Pituitary Agents for Acromegaly
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Questions and Answers

What is the primary mechanism of action of spironolactone?

  • Increases Na+ channel permeability to promote Na+ reabsorption
  • Decreases K+ retention through diuresis
  • Stimulates aldosterone biosynthesis
  • Inhibits mineralocorticoid receptors to reduce Na+ reabsorption (correct)

    • In which condition is spironolactone NOT typically used?

  • Aldosteronism
  • Heart failure
  • Cushing syndrome
  • Primary hyperaldosteronism (correct)

    • What is a common adverse effect of spironolactone?

  • Increased muscle mass
  • Gynecomastia (correct)
  • Sodium retention
  • Hypokalemia

    • What is the recommended dose of hydrocortisone for treating Addison's disease?

    <p>15-20 mg PO in the a.m. and 10 mg in the p.m.</p> Signup and view all the answers

    Which mineralocorticoid is recommended to prevent hyperkalemia in Addison's disease?

    <p>Fludrocortisone</p> Signup and view all the answers

    What is the mechanism of action of pegvisomant?

    <p>Binds to GH receptors in the liver and inhibits IGF</p> Signup and view all the answers

    Which of the following is a common adverse drug reaction associated with somatostatin analogues?

    <p>Gallstones</p> Signup and view all the answers

    Which of the following statements correctly describes the role of dopamine agonists in treating acromegaly?

    <p>Decrease GH and IGF levels</p> Signup and view all the answers

    What is a significant characteristic of prolactin compared to GH?

    <p>Its production can be impaired by dopamine transport issues</p> Signup and view all the answers

    Which adverse effect is most commonly reported with pegvisomant?

    <p>Hepatotoxicity</p> Signup and view all the answers

    What is a long-acting dopamine agonist utilized in the treatment of acromegaly?

    <p>Cabergoline</p> Signup and view all the answers

    What potential adverse effect occurs in 75% of patients treated with somatostatin analogues initially?

    <p>Diarrhea or abdominal discomfort</p> Signup and view all the answers

    In addition to acromegaly, which other condition can be treated using dopamine agonists?

    <p>Microprolactinemia</p> Signup and view all the answers

    What is the result of normal glucocorticoid levels in the body?

    <p>They are essential for maintaining glucose levels.</p> Signup and view all the answers

    How do glucocorticoids affect immunity?

    <p>They decrease the body’s ability to fight infections.</p> Signup and view all the answers

    What effect do glucocorticoids have on bone health?

    <p>They antagonize vitamin D-stimulated calcium transport.</p> Signup and view all the answers

    What is one potential consequence of glucocorticoid use on the bones?

    <p>Inhibition of bone formation due to decreased osteoblast precursors.</p> Signup and view all the answers

    Which of the following describes the catabolic effect of glucocorticoids?

    <p>Promotion of protein breakdown.</p> Signup and view all the answers

    Which physiological change occurs due to glucocorticoids in relation to calcium?

    <p>Increased renal calcium excretion.</p> Signup and view all the answers

    How might cortisol affect a person during an infection?

    <p>By impairing the immune response.</p> Signup and view all the answers

    What is a possible health risk associated with high glucocorticoid levels?

    <p>Increased risk of infections.</p> Signup and view all the answers

    Which type of therapy involves the use of glucocorticoids?

    <p>Immunosuppressive therapy.</p> Signup and view all the answers

    Which of these is NOT a function of glucocorticoids in the body?

    <p>Promoting muscle growth.</p> Signup and view all the answers

    What is the primary mechanism of action of Osilodrostat?

    <p>Steroidogenesis inhibitor</p> Signup and view all the answers

    Which adverse drug reaction is NOT associated with Ketoconazole?

    <p>Adrenal insufficiency</p> Signup and view all the answers

    What potential side effect is associated with Mifepristone?

    <p>Excessive vaginal bleeding</p> Signup and view all the answers

    Which statement is true regarding Cyproheptadine?

    <p>It acts as a central neuromodulator.</p> Signup and view all the answers

    Which of the following is an adverse drug reaction of Mitotane?

    <p>Rash</p> Signup and view all the answers

    What is the main mechanism of action (MOA) of somatropin?

    <p>Stimulates linear bone growth and increases muscle mass</p> Signup and view all the answers

    Which of the following are common adverse drug reactions (ADRs) associated with somatropin?

    <p>Intracranial hypertension and vision changes</p> Signup and view all the answers

    What is a common drug-drug interaction property associated with Osilodrostat?

    <p>CYP3A4 inducer and inhibitor</p> Signup and view all the answers

    How does somatropin interact with growth hormone receptors (GHR)?

    <p>Upon binding, GHR dimerizes and activates Janus Kinase 2 (JAK2)</p> Signup and view all the answers

    Which of the following drugs primarily works by decreasing ACTH release?

    <p>Cyproheptadine</p> Signup and view all the answers

    What is a potential drug-drug interaction (DDI) with somatropin?

    <p>Glucocorticoids may inhibit the effects of somatropin</p> Signup and view all the answers

    Which of the following is an adverse effect that can increase androgen levels?

    <p>Hirsutism</p> Signup and view all the answers

    What is NOT an adverse reaction of Osilodrostat?

    <p>CNS depression</p> Signup and view all the answers

    Which of the following statements about somatropin is accurate?

    <p>Patients may experience edema as a side effect</p> Signup and view all the answers

    Which of the following conditions could somatropin help to manage?

    <p>Growth hormone deficiency</p> Signup and view all the answers

    What effect does high-dose Ketoconazole have on testosterone levels?

    <p>It decreases testosterone levels.</p> Signup and view all the answers

    What physiological effects does somatropin have related to blood glucose levels?

    <p>Increases blood glucose levels</p> Signup and view all the answers

    Which of the following is NOT a direct action of somatropin?

    <p>Inhibiting protein synthesis</p> Signup and view all the answers

    Somatropin may cause which of the following side effects?

    <p>Visual disturbances and headaches</p> Signup and view all the answers

    What role does insulin-like growth factor-1 (IGF-1) play in the action of somatropin?

    <p>Mediates some of the effects of somatropin indirectly</p> Signup and view all the answers

    Match the following drugs used to treat acromegaly with their primary action:

    <p>Octreotide = Reduces GH secretion Bromocriptine = Stimulates dopamine receptors Pegvisomant = Blocks GH action at the receptor Lanreotide = Similar action to octreotide</p> Signup and view all the answers

    Match the following drug administration routes to their respective drugs for treating acromegaly:

    <p>Octreotide = Subcutaneous or intramuscular injection Bromocriptine = Oral administration Cabergoline = Oral administration Pegvisomant = Subcutaneous injection</p> Signup and view all the answers

    Match the following treatment options for acromegaly with their characteristics:

    <p>Surgical options = Transsphenoidal surgery to remove the tumor Radiation therapy = Can take years to reduce GH levels Somatostatin analogs = Administered via injection Dopamine agonists = Effective for mild symptoms</p> Signup and view all the answers

    Match the following drugs with their frequency of dosing:

    <p>Bromocriptine = Usually taken daily Cabergoline = Less frequent dosing compared to bromocriptine Lanreotide = Administered every few weeks Octreotide = Administered frequently as needed</p> Signup and view all the answers

    Match the following medications to their classifications:

    <p>Octreotide = Somatostatin analog Bromocriptine = Dopamine agonist Pegvisomant = GH receptor antagonist Radiation therapy = Adjuvant treatment option</p> Signup and view all the answers

    What is the primary use of dopamine in treating patients with acromegaly?

    <p>To inhibit the secretion of prolactin</p> Signup and view all the answers

    What characterizes the condition known as acromegaly?

    <p>Abnormal growth of hands, feet, and face</p> Signup and view all the answers

    What role does dopamine (DA) play in relation to growth hormone (GH) secretion in healthy individuals?

    <p>DA enhances GH secretion</p> Signup and view all the answers

    Which hormone's overproduction can lead to hyperprolactinemia?

    <p>Prolactin</p> Signup and view all the answers

    What is the half-life of dopamine, making it a long-acting drug?

    <p>65 hours</p> Signup and view all the answers

    Which therapy combined with dopamine is used to treat acromegaly?

    <p>GH antagonists and somatostatin analogs</p> Signup and view all the answers

    What causes the overproduction of prolactin in affected individuals?

    <p>Adenomas or impaired dopamine transport</p> Signup and view all the answers

    What is the primary therapeutic use of somatropin?

    <p>To manage growth failure due to inadequate endogenous GH secretion in children</p> Signup and view all the answers

    What mechanism does somatropin use to exert its effects?

    <p>Mimics the actions of endogenous growth hormone and interacts with IGF-1</p> Signup and view all the answers

    Which of the following is a common adverse drug reaction (ADR) associated with somatropin?

    <p>Intracranial hypertension</p> Signup and view all the answers

    How does glucocorticoid use affect the efficacy of growth hormone?

    <p>Inhibits the effects of growth hormone</p> Signup and view all the answers

    What indirect effect does somatropin have on blood glucose levels?

    <p>Decreases insulin sensitivity</p> Signup and view all the answers

    What is the primary mechanism of action of oxytocin?

    <p>Act through G protein to contract the uterus</p> Signup and view all the answers

    What is a primary use of oxytocin in clinical settings?

    <p>Induce labor</p> Signup and view all the answers

    What is the mechanism of action of Atoxiban?

    <p>Prevent uterine contraction</p> Signup and view all the answers

    In which situation would Atoxiban be used?

    <p>To prevent premature labor</p> Signup and view all the answers

    Which of the following is NOT an effect of oxytocin?

    <p>Prevents preterm labor</p> Signup and view all the answers

    Which of the following drugs is known to induce hyperprolactinemia (hyper-PRL)?

    <p>Verapamil</p> Signup and view all the answers

    What is a common adverse effect associated with prolonged use of glucocorticosteroids?

    <p>Adrenal suppression</p> Signup and view all the answers

    What is the potential consequence of rapid discontinuation of glucocorticoids?

    <p>Worsening symptoms of the original disease</p> Signup and view all the answers

    Which of the following can lead to weight gain as an adverse effect?

    <p>Glucocorticoids</p> Signup and view all the answers

    Which of these conditions is a result of glucocorticoid action on bone health?

    <p>Osteoporosis</p> Signup and view all the answers

    What is the mechanism of action of Metyrapone in treating Cushing syndrome?

    <p>Inhibits the last step of cholesterol synthesis</p> Signup and view all the answers

    Which of the following adverse drug reactions is associated with Ketoconazole?

    <p>Gynecomastia</p> Signup and view all the answers

    What potential drug-drug interaction is notable with Osilodrostat?

    <p>Induces CYP3A4</p> Signup and view all the answers

    What common adverse effect may occur when using Aminoglutethimide?

    <p>Sedation</p> Signup and view all the answers

    Which mechanism of action is shared by both Ketoconazole and Mifepristone?

    <p>Steroidogenesis inhibition</p> Signup and view all the answers

    What is a serious risk associated with the handling of Mitotane?

    <p>Cytotoxicity to adrenal cortex</p> Signup and view all the answers

    Which drug is known to block mineralocorticoid receptors and is used for hirsutism treatment?

    <p>Spironolactone</p> Signup and view all the answers

    What is the common effect of Mifepristone associated with its use?

    <p>Excessive vaginal bleeding</p> Signup and view all the answers

    Which of the following adverse effects can result from the use of Cyproheptadine?

    <p>CNS depression</p> Signup and view all the answers

    What is a distinguishing feature of Aminoglutethimide's mechanism of action compared to other Cushing syndrome treatments?

    <p>Cholesterol desmolase inhibition</p> Signup and view all the answers

    What is the primary mechanism of action of Metyrapone in the treatment of Cushing Syndrome?

    <p>Inhibits the last step of cholesterol synthesis</p> Signup and view all the answers

    Which drug is known to possibly cause adrenal insufficiency as an adverse drug reaction?

    <p>Osilodrostat</p> Signup and view all the answers

    What is a common adverse drug reaction of Ketoconazole?

    <p>Gynecomastia</p> Signup and view all the answers

    Which drug primarily blocks mineralocorticoid receptors to help manage symptoms of Cushing Syndrome?

    <p>Spironolactone</p> Signup and view all the answers

    What adverse drug reaction is most commonly associated with Mifepristone?

    <p>Excessive vaginal bleeding</p> Signup and view all the answers

    Which drug acts by inhibiting cholesterol desmolase as its mechanism of action?

    <p>Aminoglutethimide</p> Signup and view all the answers

    What potential side effect may occur when using Mitotane?

    <p>CNS depression</p> Signup and view all the answers

    Which drug interacts with many medications as a notable adverse drug reaction?

    <p>Ketoconazole</p> Signup and view all the answers

    What is a side effect of Aminoglutethimide that patients should be aware of?

    <p>Sedation</p> Signup and view all the answers

    Which of the following drugs does NOT have reported drug-drug interactions?

    <p>Cyproheptadine</p> Signup and view all the answers

    Study Notes

    Pituitary Agents for Acromegaly

    • Pegvisomant (Somavert): A GH Antagonist (GHA) that binds to GH receptors in the liver and inhibits IGF (Insulin-like Growth Factor). Does not inhibit GH production, but blocks its effects on tissues.

      • Adverse Drug Reactions (ADRs): Hepatotoxicity, increased liver function tests (LFTs), nausea, diarrhea, pain at injection site.

    • Somatostatin Analogues (SSAs):

      • Octreotide and Lanreotide
      • MOA: Inhibit GH and IGF1.
      • ADRs: Nausea, flatulence, gallstones, bradycardia, vitamin B12 deficiency, chest pain, hyperglycemia in type 2 diabetes mellitus (T2DM), severe hypoglycemia in type 1 diabetes mellitus (T1DM), malaise, fever, diarrhea/abdominal discomfort (occurs in 75% of patients, but episodes decrease after 10-14 days).

    • Dopamine Agonists (DAs):

      • Bromocriptine (Parlodel) and Cabergoline
      • MOA: Decrease GH, IGF, and Prolactin.
      • ADRs: Bromocriptine: Nausea, headache, orthostatic hypotension, fatigue, abdominal pain.

    Dopamine, GH, Prolactin, and Acromegaly

    • Acromegaly is characterized by abnormal growth of hands, feet, and face due to increased GH and IGF-1 production during adulthood.
    • Prolactin is a hormone structurally similar to GH. Its production is not regulated by negative feedback.
    • Overproduction of prolactin can be caused by pituitary adenoma or impaired dopamine transport, leading to decreased estrogen levels.
    • Dopamine inhibits prolactin secretion, making it the drug of choice for micro- or macroprolactinemia.
    • In patients with acromegaly, dopamine acts as a suppressor of GH secretion, even though it stimulates GH secretion in healthy individuals.

    Recombinant Human Growth Factor (Somatropin)

    • MOA: Mimics and restores the actions of endogenous growth hormone. Stimulates linear bone growth, increases bone mass, increases muscle mass, reduces fat mass, regulates blood glucose and lipid levels. Somatropin acts directly through its binding to GHR (growth hormone receptor) and indirectly via IGF-1. Upon binding, GHR dimerizes and interacts with Janus Kinase 2 (JAK2), triggering downstream signaling.
    • ADRs: Generally well tolerated in most cases. Potential complications include intracranial hypertension (headache, vision changes, nausea, edema), hypothyroidism, pancreatitis, gynecomastia, myalgia, fluid imbalances, pain at injection site, increased ALT and AST.
    • Drug-Drug Interactions (DDI):
      • Glucocorticoids: May inhibit the effect of GH, increasing the risk of infection (16-18%).
      • Normal glucocorticoid levels are crucial: Maintain glucose levels to provide energy for the body to fight stress due to trauma or infection.
      • Cortisol: Can lead to decreased lymphocytes, reducing the body's ability to fight infection.
      • Osteoporosis: Glucocorticoids can alter bone mineral homeostasis by antagonizing Vitamin D-stimulated calcium transport, stimulating renal calcium excretion, increasing osteoclast activity, and blocking bone formation.

    Other Pituitary Agents

    • Ketoconazole (Nizoral): A steroidogenesis inhibitor at very high doses.

      • ADRs: Decreased thyroid function (hypothyroidism), decreased libido, increased hepatic enzymes, gynecomastia, nausea, vomiting.
      • DDIs: Many serious drug-drug interactions.

    • Osilodrostat (Isturisa): Inhibits the 11-beta-hydroxylase enzyme involved in the biosynthesis of cortisol.

      • ADRs: Adrenal insufficiency, fatigue, nausea, headache, edema.
      • DDIs: CYP3A4 inducer and inhibitor, CYP2D6 inducer.

    • Mifepristone (Korlym, Mifeprex): An anti-progesterone agent that acts as a glucocorticoid receptor antagonist. Potential agent to block excessive glucocorticoids.

      • ADRs: Vomiting, diarrhea, pain, excessive vaginal bleeding, abdominal and uterine cramping, nausea, hypokalemia.

    • Cyproheptadine (Periactin): A central neuromodulator that reduces ACTH release.

      • ADRs: Sedation, hyperphagia, anticholinergic effects.

    • Mitotane (Lysodren): An adrenocytotoxic drug that decreases cortisol production, leading to adrenal inhibition without causing cellular destruction.

      • ADRs: Lethargy, rash, central nervous system depression, nausea, vomiting.
      • DDIs: n/a

    Spironolactone

    • MOA: Blocks mineralocorticoid receptors (MR), preventing the formation of aldosterone-induced proteins (AIPs). This indirectly reduces sodium channel permeability, decreasing sodium reabsorption, increasing potassium retention, and inhibiting aldosterone action.
    • Uses: Cushing syndrome (for symptomatic relief of hypertension and hypokalemia), aldosteronism (inhibits aldosterone biosynthesis, lowering hypertension), diagnosis tool for aldosteronism, treatment of hirsutism in women, heart failure.
    • ADRs: Hyperkalemia, metabolic acidosis, gynecomastia, gastrointestinal discomfort, fatigue, menstrual irregularities, hypotension.

    Drugs for Addison's Disease

    • Corticosteroids: Mimic endogenous cortisol levels: Hydrocortisone, cortisone, prednisone.

      • Dosage: Lowest effective dose to minimize ADRs
      • Agent of choice: Hydrocortisone 15-20 mg orally at 8:00-9:00 a.m. and 10 mg orally at 4:00-5:00 p.m. This regimen mimics a normal cortisol production pattern, with a larger dose in the morning and a smaller dose in the afternoon.

    • Mineralocorticoids: Prevent hyperkalemia: Fludrocortisone

      • Dosage: Fludrocortisone acetate 50-200 mcg/day
      • Sodium Intake: Limit sodium intake to less than 3-4 grams per day.

    • Dehydroepiandrosterone (DHEA): Optional supplement for improved energy levels and libido in females. Dosage: 25-50 mg/day.

    Acromegaly Treatment Drugs

    • Acromegaly is caused by excess growth hormone (GH) primarily due to a pituitary tumor.
    • Treatments aim to reduce GH levels and alleviate symptoms.

    Somatostatin Analogs

    • Octreotide (Sandostatin) and Lanreotide (Somatuline) reduce GH secretion.
    • They're administered via subcutaneous or intramuscular injection.

    Dopamine Agonists

    • Bromocriptine (Parlodel) and Cabergoline (Dostinex) stimulate dopamine receptors, inhibiting GH secretion.
    • They're administered orally.
    • Cabergoline is more potent than bromocriptine and requires less frequent dosing.

    GH Receptor Antagonists

    • Pegvisomant (Somavert) directly blocks the action of GH at the receptor level.
    • It's administered via subcutaneous injection and may normalize IGF-1 levels, providing symptom relief.

    Radiation Therapy

    • Used for patients not responding to medications or surgery.
    • Takes several years to achieve GH reduction.
    • Options include stereotactic radiosurgery and conventional fractionated radiation.

    Surgical Options

    • Transsphenoidal surgery removes the tumor.
    • It's an option for optimal results when combined with medical treatment.

    Monitoring and Considerations

    • Regular monitoring of IGF-1 and GH levels is crucial to assess treatment effectiveness.
    • Side effects and management strategies for each medication should be discussed with patients.
    • Individual treatment plans may vary based on tumor size, patient health, and response to therapy.

    Dopamine

    • Dopamine is the drug of choice for treating micro- or macro-prolactinemia
    • Dopamine is useful for patients with pituitary tumors that secrete excess prolactin and/or growth hormone, or when patients are resistant to bromocriptine
    • Dopamine has a long half-life (t1/2 is 65 hours) and is highly selective

    Dopamine's Use

    • Dopamine is used to treat hyperprolactinemia, Parkinson's disease, and acromegaly

    Relationship Between Dopamine, Growth Hormone, Prolactin, and Acromegaly

    • Acromegaly is characterized by abnormal growth of hands, feet, and face due to increased production of growth hormone and IGF-1 during adulthood.
    • Acromegaly is treated with dopamine alongside growth hormone antagonists and somatostatin analogs.
    • Prolactin has a similar structure to growth hormone.
    • Unlike growth hormone, prolactin is not regulated by negative feedback.
    • Overproduction of prolactin can be caused by adenoma or impaired dopamine transport, leading to decreased estrogen levels.
    • Dopamine inhibits prolactin secretion, making it the preferred treatment for prolactinemia.
    • While dopamine stimulates growth hormone secretion in healthy individuals, it suppresses growth hormone secretion in patients with acromegaly.
    • This makes dopamine a valuable treatment for both prolactinoma and acromegaly.

    Somatropin

    • Mimics and restores the actions of endogenous growth hormone
    • Stimulates linear bone growth
    • Increases bone mass
    • Increases muscle mass
    • Reduces fat mass
    • Regulates blood glucose and lipid levels
    • Acts directly through somatropin and indirectly through insulin-like growth factor-1 (IGF-1)
    • Binds to the human growth hormone receptor (GHR)
    • Upon binding, GHR dimerizes and interacts with Janus Kinase 2 (JAK2)

    Adverse Drug Reactions (ADRs)

    • Generally well-tolerated
    • Intracranial hypertension: vision disturbances, headache, nausea, edema
    • Hypothyroidism
    • Pancreatitis
    • Gynecomastia
    • Myalgia
    • Fluid imbalance
    • Pain at injection site
    • Increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST)

    Drug-Drug Interactions (DDI)

    • Glucocorticoids may inhibit the effects of growth hormone
    • Growth hormone may induce insulin resistance in patients with diabetes mellitus or cause hyperglycemia

    Uses

    • Treatment of growth failure in children due to inadequate endogenous growth hormone secretion
    • Treatment of growth hormone deficiency in adults due to deficiency of growth hormone or other hormones (hypopituitarism)
    • Treatment of lean body wasting in adults

    Oxytocin

    • Acts through G protein-coupled receptors to contract the uterus and induce labor.
    • Contracts mammary glands, causing the release of milk ("milk let-down").
    • Increases the synthesis of oxytocin receptors.
    • Used to induce labor.

    Atoxiban (Oxytocin Antagonist)

    • Prevents uterine contractions.
    • Used to prevent preterm labor.

    Drugs Inducing Hyperprolactinemia (Hyper-PRL)

    • Antipsychotics (don't discontinue psychoactive drugs): These medications often block dopamine receptors, leading to increased prolactin levels.
    • Dopamine Antagonists: These drugs interfere with the normal function of dopamine, which can result in hyper-PRL.
    • Metoclopramide: This drug, used for nausea and vomiting, can also trigger hyper-PRL.
    • Tricyclic Antidepressants: Certain tricyclic antidepressants have been linked to elevated prolactin levels.
    • Monoamine Oxidase Inhibitors (MAOIs): MAOIs can cause hyper-PRL as a side effect.
    • Selective Serotonin Reuptake Inhibitors (SSRIs): Some SSRIs can lead to increased prolactin levels.
    • H2 Blockers: These medications, used for acid reflux, can sometimes lead to elevated prolactin levels.
    • Verapamil: This calcium channel blocker can contribute to hyper-PRL.
    • Methyldopa: This medication, used to treat high blood pressure during pregnancy, can also cause hyper-PRL.

    Adverse Drug Reactions (ADRs) of Glucocorticosteroids

    • Adrenal Suppression: Long-term use of oral glucocorticosteroids can suppress the adrenal glands' ability to produce cortisol.
      • Rapid dose reduction can lead to disease symptom reappearance or worsening.
      • Full recovery of the hypothalamic-pituitary-adrenal (HPA) axis can take 2-12 months, with normal cortisol levels potentially taking 6-9 months.
    • Hyperglycemia: Glucocorticoids can raise blood sugar levels.
      • They promote fat breakdown (lipolysis), leading to increased free fatty acids.
      • They stimulate gluconeogenesis (glucose production) in the liver.
      • They decrease glucose uptake by muscles.
    • Hypertension and Hypokalemia: Glucocorticoids can cause high blood pressure and low potassium levels.
      • They increase sodium and water retention.
      • They increase potassium secretion.
      • They increase vasopressin release, reducing water excretion.
    • Increased Risk of Infection: Glucocorticoids can weaken the immune system.
      • Normal cortisol levels are crucial for maintaining glucose levels, which provide energy for the body to fight stress, trauma, and infection.
      • Glucocorticoids decrease lymphocytes, reducing the body's ability to fight infections.
    • Osteoporosis: Glucocorticoids can contribute to bone loss.
      • They interfere with vitamin D-stimulated calcium transport.
      • They increase renal calcium excretion.
      • They decrease osteoblast precursors and stimulate osteoclasts.
    • Catabolic Effect: Glucocorticoids break down protein in muscles, fats, and skin.
      • They increase protein synthesis in the liver.
      • They can lead to muscle weakness (myopathy).
      • They can cause excessive protein catabolism, resulting in protein wasting.
      • They can lead to bruising and skin thinning.
    • Behavioral Changes: Glucocorticoids can affect mood, behavior, and brain activity.
      • They can cause depression, insomnia, psychosis, or hypomania, potentially due to effects on neurosteroids.
      • Withdrawal of glucocorticoids can also lead to depression or hypomania.
    • Peptic Ulcer: Glucocorticoids can increase the risk of ulcers.
      • They stimulate the production of gastric acid and pepsin, worsening ulcers.
      • They suppress local immune responses against Helicobacter pylori, making infections more likely.
    • Weight Gain: Glucocorticoids can contribute to weight gain.
      • They stimulate lipolysis, leading to increased fatty acids and fat deposition.
      • They increase blood glucose levels and decrease glucose uptake by muscles.
      • They can increase appetite.
    • Glaucoma and Cataracts: Glucocorticoids can affect the pressure in the eyes.
    • Iatrogenic Cushing Syndrome: Long-term use can mimic the symptoms of Cushing's syndrome, including fat distribution in the back ("buffalo hump"), neck, and face ("moon face").
      • These metabolic changes can include: myopathy, increased amino acid diversion to glucose production, hyperglycemia, osteoporosis, and others.
    • Growth Retardation: Glucocorticoids can hinder growth during childhood.
      • They decrease osteoblast precursors, which are important for bone growth.
      • Synthetic glucocorticoids have a stronger growth-suppressing effect than natural cortisol, even at equivalent doses.

    Cushing Syndrome Medications

    • Aminoglutethimide (Cytadren)

      • MOA: Inhibits cholesterol desmolase, the first step in cholesterol synthesis. May also inhibit aromatase.
      • ADRs: Sedation, nausea, skin rash, anorexia. Administer every 6 hours.
      • DDIs: Decreases warfarin effect, increases metyrapone efficacy and reduces its ADRs. Use a lower dose of aminoglutethimide when combined with metyrapone.

    • Metyrapone (Metopirone)

      • MOA: Inhibits the final step of cholesterol synthesis. Steroidogenesis inhibitor.
      • ADRs: Nausea, sedation, hypertension, hirsutism, acne (due to increased androgens), salt and water retention.

    • Ketoconazole (Nizoral)

      • MOA: Steroidogenesis inhibitor at very high doses.
      • ADRs: Decreased testosterone, decreased libido, increased hepatic enzymes, gynecomastia, nausea, vomiting.
      • DDIs: Many serious drug interactions.

    • Osilodrostat (Isturisa)

      • MOA: Inhibits the 11-beta-hydroxylase enzyme, crucial for cortisol biosynthesis. Steroidogenesis inhibitor.
      • ADRs: Adrenal insufficiency, fatigue, nausea, headache, edema.
      • DDIs: CYP3A4 inducer and inhibitor, CYP2D6 inducer.

    • Mifepristone (Korlym, Mifeprex)

      • MOA: Anti-progesterone, but also acts as a glucocorticoid receptor antagonist, potentially blocking excessive glucocorticoids.
      • ADRs: Vomiting, diarrhea, pain, excessive vaginal bleeding, abdominal and uterine cramping, nausea, hypokalemia.

    • Cyproheptadine (Periactin)

      • MOA: Central neuromodulator that decreases ACTH release.
      • ADRs: Sedation, hyperphagia, anti-cholinergic effects.

    • Mitotane (Lysodren)

      • MOA: Adrenocytotoxic, decreases cortisol production. Adrenal inhibition without causing cellular destruction. Selectively targets adrenal cortex cells.
      • ADRs: Lethargy, rash, CNS depression, nausea, vomiting.

    Spironolactone

    • MOA: Blocks mineralocorticoid receptors (MRs), preventing the formation of aldosterone-induced proteins (AIPs). Indirectly decreases sodium channel permeability, reducing sodium reabsorption and increasing potassium retention. Inhibits aldosterone action.
    • Uses: Cushing syndrome (for symptomatic relief of hypertension and hypokalemia), aldosteronism (inhibits aldosterone biosynthesis in the adrenal gland, reducing hypertension), diagnostic tool for aldosteronism, treatment of hirsutism in women, heart failure.
    • ADRs: Hyperkalemia, metabolic acidosis, gynecomastia, GI discomfort, fatigue, menstrual irregularities, hypotension.

    Addison's Disease Medications

    • Corticosteroids: Mimic endogenous cortisol levels. Hydrocortisone, cortisone, or prednisone are preferred. The lowest dose is used to prevent ADRs.
      • Agent of Choice: Hydrocortisone. 15-20 mg PO in the morning and 10 mg PO in the late afternoon. Dosing should mimic endogenous cortisol production. The majority of the daily dose (67%) should be given in the morning, and the remainder (33%) in the afternoon.
    • Mineralocorticoids: Prevent hyperkalemia. Fludrocortisone is the preferred agent.
      • Agent of Choice: Fludrocortisone acetate 50-200 mcg/day.
      • Sodium Restriction: Avoid consuming more than 3-4 grams of sodium per day.
    • DHEA Supplementation: May increase energy and libido. Use 25-50 mg/day.

    ### Cushing Syndrome Drugs

    • Aminoglutethimide (Cytadren)

      • MOA: Inhibits cholesterol desmolase, the first step in cholesterol synthesis.
      • ADRs: Sedation, nausea, skin rash, anorexia. Administer every 6 hours.
      • DDI: Decreases warfarin effect, increases metyrapone efficacy and reduces its ADRs. Use a lower dose of aminoglutethimide when combined with metyrapone.

    • Metyrapone (Metopirone)

      • MOA: Inhibits the final step of cholesterol synthesis. Acts as a steroidogenesis inhibitor.
      • ADRs: Nausea, sedation, hypertension, hirsutism, acne (increased androgen), salt and water retention.

    • Ketoconazole (Nizoral)

      • MOA: Acts as a steroidogenesis inhibitor at very high doses.
      • ADRs: Decreased testosterone, decreased libido, increased hepatic enzyme, gynecomastia, nausea, vomiting .
      • DDI: Numerous serious drug interactions.

    • Osilodrostat (Isturisa)

      • MOA: Inhibits the 11-beta-hydroxylase enzyme, crucial for cortisol biosynthesis. Acts as a steroidogenesis inhibitor.
      • ADRs: Adrenal insufficiency, fatigue, nausea, headache, edema.
      • DDI: CYP3A4 inducer and inhibitor, CYP2D6 inducer.

    • Mifepristone (Korlym, Mifeprex)

      • MOA: Anti-progesterone, also acts as a glucocorticoid receptor antagonist, potentially blocking excessive glucocorticoids.
      • ADRs: Vomiting, diarrhea, pain, excessive vaginal bleeding, abdominal and uterine cramping, nausea, hypokalemia.

    • Cyproheptadine (Periactin)

      • MOA: Central neuromodulator that decreases ACTH release.
      • ADRs: Sedation, hyperphagia, anti-cholinergic effects.

    • Mitotane (Lysodren)

      • MOA: Adrenocytotoxic, decreases cortisol production. Adrenal inhibition without cellular destruction. Selectively targets adrenal cortex cells, cytotoxic (significant harm to the patient if handled improperly).
      • ADRs: Lethargy, rash, CNS depression, nausea, vomiting.

    ### Spironolactone

    • MOA: Blocks mineralocorticoid receptors (MR), preventing the formation of aldosterone-induced proteins (AIPs). Indirectly decreases sodium channel permeability, decreases sodium reabsorption, increases potassium retention, inhibits aldosterone action.
    • Use: Cushing syndrome (for symptomatic relief of hypertension and hypokalemia), aldosteronism (inhibits aldosterone biosynthesis in the adrenal gland, decreases hypertension), diagnostic tool to detect aldosteronism, treatment of hirsutism in women, heart failure.
    • ADRs: Hyperkalemia, metabolic acidosis, gynecomastia, gastrointestinal discomfort, fatigue, menstrual irregularities, hypotension.

    ### Addison's Disease Drugs

    • Corticosteroids
      • To mimic endogenous levels: hydrocortisone, cortisone, or prednisone.
      • Agent of Choice: Hydrocortisone 15-20 mg PO in the morning and 10 mg PO at 4:00-5:00 pm. Administration mimics endogenous cortisol production.
      • Majority of the total daily dose (67%) is given in the morning, the remainder (33%) is given in the afternoon.
    • Mineralocorticoids
      • To prevent hyperkalemia: Fludrocortisone
      • Agent of Choice: Fludrocortisone acetate 50-200 mcg/day.
      • Do not consume more than 3-4 grams of sodium per day.
    • DHEA supplementation
      • Increases energy and libido.
      • Use 25-50 mg/day.

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