Drugs Used in the Treatment of Hypothalamic, Pituitary, Thyroid, and Adrenal Disorders

Chapter 23 Drugs Used in the Treatment of Hypothalamic, Pituitary, Thyroid, and Adrenal Disorders

1. A hormone is a substance secreted by one tissue or gland that is transported via the circulation to a site where it exerts its effects on different tissues.

Hormone is a substance secreted by one tissue but has actions at remote tissues.

2. See Endocrine Physiology section of Rapid Review Physiology for a review of hormone signaling pathways and physiological mechanisms.

B. Uses for hormones and synthetic analogues

1. Diagnostic tools in endocrine disorders

2. Replacement therapy in endocrine disorders

3. Treatment of non-endocrine disorders

C. Review hypothalamic/pituitary/target organ interactions: (Table 23-1 and Fig. 23-1)

TABLE 23-1 Relationships Among Hypothalamic, Pituitary, and Target Gland Hormones

23-1 Regulation of hormone synthesis and secretion. A negative feedback mechanism is an example of a negative effect. CNS, central nervous system.

Understand the negative feedback principle of the hypothalamic/pituitary/target organ axis.

II. Hypothalamic Hormones and Related Drugs (Box 23-1)

A. Sermorelin (growth hormone-releasing hormone)

The ending -relin indicates a hypothalamus-related hormone.

1. Mechanism of action

• Causes rapid elevation of growth hormone in the blood

2. Uses

a. Assessment of responsiveness

b. Treatment of growth hormone deficiency

B. Somatostatin (growth hormone-inhibiting hormone)

1. Octreotide

• Synthetic analogue used as a drug

2. Mechanism of action

a. Inhibits release of pituitary hormones

b. Inhibits the release of gastrointestinal hormones

3. Uses

a. Symptomatic treatment of hormone-secreting tumors

(1) Pituitary tumors

(2) Carcinoid tumors

(3) Insulinomas

(4) Vasoactive intestinal peptide tumors (VIPomas)

(5) Glucagonoma

(6) Zollinger-Ellison (ZE) syndrome

Octreotide used to treat various peptide secreting tumors; pituitary tumors, carcinoid tumors, insulinomas, vasoactive intestinal peptide tumors (VIPomas), ZE, glucagonoma

b. Esophageal varices

• Octreotide reduces portal vein blood flow

4. Adverse effects

a. Abdominal pain

b. Diarrhea

c. Nausea and vomiting

C. Protirelin (thyrotropin-releasing hormone; TRH)

1. Mechanism of action

• Stimulates synthesis and release of thyrotropin and prolactin from the anterior pituitary

2. Uses

a. Assessment of thyroid function in patients with pituitary or hypothalamic dysfunction

b. Detection of defective control of prolactin secretion

TRH levels are useful in diagnosing thyroid and prolactin disorders.

D. Corticotropin-releasing hormone (CRH; corticorelin)

1. Mechanism of action

• Stimulates release of corticotropin and β-endorphin from the anterior pituitary

2. Uses

a. Diagnostic test in distinguishing causes of Cushing’s syndrome (pituitary, ectopic, adrenal)

(1) Further increase in plasma adrenocorticotropic hormone (ACTH) in pituitary Cushing’s

(2) No effect in ectopic Cushing’s (tumor production of ACTH)

(3) ACTH is suppressed due to increase cortisol production in adrenal Cushing’s.

b. Differentiate hypothalamic from pituitary dysfunction as a cause of hypocortisolism

• Delayed increase in plasma ACTH with hypothalamic dysfunction but no increase with hypopituitarism

CRH levels are useful in diagnosing adrenocorticoid disorders.

E. Gonadotropin-releasing hormone (GnRH)-related preparations

2. Mechanism of action

a. Stimulate secretion of follicle-stimulating hormone (FSH) and luteinizing hormone (LH)

• Pulsatile intravenous administration every 1 to 4 hours

b. Inhibit gonadotropin release

• Continuous administration of longer-lasting synthetic analogues

Pulsatile administration of GnRH increases but continuous administration inhibits gonadotropin release from pituitary.

3. Uses

a. Shorter-acting preparations (gonadorelin)

(1) Treatment of delayed puberty

(2) Induction of ovulation in women with hypothalamic amenorrhea

(3) Stimulation of spermatogenesis in men with hypogonadotropic hypogonadism (infertility)

b. Longer-acting GnRH analogues

(2) Suppression of FSH and LH in polycystic ovary syndrome

(3) Endometriosis

(4) Precocious puberty

(5) Prostate cancer

(6) Leuprolide for anemia caused by uterine leiomyomata (fibroids)

(7) Breast cancer, premenopausal ovarian ablation (unlabeled use of leuprolide)

GnRH analogues used to treat both prostate and breast cancer.

GnRH analogues produce a transient initial increase of testosterone levels, prevented by concomitant flutamide

c. Stimulation test to distinguish hypothalamic from pituitary dysfunction in patients with decreased FSH and LH

(1) No increase in serum FSH and LH in pituitary dysfunction (e.g., hypopituitarism)

(2) Delayed increase in serum FSH and LH in hypothalamic dysfunction (e.g., Kallmann’s syndrome)

4. Adverse effects

a. Menopausal symptoms

b. Amenorrhea

c. Testicular atrophy

(1) To prevent premature surges of LH during controlled ovarian hyperstimulation

GnRH antagonists are now available to prevent ovulation until the follicles are of adequate size.

(2) May be effective in endometriosis, uterine fibrinoids in women, and prostate cancer in men.

F. Therapeutic summary of selected hypothalamic hormone related drugs (Table 23-2)

III. Anterior Pituitary Hormones and Related Drugs (Box 23-2)

TABLE 23-2 Therapeutic Summary of Selected Hypothalamic Hormone Related Drugs

Drugs that end in -tropin are related to the pituitary hormones.

A. Growth hormone-related preparations

1. Physiology (Fig. 23-2)

a. Human growth hormone (GH)

(1) Stimulates normal growth in children and adolescents

(2) Controls metabolism in adults

(3) Stimulates uptake of amino acids in muscle

(4) Stimulates erythropoietin (increases red blood cell mass)

(5) Has insulin-like and diabetogenic effects (stimulates gluconeogenesis)

(6) Enhances transmucosal transport of water, electrolytes, and nutrients across the gut

(7) Stimulates the liver to secrete insulin-like growth factor-1 (IGF-1); anabolic actions include:

• Stimulates growth of bone (linear, lateral), cartilage, soft tissue, and organs

2. Pathology

a. Disorders of excess of GH

(1) Gigantism (before puberty)

(2) Acromegaly (after fusion of epiphyseal plates of the long bones)

23-2 Physiologic actions of growth hormone. GH, growth hormone; GHRH, growth hormone-releasing hormone; IGF, insulin-like growth factor.

(From Brown TA: Rapid Review Physiology. Philadelphia, Mosby, 2007, Figure 3-17.)

Don’t administer growth hormone products to children after epiphyseal plate closure.

b. Disorders of deficiency of GH

• Dwarfism

Excess growth hormone production results in gigantism and acromegaly; deficiency results in dwarfism.

3. Pharmacology

a. Somatropin

• Recombinant human growth hormone (rhGH)

(1) Mechanism of action

(a) Increase production of somatomedins, such as IGF-1, in the liver and other tissues

Growth hormone increases production of IGF-1.

(b) Oppose the actions of insulin

(2) Uses in children with growth failure:

(a) Inadequate endogenous growth hormone secretion

(b) Born small for gestational age and who fail to manifest catch-up growth by 2 years of age

(3) Uses in children with short stature; examples include:

(a) Turner syndrome

(b) Noonan syndrome

(d) Homeobox gene (SHOX) deficiency

(4) Used in children with Prader-Willi syndrome

Growth hormone has been misused by athletes.

(5) Uses in adults:

(a) HIV patients with wasting or cachexia with concomitant antiviral therapy

(b) Endogenous growth hormone deficiency who meet appropriate criteria

• Malabsorption due to surgical removal of small bowel

(6) Adverse effects

(a) Arthralgia

(b) Edema

(d) Adverse effects are less in children than adults.

• Only use synthetic GH (Creutzfeldt-Jakob disease resulted from the use of cadaveric GH).

b. Mecasermin

(1) Mechanism of action

• IGF-1 produced by using recombinant DNA technology

Mecasermin is a recombinant IGF-1 product that promotes growth.

(2) Uses

(a) Growth failure in children with severe primary IGF-1 deficiency

(b) Treatment of patients with GH gene deletions who have developed neutralizing antibodies to GH

(3) Adverse effects

(a) Cardiac murmur

(b) Hyper/hypoglycemia

c. Pegvisomant

(1) Mechanism of action

(a) A protein of recombinant DNA origin covalently bound to polyethylene glycol (PEG) polymers

(b) GH analogue that selectively binds GH receptors

• Blocks the binding of endogenous GH

• Leads to decreased serum concentrations of IGF-1 and other GH-responsive proteins

Pegvisomant is a GH antagonist useful in the treatment of acromegaly.

(2) Use

• Acromegaly (patients resistant to or unable to tolerate other therapies)

(3) Adverse effects

(a) Pain

(b) Abnormal liver function tests

B. Thyrotropin (thyroid-stimulating hormone; TSH)

1. Mechanism of action

a. Stimulates growth of thyroid gland

b. Stimulates the synthesis and release of thyroid hormones

2. Use

a. Diagnosis of hypothyroidism

(1) Increased in primary hypothyroidism

(2) Decreased in secondary hypothyroidism

b. Diagnosis of thyrotoxicosis (decreased)

TSH kevels are the best indicator of thyroid status.

C. Adrenocorticotropin (ACTH; corticotropin)-related preparations

1. Examples

a. Corticotropin

b. Cosyntropin

2. Regulation of secretion

a. ACTH levels undergo daily cyclic changes (circadian rhythms).

b. Peak plasma levels (6:00 AM); lowest levels occur about midnight (see Fig. 23-7)

23-7 Diurnal secretion of adrenocorticotropic hormone and cortisol. ACTH, adrenocorticotropic hormone.

(From Brown TA: Rapid Review Physiology. Philadelphia, Mosby, 2007, Figure 3-6.)

ACTH and glucocorticoid levels undergo daily circadian changes.

c. Stress increases the release of ACTH.

Stress markedly affects multiple hormonal systems.

3. Mechanism of action

a. Stimulate growth of the adrenal gland

b. Stimulate the production and release adrenocorticoids from adrenal glands

(1) Glucocorticoids

• 11-Deoxycortisol and cortisol

(2) Mineralocorticoids

• All mineralocorticoids except aldosterone, which requires angiotensin II conversion of corticosterone to aldosterone

(3) Androgens

(a) 17-Ketosteroids dehydroepiandrosterone and androstenedione

(b) Testosterone and dihydrotestosterone (peripheral conversion by 5-α-reductase)

4. Used to differentiate between adrenocortical insufficiencies

a. Primary (adrenal malfunction)

• ACTH is increased

b. Secondary (pituitary malfunction)

• ACTH is decreased

5. Adverse effects (corticotropin or glucocorticoids) known as Cushing’s syndrome

ACTH and glucocorticoids cause iatrogenic Cushing’s syndrome.

a. General

(1) Weight gain

(2) Cushing’s appearance (“moon face”)

Patients with Cushing’s syndrome can be recognized by their appearance: “moon facies” and “buffalo hump.”

(3) Growth retardation (children)

(1) Diabetes mellitus

(2) Peptic ulcer disease

(3) Psychosis

(4) Decreased resistance to infection

D. Follicle-stimulating hormone (FSH)

a. Urofollitropin is a preparation of

• Highly purified FSH extracted from the urine of postmenopausal women

b. Follitropin alfa and follitropin beta

• Recombinant preparations of FSH

3. Mechanism of action

a. Stimulates ovarian follicle growth (females)

• Also stimulates granulosa cell synthesis of aromatase for conversion of testosterone synthesized in the theca interna to estradiol.

b. Stimulates spermatogenesis (males)

4. Uses

a. Infertility

Multiple preparations with FSH, LH, or both activities are available to use in programs designed to increase fertility.

b. Polycystic ovarian syndrome

5. Adverse effects

a. Multiple births

b. Ovarian enlargement

E. Luteinizing hormone (LH)

1. Examples and sources

a. Menotropins

• Extracted from urine of postmenopausal women (both FSH and LH activity)

b. Chorionic gonadotropin (human)

• LH obtained from the urine of pregnant women

c. Chorionic gonadotropin (recombinant)

• LH analogue produced by recombinant DNA techniques

d. Lutropin alfa

• LH prepared using Chinese hamster cell ovaries

2. Mechanism of action

a. Increases follicular estradiol secretion

b. Required for FSH induced follicular development

Preparations containing FSH and LH activity are used in various fertility paradigms.

3. Uses

a. Menotropins

(1) In conjunction with chorionic gonadotropins (human) to induce ovulation and pregnancy in infertile women

(2) Stimulation of multiple follicle development in ovulatory patients as part of an assisted reproductive technology (ART)

(3) Stimulation of spermatogenesis in primary or secondary hypogonadotropic hypogonadism in males

b. Lutropin

(1) Stimulation of follicular development in infertile hypogonadotropic hypogonadal women with profound LH deficiency

(2) Given in combination with follitropin alfa

c. Chorionic gonadotropin (recombinant)

(1) As part of an ART program, induces ovulation in infertile females who have been pretreated with FSH

(2) To induces ovulation and pregnancy in infertile females when the cause of infertility is functional

F. Prolactin and related preparations

1. Prolactin

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Tags: Rapid Review Pharmacology

Apr 8, 2017 | Posted by admin in PHARMACY | Comments Off

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