Adrenal & Pituitary Gland Disorders Notes PDF (RHCHP Fall 2024)

Adrenal and Pituitary Gland Disorders RHCHP School of Pharmacy Integrated Pharmacotherapy 2 Fall 2024 Facilitators Readings & References Dan Berlau, PhD...

Adrenal and Pituitary Gland Disorders RHCHP School of Pharmacy Integrated Pharmacotherapy 2 Fall 2024 Facilitators Readings & References Dan Berlau, PhD Required [email protected] Integrated Pharmacotherapy 2 Adrenal and Pituitary Gland Disorders course notes 303-964-6178 Optional Leah Behrmann, PharmD, BCPS, BCCCP Harper’s Illustrated Biochemistry (Chapter 41, up to 1,25(OH)2-D3 (Calcitriol) is synthesized from a cholesterol derivative. [email protected] Chapter 42, up to A. Adenylyl cyclase.) 303-458-4056 Review of Medical Physiology (Chapter 14, Hypothalamus through Relation to Pituitary Gland, and Control of Anterior Pete Cogan, PhD Pituitary Secretion to Significance and Clinical Implications, Chapter 20, up to Enzyme Deficiencies. Chapter 20, [email protected] Pharmacologic & Pathologic Effects of Glucocorticoids up to Effects of Mineralocorticoids. Chapter 20, Summary of the Effects 303-964-6154 of Adrenocortical Hyper- & Hypofunction in Humans. Chapter 22, Introduction. Smith SM, Piszczatoski CR, Gums JG. Adrenal Gland Disorders. In: DiPiro JT, Yee GC, Posey L, Haines ST, Nolin TD, Ellingrod V, Posey L. eds. DiPiro;s Pharmacotherapy: A Pathophysiologic Approach, 12e. McGraw-Hill; 023. Accessed October 16, 2023. https://accesspharmacy-mhmedical-com.dml.regis.edu/content.aspx?bookid=3097&sectionid=264604996 Netter’s Illustrated Pharmacology, pages 129-131,147, 149-154 Goodman & Gilman’s The Pharmacologic Basis of Therapeutics Chapters 55 and 59 Learning Objectives 1. Describe the fundamental principles of the endocrine system. 2. Define a hormone and list the potential biological effects mediated by a hormone. 3. Contrast the structure and function of a steroid and peptide hormone. 4. Describe the three mechanisms that control synthesis and release of hormones. 5. Describe the role of positive and negative feedback systems on the endocrine system. 6. Compare and contrast the structure and function of the anterior and posterior pituitary gland. 7. Describe the function and site of production of glucocorticoids, mineralocorticoids, and gonadocorticoids. 8. Discuss the mechanisms that induce and inhibit release of ACTH and prolactin. 9. Compare the biological roles of ACTH and prolactin. 10. Describe the structure and function of the adrenal gland including the secretions specific to each of the cortex layers. 11. List the three primary endogenous steroids synthesized from cholesterol in the adrenal gland. 12. Define the biological functions of cortisol and describe its diurnal pattern. 13. Define the biological functions of aldosterone. 14. Discuss the regulation of aldosterone release. 15. Describe the pathophysiology (including causes) of Cushing’s syndrome, adrenal insufficiency, hyperaldosteronism, and hyperprolactinemia. 16. Describe the presentation of Cushing’s syndrome, adrenal insufficiency, hyperaldosteronism, and hyperprolactinemia. 17. Describe diagnostic tests for Cushing’s syndrome, adrenal insufficiency, hyperaldosteronism, and hyperprolactinemia. 18. Describe the complications of Cushing’s syndrome, adrenal insufficiency, hyperaldosteronism, and hyperprolactinemia. 19. Identify the role of corticosteroids (mineralocorticoids and glucocorticoids) for the treatment of primary and secondary Adrenal Insufficiency. 20. Define long-term (chronic) steroid use. 21. Describe chronic corticosteroid therapy’s effect on HPA axis. 22. Describe adrenal crisis and how/why it occurs. 23. Describe agents used for the treatment of Cushing’s syndrome, adrenal insufficiency, adrenal crisis, hyperaldosteronism, and hyperprolactinemia. 24. When given chemical structures, identify a drug with a corticosteroid pharmacophore. 25. Describe three clinically relevant outcomes arising from chemical modifications to the cortisol pharmacophore. 26. Explain the rationale for use of corticosteroids in the pharmacologic management of adrenal insufficiency, use of steroidogenic inhibitors in the pharmacologic management of Cushing’s syndrome, use of dopamine agonists in the pharmacologic management of hyperprolactinemia, and use of aldosterone antagonists in the management of hyperaldosteronism. 27. Identify the pharmacologic classification of cortisone, hydrocortisone, prednisone, dexamethasone, mitotane, metyrapone, ketoconazole, osilodrostat, levoketoconazole, bromocriptine, cabergoline, spironolactone, eplerenone, amiloride, and fludrocortisone. 28. Describe special administration instructions for patients given medication therapy for Cushing’s Syndrome, Adrenal Insufficiency, hyperaldosteronism, and hyperprolactinemia. 29. Compare and contrast glucocorticoids and mineralocorticoids. 30. Identify the two corticosteroids with the highest glucocorticoid activity. 31. Identify the corticosteroid with the highest mineralocorticoid activity. 32. Describe short-term and long-term adverse reactions of corticosteroids. 33. Predict, identify or explain adverse effects common to corticosteroids, dopamine agonists, steroidogenic inhibitors, aldosterone antagonists, and potassium sparing diuretics. 34. Describe the role of CYP450 enzymes in the synthesis of endogenous corticosteroids and metabolism of exogenous corticosteroids. 35. Identify and predict drug-drug interactions common to ketoconazole, levoketoconazole, corticosteroids, dopamine agonists, aldosterone antagonists, and potassium sparing diuretics. 36. Explain how the mechanism of action for ketoconazole increases the risk for drug-drug interactions and identify CYP450 isoforms affected by ketoconazole. 37. Describe and identify the drug-drug interaction between ketoconazole, levoketoconazole, and acid suppressants. 38. Be familiar with the steroid ring numbering system. 39. Be able to identify the structural features of bromocriptine and cabergoline which mimic dopamine at D2 receptors (Figure 21). 40. Be able to explain the pH dependence of the solubility of ketoconazole. 41. Be able to explain why both Cushing’s syndrome AND adrenal insufficiency are potential problems when administering corticosteroid replacement therapy. 42. Define the goals of treatment to alleviate the signs and symptoms associated with Cushing’s syndrome, Adrenal Insufficiency, hyperaldosteronism, and hyperprolactinemia. 43. Identify recommended therapy to treat Cushing’s syndrome, Adrenal Insufficiency, hyperaldosteronism, and hyperprolactinemia. 44. Identify the role in treatment of each medication used to treat Cushing’s Syndrome, Adrenal Insufficiency, hyperaldosteronism, and hyperprolactinemia. 45. Know brand and generic names of prednisone, dexamethasone, fludrocortisone, ketoconazole, spironolactone, and eplerenone. Learning Objectives for the Applications and Exam In addition to the above learning objectives, the applications and exam will cover the following objectives: Refer to all required readings, class applications, and class discussion to address the following objectives: 46. **Interpret diagnostic tests for Cushing’s syndrome, adrenal insufficiency, hyperaldosteronism, and hyperprolactinemia. 47. ** Know, identify, understand, and describe the pathophysiology, classification, pharmacotherapy, and therapeutic recommendations for adrenal and pituitary disorders. 48. ** Assess, evaluate, and apply the pathophysiology, classification, pharmacotherapy, and therapeutic recommendations for adrenal and pituitary disorders. 49. **Develop/recommend a treatment plan to treat Cushing’s Syndrome, Adrenal Insufficiency, hyperaldosteronism, and/or hyperprolactinemia. (must know: pharmacologic and non-pharmacologic recommendations, rationale for therapeutic choice including role in therapy, drug name, dose and titration regimen, frequency, route of administration, duration, side effects, monitoring parameters, drug-interactions, and other special considerations). 50. **Explain/identify why, when, and how steroid therapy must be tapered to reduce risk of adrenal crisis. 51. **Develop a treatment plan to reduce the risk of adrenal crisis in times of stress. 52. ** Use correct pronunciation of medical terminology and medication names. ** Objectives will not be covered by the RAT, but will be covered on applications and/or exams. Information presented in this unit note packet, on applications, and in discussion will help you study for the unit objectives. Applications are meant to drive home important learning points from the packet. TBL class time is limited and not all important concepts can be covered with applications; therefore, it is the student’s responsibility to ensure understanding and mastery of learning objectives. FYI (for your information): in this unit, FYI means that you do not have to memorize this information. It is used to help you understand the concepts. The faculty might use this information on applications for better understanding of the material, but it will not be tested on for the RAT or exams. INTRODUCTION TO THE ENDOCRINE SYSTEM Figure 1. Location of endocrine gland Human Anatomy and Physiology, 7th Edition, Marieb. This packet will cover four gland disorders: Cushing’s Syndrome, Adrenal Insufficiency, Hyperaldosteronism, and Hyperprolactinemia. The endocrine system regulates and coordinates many of the diverse activities of the body through the use of hormones. Endocrine glands are ductless organs which release the hormone into the surrounding area. The hormone is received by the rich vasculature and lymph drainage that surrounds the gland and is transported to the effector cells. Figure 1 indicates the location of the endocrine glands in the body. Hormones are chemical messengers/molecules released into the blood and transported throughout the body. The hormone binds to a receptor, either on the plasma membrane or intracellularly, eliciting a biological response. Lipid-soluble hormones are often derived from cholesterol (steroid hormones) and diffuse across the plasma membrane and bind to a cytosolic or nuclear receptor. Peptide hormones bind to cell surface receptors initiating an intracellular response. To maintain target cell specificity, the target cell is the only cell that expresses the specific hormone receptor. The biological response elicited by the hormone is either on the cell that released the hormone (autocrine) or on a different cell than the one that released the hormone (paracrine). The duration of the hormone response varies greatly. Hormones are either degraded by an enzyme in the target cell or metabolized by the liver or kidneys and excreted in the urine or feces (via the bile). The biological activity altered by a hormonal stimulus typically includes one or more of the following changes: Alteration of plasma membrane permeability or membrane potential through changes in ion channel activity. Stimulation of protein synthesis and/or cell division (mitosis). Regulation of the activity of molecules such as enzymes or transcription factors. Induction of synthesis and/or release of other molecules, such as hormones. There are several types of stimuli that control the synthesis and release of hormones from endocrine glands: 1. Humoral (related to molecules in blood or bodily fluids), which includes changes in blood contents such as ions and nutrients. 2. Neural (nerve fibers directly stimulating hormone release), for example when the sympathetic nervous system directly triggers the release of catecholamines from the adrenal medulla. 3. Hormonal (hormone synthesis and release) can be Figure 2. Pituitary Gland: Stimuli for synthesis and release of hormones regulated by the signaling of other hormones, referred Human Anatomy and Physiology, 7th Edition, Marieb. to as tropic hormones. These tropic hormones can be either stimulatory or inhibitory on secondary hormone release. For example, hypothalamic neurons secrete either prolactin inhibiting hormone (PIH) or prolactin releasing hormone (PRH) to inhibit or stimulate the release of prolactin from the anterior pituitary, respectively. Feedback Systems The endocrine system has controls in place to limit the amount of hormone released into the blood through a negative feedback system. Basically, the hormone released triggers some biological response that prevents further hormone release, thereby controlling hormone levels. It is important to note that positive feedback can also occur. That is, low hormone levels result in reduced inhibition leading to augmented (increased) synthesis and secretion of the hormone. Integrated Pharmacotherapy 2 3 Adrenal and Pituitary Gland Disorders ENDOCRINE ORGANS Figure 3. The hypothalamic-pituitary- adrenal (HPA) axis and control of prolactin secretion The Pituitary Gland The pituitary gland is a pea sized gland that secretes at least nine hormones. Figure 2 on page 3 Hypothalamus demonstrates the structure of the pituitary gland (and the relationship between the pituitary gland and hypothalamus). It consists of two lobes: the anterior pituitary and the posterior pituitary. The posterior pituitary is actually brain neural tissue. The hypothalamus-hypophyseal tract is a set of three nerve bundles whose nuclei reside in the hypothalamus and axons extend into the posterior PIH (DOPAMINE) CRH / PRH pituitary. The anterior pituitary is glandular tissue which manufactures and releases hormones directly into the blood. Two hormones relevant to this topic are ACTH and prolactin. Control of prolactin and ACTH release is demonstrated in Figure 3. Anterior Pituitary ACTH (Corticotropin) The hypothalamus releases corticotropin-releasing hormone (CRH), a 41 amino acid peptide, which stimulates release of adrenocorticotropic hormone (ACTH), a 39 amino acid peptide, from PROLACTIN ACTH corticotroph cells of the anterior pituitary. ACTH then travels through the circulatory system and stimulates the adrenal cortex via interaction with G-protein coupled cell surface ACTH receptors. Binding to these receptors leads to the production of cyclic-AMP, a second messenger Mammary Adrenal Gland which ultimately upregulates several enzymes involved in the synthesis of corticosteroids such Gland as glucocorticoids. The interaction between the three secretory organs involved in this process is known as the hypothalamic-pituitary-adrenal axis (HPA axis). The major glucocorticoid is cortisol and elevated levels of cortisol feedback to inhibit both CRH and ACTH release (Figure 3). The role MILK PRODUCTION CORTISOL of cortisol is explained in greater detail below. Figure 4. Microscopic structure of the adrenal gland. Prolactin Prolactin is a protein hormone synthesized and released by lactotroph cells of the anterior pituitary, and controls milk production in (but not release from) mammary glands. The release of this molecule is controlled by the hypothalamus, and is elevated in persons who are pregnant or lactating. The hypothalamus can release either inhibitory or stimulatory molecules The superficial layer is called the zona glomerulosa and releases predominantly in its control of prolactin release--PIH (prolactin- mineralocorticoids. Mineralocorticoids, primarily aldosterone, regulate electrolyte inhibiting hormone or dopamine), and PRH (e.g., Na+ and K+) and water levels in the (prolactin-releasing hormone), respectively. extracellular fluid. Figure 3 shows the mechanisms that control The middle zona fasciculata releases mostly prolactin secretion. Normally, the hypothalamus glucocorticoids, such as cortisol, which controls metabolic processes of most cells releases dopamine, which inhibits the production (e.g., regulation of fat, carbohydrate, and of prolactin in the anterior pituitary. Dopamine protein metabolism) and helps the body to resist stress. is secreted by dopaminergic neurons into The innermost cortical layer is the zona the hypothalamus, where it is absorbed by reticularis which releases predominantly capillaries that deliver it directly to the anterior adrenal sex steroids (e.g., testosterone and estradiol) and gonadocorticoids, both of pituitary. Dopamine then binds to dopamine which appear to be byproducts of cortisol receptors on lactotroph cells, inhibiting prolactin production. release. Conversely, both serotonin and estrogen are known to stimulate prolactin release. Adrenal Gland A pyramid-shaped adrenal gland sits atop each kidney. Each gland is comprised of two sections, an outer cortex and inner medulla (Figure 4). The adrenal medulla consists of neural tissue (modified post-ganglionic neurons), whereas the adrenal cortex consists of glandular tissue. The adrenal medulla is responsible for the release of catecholamines (e.g., epinephrine). The adrenal cortex releases sex hormones and two types of corticosteroids: glucocorticoids and mineralocorticoids. Integrated Pharmacotherapy 2 4 Adrenal and Pituitary Gland Disorders Cortisol Cortisol is the main glucocorticoid in humans, and is synthesized and secreted from Figure 5. CRH diurnal pattern cells in primarily the fasciculata layer of the adrenal cortex. Cortisol has a broad range of actions. It acts to maintain blood glucose levels by stimulating gluconeogenesis (synthesis of glucose). Additional actions include the elevation of cardiac function, immunosuppression, reduction of reproductive behavior and function, reduction of Ca2+ absorption, and reduction in bone density. Cortisol has a pronounced diurnal pattern (as a result of the diurnal pattern of CRH). Cortisol secretion peaks shortly before we wake in the morning and is at its lowest in the evening just before we fall asleep (Figure 5). Remember that ACTH stimulates cortisol release, and cortisol feeds back to inhibit both pituitary ACTH and hypothalamic CRH release. During times of stress, cortisol is often released outside of its diurnal pattern. It is a Figure 6. Regulation of aldosterone release highly nonpolar molecule and is transported in the blood bound to lipoprotein with a small percent of total cortisol present as free cortisol (not bound to a protein). In Low Blood Volume other words, cortisol is in the blood as an equilibrium between bound and unbound cortisol. Free cortisol is filtered by the kidneys and excreted in the urine, and is used as a laboratory test to screen for disorders in which cortisol is overproduced. Aldosterone Ang II Aldosterone is the body’s main mineralocorticoid and is released from cells in the High K+ ACTH glomerulosa layer of the adrenal cortex. Aldosterone works in many parts of the Blood Levels body, but the most important is its effect on the kidneys. The kidneys’ main function is to filter blood and to excrete that filtered solution as urine (we call this filtrate). Aldosterone activates specific cells in the kidneys (FYI: tubule cells) to increase reabsorption of sodium ions from the filtrate back into the blood. Through the Aldosterone same mechanism, aldosterone increases the secretion of potassium ions from the blood into the filtrate (which is then excreted in the urine). It is important to realize that with the reabsorption of sodium, both chloride ions and water move with sodium back into the blood. While the specific mechanism will be explained in IP 2 Hypertension 1, know that aldosterone drives sodium and water reabsorption back Potassium Sodium/Water into the bloodstream while excreting potassium in the urine. Because aldosterone Excretion Retention causes sodium and water retention, extracellular fluid volume increases in the vasculature. Release of aldosterone is regulated by three substances (Figure 6): DECREASED INCREASED POTASSIUM LEVELS BLOOD VOLUME 1. Angiotensin II (of the renin-angiotensin-aldosterone system, or RAAS, which is described below) 2. Excessive blood potassium levels 3. ACTH The RAAS is a complex enzyme system that regulates extracellular fluid volume and blood pressure, and will also be covered in detail in IP 2 Hypertension I. Briefly, in response to decreased blood volume resulting in decreased perfusion of blood to the kidneys (e.g. during times of dehydration), the kidneys work to retain fluids and increase blood volume. Specialized cells within the kidneys secrete a stored protein called renin. Renin is an enzyme, specifically a protease, that enters the blood stream and cleaves a fragment off an inactive circulating precursor protein, angiotensinogen. The result of this cleavage is angiotensin I (Ang I), which is still inactive. Located on vascular endothelium throughout the body, and enriched in lung tissue, is angiotensin-converting enzyme (ACE), which performs a second cleavage event by cutting off a couple of amino acids from Ang I. This results in formation of the active peptide angiotensin II (Ang II). Ang II is itself a potent vasoconstrictor (to be discussed in IP 2 Hypertension I), but also stimulates release of aldosterone from adrenal glomerulosa cells. In summary, dehydration causes an increase in aldosterone release, which leads to sodium and water retention and increased blood volume. An increase in blood potassium also promotes aldosterone secretion, while low levels of potassium reduce aldosterone secretion. ACTH stimulates aldosterone release from the adrenal gland, but this action is not sustained. If ACTH is elevated, it will not cause a prolonged increase in aldosterone. Aldosterone secretion will return to normal within 1-2 days in the presence of elevated ACTH. Integrated Pharmacotherapy 2 5 Adrenal and Pituitary Gland Disorders BIOSYNTHESIS OF STEROID HORMONES To facilitate an understanding of corticosteroid synthesis, it is helpful to have an appreciation of the numbering system employed on the steroid core. Figure 7 shows the four rings (A, B, C, and D) common to all steroids. Figure 8 shows the numbering system used to designate the individual carbons of the core structure, within the context of the cholesterol molecule. Following conversion of cholesterol to pregnenolone (Figure 8), and given the numbering system for the ring carbons, a simple analysis of the enzymes involved and the names of the intermediates seen in Figure 9 should suffice to clarify the structures of the various intermediate steroids prepared in the synthesis of aldosterone and cortisol. You may also notice the use of α and β as designations of the various enzymes involved in steroid biosynthesis (Figure 9). These designations refer to the two different “faces” of the core steroid structure. For simplicity, when the steroid is drawn with the 5 membered ring on the top right side of the structure, any substituent coming toward you is on the β face of the molecule, while those going away from you are on the α face of the molecule. So 11-β-hydroxylase will hydroxylate the steroid at carbon #11 and the resulting hydroxyl group will be on the β face of the molecule. Figure 8. Numbering of cholesterol and conversion to pregnenolone Figure 7. The steroid core 21 22 24 21 18 18 O 20 23 25 C D 20 12 12 17 17 11 H 11 19 13 19 13 A B 1 H 14 16 CYP11A1 1 H 14 16 9 9 2 15 2 15 10 8 10 8 H H H H 3 5 7 3 5 7 HO 4 6 HO 4 6 Cholesterol Pregnenolone Figure 9. Biosynthesis of adrenal cortical steroid hormones (HSD = hydroxysteroid dehydrogenase) H H H H H CYP11A1 HO 17-α-hydroxylase 17, 20-lyase CHOLESTEROL (CYP17) (CYP17) Pregnenolone 17-OH-Pregnenolone Dehydroepiandosterone (DHEA) 3-β-HSD 3-β-HSD 3-β-HSD 17-α-hydroxylase 17, 20-lyase (CYP17A1) (CYP17A1) Testosterone Progesterone 17-OH-Progesterone ANDROSTENEDIONE Estrogens O 21-Hydroxylase 21-Hydroxylase (CYP21) (CYP21) H H H Deoxycorticosterone 11-Deoxycortisol O 11-β-Hydroxylase 11-β-Hydroxylase (CYP11B2) (CYP11B2) Corticosterone CORTISOL O OH HO OH 18-Hydroxylase (Aldosterone Synthase) H H H ALDOSTERONE O O O OH HO H H H O Integrated Pharmacotherapy 2 6 Adrenal and Pituitary Gland Disorders The enzymes catalyzing each of the chemical conversions are located in either the smooth endoplasmic reticulum or the mitochondria. The cells of the adrenal gland, like other cells producing steroid hormones, have two sources for cholesterol: 1) circulating low-density lipoprotein (LDL), which is quantitatively the most important, and 2) de novo synthesis from acetate. Formation of pregnenolone from cholesterol is the first step in the biosynthesis of adrenocortical steroids, and is catalyzed by cholesterol desmolase (CYP11A1). This initial reaction appears to be the rate-limiting step for the overall process of synthesizing steroid hormones. Binding of ACTH to its cell surface receptors affects most of these processes by 1) increasing cellular uptake of LDL, 2) trafficking cholesterol to the mitochondria, and 3) upregulating the activity of CYP11A1. Conversion of pregnenolone to aldosterone in the adrenal zona glomerulosa requires 21-hydroxylase, 11-β-hydroxylase, and 18-hydroxylase, also known as aldosterone synthase. Aldosterone synthase is only expressed in glomerulosa cells, which is why these cells are the exclusive site for aldosterone synthesis. To form cortisol, primarily in the zona fasciculata, 17- hydroxylase, 21-hydroxylase, and 11-β-hydroxylase are required. To form sex steroids, cholesterol is converted to pregnenolone and progesterone in the zona reticularis. Progesterone is transformed into testosterone and pregnenolone is converted to dehydroepiandosterone (DHEA) and then to androstenedione and testosterone. Dysfunction of one or several of these key enzymes in steroid hormone biosynthesis can result in excessive production of other steroid products. What do you foresee would result from the underexpression of 21-hydroxylase, as occurs in congenital adrenal hyperplasia, on specific steroid hormone synthesis? Integrated Pharmacotherapy 2 7 Adrenal and Pituitary Gland Disorders  CUSHING’S SYNDROME PATHOPHYSIOLOGY Figure 10. Cushing’s syndrome presentation Cushing’s syndrome (CS), also known as hypercortisolism, results from prolonged exposure to excessive glucocorti­ coids from either exogenous (something put into the body) administration or endogenous (body makes its own) overproduction. Overproduction can occur at the level of the anterior pituitary (ACTH dependent) or the adrenal glands (ACTH independent). ACTH dependent CS is typically caused by pituitary tumors (70% of cases), and is specifically referred to as Cushing’s disease. Other causes of CS include: adrenal tumors and ectopic ACTH or CRH producing tumors. Determining the correct etiology (cause) of CS is important to managing patients with CS. If left untreated, most patients will only live 4-5 years with CS as a result of significant morbidity (complications) of disease. Hypercortisolism has been associated with increased cardiovascular risk. It contributes to developing cardiovascular risk factors including diabetes mellitus (high blood glucose), dyslipidemia (high cholesterol), hypertension, and coagulopathy (blood clotting disorders) as well as electrolyte abnormalities. Additionally, corticosteroids cause Figure 11. Cushing’s syndrome in literature osteoporosis (disease of bone loss/degradation) by inhibiting calcium absorp­ tion among other mechanisms covered later in IP. The increase in morbidity and mortality is attributed to complications related to chronic glucocorticoid excess. Figure 10 illustrates the effects excessive glucocorticoids have on the body. This is important when it comes to identifying common adverse effects of corticosteroid use! See “APPENDIX A (FYI Only)” on page 24 for presentation and differential diagnosis (alternative diagnoses) of CS. CLINICAL PRESENTATION There is no single identifying clinical feature that can be used to diagnose CS. Patients with Cushing’s syndrome can present with any number of symptoms The appearance of Tweedledee and Tweedledum, consistent with chronic glucocorticoid overexposure. Central obesity is the from Alice and Wonderland, was inspired by CS. These most common presenting symptom, occurring in over 90% of patients with characters exhibited classic signs of untreated Cushing’s CS (Figure 11). The weight is also redistributed to the face (moon face), upper including central obesity, moon face, and psychosis. This is back (buffalo hump), and abdomen. Nearly 70% of patients with CS will present an exaggeration of symptoms that will help you remember. with psychiatric symptoms such as depression, anxiety, and psychosis. Other symptoms include decreased libido, muscle weakness, hirsutism (hair growth), osteoporosis, and glucose intolerance (glucose intolerance = diabetes; FYI: up Clinical Features of Cushing’s Syndrome to 60% develop diabetes). In addition, thinning skin with purple striae (stretch Obesity or weight gain (95%) marks) is often seen in patients with CS. Hypertension is seen in up to 85% Facial plethora (90%) of patients with CS. Most CS patients meet criteria for diagnosis of metabolic Rounded face (90%) syndrome (discussed later in your curriculum, just know that they are high risk Decreased libido (90%) for cardiovascular disease). See the box at the right for a more comprehensive Thin skin (85%) list of CS symptoms. These symptoms are consistent with high cortisol consistent Decreased linear growth in children (70-80%) with CS, but also note that these are adverse effects of corticosteroid use in Menstrual irregularity (80%) general. Hypertension (75%) Since symptoms vary widely between individuals, they can only be useful Hirsutism (75%) in raising the suspicion for the presence of CS. In the absence of the above Depression / emotional lability (70%) symptoms, screening may be appropriate in patients with uncontrolled diabetes Easy bruising (65%) or in male patients with osteoporosis where there is no obvious cause. In order Glucose intolerance (60%) to confirm the diagnosis of CS and identify the underlying cause, laboratory Weakness (60%) investigation is required. Due to limitations in the specificity and sensitivity of Osteopenia /osteoporosis or fracture (50%) most laboratory tests used to diagnose CS, multiple tests are usually required for Nephrolithiasis (50%) confirmation. In addition, imaging is usually required to identify tumor location FYI: Percent of CS patients with symptom in parenthesis, and size since this is the most frequent cause of CS. In most cases, a patient you don’t have to know percentages suspected of having CS will be referred to an endocrinologist for further workup. Adapted from The Lancet 2006;367:1605-17. Integrated Pharmacotherapy 2 8 Adrenal and Pituitary Gland Disorders DIAGNOSIS When there is clinical suspicion that a patient has CS, the three most Figure 12. Typical process for diagnosis of CS commonly used diagnostic tests include measuring late-night salivary cortisol, Adapted from The Lancet 2006;367:1605-17 daily urinary free cortisol excretion, and low-dose dexamethasone suppression Clinical suspicion / Screening at-risk groups testing (DST). Late-night salivary cortisol is often used to screen for CS. Urinary free cortisol and low-dose DST are usually conducted for additional confirmation of CS. Figure 12 illustrates the typical process for diagnosing CS. In patients with CS, one of the earliest biochemical changes is a loss of Elevated urinary free cortisol (3 x 24 h collections) plasma cortisol suppression which usually reaches its nadir (lowest level) Serum cortisol > 50 nmol/L on dexamethasone-suppression test Plasma midnight cortisol: sleeping > 50 nmol/L; awake > 207 nmol/L around midnight. Multiple (often three) 11:00 p.m. salivary cortisol samples Elevated late-night salivary cortisol are collected while the patient sleeps. Salivary cortisol is highly correlated to free serum cortisol and can be easily collected at home for the convenience AS NEEDED of the patient. In the hospital setting, a midnight serum free cortisol level can Dexamethasone-CRH test be drawn. A sleeping serum (or salivary) free cortisol level > 50 nmol/L is Desmopressin test indicative of CS, while a level of < 50 nmol/L could be used to rule out CS. Another test that can be performed is the urinary free cortisol excretion test. Hypercortisolism / Cushing’s syndrome confirmed Serum cortisol levels can fluctuate intermittently in everyone, with or without CS. Therefore, it is thought that multiple (often up to 3) 24-hour measurements of urinary cortisol excretion minimizes the impact of fluctuating cortisol levels by obtaining a measurement for the entire day. Patients are instructed to collect If doubt remains then repeat and seek further options all urine output in the outpatient setting over a 24-hour period. Consistently elevated daily urinary excretion of free cortisol is highly suggestive of CS. The low-dose DST is another test used to confirm the diagnosis of CS. Dexamethasone mimics endogenous cortisol and, in healthy patients without CS, it should suppress the secretion of corticotropin (ACTH), which in turn should result in the suppression of cortisol secretion (negative feedback). The typical overnight low-dose DST consists of administration of 1mg dexamethasone orally at 11:00 p.m. and measuring serum cortisol at 9:00 a.m. the following morning. A serum concentration of greater than 50 nmol/L is supportive of the diagnosis of CS. Limitations of this test include lack of suppression due to decreased dexamethasone absorption, drugs that stimulate liver enzyme activity, and glucocorticoid resistance. Desmopressin can be used to test for CS, but it will not be discussed. It is recommended to perform 2-3 tests on separate days to confirm diagnosis. Once the diagnosis has been confirmed, additional tests and imaging must be performed to differentiate the cause. Figure 22 on page 24 (in Appendix A) illustrates the differential diagnosis of CS (do not memorize this chart; just be able to interpret it). Additional laboratory tests include high-dose (8 mg) dexamethasone suppression test, CRH stimulation test, and plasma corticotropin (ACTH) measurement. (FYI: Plasma corticotropin measurement is effective for differentiating between ACTH-dependent and ACTH-independent CS. Imaging with computed tomography (CT) and/or magnetic resonance imaging (MRI) is required to localize and size tumors of the pituitary and adrenal glands. CT and MRI of the chest and abdomen should be performed in patients with suspected ectopic corticotropin production.) THERAPEUTIC AGENTS FOR CUSHING’S SYNDROME Many different drugs have been used to manage the symptoms of Cushing’s syndrome while Steroidogenic Inhibitors patients await non-pharmacological procedures, such as surgery. However, the number of drugs that are reasonably effective for diagnosis or management of Cushing’s syndrome are small, Ketoconazole (Nizoral®)* and mostly consist of drugs that prevent steroid synthesis in the adrenal glands. These drugs Route: PO Availability: Rx only are called steroidogenic inhibitors, and include ketoconazole, mitotane, and metyrapone. Levoketoconazole is a single stereoisomer of ketoconazole that was approved in 2021. Levoketoconazole (Recorlev®) Route: PO Availability: Rx only Drug Formulation, Delivery and Absorption Metyrapone (Metopirone®) Steroidogenic Inhibitors Route: PO Metyrapone, mitotane, and osilodrostat are only formulated as solid oral products. Metyrapone Availability: Rx only is extensively absorbed from the GI tract; less than half of an oral dose of mitotane is absorbed Mitotane (Lysodren®) from the GI tract, but this is sufficient for clinical efficacy. Asian populations absorb ~20% more Route: PO osilodrostat than do caucasians. Availability: Rx only Osilodrostat (Isturisa®) For adrenal gland disorders, ketoconazole is administered as a solid oral tablet. (FYI: Route: PO ketoconazole is a dibasic drug with pKa values of 6.2 and 2.9 (as indicated in Figure 13)). Availability: Rx only Solubility is greatly dependent upon pH, as the unprotonated (uncharged) molecule is * must know brand and generic names insoluble in aqueous media. In contrast, aqueous solutions with pH less than 3 render for medications marked with asterisk Integrated Pharmacotherapy 2 9 Adrenal and Pituitary Gland Disorders  Figure 13. pKa values of protonizable nitrogens of ketoconazole Figure 14. Sites of drug action at the HPA axis pKa = 6.2 N Glucocorticoid feedback inhibition CRH N pKa = 2.9 O Dopamine agonists O suppress prolactin release Pituitary Gland N N O O Bromocriptine H 3C Cl Cl Cabergoline Levoketoconazole Glucocorticoid feedback inhibition PROLACTIN ACTH ketoconazole as a freely soluble salt. Therefore, the oral bioavailability of ketoconazole is pH dependent because dissolution of the drug does not Steroidogenesis Inhibitors occur unless the gastric environment is acidic. Accordingly, ketoconazole Mammary Adrenal Gland Ketoconazole should not be taken with drugs that raise the gastric pH (review IP 2 GERD Gland Mitotane if you cannot remember three classes of drugs that do this). Administration Metyrapone of ketoconazole with food may be helpful as food enhances the release of gastric acid. Ketoconazole is also an antifungal agent, but its use as MILK PRODUCTION CORTISOL an antifungal will not be covered in this packet. Being a stereoisomer of ketoconazole, the above solubility considerations also pertain to Corticosteroids levoketoconazole. Cortisol binds with Hydrocortisone glucocorticoid Cortisone receptor in nucleus of cells Prednisone Dexamethasone Drug Distribution, Action and Effects Fludrocortisone* Figure 14 shows the site of action in the HPA axis for the steroidogenesis *Also has potent mineralocorticoid activity inhibitors. Steroidogenic Inhibitors The main concept to understand about how steroidogenic inhibitors work is that they interfere with the function of one or more enzymes in the endogenous steroid synthesis pathway. Most of the enzymes are CYP450 isoforms (however, unlike other CYP450 isoforms, these isoforms are not usually involved in drug metabolism). However, steroidogenic inhibitors aren’t completely selective for the CYP450 isoforms responsible for steroid synthesis and in some cases (particularly ketoconazole/levoketoconazole) may inhibit CYP450 isoforms important to drug metabolism, potentially leading to drug-drug interactions. Figure 18 on page 16 shows the site of action for the steroidogenic drugs within the steroid synthesis pathways. The steroidogenic inhibitors are a chemically diverse group of drugs. Figure 13 shows their chemical structures, the main point being that while these drugs interfere with steroid synthesis enzymes, they are not steroidal in structure. Figure 15. Steroidogenic Inhibitors Cl Cl F Cl O N N N Cl NC N Mitotane Metyrapone Osilodrostat N N O O N N O O H 3C Cl Cl Ketoconazole Integrated Pharmacotherapy 2 10 Adrenal and Pituitary Gland Disorders  Figure 16. Sites of corticosteroid biosynthesis inhibition of steroidogenic inhibitors H H Ketoconazole H Mitotane H H CYP11A1 HO 17-α-hydroxylase 17, 20-lyase CHOLESTEROL (CYP17) (CYP17) Pregnenolone 17-OH-Pregnenolone Dehydroepiandosterone (DHEA) Ketoconazole 3-β-HSD 3-β-HSD 3-β-HSD 17-α-hydroxylase 17, 20-lyase (CYP17A1) (CYP17A1) Testosterone Progesterone 17-OH-Progesterone ANDROSTENEDIONE Estrogens O 21-Hydroxylase 21-Hydroxylase (CYP21) (CYP21) H H H Deoxycorticosterone 11-Deoxycortisol O Metyrapone 11-β-Hydroxylase 11-β-Hydroxylase (CYP11B2) Mitotane (CYP11B1) (CYP11B2) Osilodrostat Corticosterone CORTISOL O OH HO OH 18-Hydroxylase Mitotane (Aldosterone Synthase) H H H ALDOSTERONE O O O OH HO H H H O FYI: Important Ketoconazole Drug Interactions Ketoconazole = Azole Antifungal = Drug-Drug Interactions Warfarin Warfarin is a blood thinner with a narrow therapeutic index Inhibition of CYP2C9 by ketoconazole decreases warfarin clearance leading to increased warfarin concentration and effect in the body HIV Protease Inhibitors (PIs) PIs are antiretrovirals for the management of HIV/AIDS. CYP3A4 inhibition by ketoconazole decreases PI clearance and increases PI concentration PI dose reduction may be necessary Benzodiazepines Benzodiazepines are sedative-hypnotic drugs, some of which are metabolized by CYP3A4 CYP3A4 inhibition by ketoconazole may decrease clearance of some benzodiazepines, leading to increased sedative-hypnotic effect HMG-CoA Reductase Inhibitors These are used to treat cholesterol disorders and some (simvastatin (Zocor®), lovastatin (Mevacor®), atorvastatin (Lipitor®)) are metabolized by CYP3A4 CYP3A4 inhibition by ketoconazole decreases clearance of these agents and increases risk of hepatotoxicity or severe muscle damage Integrated Pharmacotherapy 2 11 Adrenal and Pituitary Gland Disorders Of the steroidogenic inhibitors, ketoconazole (Nizoral®) is the most effective inhibitor of steroid synthesis in Cushing’s syndrome via inhibition of CYP11A1 and CYP17A1. It must be used in doses higher than those used for fungal infections (ketoconazole is also an antifungal drug). At this dosage range (600 - 1200 mg/day) ketoconazole essentially inhibits synthesis of all steroids, particularly by inhibition of CYP11A1. Levoketoconazole (Recorlev®) is the single stereoisomer of ketoconazole that is primarily responsible for steroidogenic inhibition. Because of this, it is more potent than the isomeric mixtures of ketoconazole traditionally administered and may also have fewer side effects. However, as a newly approved agent that is only available as a branded formulation, it is of questionable added value relative to the generic isomeric mixture of ketoconazole that is long established as the standard of care. Metyrapone (Metopirone®) and osilodrostat (Isturisa®) both inhibit CYP11B1 (aka: 11-β-hydroxylase) which is responsible for the final step of cortisol synthesis. These two agents also inhibit the CYP11B2 isoform of 11-β-hydroxylase that is involved in aldosterone synthesis, which does not affect cortisol synthesis. Mitotane (Lysodren®) has a broader spectrum of steroid enzyme inhibition. Mitotane is unique in that it causes atrophy and degeneration of the adrenal cortex (adrenolytic properties). In fact, mitotane has been said to produce a “chemical adrenalectomy”, though the complete mechanism by which it accomplishes this is not well understood. Adverse Effects Ketoconazole/levoketoconazole may cause hepatic dysfunction ranging from mild to severe hepatic injury. Patients taking ketoconazole for CS should be monitored for lab values that indicate hepatic dysfunction and toxicity (liver transaminases such as ALT and AST). Metyrapone, mitotane, and osilodrostat may cause gastrointestinal and neurologic adverse effects manifesting as nausea, vomiting, ataxia, lethargy, vertigo, abnormal gait, confusion, and problems with language expression. On account of their inhibiting downstream steroidogenic enzymes (i.e. the final step in the synthesis of cortisol), metyrapone and orlisodrostat can also have androgenic activity on account of a shift of cortisol precursor molecules to be used as substrates in alternate metabolic pathways (e.g. precursors of cortisol instead get used to make testosterone). Likewise, these agents can also lead to increased mineralocorticoid activity because, despite their inhibition of aldosterone synthesis, the common steroidal precursors of aldosterone and cortisol themselves have mineralocorticoid activity. When these molecules can’t be converted into aldosterone or cortisol, they can be released into the bloodstream and lead to symptoms related to excess mineralocorticoid exposure (e.g. hypokalemia, edema). In summary, all of these agents produce potent antisteroidogenic effects. This type of pharmacologic action is associated with many adverse effects, ranging from bothersome to life-threatening. Relative to most classes of drugs, steroidogenic inhibitors require especially careful monitoring of adverse effects. Elimination Steroidogenic Inhibitors The enzymes responsible for mitotane and metyrapone metabolism have not been fully characterized. Both drugs are metabolized extensively; metyrapone is metabolized by non-CYP450 enzymes. Osilodrostat is metabolized by several p450 isoforms (eg, CYP3A4, CYP2B6, CYP2D6) and glucuronosyl transferases. No single metabolic pathway is responsible for ≥25% of osilodrostat elimination. Ketoconazole/levoketoconazole is extensively metabolized by CYP3A4 to inactive metabolites. Excretion of ketoconazole and its metabolites occurs mostly by biliary excretion, with renal excretion playing a minor role. Drug Interactions Steroidogenic Inhibitors Of the steroidogenic inhibitors, drug-drug interactions are most important with ketoconazole. Ketoconazole belongs to a class of antifungals known as “azole antifungals.” This class of drugs is well known for their involvement in drug-drug interactions. As a general rule, when you hear “azole antifungal” think “I need to screen this patient’s medication profile for drug-drug interactions”. Ketoconazole (and levoketoconazole) inhibits CYP450 isoforms involved in steroid biosynthesis; however, it is not 100% selective for these enzymes and also inhibits other CYP450 isoforms. Most important is its potent inhibition of CYP3A4, the isoform responsible for more drug metabolism reactions than any other CYP450 isoform. It also inhibits the activity of CYP2C9 and CYP2C19. Inhibition of CYP3A4, CYP2C9, and CYP2C19 by ketoconazole may lead to a decrease in clearance of other drugs that are metabolized by these isoforms. Examples of clinically important drug-drug interactions due to ketoconazole CYP450 inhibition are provided in the box on page 11. (When you think of ketoconazole, think of drug interactions). Integrated Pharmacotherapy 2 12 Adrenal and Pituitary Gland Disorders THERAPEUTIC MANAGEMENT The goal of treatment is to correct the hypercortisolism to decrease the risk of complications and mortality. The primary treatment for CS is surgical. Occasionally, irradiation is used for pituitary tumors where surgery is not effective or optional. The role of pharmacotherapy (treatment using medications) in the treatment of CS is to decrease glucocorticoid secretion until surgical removal or irradiation of the tumor can be performed. In cases where a tumor is inoperable, pharmacologic agents may be used indefinitely. Pharmacologic options include drugs that act by glucocorticoid receptor antagonism, modulation of ACTH secretion, and inhibition of steroidogenesis. Of these, evidence has consistently demonstrated that the steroidogenesis inhibitors ketoconazole, levoketoconazole, metyrapone, mitotane, and osilodrostat are most effective at decreasing serum free cortisol. Since there has been little or inconsistent evidence supporting the effectiveness of agents that act at the glucocorticoid receptor or inhibit the release of ACTH, this discussion will focus on the steroidogenesis inhibitors listed above. Unless otherwise contraindicated (absolutely cannot use), the antifungal ketoconazole is the initial drug of choice (first-line) given its efficacy as a single agent and its favorable side effect profile. Studies have shown normalization of serum free cortisol levels in up to 70% of patients treated with ketoconazole. Ketoconazole inhibits the production of cortisol, but also has some anti-androgenic effects (reduced hirsutism, less acne, more gynecomastia). Therapeutic effects of ketoconazole are rapid and efficacy is dose dependent. The daily dose should be adjusted based on 24-hour urine free cortisol levels to obtain a normalized serum free cortisol level. (FYI: the suggested ketoconazole starting dose is 200 mg PO BID or TID. Maintenance doses of 800-1200 mg PO daily are typically reached). In studies investigating the use of ketoconazole for Cushing’s disease, between 5%- 10% of subjects experienced elevations is hepatic transaminases (liver enzymes); therefore, it is critical to closely monitor hepatic (liver) function while taking ketoconazole. Since ketoconazole is a potent inhibitor of cytochrome P450 isoforms, particularly CYP3A4 and CYP2C9, potentially significant drug interactions should be avoided before starting therapy and alternative agents used when possible. If ketoconazole fails to normalize serum free cortisol levels as a single agent, the addition of one of the alternate steroidogenesis inhibitors is appropriate. The clinical role of levoketoconazole is unclear. It is very similar to ketoconazole with a theoretical decreased risk of liver toxicity in vitro. Given that this medication is available as a brand name only drug, it is unclear if it will be used often in this patient population. Metyrapone decreases cortisol synthesis through enzyme inhibition and has a rapid onset of action. Interestingly, the decrease in cortisol resulting from metyrapone therapy stimulates increased ACTH secretion which in turn shifts production in the adrenal cortex to production of androgen and mineralocorticoid. This accounts for the most common side effects associated with metyrapone use such as hirsutism, acne, hypertension, and edema. Metyrapone is usually initiated at a low dose (FYI: 250 mg PO TID) and titrated until normalization of serum free cortisol is obtained or a maximum dose is reached (FYI: 6 g PO daily). Due to the significant adverse effect profile of metyrapone, it is only provided through the manufacturer for “compassionate use.” Anti-androgenic effects of ketoconazole may offset the androgenic side effects seen with metyrapone and may be another reason to use the combination. Mitotane efftects may be rapid, but can take weeks to months for its full effect. It not only decreases cortisol synthesis through enzyme inhibition, but it also has adrenolytic action at daily doses of 4 g. The adrenolytic action of mitotane could make this agent preferred in patients who are not candidates for surgical intervention. Mitotane is initiated at low doses (FYI: 250 mg PO in the evening) and slowly titrated to higher doses (FYI: 4-12 g PO daily). The side effects of hypercholesterolemia, thin blood (higher bleed risk), gastrointestinal intolerance, and CNS disturbances limit the utility of mitotane. At higher doses, CNS side effects are prevalent. Due to its potential to rapidly decrease serum cortisol levels leading to adrenal crisis, the manufacturer has issued a BLACK BOX WARNING instructing mitotane therapy to be initiated under the supervision or administered by a “qualified physician experienced in the uses of cancer chemotherapeutic agents.” Therefore, administration of mitotane is most practically accomplished in the hospital setting. Osilodrostat is making its way quickly to a preferred agent. Studies showed an 86% rate of cortisol normalization. It is FDA approved for patients with hypercortisolism who are not surgical candidates or when surgery was not curative. It has a quick onset of effect with rapid cortisol reduction. Side effects include androgenic (abnormal hair growth) and hyperaldosteronism (discussed later in this packet) effects. Monitor for hypokalemia and cardiac rhythm changes (QTc prolongation). FYI: Pasireotide (approved in 2018) was FDA approved for treatment of Cushing’s Disease in patients unable to undergo pituitary surgery or who have continued disease after surgery. Etomidate, a medication used for anesthesia also has very potent steroidogenic inhibition and can be used for severe hypercortisolism in an emergency setting. Patients with Cushing’s Syndrome are considered immunocompromised (steroids suppress the immune system). As a result of hypercortisolemia, patients with Cushing’s Syndrome should receive influenza, herpes zoster, and pneumococcal vaccinations. Integrated Pharmacotherapy 2 13 Adrenal and Pituitary Gland Disorders  ADRENAL INSUFFICIENCY PATHOPHYSIOLOGY Adrenal Insufficiency results in the opposite problem as Cushing’s Syndrome and is a result of deficient cortisol production. Adrenal insufficiency (AI), or hypofunctioning of the adrenal gland, can be categorized as either primary or secondary based on causation. Primary means that the cause of the disorder is directly from the affected site. In this case, primary AI is caused from the adrenal gland itself. Primary AI, also known as Addison’s disease, is most often the result of an autoimmune process that leads to the destruction of the adrenal cortex and is a rare but life-threatening disorder. In response to low levels of cortisol, the anterior pituitary releases high levels of ACTH (Figure 3 on page 4 may help you understand this mechanism), but the adrenal cortex can no longer secrete cortisol, aldosterone, and some androgens. Clinical manifestations rarely occur until greater than 90% of the adrenal cortex is destroyed. If untreated, AI can lead to adrenal crisis, which is characterized Table 1. Clinical features of adrenal insufficiency by hypotension, fever, and shock. Adrenal crisis is life-threatening. Symptom Pathophysiology Secondary means that the disorder is caused from something else affecting Fatigue, lack of energy, reduced strength GD, AAD the site. For example, secondary AI could be a result of a hypofunctioning Anorexia, weight loss GD tissue growth on the pituitary gland leading to low levels of ACTH Gastric pain, nausea, vomiting GD, MD production, thereby, causing low adrenal gland stimulation. Secondary adrenal insufficiency most often occurs from suppression of the HPA axis Myalgia, joint pain GD through exogenous steroid use. Long-term, high dose steroid use results Dizziness MD, GD in atrophy of the anterior pitu­itary and hypothalamus, preventing positive Salt craving MD feedback to the adrenal glands. Long-term steroid use is defined as greater Dry, itchy skin (women) AAD than 14 days at doses equivalent to prednisone > 5 mg daily. Loss or impairment of libido AAD Another potential cause of secondary AI is medications that cause Fever GD decreased production of cortisol in patients with impaired pituitary or adrenal function. Drugs that inhibit cortisol synthesis and subsequent Low blood pressure, postural hypotension MD, GD secretion include ketoconazole (well...this makes sense) and etomidate Hyponatremia MD, GD (an anesthetic). Hypothalamic or anterior pituitary failure can also lead to Hyperkalemia (primary AI only) MD secondary adrenocortical insufficiency. Increased TSH (primary only) GD CLINICAL PRESENTATION Hyperpigmentation (tanning) ACTH GD = Glucocorticoid Deficiency The clinical signs and symptoms of AI are often vague and frequently appear MD = Mineralocorticoid Deficiency insidiously (slowly over time). The presenting signs and symptoms are those associated with decreased serum glucocorticoid, mineralocorticoid, and AAD = Adrenal Androgen Deficiency Adapted from The Lancet 2003;361:1881-93 adrenal androgen levels. The most common symptoms include weakness, weight loss, anorexia, nausea, vomiting, hypotension, tanned skin, and salt Figure 17. Adrenal insufficiency flow chart craving. See Table 1 for additional signs and symptoms. Harrison’s Principles of Internal Medicine, Chapter 336, Figure 12 One of the most serious complications of AI is the development of adrenal crisis. Adrenal crisis occurs when there is a sudden decrease in adrenal steroids as a result of corticosteroid dosing decreases or failure to administer additional exogenous corticosteroids in times of stress. Adrenal crisis is a potentially fatal condition if it is not diagnosed early or treatment is delayed. DIAGNOSIS As with Cushing’s syndrome, symptoms alone are not adequate to diagnose AI. Once AI is suspected based on clinical manifestations, laboratory testing is required to confirm the diagnosis and differentiate the etiology (cause). Initially, serum electrolytes should be obtained since hyponatremia and hyperkalemia are present in most patients with AI. However, the diagnosis of AI should only be made after an ACTH stimulation test has been performed to assess the HPA axis. Figure 17 on page 14 depicts a flowchart for evaluation of potential AI. The ACTH stimulation test consists of administering 250 μg cosyntropin (Cortrosyn), a synthetic corticotropin (ACTH), IM/IV and measuring serum cortisol after 30 and 60 minutes. In Integrated Pharmacotherapy 2 14 Adrenal and Pituitary Gland Disorders a normal healthy patient, stimulation of the adrenal cortex with corticotropin results in cortisol release from the adrenal glands and serum cortisol levels increase. Serum cortisol of greater than 18 μg/dL is a normal response to this stimulation test and rules out AI. Patients with primary AI do not have a functional adrenal cortex and it does not respond to corticotropin stimulation. If the results are between 13-17 μg/dL further testing is necessary (indeterminate result). A serum cortisol of less than 13 μg/dL confirms the diagnosis of AI. To differentiate between primary and secondary AI, an ACTH level should be obtained. An elevated ACTH level suggests primary AI, while a decreased or normal ACTH indicates secondary AI. (FYI: If corticotropin is not available, morning cortisol < 5 μg/ dL and elevated ACTH can be used as a preliminary screening test for primary AI). Once primary AI is diagnosed, an autoimmune work-up should be completed to identify the cause. In patients with primary AI, plasma renin and aldosterone levels should be measured to identify mineralocorticoid deficiency. Corticosteroids THERAPEUTIC AGENTS FOR ADRENAL INSUFFICIENCY Cortisone Corticosteroids are important for the management of adrenal insufficiency. While Route: PO the corticosteroid family is large, prednisone, cortisone, hydrocortisone (another Availability: Rx only name for cortisol), and fludrocortisone are most commonly used for adrenal Hydrocortisone (Cortef®, Solu-Cortef®)* insufficiency. Dexamethasone, a corticosteroid useful as a diagnostic agent Route: PO, IV for Cushing’s syndrome, will also be covered with the corticosteroids used for adrenal Availability: Rx only insufficiency though it is not used as a therapeutic (mainly used for diagnosis). Prednisone (Deltasone®)* Route: PO (tablets, solution) Availability: Rx only Drug Formulation, Delivery and Absorption Dexamethasone (Decadron®)* Route: PO (tablets, solution), IV Corticosteroids Availability: Rx only The corticosteroids comprise a large family of drugs that are administered by a Fludrocortisone (Florinef®)*Route: PO (tablets) variety of routes. For the management of adrenal gland disorders, however, Availability: Rx only corticosteroids are mostly administered orally. Many corticosteroids are available in both solid and liquid oral formulations, with the liquid products preferred * must know brand and generic names for medications for children and patients with swallowing difficulties. In general, all corticosteroids marked with asterisk are absorbed well from the gastrointestinal tract. Food does not usually alter absorption, but administration of oral corticosteroids with food is recommended to minimize gastrointestinal irritation. Drug Distribution, Action and Effects Figure 14 on page 10 shows the site of action in the Table 2. Glucocorticoid and mineralocorticoid activity and potency data HPA axis for the corticosteroids. Corticosteroid Comparison Corticosteroids Glucocorticoid Mineralocorticoid Equivalent Dose Corticosteroids may be divided into two subtypes: Activity Activity (mg) glucocorticoids and mineralocorticoids. Glucocorticoids Short Acting were named for their effects on carbohydrate Hydrocortisone (Cortisol) 1 1 20 Cortisone 1 1 25 metabolism, while mineralocorticoids were named for their effects on fluid and electrolyte balance. Most Intermediate Acting corticosteroids have a mixture of glucocorticoid and Prednisone 4 0.8 5 Prednisolone 4 0.8 5 mineralocorticoid activity, usually with one or the Methylprednisolone 5 0.5 4 other activity dominating. Glucocorticoid activity Triamcinolone 5 0 4 is measured by anti-inflammatory activity, while Long Acting mineralocorticoid activity is expressed as sodium- Betamethasone 25 0 0.6 retaining activity (or salt-retaining). Table 2 shows the Dexamethasone 25 0 0.75 relative activities and potency for the corticosteroids Fludrocortisone 12 125 ----- covered in this unit. The equivalent dose column is the measure for glucocorticoid potency equivalency. For example, prednisone is approximately 4 times as potent as cortisol because only 5 mg of prednisone are required to produce a glucocorticoid effect equal to 20 mg of cortisol. Note that the most potent glucocorticoid activity is found with dexamethasone. In Table 2, you do not have to memorize the specific numbers of glucocorticoid and mineralocorticoid activity, but you should know which ones are mainly glucocorticoid and which are mainly mineralocorticoid. Also, know the relative potency (again, don’t memorize specific numbers, but know which ones are more or less potent in relation to the others). Integrated Pharmacotherapy 2 15 Adrenal and Pituitary Gland Disorders Corticosteroids are lipophilic, distribute readily throughout the body, and Figure 18. General mechanism of action for corticosteroids have effects in all tissues and organs. Corticosteroids share the same general mechanism of penetrating the cell and binding with either a glucocorticoid receptor (GCR) or mineralocorticoid receptor (MR) in the cytosol (or in some Cell Nucleus cases the nucleus). Once bound to the GCR or MR (collectively called steroid receptors), the complex travels into the nucleus and associates with DNA (Figure 188). The interaction with DNA causes increased transcription of genes DNA Associates with DNA coding for a wide variety of proteins. The GCR interaction with DNA results in Increased Gene production of proteins that affect carbohydrate metabolism and inflammatory + Transcription processes, while the MR interaction with DNA causes production of proteins Steroid Receptor important to sodium retention in the kidneys. Corticosteroids produce Corticosteroid Increased Protein Translation additional important effects, such as immunosuppression, that will be covered in future IP courses. Small chemical modifications (Figure 19) to the cortisol pharmacophore give rise to the large family of different corticosteroids. These modifications result in three general differences relative to cortisol that affect clinical use: 1) potency, 2) glucocorticoid activity, and 3) mineralocorticoid activity. The endogenous Figure 19. Corticosteroid chemistry glucocorticoid, cortisol, is also marketed as a drug called hydrocortisone, and has O 19 HO mineralocorticoid and glucocorticoid activity (even though it is considered to be 12 18 OH O HO 17 OH O an endogenous glucocorticoid). Cortisone is nearly equivalent to hydrocortisone 11 13 OH H 16 H in all aspects, though it is only active upon reduction of the ketone (FYI: at 1 9 14 2 15 carbon 11 to a β-hydroxy group), which yields hydrocortisone. Prednisone 3 10 H 8 H H H contains an “A” ring double-bond (FYI: a 1-dehydro derivative, referring to a O 4 5 6 7 O double-bond between the 1 and 2 position of the ring structure) that increases Hydrocortisone Cortisone potency, increases glucocorticoid activity and decreases mineralocorticoid (cortisol) O HO activity. Prednisone must undergo hepatic metabolism to change to its active OH O form prednisolone (FYI: 11b-hydroxydehydrogenase enzyme metabolizes O OH HO OH prednisone). Patients with hepatic impairment must be given the active form H H prednisolone. Dexamethasone contains a 16-methyl substitution that increases H H F H drug chemical stability and lipophilicity, resulting in a longer-acting and more O O potent corticosteroid (lipophilicity enhances potency because corticosteroids Prednisone Dexamethasone must penetrate into the cell to have an effect). The 16-methyl substitution also eradicates mineralocorticoid activity, as can a variety of other substituents O OH at carbon 16. Fludrocortisone is a 9-α-fluorinated cortisol analog. This HO OH modification results in increased potency for both mineralocorticoid and H glucocorticoid activity; however, the mineralocorticoid activity is greater, and as such fludrocortisone is considered a mineralocorticoid corticosteroid. (FYI: F H The increased potency is thought to come about as a result of the electronegative O 9-fluoro substituent withdrawing electron density from the 11-hydroxy group, Fludrocortisone thereby increasing the acidity of the hydroxyl group and rendering it a better hydrogen bond donor which can form stronger interactions with the receptor). There is extensive SAR information available on the corticosteroids. Various substitutions have been made to every carbon of the steroid core, both alone and Table 3. Adverse effects of corticosteroids in combination. While the implications of these studies may be seen as excessive Short-term effects Long-term effects in relation to our concerns here, interested students are directed to chapter 33 Fluid retention Cataracts of “Foye’s Principles of Medicinal Chemistry, 6th edition” for a more thorough Hyperglycemia Cushing’s syndrome introduction to a SAR analysis of the corticosteroids. Hypertension Delayed wound healing Increased appetite Diabetes Corticosteroids have a variety of adverse effects (Table 3). Despite being powerful Insomnia Glaucoma immunosuppressants, corticosteroids often cause leukocytosis as measured Leukocytosis Hypertension in a CBC. This is because they upregulate the production of neutrophils Mood changes (psychosis) Infection (polymorphonuclear leukocytes; PMNs). It is important to remember this so Muscle weakness any leukocytosis can be put in the appropriate context of the patient. Chronic Myopathy Osteoporosis administration of superphysiologic (above your normal body’s production) Peptic ulcer corticosteroid doses (in general, greater than 5 mg prednisone or equivalent Reduced growth in children glucocorticoid dose for longer than 14 days) will put all patients at risk for two Skin thinning main adverse effects: 1) Cushing’s syndrome (CS) and 2) secondary adrenal Weight gain insufficiency (secondary AI) if abruptly discontinued. Integrated Pharmacotherapy 2 16 Adrenal and Pituitary Gland Disorders Central to understanding why patients receiving chronic superphysiologic doses of corticosteroids are at risk for secondary AI is the understanding that cortisol feedback inhibits the release of CRH and ACTH. Exogenous corticosteroids with glucocorticoid activity produce this same feedback inhibition, and chronic high doses will suppress the HPA axis such that little to no cortisol is produced and released from the adrenal gland. If exogenous corticosteroid therapy is withdrawn abruptly, then the body will be in a state of adrenal insufficiency. Since the adrenal insufficiency in this case is the result of the abrupt withdrawal of corticosteroid therapy, and not due to an inherent malfunction of the adrenal glands, it is designated as a form of secondary AI. To avoid potentially life-threatening secondary AI in patients discontinuing chronic corticosteroid therapy, the corticosteroid dose MUST be tapered down over several weeks. Short-course steroid use 5 mg daily. Signs and symptoms of adrenal crisis Opponents used as campaign tool, may present upon abrupt discontinuation of steroids. In cases like this, the HPA suggesting too ill to serve axis has reduced its own hormonal output because the exogenous corticosteroids