Endocrine Pharmacology


Hormones are natural secretions of endocrine glands that can exert powerful effects on other cells/tissues. Compounds that produce hormonelike effects have important therapeutic uses for the treatment of endocrine hypofunction. Compounds that inhibit the hormone synthesis or blocking receptors can be used for the treatment of endocrine hyperfunction.

A. Overview of basic information
1. Mechanism of action. Many hormones effect signal transduction through one of four major mechanisms. For detailed information, see Chapter 1, III A 3.
a. GTP-binding proteins (G-proteins) in the plasma membrane: Gs, Gi/o, and Gq.

b. Tyrosine kinase
(1) Receptors with tyrosine kinase activity.

(2) Cystosolic tyrosine kinase.

c. Guanylyl cyclase.

d. Intracellular receptors.

2. Pharmacokinetics
a. Polypeptides and proteins
(1) Absorption. They are destroyed in the GI tract following oral administration, thus they should not be administered via this route. They are well absorbed from the injection sites.

(2) Fate
(a) Distribution. They are evenly distributed in the body. In general, they do not penetrate the blood–brain barrier (BBB).

(b) Metabolism. They are usually rapidly metabolized in the liver and kidney by proteases. Despite their short plasma t½ (5–20 minutes), their biological actions usually last several hours.

(c) Excretion. Very little is excreted in the urine or feces, if any.

b. Glycoproteins
(1) Absorption. They are destroyed in the GI tract following oral administration. They are well absorbed from the injection sites.

(2) Fate
(a) Distribution. They are evenly distributed in the body. In general, they do not penetrate the BBB.

(b) Metabolism. They are slowly metabolized by the liver and kidneys. In general, the more carbohydrates in the chemical structure, the more resistant the compound is to metabolism. The plasma t½ ranges from 1 to 24 hours.

(c) Excretion. They are usually not detectable in the urine or feces following parenteral administration.

c. Steroids and thyroid hormones
(1) Absorption. They are well absorbed from the gut following oral administration. However, because the natural steroids are rapidly metabolized by the liver following oral administration, only thyroid hormones and synthetic steroids that are resistant to liver enzymes can be effectively administered orally.

(2) Fate. At least 90% of the circulating steroids and thyroid hormones are bound to plasma-binding proteins (albumin and specific globulins) and are evenly distributed throughout the body, including CNS. Because they are protected by plasma proteins, they have much longer t½ (hours to days) than polypeptide and protein hormones.

(3) Excretion. When steroids and thyroid hormones are metabolized, they are hydroxylated and then undergo conjugation to form glucuronides and sulfates, which are water-soluble and thus are readily excreted into the urine and feces.


A. Anterior pituitary disorders
1. Hypopituitarism (pituitary dwarfism)

2. Acquired growth hormone (GH) deficiency

3. Neoplasia (functional and nonfunctional)

4. Hypersecretion of pituitary hormones
a. Acromegaly results from excess of GH.

b. Cushing’s syndrome (hyperadrenocorticism) results from excess of ACTH.

c. Galactorrhea results from excess of prolactin.

B. Posterior pituitary disorders. Diabetes insipidus results from vasopressin deficiency or vasopressin receptor abnormality.

C. Thyroid disorders
1. Hypothyroidism is usually seen in dogs and horses, which can be treated with thyroid hormones. Overzealous treatment of feline hyperthyroidism can cause this disorder as well.

2. Hyperthyroidism is usually seen in cats. Hyperthyroidism in species other than cats is frequently caused by adenocarcinoma, and the prognosis in these animals is usually poor. Thus, antithyroid agents are only recommended for cats.

D. Parathyroid disorders
1. Hypoparathyroidism leads to hypocalcemia, which is characterized by neuromuscular dysfunction (tetany and paresis), bradycardia, and convulsions.

2. Hyperparathyrodism causes hypercalcemia, which has renal, skeletal, GI, and neurological ramifications.

E. Adrenal dysfunction
1. Hypoadrenocorticism (Addison’s disease) is usually the result of primary insufficiency, usually due to autoimmune disorder. Secondary insufficiency, due to a decrease in ACTH secretion, can occur as well.

2. Hyperadrenocorticism (Cushing’s syndrome) is usually the result of overproduction of ACTH. The neoplasm of the adrenal cortex can cause this disorder as well.

3. Pheochromocytoma causes excessive production of catecholamines, resulting in hypertension.

F. Disorders of endocrine pancreas
1. Hyperglycemia. Diabetes mellitus is the most common cause.

2. Hypoglycemia (hyperinsulinemia) may be caused by insulin overdose or insulinoma.

G. Gonadal dysfunction results in hypogonadism and ovarian cystic disorders (e.g., follicular cysts and luteal cysts).

FIGURE 12-1. Mechanism of action of growth hormone (GH). The GH receptor has single subunits that contain both GH-binding and signaling domains. These receptors are associated with Janus kinase (JAK), a cytosolic form of tyrosine kinase. Upon activation and dimerization of GH receptors, 2 JAKs undergo reciprocal phosphorylation, which further attracts signal transduction and activation of transcription-2 (STAT2) proteins. The homodimer of STAT2 binds to DNA and stimulates gene transcription.



A. Growth hormone is a protein molecule containing 191 amino acids. Because it resembles prolactin and placental lactogen in structure, these three proteins may be evolved from a common ancestral cell. Their function may overlap as well.
1. Synthesis and secretion. GH is produced and secreted by somatotrope of the pituitary gland. Production of GH is under hypothalamic control; it is stimulated by GH-releasing hormone (GHRH) and ghrelin and inhibited by somatostatin.

2. Preparations. Sometribove [bovine somatotropin (BST)] is a prolonged-release injectable formulation of a recombinant DNA-derived BST analog.

3. Mechanism of action (Figure 12-1). GH activates Janus kinase (JAK2)-signal transduction and activation of transcription (STAT) pathway, which leads to an increase in transcription and protein synthesis. GH also stimulates the secretion of insulinlike growth factor-1 (IGF-1, somatomedin) from the liver, which in turn participates in some of the effects of GH (e.g., growth, cartilage, protein metabolism).

4. Pharmacologic effects. GH promotes growth of all tissues of body that are capable of growing, including bone, muscle, and mammary gland. GH promotes the growth of epiphyseal plate, which is essential for long bone growth. The following are additional effects of GH:
a. It increases uptake of amino acids into cells and promotes lipolysis.

b. It increases milk production, probably due to proliferation of the pituitary gland and prolactin-like activities.

5. Therapeutic uses. Sometribove (Posilac®) is used in cattle to promote milk production.

6. Administration. It is injected SC (500 mg) once every 2 weeks, beginning at ninth week after calving and until the end of lactation period.

7. Pharmacokinetics. GH is metabolized in the liver and kidney; the unformulated GH has an elimination t½ of < 20 minutes (see I A 2 for general information). However, Sometribove is in the slow release form, which can last > 2 weeks.

8. Adverse effects
a. Injection site irritation, swelling, and lameness.

b. Anorexia and weight loss.

c. Mastitis and hypogalactia.

d. Reduced pregnancy rate, due to cystic ovaries and/or uterine disorders, and abortion.

e. Short gestation periods, decreased birth weights, and increased rates of twinning and placental retention.

B. Corticotropin, corticosteroids, and inhibitors
1. General considerations
a. The adrenal cortex serves as a homeostatic organ, regulating reactions to stress.

b. Corticosteroid pathway. The release of adrenal corticosteroids is controlled by a pathway that includes the CNS.
(1) A number of stimuli, including trauma, chemicals, diurnal rhythms, and stress, can cause the hypothalamus to release corticotrophin-releasing hormone (CRH).

(2) CRH moves down the hypophyseal portal system and stimulates the anterior pituitary gland to release ACTH. CRH receptors are coupled to Gq.

(3) ACTH stimulates the adrenal cortex to produce corticosteroids.
(a) Endogenous glucocorticoids include cortisol and corticosterone.

(b) Endogenous mineralocorticoids
i. Deoxycorticosterone is produced by the adrenal cortex in response to ACTH stimulation.

ii. Aldosterone secretion is stimulated by high plasma angiotensiin, ACTH, or K+ concentrations.

(4) A negative feedback pathway maintains homeostasis. When the levels of endogenous corticosteroids increase, the hypothalamus–pituitary–adrenal axis is suppressed and the production of CRH and ACTH is decreased.

2. ACTH is a polypeptide hormone consisting of 39 amino acids.
a. Preparations. Synthetic ACTH [ACTH (124)] possesses the biological activity of ACTH and is identical for all species.

b. Mechanism of action. ACTH receptors are coupled to the Gs-adenylyl cyclase system.

c. Therapeutic uses. ACTH is used mainly as a diagnostic tool for distinguishing the two types of adrenal insufficiency.
(1) Primary adrenal insufficiency. IM administration of ACTH produces little or no increase in cortisol secretion because of the underlying adrenal cortical dysfunction.

(2) Secondary adrenal insufficiency (i.e., anterior pituitary dysfunction). ACTH administration may or may not produce large increase in cortisol secretion, depending on the status of the adrenal cortex; if the cortex is atrophied, ACTH would not evoke a pronounced increase in cortisol secretion.

d. Pharmacokinetics. See I A 2 for general information.

e. Adverse effects. ACTH (1–24) is safe when used as directed.

3. Corticosteroids
a. Chemistry. The general structure of corticosteroids is shown in Figure 12-2.

b. Physiological and pharmacological effects
(1) Glucocorticoids
(a) Effects on intermediary metabolism. Glucocorticoids increase liver glycogen synthesis and storage, gluconeogenesis, and lipolysis and redistribution of lipids.
i. The increased gluconeogensis can lead to hyperglycemia and liver glycogen synthesis.

ii. Hyperglycemia should trigger insulin secretion, which would bring plasma glucose concentrations to the normal range. However, diabetic and diabetes-prone patients would not be able to handle glucocorticoid-induced hyperglycemia.

iii. Chronic administration of a glucocorticoid may further damage β-cells.

iv. Glucocorticoids do not promote glycogenolysis.

v. Glucocorticoids increase protein breakdown. The amino acids generated can be used for gluconeogenesis and liver protein synthesis.

(b) CNS effects. Glucocorticoids may stimulate the CNS, leading to euphoria. CNS depression is associated with the deficiency (hypoadrenocorticism). However, the mechanisms underlying CNS effects of glucocorticoids are not well understood.

(c) Cardiovascular effects
i. Glucocorticoids increase vasomotor responses and myocardial contractions.

ii. Glucocorticoids increase epinephrine synthesis by increasing the expression of phenylethanolamine N-methyl transferase activity.

iii. Glucocorticoids increase the expression of α-adrenergic receptors in the vascular smooth muscle and β-adrenergic receptors in the myocardium.

iv. Glucocortioids facilitate the angiotensin system by increasing expression of angiotensinogen, angiotensin converting enzyme (ACE), and angiotensin II receptors. v. Glucocorticoids promote breakdown of bradykinin by increasing the expression of ACE and neutral endopeptidase.

vi. Glucocorticoids decrease capillary permeability (decongestion).

(d) Respiratory effects
i. Glucocorticoids cause bronchodilation by increasing expression of β2-receptors

ii. Glucocorticoids decrease the retention of mast cells in the respiratory tract and decrease the expression of autacoids, for example, histamine and bradykinin.

iii. Glucocorticoids induce decongestion of the airway (see cardiovascular effects).

(e) Skeletal muscle effects. At physiologic doses, glucocorticoids maintain skeletal muscle function; deficiency causes weakness due to hypoglycemia and poor circulation.

Long-term administration of high doses of glucocorticoids may cause wasting of muscle mass (due to muscle protein breakdown).

(f) Effects on blood cells and lymphoid tissue. Glucocorticoids increase number of circulatory erythrocytes, neutrophils, monocytes, and platelets, while decreasing number of circulatory lymphocytes, eosinophils, and basophils. Glucocorticoids decrease the size of lymph nodes and thymus.
i. Polycythemia results from decreased phagocytosis of erythrocytes.

ii. Neutrophilia results from increased entry of neutrophils into the circulation, combined with decreased removal of cells from the circulation. The function of neutrophils, however, is suppressed.

iii. Eosinopenia, basophilia, and lymphocytopenia result from redistribution of these cells to systems other than blood.

iv. Apoptosis of lymphocytes may be induced by glucocorticoids.

v. Production of interleukens (ILs) by macrophages and T-lymphocytes is inhibited; as a result, proliferation of B-lymphocytes and production of immunoglobulins, and activation of T-lymphocytes are suppressed. Phagocytosis activity of macrophages is also suppressed.

(g) Immunological effects
i. Too little or too much of glucocorticoids can increase susceptibility to infection.

ii. Glucocorticoids can treat lesions that result from excessive immune reactions; for example, urticaria (humoral immunity) and rejection of transplantation (cellular immunity). iii. Glucocorticoid-induced suppression of immunity may be attributable to decreased cytokine production, which can have very serious consequences in animals, particularly exotic birds. iv. Involution of the lymph nodes, thymus, and spleen occurs. (h) Anti-inflammatory and anti-allergic effects occur with pharmacologic doses. Glucocorticoids suppress inflammatory processes in response to multiple inciting events. Glucocorticoids do not address underlying cause of the inflammatory disorders. Anti-inflammatory effects of glucocorticoids are linked to suppression of immune responses. The glucocorticoid-induced anti-inflammation is of enormous clinical utility. i. Leukocyte migration and function are suppressed, which are due to decreased expression of chemoattractive factors (e.g., IL-8) and adhesion factors. ii. Plasma and lysosomal membranes are stabilized, resulting in decreased release of proteolytic enzymes and autacoids; the latter effect can lead to decreased capillary permeability. This membrane-stabilizing effect is attributed to a decrease in phospholipase A2(PLA2) activity. PLA2 converts phospholipids into arachidonic acid, which is a precursor of eicosanoids (see Chapter 3 for more information).

iii. Synthesis of prostaglandins and leukotriene (eicosanoids) is suppressed as a result of inhibition of PLA2.

iv. Fibroblast activity, collagen synthesis, and tissue repair are reduced in inflamed areas.

v. The hair and skin growth is inhibited.

(2) Mineralocorticoids. They increase reabsorption of sodium and bicarbonate in exchange for excretion of potassium, proton, and chloride in the renal tubules and, to a lesser extent, in the GI tract (see Figure 9-4). The following events are associated with the changes of these electrolytes:
(a) Hypernatremia increased blood pressure.

(b) Hypokalemia decreases excitability of nerves and skeletal muscle and smooth muscle.

(c) Hypokalemia increases excitability of cardiac muscle. Hypokalemia causes a poor exchange with intracellular Na+ by Na+, K+-ATPase, resulting in retention of Na+ in myocardium. Increased myocardial Na+ concentration promotes Ca2+ influx via Na+–Ca2+ antiport. Increased myocardial Ca2+ concentration increases myocardial contractility (see Figure 8-2).

c. Mechanism of action. Like other steroid hormones, corticosteroids act by altering mRNA synthesis (Figure 12-3). For example, glucocorticoids increase mRNA synthesis of adrenergic receptors; enzymes for breaking down bradykinin, for example, ACE and neutral endopeptidase; enzymes in gluconeogenesis, while decreasing mRNA synthesis of cytokines and their receptors, PLA2, and cyclooxygenase (COX).

Aldosterone increases the mRNA synthesis of Na+ channels, K+ channels, and H+-ATPase (in the apical side) and Na+, K+-ATPase, and img an-tiport in the distal renal tubule (see Figure 9-4), and intestine.

d. Pharmacokinetics.
(1) Absorption. Corticosteroids are readily absorbed from the GI tract, mucous membranes, and skin.

(2) Fate. The majority of corticosteroids are bound by plasma proteins (corticosteroid-binding globulin and albumin).

(3) Metabolism
(a) The C3 keto group is reduced to an –OH group, which then undergoes conjugation.

(b) Reduction of the C11 keto group to an –OH group is necessary to convert cortisone to cortisol (hydrocortisone) and prednisone to prednisolone, these are biologically active forms.

(4) Excretion. The conjugates are excreted by the kidneys.

e. Preparations
(1) Depending on duration of action, corticosteroids can be classified as short-acting (biological t½ of ≤12 hours), intermediate-acting (biological t½ of 12–36 hours), and long-acting preparations (biological t½ of 36–72 hours). See Table 12-1.

(2) For injectable preparations, corticosteroids can be water-soluble or water-insoluble (suspension). Water-soluble injectables are in phosphate or succinate form, or dissolved in polyethylene glycol. These preparations can be administered IV, IM, or SC. Water-insoluble injectables are in acetate, pivalate, or acetonide form. These preparations can be administered IM or SC, but not IV (to avoid embolism). IM or SC administration of suspensions can attain duration of action of the corticosteroid up to 3 weeks.

f. Therapeutic uses
(1) Glucocorticoids
(a) Short-acting drugs (see Table 12-1) are available without prescription for topical use to treat pruritus and inflammation associated with allergy.

(b) Intermediate-acting drugs (see Table 12-1) are used for long-term control of allergy, chronic inflammation (e.g., arthritis), and immunosuppression. They can be used orally in the manner of alternate-day therapy.

(c) Long-acting drugs (see Table 12-1)
i. Long-acting drugs are used for the immediate relief of hypersensitivity and shock (particularly hemorrhagic and septic shock) and the long-term control of allergy in cats. They are used topically to treat pruritus and inflammation associated with allergy. In addition to the ones listed in Table 12-1, potent glucocorticoids, for example, mometasone and flucinolone are also used topically.

ii. They may be used to induce parturition.

iii. Isoflupredone is used to treat ketosis in cattle.

(2) Mineralocorticoids
(a) Aldosterone is not available as a pharmacologic agent because of its short duration of action, particularly when it is administered orally.

(b) Deoxycorticosterone and fludrocortisone are used in the replacement therapy for hypoadrenocorticism. Deoxycorticosterone pivalate (DOCP, Percorten®-V) is used for mineralocorticoid replacement at 2.2 mg/kg, IM, once every 25 days). Fludrocortisone has high mineralocorticoid and glucocorticoid potency; thus, it is the preferred drug for the treatment of hypoadrenocorticism. Fludrocortisone acetate is administered orally at a dose of 0.01 mg/kg, once a day or twice a day as the initial dose. The subsequent doses should be adjusted according to the need.

g. Administration
(1) Oral. All synthetic corticosteroids can be administered orally. Alternate-day oral administration of an intermediate-acting drug helps reduce the inhibition of ACTH secretion. The natural products (hydrocortisone, deoxycorticosterone) should not be administered orally, because they are quickly metabolized by the liver via enterohepatic circulation.

(2) IV. Water-soluble drugs (e.g., the succinate, phosphate), and polyethylene glycol form), may be given IV.

(3) IM administration of steroids, particularly aqueous suspension [e.g., deoxycorticosterone pivalate, methylprednisolone acetate (DepoMedrol®)], may be performed at weekly intervals for chronic use.

(4) Topical. Water-insoluble drugs are available in water suspension, cream and ointment forms.

h. Adverse effects
(1) Iatrogenic hypoadrenocorticism may follow withdrawal from long-term use of high doses due to a decrease in ACTH secretion.

(2) Toxic effects following continued use of high doses are extensions of the pharmacologic effects and include
(a) Decreased wound healing.

(b) Increased susceptibility to infection.

(c) Fluid and electrolyte imbalance.

(d) Myopathy.

(e) Osteoporosis is due to decreased calcium absorption from the GI tract and reabsorption from the kidneys. The slight decrease in plasma Ca2+ concentration, sends a signal to the parathyroid gland to increase parathyroid hormone secretion, which promotes bone resorption. Also, glucocorticoids inhibit bone formation by decreasing osteoblast activity.

(f) Edema (from increased Na+ retention).

(g) Congestive heart failure in cats.

(h) Thrombosis (due to increase in platelets in the blood).

(i) Hepatotoxicity in dogs, which is manifested by micronodular cirrhosis and hepatomegaly.

(j) GI ulceration.

(k) Diabetes mellitus, particularly when used chronically in animals that already have mild diabetes.

(l) Abortion in late pregnancy.

(m) Laminitis in horses due to vasoconstriction of venules.

i. Contraindications include uncontrolled infections, diabetes mellitus, corneal ulcers, cardiac disorders, burns, and pregnancy.

4. Adrenal steroid inhibitors a. Mitotane (o,p’-DDD)
(1) Chemistry. Mitotane is related to DDT, an insecticide. It is a highly lipophilic drug.

(2) Mechanism of action. Its mechanism of action is not understood. Mitotane is cytotoxic to zonae fasciculata and reticularis of the adrenal cortex, which secrete all endogenous steroids except aldosterone. Zona glomerulosa, which secretes aldosterone, is not affected by mitotane.

(3) Pharmacokinetics
(a) Absorption of mitotane through the GI tract is variable, since it is a lipid-soluble drug. The GI absorption can be enhanced by giving the drug with food (especially high in oil/fat content) to increase bile secretion, which will help dissolve mitotane to increase absorption. Distribution of the drug occurs to virtually all tissues in the body. The drug is stored in the fat and does not accumulate in the adrenal glands.

(b) Mitotane has a very long plasma t½ (in humans), ranging from 18 to 159 days. The drug is metabolized in the liver and is excreted as metabolites in the urine and bile. Approximately 15% of an oral dose is excreted in the bile, and 10% in the urine within 24 hours of dosing.

(4) Therapeutic uses include hyperadrenocorticism (Cushing’s syndrome) and adrenal adenoma and carcinoma.

(5) Administration. Mitotane is administered orally (25 mg/kg, twice daily for 10–14 days, followed by 25–50 mg/kg, once per week).

(6) Adverse effects
(a) Animals may show lethargy, ataxia, weakness, anorexia, vomiting, or diarrhea, attributable to lowered corticosteroid secretion.

(b) Hepatotoxicity (i.e., congestion, centrolobular atrophy, and fatty degeneration) may be seen.

(c) Mitotane-induced hypoadrenocorticism may occur.
i. In ~5% of dogs treated with mitotane, fludrocortisone may be needed as the replacement therapy.

ii. All animals treated with mitotane should receive glucocorticoid supplementation when undergoing stress.

b. Ketoconazole inhibits adrenal steroidogenesis and is used to treat hypera-drenocorticism in dogs that is resistant to mitotane. It is also used as a palliative therapy in dogs with large, malignant, or invasive tumors and in whom surgery is not an option. The recommended dose is 15 mg/kg, twice daily for as long as necessary. The inhibition of steroid synthesis by ketoconazole is reversible.
(1) Mechanism of action. Ketoconazole inhibits cytochrome P450 enzymes that are involved in steroid synthesis (see also Chapter 15).

(2) Pharmacokinetics
(a) Since ketoconazole has a low pKa of 2.9, oral bioavailability of the drug in dogs is highly variable. Peak serum concentrations occur between 1 and 4 hours after dosing. This wide interpatient variation may have significant clinical implications from both a toxicity and efficacy standpoint. Administration with food may increase GI absorption, since gastric acid will be secreted to increase nonionized form of the drug.

(b) Ketoconazole is > 85% bound to plasma proteins. The drug can be found in bitch’s milk.

(c) It is metabolized extensively by hepatic cytochrome P450 enzymes into several inactive metabolites. These metabolites are excreted primarily into the feces via the bile. About 13% of a given dose is excreted into the urine and only 2–4% of the drug is excreted unchanged in the urine. t½ in dogs is 1–6 hours (average 2.7 hours).

(3) Adverse effects
(a) Anorexia, vomiting, and/or diarrhea are the most common adverse effects seen with ketoconazole therapy.

(b) Hepatic toxicity consisting of cholangiohepatitis and increased liver enzymes may be seen.

(c) Reproductive disturbances may be seen while the dogs are on ketocona-zole therapy, since it inhibits the synthesis of all steroids.

(d) Ketoconazole can inhibit the metabolism of other drugs that are subjected to cytochrome P450 enzymes. Drug interaction is a very important feature of ketoconazole. For example, ketoconazole and mitotane should not be used concurrently, since the metabolism of mitotane is inhibited by ketoconazole.

(e) Avoid ketoconazole in cats, since they already have deficiency in phase I enzymes.

c. Trilostane (Vetoryl®, Desopan®, Modrenal®)
(1) Chemistry. It is a synthetic steroid analog.

(2) Mechanism of action. Trilostane is a competitive inhibitor of 3-β hydroxy-steroid dehydrogenase, and thus inhibits corticosteroid synthesis.

(3) Therapeutic uses. Trilostane is used in dogs for treatment of hyperadrenocorticism. Initial therapy is at 2–10 mg/kg, orally once a day. It can be obtained from a compounding pharmacy.

(4) Pharmacokinetics
(a) In dogs, after oral administration, trilostane is erratically absorbed (because of high lipid solubility) with peak levels occurring within 2 hours. The presence of food in the gut to stimulate bile flow should increase absorption.

(b) Trilostane is eliminated from the plasma within 18 hours of oral administration (elimination t½ = ~1 hour). Inhibition on corticosteroid production apparently last for ≤20 hours after dosing.

(c) Trilostane is metabolized in the liver to several metabolites including ketotrilostane, which is active. The hydroxylated metabolites further undergo conjugation, which will be excreted into urine and feces.

(5) Adverse effects. Lethargy, anorexia, vomiting, electrolyte abnormalities, and diarrhea. Because trilostane inhibits progesterone synthesis, it should not be used in pregnant animals. Trilostane does not affect the synthesis of estrogens or androgens.

d. Selegiline (Anipryl®)
(1) Mechanism of action. Selegiline inhibits ACTH secretion by increasing dopamine concentration around corticotrope of the anterior pituitary. Selegiline increases dopamine concentration by inhibiting the metabolism by monoamine oxidase B (MOA-B) and decreasing the reuptake of dopamine.

(2) Therapeutic uses. Selegiline is labeled for treatment of the pituitary-dependent hyperadrenocorticism in dogs, which is due to excess of ACTH secretion. However, a recent study published in the Australian Veterinary Journal (Vol. 82:272, 2004) showed that selegiline was not effective in the treatment of this disease. In addition, it is used to treat canine cognitive dysfunction syndrome (see Chapter 5 for more information). It is administered orally at 1–2 mg/kg/day.

(3) Pharmacokinetics
(a) Selegiline is absorbed rapidly and has an absolute bioavailability of ~10%. Elimination t½ is ~1 hour.

(b) Selegiline is metabolized in the liver into L-desmethylselegiline, metam-phetamine, and L-amphetamine. Each of these metabolites is active. While l-desmethylselegiline does inhibit MAO-B, the others do not, but are CNS stimulants. The drug is excreted in the urine, primarily as conjugated and unconjugated metabolites.

(4) Adverse effects. Adverse effects include vomiting and diarrhea; CNS disturbances manifested by restlessness, repetitive movements, or lethargy; and salivation and anorexia. Diminished hearing/deafness, pruritus, licking, shivers/trembles/shakes have also been reported. Selegiline has the potential to be abused by humans.

FIGURE 12-2. General structure of corticosteroids. Certain structural features relevant to activity. Positions 1 and 2: The presence of a double bond (delta group) prolongs the activity, especially gluco-corticoid activity (most synthetic glucocorticoids have this change). Position 3: The presence of keto group is essential for corticoid function. Positions 4 and 5: The presence of a delta group is essential for corticoid function. Position 6 or 9: Fluorination or methylation potentiates activity, especially glucocorticoid activity. Position 11: The presence of OH increases glucocorticoid activity; the absence of OH increases mineralocorticoid activity. The presence of the 11-keto group abolishes corticoid activity. Examples: cortisone and prednisone; thus, they need to be metabolized to cortisol and prednisolone by having the 11-OH group, respectively. Position 16: The presence of OH or methyl group increases glucocorticoid activity (many synthetic glucocorticoids have this change). Position 17: The presence of OH increases glucocorticoid activity. The presence of acetonide on position 16 or 17 further enhances and prolongs glucocorticoid activity (many synthetic glucocorticoids for topical use have this feature). (From Figure 8-1, NVMS Pharmacology.)


FIGURE 12-3. Mechanism of action of cytosolic corticosteroid receptors. The inactive receptor is surrounded by receptor-associated proteins (RAPs), for example, heat-shock proteins (HSPs). Hormone (H) binding leads to the dissociation of RAPs, and formation of dimers that penetrate into the nucleus and bind to corticosteroid-response element (CRE) of DNA to alter mRNA synthesis. Synthesis of certain mRNAs is increased, while that of others is decreased, particularly in the case of the glucocorticoid receptor. NKR, neurokinin receptor; COX-2, cyclooxygenase 2; ET-1, endothelin-1; PLA2, phospholipase A2; NOS, nitric oxide synthase; LC-1, lipocortin-1; ADR, adrenergic receptor; NEP, neutral endopeptidase; Eases, endonucleases; ACE, angiotensin-converting enzyme.


TABLE 12-1. Corticosteroids: Anti-Inflammatory and Sodium-Retaining Potencies (Oral Administration)

Corticosteroid Anti-Inflammatory Potency Sodium-Retaining Potency
Short-acting (≤12 hours)*    
   Hydrocortisone 1 1
   Cortisone 0.8 0.8
   Fludrocortisone 10 125
Intermediate-acting (12–36 hours)*    
   Prednisone 4 0.8
   Prednisolone 5 0.8
   Methylprednisolone 5 0.5
   Triamcinolone 5 0
Long-acting (36–72 hours)*    
   Paramethasone 10 0
   Betamethasone 25 0
   Dexamethasone 25 0
   Flumethasone 30 0

* Biologic half-life.

C. Gonadotropins are glycoprotein hormones
1. Synthesis, secretion, and actions
a. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are produced and secreted by the gonadotrope of the pituitary gland. Production of FSH and LH is under hypothalamic control; it is stimulated by gonadotropin-releasing hormone (GnRH). GnRH receptors are coupled to Gq and increases [Ca2+]i.
(1) In male animals, FSH increases the diameter of the seminiferous tubules and promotes spermatogenesis. LH increases testosterone synthesis from Leydig cells. Secretion of FSH and LH is rather consistent in male animals.

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May 28, 2017 | Posted by in GENERAL | Comments Off on Endocrine Pharmacology

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