but fails to increase cortisol levels in persons with adrenal insufficiency. Then to distinguish primary adrenal insufficiency from secondary adrenal insufficiency, endogenous plasma corticotropin concentrations are measured. In patients with primary adrenal insufficiency, corticotropin concentrations are high because of the lack of negative feedback inhibition of the hypothalamus and pituitary gland by the adrenal corticosteroids. In patients with secondary adrenal insufficiency, corticotropin concentrations are low because of inadequate production of corticotropin by the pituitary gland.




Growth Hormone and Related Drugs


Growth hormone (somatotropin), a large peptide that contains 191 amino acids, is produced by the anterior pituitary and has both direct and indirect actions on target organs. Growth hormone acts directly to stimulate lipolysis and antagonize insulin to elevate blood glucose levels. Most of the effects of growth hormone, however, are mediated by insulin-like growth factor 1 (IGF-1) peptides, which are peptides produced in the liver and cartilage. The IGF-1 peptides stimulate skeletal growth, amino acid transport, protein synthesis, nucleic acid synthesis, and cell proliferation.


The secretion of growth hormone is stimulated by GHRH and is inhibited by somatostatin. Several preparations of growth hormone, GHRH, and somatostatin are available for use in the diagnosis and treatment of growth disorders associated with excessive or inadequate secretion of growth hormone.



Growth Hormone Preparations


Growth hormone preparations obtained from animal sources are not active in humans. In the past, growth hormone obtained from human cadavers was used to treat patients with growth hormone deficiency and short stature, but some of the patients subsequently developed Creutzfeldt-Jakob disease. This fatal disease, as with mad cow disease and kuru, is characterized by spongiform encephalopathy and is thought to be transmitted by unconventional neurotoxic agents called prions.


A biosynthetic form of human growth hormone known as recombinant somatropin is used to treat children with various forms of growth hormone deficiency, including idiopathic growth hormone deficiency, Turner syndrome, chronic renal failure, Prader-Willi syndrome, and cystic fibrosis. Somatropin preparations have been clearly shown to improve height velocity and final height in these conditions. Children who received craniospinal irradiation for treatment of a childhood malignancy are less responsive to growth hormone replacement than children with idiopathic growth hormone deficiency, and they have a tendency to enter puberty at an earlier age. These children may respond to supraphysiologic doses of growth hormone preparations and suppression of early puberty using a GnRH analogue (see later). Somatropin is usually administered subcutaneously once daily to children with growth hormone deficiency. Growth hormone deficiency is often accompanied by other pituitary hormone deficiencies, which should also be treated with appropriate hormones.


Mecasermin is a recombinant form of human IGF-1. It is produced by Escherichia coli bacteria that have been stably transfected with the human gene for IGF-1. Mecasermin is indicated for the treatment of growth failure in children with severe primary IGF-1 deficiency, those with a growth hormone receptor mutation, and those who have developed neutralizing antibodies to growth hormone. The main adverse effect is hypoglycemia, which is controlled by eating a meal or snack before or soon after the time of the injection.

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Jul 23, 2016 | Posted by in PHARMACY | Comments Off on Hypothalamic and Pituitary Drugs

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