Medical Pharmacology Chapter 28:  Physiology and Pharmacology: Adrenocorticosteroids / Adrenocortical Antagonists

• Cushing's Syndrome

  • Primary Cause: iatrogenic administration of steroids

  • Primary Non-iatrogenic Cause:

    • Bilateral adrenal hyperplasia due to pituitary adenoma (basophilic tumor)

      • Pituitary Tumor: Diagnosis

        Attribution: Norvartis:  Pituitary Tumor Roundtable-Diagnosis (Roundtable Part 1 of 2)https://www.youtube.com/watch?v=zbX8YQ4iTjc (4/2014) Novartis YouTube Channel:  https://www.youtube.com/channel/UCSg28bDoEVjVegY4-htQM7A

      •  

        Pituitary Tumor:  Management of Cushing's Disease

        Attribution: Norvartis:  Pituitary Tumor Roundtable-Management of Cushing's Disease (Roundtable Part 2 of 2) https://www.youtube.com/watch?v=sOWQXb_R6Mw (4/2014) Novartis YouTube Channel:  https://www.youtube.com/channel/UCSg28bDoEVjVegY4-htQM7A

    • About 20 to 25 percent of Cushing's syndrome patients have adrenal neoplasm

    • ACTH Hypersecretion

  • Other Causes:

    • Adrenal tumors

    • Nodular adrenal hyperplasia-- causes:

      • Familial autoimmune (children/young adults)-- pigmented multinodular cortical dysplasia

      • Hypersensitivity to gastric inhibitory peptide (increased peptide receptor expression in adrenal cortex)

    • Ectopic, nonendocrine tumors that produce ACTH

  • Incidence:

    • Three times greater in women

    • Most frequent age of onset: 30s to 40s

  • Manifestations:

    • Abnormal fat deposition:

      • Truncal obesity-- mesenteric bed

      • Rounded face ("moon facies")

      • Interscapular area ("buffalo hump")

    • Hirsuitism;

    • Effects of protein loss --

      1. Muscle wasting

      2. Skin thinning

      3. Striae:  secondary to weakening/rupture of dermal collagen fibers

      4. Poor wound healing

      5. Bruising

      6. Osteoporosis

    • Mental disorders--

      • Irritability/emotional lability

      • Severe depression, confusion, psychosis

    • Diabetes

      • Frequency < 20%

      • Impaired glucose tolerance:

        1. Increased hepatic gluconeogenesis

        2. Insulin resistance

    • Hypertension-- common

• Short-termTreatment:

  • Surgical pituitary tumor removal

  • Irradiation/removal of pituitary adenomas (ACTH producing)

    • 

    • "Autopsy case. Unoperated macroadenoma of pituitary."

      • 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

      • For more information concerning endocrine pathology

    •  Microadenoma surgical resection is associated with recurrence rate that may be greater than 20 percent

  • About 20% -- 25% of Cushing's patients have an adrenal neoplasm.

    • Usually unilateral;  about 50%, malignant

    •  Adrenal carcinoma diagnosis: approximate three-year post-diagnosis survival time

      • Associated with liver and lung metastasis

      • Primary chemotherapeutic agent: mitotane which suppresses cortisol production, decreasing plasma and urine steroid levels

      • Mitotane: -- relatively selective for glucocorticoid-secreting adrenal cortex zone; extra-adrenal cortisol metabolism may also be affected

        1. One-third of patients: tumor and metastasis regress

        2. In many patients:

           • Steroidogenesis -- inhibited

           • No regression of tumor metastases

  • Resection of hyperplastic adrenals  if source of ACTH is apparent

    • Cure rate approximates 100%

    •  Adverse effects:

      • Lifelong glucocorticoid and mineralocorticoid replacement

      • 10% to 20% probability of developing pituitary tumor over following ten year period (Nelson's syndrome)

  • In surgical approach not feasible, "medical" adrenalectomy may be required:

    • "Medical" adrenalectomy:

      • High-dose ketoconazole (Nizoral) (inhibit steroidogenesis)

      • Mitotane (Lysodren) and/or aminoglutethimide (blocks steroid synthesis) and metyrapone

• Patient management:(surgical intevention)

  • Before surgery: large doses of cortisol

  • During and immediately after surgery: large doses of cortisol

  • Tapered cortisol to normal replacement doses (long-term maintenance)

• Diagnosis: Dexamethasone suppression testing

  • Initial Screening

    1. Demonstration of increased cortisol production

    2. Cortisol > , following dexamethasone (Decadron) at midnight

  • Definitive diagnosis:

    1. Failure of urinary cortisol to fall to less than reference level; plasma cortisol to fall to less than the reference level following standard low-dose dexamethasone (Decadron) suppression testing.

• Primary aldosteronism

  • Overview:

    • Twice as common in women as in man

    • Most often presents between 30 in 50 years of age

  • Most common cause:

    • Adrenal adenoma associated with excessive aldosterone production; however, another contending idea is that an idiopathic bilateral adrenal hyperplasia may be responsible for primary aldosteronism.

      • Unilateral adenoma (usually small; either side)

    • Conn's syndrome

      • Conn's --primary aldosteronism: "Adrenal cortical adenoma There is a solitary, well-demarcated mass with the typical mottled yellow color of adrenal cortex." 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

     

  • Other causes:

    • Hyperplastic adrenal glands -- abnormal secretion

    • Malignant tumor

      • Adrenal carcinoma (rare)

  • Physiological Effects of aldosterone hypersecretion:

    • Increased renal distal tubule or exchange of sodium for secreted potassium and hydrogen ions -- body potassium depletion/hypokalemia

  • Diagnosis:  Criteria:

    1. Diastolic hypertension (no edema)

    2. Renin hyposecretion (low plasma renin activity)

       • Renin secretion does not increase with volume depletion

    3. Aldosterone hypersecretion that is not suppressed with volume expansion

  • Clinical Presentation:

    • Diastolic hypertension (not very severe)

      • Secondary to increase sodium reabsorption/volume expansion

    • Headaches

    • Polyuria, polydipsia

      • Impairment of urinary concentrating ability

    • Weakness

      • Due to effects of potassium depletion

    • Tetany

    • Electrocardiographic changes:  consistent with potassium depletion (hypokalemia-- which increases ectopy)

      • Prominent U waves

      • Cardiac arrhythmias

      • Premature contractions

    • Many effects secondary to potassium loss associated with:

      • Hypokalemia

        •  May be severe (< 3 mmol/L)

      • Hypernatremia-- due to:

        • Sodium retention

        • Water loss from polyuria

      • metabolic alkalosis-- due to

        • Urinary hydrogen ion loss

        • Movement of hydrogen ion into potassium-depleted cells

        • Alkalosis enhanced by potassium deficiency which increases proximal convoluted tubule capacity to reabsorb filtered bicarbonate.

  • Treatment:

    • Due to adenoma -- usually treated surgically

      • May be treated by:

        • Sodium intake restriction

        • Aldosterone antagonist (spironolactone (Aldactone))

          •  Prolonged medical management (chronic therapy) may be side effect limited (males)

            1. Gynecomastia

            2. Decreased libido

            3. Impotence

    • Due to idiopathic bilateral hyperplasia

      • Symptomatic hypokalemia treated by:

        1. Spironolactone (Aldactone)

        2. Triamterene (Dyrenium)

        3. Amiloride (Midamor)

      • Surgery if pharmacological treatment fails

• Secondary aldosteronism

  • Cause:  inappropriate increase in aldosterone production due to renin-angiotensin system activation

  • Associated with:

    •  Accelerated hypertension

    •  Presence of edema disorder 

  • In pregnancy:

    • Normal physiologic response to estrogen-induced increased plasma renin substrate and plasma renin activity and to antialdosterone actions of progestogens

  • In hypertension:  cause:

    • Over production of renin (primary reninism)

    • Renin over production secondary to reduced renal blood flow/perfusion pressure

      •  Reduced renal artery lumen secondary to atherosclerosis or fiber muscular hyperplasia

    •  Severe arteriolar nephrosclerosis (malignant hypertension)

    •  Profound renal vasoconstriction (accelerated hypertension)

  • May be caused by rare renin-producing tumors (primary reninism)

    • Juxtaglomerular cell tumor

  • Physiological characteristics:

    • Increased plasma renin activity

    • Moderate/marked increases in aldosterone levels

    • Hypokalemic alkalosis

• Adrenocorticosteroids and Fetal Lung Maturation

  • Lung maturation is dependent on fetal cortisol

  • If delivery is expected before 34 weeks gestation, maternal glucocorticoid supplementation reduces likelihood of respiratory distress syndrome.

  • Betamethasone (Celestone) preferred due to reduced protein binding -- making more available for placental transfer to the fetal circulation.

1. Goldfien, A.,Adrenocorticosteroids and Adrenocortical Antagonists, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 635-650.

2. Williams, G. H and Dluhy, R. G. , Diseases of the Adrenal Cortex, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 2035-2056