Adrenal Cortex Pharmacology

• The lecture covers the pharmacology of the adrenal cortex.

Case Study Introduction

• A 76-year-old female with a six-month history of immobility and falls was found to have Cushing's Disease following an investigation which revealed proximal muscle weakness.

Common Indications

• Inhibitors of adrenal steroid synthesis can be indicated for Cushing's Syndrome, which is caused by the excess secretion of glucocorticoids.
• Cushing's Syndrome causes overmedication with corticosteroids, adrenal hypersecretion from a tumor, and/or excessive ACTH release from pituitary adenoma or metastatic tumors.

Primary Hyperaldosteronism

• Primary Hyperaldosteronism involves an excess secretion of aldosterone caused by an adrenal adenoma.

Aminoglutethimide

• Aminoglutethimide has clinical applications primarily in the treatment of Cushing's syndrome and estrogen-receptor-positive breast carcinoma in postmenopausal women.
• Aminoglutethimide blocks aromatase, inhibiting estrogen production from androstenedione and testosterone, and it blocks cholesterol conversion to pregnenolone by inhibiting the P450scc enzyme, thus decreasing the synthesis of all hormonally active steroids.
• The half-life ranges from 7 to 15 hours, and it is shorter with multiple doses compared to single doses.
• Common adverse effects include drowsiness and lethargy.
• Aminoglutethimide falls under Pregnancy Category D

Ketoconazole

• Ketoconazole is an antifungal agent with a broad spectrum of activity.
• Ketoconazole has been used in the treatment of advanced prostate cancer, Cushing's syndrome and hyperandrogenism.
• Large doses of Ketoconazole inhibit several enzymes involved in glucocorticoid synthesis.
• Ketoconazole is well absorbed after oral administration, with a bioavailability of 75%, but requires an acid environment for absorption.
• Hepatic microsomal enzymes degrade ketoconazole into inactive metabolites that are excreted primarily in the bile or feces.
• Ketoconazole is 99% bound to plasma proteins.
• Hepatitis and hypoadrenalism are potential cautions.
• Adverse effects may include blood dyscrasias, headache, dizziness, fatigue, gynecomastia, hyperuricemia, hypothyroidism, nausea, abdominal pain, and skin rash.
• Ketoconazole falls under Pregnancy Category C.
• It can cause cardiac effects when combined with cisapride, potentiate triazolam, midazolam, and oral hypoglycemics.
• Combining Ketoconazole with other hepatically metabolized drugs can increase the risk of hepatotoxicity, specifically cyclosporin, rifampin, isoniazid, and phenytoin.
• Ketoconazole may also potentiate digoxin toxicity.
• The FDA issued a safety alert in 2013, noting that oral ketoconazole tablets may cause severe liver injuries and adrenal gland problems, and can lead to harmful drug interactions.
• Oral tablets should not be a first-line treatment for any fungal infection.
• Topical formulations of Ketoconazole, unlike the oral tablets, have not been associated with liver damage, adrenal problems, or drug interactions.

Pasireotide (Signifor)

• Pasireotide is indicated for adult patients with Cushing's disease for whom pituitary surgery is not an option or has not been curative.
• The recommended subcutaneous dosage of Pasireotide is between 0.3 to 0.9 mg twice a day.
• An initial dose of either 0.6 mg or 0.9 mg twice daily is recommended.
• Pasireotide dosage should also be titrated based on response and tolerability
• Pasireotide operates as a somatostatin analogue, exerting its activity via binding to somatostatin receptors (ssts).
• Five human somatostatin receptor subtypes are known: hsst 1, 2, 3, 4, and 5.
• Tumor cells from Cushing's disease patients frequently over-express hsst5, while the other receptor subtypes are often not expressed or expressed at lower levels.
• Pasireotide binds and activates hsst receptors, inhibiting ACTH secretion, which leads to decreased cortisol secretion.
• Adverse reactions include hypocortisolism, hyperglycemia, bradycardia, QT prolongation, liver test elevations, cholelithiasis, and pituitary hormone deficiency.
• Administering antiarrhythmic medicines and other drugs that may prolong the QT interval should be done with caution when using Pasireotide.
• Cyclosporine may see a decrease in relative bioavailability when administered with Pasireotide, requiring dose adjustments to maintain therapeutic levels.
• Co-administration with bromocriptine may increase blood levels of bromocriptine, so dosage reduction might be necessary.

Spironolactone (Aldactone)

• Spironolactone is an effective aldosterone antagonist used for treating primary aldosteronism, hypertension, congestive heart failure, and ascites due to liver disease.
• It is also used for hirsutism associated with polycystic ovary syndrome and menstrual irregularities.
• Spironolactone competes for the mineralocorticoid receptor and inhibits sodium reabsorption in the kidney.
• It also antagonizes aldosterone and testosterone synthesis.
• Adverse effects include nausea, vomiting, gastric bleeding, gastritis, ulceration, thrombocytopenia, agranulocytosis, gynecomastia, hyperkalemia, acidosis, impotence, hepatitis and systemic lupus erythematosus.
• Spironolactone falls under Pregnancy Category C.
• Drug interactions to be aware of include hyperkalemia which can be potentiated by certain diuretics, K supplements, lithium, and ACE inhibitors.
• Spironolactone also potentiates ganglionic blockers, may increase the risk of digitalis toxicity, and is antagonized by NSAIDs.

Eplerenone (Inspra)

• Eplerenone functions as an aldosterone receptor blocker (mineralocorticoid selective), and treats hypertension whether alone or in combination with other antihypertensives.
• Eplerenone is not recommended in patients with serum K+ >5.5 meq/l, Type II DM with microalbuminuria, or serum Cr. >2.0 in males or 1.8 in females.
• Hyperkalemia, dizziness, GI upset, and abdominal pain are all adverse effects.
• CYP3A4 inhibitors and NSAIDs may antagonize the effects, while ACE inhibitors can increase hyperkalemia.

Mitotane (Lysodren)

• Mitotane's indications involve adrenocortical carcinoma and Cushing's syndrome.
• It causes cytoxic atrophy of the adrenal cells in order to alter corticoid metabolism.
• Mitotane is 40% absorbed following oral administration and it is primarily stored in fatty tissues, with an elimination half-life ranging from 18 to 159 days.
• Anorexia, nausea and vomiting occur in 80% of patients treated for Mitotane, as well as CNS depression which is seen in 40% of patients.
• Mitotane falls under Pregnancy Category C.

Metyrapone (Metopirone)

• Metyrapone inhibits endogenous adrenal corticosteroid synthesis and cortisol by reversibly inhibiting steroid 11β-hydroxylase.
• Stimulating ACTH secretion increases plasma 11-deoxycortisol levels.
• Metyrapone is indicated, in combination with other diagnostic tests, for the diagnosis of adrenal insufficiency in adult and pediatric patients.
• Side effects include hypertension, nausea, vomiting, rash, and headache.

Mifepristone (Korlym)

• Mifepristone is indicated for controlling hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing's syndrome.
• This is recommended for adults who have type 2 diabetes/glucose intolerance and have not responded to, or are not candidates for, surgery.
• Previously RU 486, Mifepristone is a cortisol receptor blocker
• Also a synthetic steroid with a high affinity for progesterone receptors that acts as an antiprogestin, and at higher doses will strongly bind to glucocorticoid receptors and, to a lesser extent, androgen receptors.
• Fatigue, nausea, vomiting, headache, hypokalemia, arthralgia, edema, adrenal insufficiency, QT prolongation, and hypertension are common adverse effects during use.
• Adrenal insufficiency cannot be confirmed biochemically because Mifepristone raises circulating cortisol levels.
• Women may experience endometrial hyperplasia, irregular uterine bleeding and abortion.
• Mifepristone is contraindicated for use during pregnancy.

Osilodrostat (Isturisa)

• Osilodrostat decreases cortisol synthesis by inhibiting 11beta-hydroxylase (CYP11B1), the enzyme responsible for the final step of cortisol biosynthesis in the adrenal gland.
• Osilodrostat can be used in adults for Cushing's disease that cannot be treated with pituitary surgery.
• Multiple CYP enzymes (eg, CYP3A4, CYP2B6, CYP2D6) and UDP-glucuronosyltransferases metabolize Osilodrostat to inactive metabolites, although no single enzyme contributes >25% to the total clearance.
• Osilodrostat side effects include irregular heartbeat, decreased adrenal hormones, stomach pain, vomiting, loss of appetite, tiredness, and/or feeling light-headed.

Androgens

• Testosterone and dihydrotestosterone act at the nuclear androgen receptor.
• DHEA (Dehydroepiandrosterone) is a precursor to testosterone and is not regulated by the FDA.
• 17-hydroxy testosterone esters (highly lipophilic) and 17-alkylated androgens can be administered orally.
• Androgens affect sex organ and secondary sex characteristics, increase muscle mass and strength, increase energy, increase aggressiveness, and increase bone mineral density.

Testosterone

• Testosterone is indicated for replacement in hypogonadal males.
• Delayed puberty can used Testosterone enanthate for treatment.
• Inoperable metastatic carcinoma of the breast may be treated with Testosterone palliatively.
• Acne, gynecomastia, increased or decreased libido, edema, decreased ejaculatory volume, hypercalcemia, jaundice, and flushing of the skin are potential cautions.
• Patients with hypogonadotropic hypogonadism should receive hypothalamic disorder therapy.
• Therapeutic effect duration depends upon the administration route and which testosterone ester is used.
• Options for testosterone delivery include intramuscular injections, skin patches, gels, buccal formulations, oral preparations, and nasal gel.

Injectable Testosterone

• While long-acting injectable testosterone delivery systems are generally safe, they include frequent intramuscular injections, usually every 2 to 4 weeks.
• Significant fluctuations in testosterone levels can also occur - Longer intervals can result in even greater fluctuations and lead to changes in libido, sexual function, energy, and mood.
• After an initial dose of 100 mg to 150 mg administered every 2 weeks, a person can be administered doses of 50 mg to 400 mg every 2 to 4 weeks.

Testosterone - Patches

• During transdermal application, serum testosterone concentration reaches maximum levels at 2 to 4 hours and returns to baseline within approximately 2 hours after removal.
• Transdermal patches are more convenient and noninvasive
• Patches also closely mimic normal diurnal changes in testosterone.
• Drawbacks include skin irritation and problems with the patch adhering properly, especially in hot climates
• Patches are applied at the same time of day, typically every evening between 8:00 PM and midnight.
• Patches should be placed on a clean dry area on the back, abdomen, thighs, or upper arms, but never on genitals or damaged skin
• Subsequent patches should be placed in a different spot for at least 1 week, but allows normal activity, such as sex, swimming, and showering.
• If excessive perspiration or moisture causes the patch to loosen or fall off, can be pressed back down or replaced if this occurs before noon.

Testosterone - Gel

• Applying 10 grams of testosterone gel topically results in a serum testosterone increase within 30 minutes, with about 10% of the applied testosterone
• This dose is absorbed across the skin during the 24-hour dosing interval.
• Steady state levels are reached by day 2 or 3.
• Gels offer therapeutic levels without large fluctuations, it is easier to use, and causes less skin irritation than patches.
• Disadvantages include risk of DHT(dihydrotestosterone) conversion, skin irritation, and transference to female partners and children.
• Avoid swimming or showering for 5 to 6 hours after applying testosterone gel .
• Patients should apply testosterone gel at a starting dose of 5 g to deliver 50 mg of testosterone once daily, preferably in the morning, to clean, dry, intact skin of the shoulders and upper arms and/or abdomen
• It can be squeezed into the palm and applied or a portion can be squeezed.
• Application sites should be allowed to dry for a few minutes prior to dressing so that the testosterone does not rub onto clothing.
• Hands should be washed with soap and water after the gel has been applied to avoid transference.
• A boxed warning is required for Solvay's AndroGel and Auxilium's Testim after reports of adverse events in children who were exposed to the testosterone gel therapies through contact with a person being treated with the products.
• As of December 1, 2008, eight cases of secondary exposure in children ranging in age from nine months to five years were reported.
• Symptoms included inappropriate enlargement of genitalia, advanced bone age and aggressive behaviour.

Testosterone - Buccal System

• The Buccal System (Striant) is a muco adhesive buccal tablet that is applied to the gum above the incisors.
• This novel system closely approximates the restoration of normal physiological testosterone levels.
• Advantages of this method include pharmacokinetic and physiologically consistent therapeutic levels of testosterone without the need for repeated titrations
• This therapy has low DHT conversion and no risk of transference to female partners or children.
• Twice-daily dosing and some initial gum irritation in some (9%) patients are some drawbacks.
• The recommended dosing schedule is once every 12 hours
• With each application, the product should be rotated to the alternate side of the mouth with rounded surface against the gum and held firmly in place over the lip for 30 seconds to ensure adhesion
• The preparation does not dissolve completely and must be removed before placing a new buccal system on the alternate side of the mouth.
• Eating, tooth brushing, gum chewing, or alcoholic beverages do not affect the system.
• People should never chew or swallow the system.

Testosterone - Drug Interactions

• Testosterone enhances the activity cyclosporin, antidiabetics, thyroxine, levothyroxine, and warfarin, which increases toxicity.
• Testosterone may cause resistance to the effects of neuromuscular blockers.

Testosterone - Axiron Topical Solution

• Axiron is a topical, alcohol-based testosterone solution that is applied to the underarm once daily
• The recommended starting dose is 60 mg to be applied at the same time each morning, users should apply antiperspirant or deodorant before applying Axiron to avoid contamination.

Testosterone - Monitoring

• Baseline testing of patients on testosterone replacement includes hemoglobin and hematocrit levels, liver function tests, PSA, digital rectal exam, lipid panel, and morning free- and total-testosterone levels.
• These laboratory tests should be repeated periodically, usually every 3 to 6 months.
• It is important to test testosterone levels in the morning due to diurnal fluctuations in testosterone production.
• Testosterone replacement therapy should be halted if a significant increase in PSA level occurs or a rectal exam is abnormal.

Testosterone - Natural Products Interactions

• Many herbal medications are being used for symptoms of hypogonadism with potential interactions.
• These include human growth hormone, dihydroepiandrosterone (DHEA), melatonin, ginkgo biloba, saw palmetto, St. John's wort (an inducer of cytochrome P450 3A4), garlic, and vitamin E.

Anabolic Steroids

• Anabolic steroids are a synthetic version of testosterone designed in the 1930s in Europe, with over 100 different types developed.
• They stimulate bone and muscle development, promote skin and hair growth, and can influence emotions and energy levels.
• Indications include bone marrow stimulation, growth stimulation, stimulation of appetite and preservation of muscle mass and HIV/AIDS, induction of male puberty, breast cancer in some women, and angioedema treatment.

Anabolic Steroids - Prescription

• Anabolic steroids that are controlled as perscription-only drugs include Oxymetholone, Nandrolone, Stanozolol, Methandrostenolone, and Oxandrolone.

Oxymetholone

• Oxymetholone is primarily indicated, combined with anti-lymphocyte globulin or anti-thymocyte globulin, to treat acquired aplastic anemia.
• This drug has been shown to provide useful treatments in situations of Fanconi's anemia, hereditary angioedema, and familial anti-thrombin III deficiency.
• Virilization is the most common adverse effect, but it also includes fluid retention, weight gain, hypertension, psychiatric symptoms, nausea, vomiting, diarrhea, lipid abnormalities, elevation of liver function test results, leukemia and hepatocellular carcinoma.

Nandrolone

• The brand named drug, Androlone-D 100, is used to treat anemia associated with chronic kidney failure.
• Drug interactions to be wary of while taking include cyclosporine, epoetin alfa, growth hormone, finasteride, anti diabetic medications, saw palmetto, and/or warfarin.
• Adverse effects include depression, nausea, vomiting, skin rash and itching, stomach pain, bleeding, swelling, weight gain, and yellowing of the eyes and/or skin.
• Men might have side effects like breast tenderness or enlargement, frequent erections, frequent or difficult urine, and groin or scrotum pain.
• Women might have side effects like irregular/vaginal bleeding, decrease in breast size, enlarged clitoris, hair loss, facial hair growth, and voice changes.

Stanozolol

• Prophylaxis and treatment of hereditary angioedema.
• Increases the synthesis of complement 1 inhibitor.
• May cause a reduction in certain clotting factors.
• Women should be monitored for virilization and menstrual irregularities.
• Diabetics should monitor dose of insulin or oral agents.
• Stanozolol should not be used in patients with cancers, severe liver dysfunction, kidney disease, or during pregnancy.
• Used with caution in the presence of cardiac function impairment and prostatic hypertrophy.

Methandrostenolone

• Methandrostenolone was discontinued in March, 1982.
• This change happened due to its unapproved use in third-world countries for appetite stimulation in children.
• Methandrostenolone does not appear available in the United States, but is available in other countries.

Oxandrolone

• Weight gain is promoted through indication for extensive surgery, chronic infection, long-term corticosteroid therapy, and/or etiology.
• Useful for constitutional delay of growth and puberty in boys as well as adjunctive to growth hormone in girls with Turner's syndrome and/or in treating alcoholic hepatitis, bone pain associated with osteoporosis, and wasting syndrome with HIV.
• Caution to adverse effects of are virilization, hepatic dysfunction, lipid abnormalities, edema, and weight gain.
• Children require small and controlled doses to prevent advancement of bone age disproportionately, and psychotic-like symptoms and dependence have also been reported in athletes using prolonged, large doses.

OTC Anabolic Steroids

• DHEA (Dehydroepiandrosterone) and Androstenedione are anabolic steroids that are available without a prescription.

DHEA

• DHEA is chemically related to testosterone.
• DHEA provides immune system, tissue maintenance and repair, and mental support.
• The concentration of DHEA peaks around puberty and slowly declines with advanced years, produced in the adrenal gland.
• Higher dosages than 10mg can cause irregular beats, though commercial DHEA is made synthetically, it's involvement in drug interactions has been suggested through the cytochrome P450 system.
• DHEA is specifically an inhibitor of the cytochrome P450-34A hormone, but should be used with caution.
• DHEA has been proven unsafe, yet has not been studied in combination with other medicines,

Androstenedione

• Androstenedione is a precursor to testosterone and estrone.
• It is synthesized from DHEA, produced in the adrenal glands/gonads in both men and women, and sometimes obtained from plants.
• Several organizations have labeled this product as illegal.

Anabolic Steroid Abuse

• Steroid abusers "stack" the drugs, leading to a two, or more, mix of oral medication and veterinary use.
• Often times, steroid abusers "Pyramid" the steroids, beginning first with low doses to allow time to recuperate in a second half in which they're cycled.

Jason Giambi Steroid Use Investigation

• In addition to GH, HGH was injected on his stomach and rubbed "undetectable steroid in a cream" along with "the clear" on his body.
• "The Clear (THG)," is an analog known as troenbolone in cattle.
• It's function to quicken recovery from muscle soreness and strength building, in conjunction with "testes shrinkage" for acne skin.

Performance Athlete - Jose Canseco

• Some users of the past include Mark Mcgwire, Jason Giambi, with a team injecting for quick recoveries, with some receiving medical information of steroids .
• Major baseball players would turn their blind eyes to avoid and turn excitement for the fame along .
• Common medications would included stanozolol.

Anabolic Steroid Abuse - Harm Indicators

• Symptoms include aggression, the enlargement of the breasts(men), acne, oily skin, and striae.
• Some might be aggressive at an high level over of HDL.
• Signs may also indicate an infection, like HIV.

Anabolic Steroids - New Black Box Warning

• Tumors or life threatening incidents may happen, if cholestatic issues begin or if blood lipid changes increase.
• Be careful with cardiac renal epilepsy and COPD.

Anabolic Steroids Abuse - Olympic Sports

• In Michael Bamberg's Sports Illustrated Article in 1995, those who "used to win" used drugs for the benefit.
• In an anonymous poll with 198 Olympic athletes - only 3 turned down use in taking those drugs, and more than 50% said yes to win to "win at all events, leading to the possibility of death".