Pharmacotherapy of Pituitary & Adrenal Disorders PDF

Laurajo Ryan, PharmD, MSc, BCPS Clinical Professor The University of Texas at Austin College of Pharmacy UT Health San Antonio Pharmacotherapy Education Research Center Department of Medicine [email protected] PHARMACOTHERAPY OF PITUITARY & ADRENAL DISORDERS Learning Objectives • Describe the rec...

Laurajo Ryan, PharmD, MSc, BCPS Clinical Professor The University of Texas at Austin College of Pharmacy UT Health San Antonio Pharmacotherapy Education Research Center Department of Medicine [email protected] PHARMACOTHERAPY OF PITUITARY & ADRENAL DISORDERS Learning Objectives • Describe the recommended treatment to include mechanism of action, contraindications & major adverse effects/drug interactions for the following disease states: • Pituitary disorders – Growth hormone disorders – Arginine vasopressin deficiency – Hyperprolactinemia • Adrenal disorders – Pheochromocytoma – Cushing’s syndrome – Adrenal insufficiency – Hyperaldosteronism Outline • Hormone release – Hypothalamic • Pituitary disorders – Growth hormone – Vasopressin – Prolactin – Luteinizing hormone & follicle stimulating hormone • Adrenal disorders – Cushing’s syndrome/disease – Hyperaldosteronism – Pheochromocytoma Hypothalamic Releasing Hormones Hormone Action Thyrotropin-releasing hormone (TRH) Stimulates TSH & prolactin secretion Corticotropin-releasing hormone (CRH) Stimulates ACTH secretion Gonadotropin-releasing hormone (GnRH) Stimulates LH/FSH secretion Somatostatin—AKA growth hormone inhibiting hormone (GHIH) & somatotropin releaseinhibiting factor (SRIF) Inhibits growth hormone secretion Dopamine (prolactininhibiting factor) (PIF) Inhibits prolactin secretion Growth hormone releasing hormone (GHRH) Stimulates growth hormone secretion Hypothalamic/Pituitary Hormones THE HORMONES Anterior Pituitary Hormones • • Growth hormone (GH) – Stimulates protein synthesis & growth Follicle-stimulating hormone (FSH) – Stimulates estrogen synthesis & follicular development – Stimulates sperm maturation • Luteinizing hormone (LH) – Stimulates ovulation, formation of corpus luteum, estrogen, progesterone & synthesis – Stimulates testosterone synthesis • Adrenocorticotropic hormone (ACTH) – Stimulates synthesis & secretion of adrenal cortical hormones • Cortisol, androgens, aldosterone • • Thyroid-stimulating hormone (TSH) – Stimulates synthesis & secretion of thyroid hormones Prolactin (PRL) – Stimulates milk production & secretion Posterior Pituitary Hormones • Oxytocin – Stimulates smooth muscle contraction • Milk ejection from breasts • Uterine contractions • Vasopressin – Antidiuretic hormone (ADH) – Arginine vasopressin (AVP) – Stimulates • Water reabsorption in principal cells of collecting ducts • Arteriolar constriction GROWTH HORMONE Growth Hormone Regulation Costanzo LS. Physiology, 5th Ed. W.B. Saunders Company, 2014 Growth Hormone • Effects • Stimulation of GH via GHRH – DEcreased peripheral glucose utilization – DEcreased protein catabolism – DEcreased insulin sensitivity – INcreased IGF-1 release – INcreased FFA release – INcreased protein production – Stimulates IGF-1 – Hypoglycemia – Stress, exercise, growth – Clonidine • Can be used to test release • Inhibition of GH via somatostatin – Obesity – Dopamine & beta agonists – IGF-1 Lippincott's Illustrated Reviews: Pharmacology, 5th Ed Growth Hormone • Endogenous GH release – Pulsatile • Q2 hours – Diurnal • Maximal secretion at night • Symptoms of deficiency – Pediatrics • Short stature – Adults • Elevated LDL • Subcutaneous & visceral adiposity • Low bone mineral density • Decreased cardiac output • Goal of therapy – Mimic effects of endogenous GH GH Deficiency • Recombinant hGH replacement – Give at night • Avoid post-prandial GH elevations • Low-dose replacement preferable to higher doses – Beneficial effects on glucose metabolism & insulin resistance – 3-6 months for benefit – Monitoring • American Academy of Clinical Endocrinologists – IGF-1, glucose, free T4 & lipids – Adverse effects • Edema, arthralgia, myalgia, pancreatitis, insulin resistance, carpal tunnel syndrome – Most AE seen in adults vs. children Insulin-Like Growth Factor (IGF-1) • Acts as insulin sensitizer & DEcreases BG – Binds IGF-1 & insulin receptors • Increase glucose uptake – Inhibits renal gluconeogenesis – Negative feedback on GH • Helps to restore insulin sensitivity Nat Rev Drug Disc 2007;6:821 Primary IGF-1 Deficiency • Mecasermin (Increlex®) – Recombinant IGF-1 – Subcutaneous dosing • BID – Adverse effects • Hypoglycemia – Give ~20 minutes of food • Hypersensitivity reactions Nat Rev Drug Disc 2007;6:821 GH Excess—Acromegaly • Consequences depend on age – Before puberty • Stimulation at epiphyseal plates ↑ linear growth • Gigantism GH Excess—Acromegaly • Consequences depend on age – After puberty • ↑ periosteal bone growth • Bone changes – Enlargement, ↑ hand & foot size, osteoporosis – Coarsening of facial features • Visceromegaly – Cardiomegaly, hepatomegaly, goiter • Metabolic – Insulin resistance & glucose intolerance • Neuropathies – Peripheral neuropathy, carpal tunnel, spinal cord compression Acromegaly • Diagnosis – Pituitary tumor most common cause • CT/MRI imaging – GH > 10 ng/mL in 90% patients • Normal fasting GH: 5 ng/mL – Oral Glucose Tolerance Test (OGTT) • High GH post 50 – 100 g glucose • GH >2 ng/mL (♂), > 5 ng/mL (♀) diagnostic – Heel pad > 33 mm – Elevated insulin-like growth factor • (IGF-1) (somatomedin) – Elevated IGF-1 binding protein-3 (IGFBP3) GH Excess—Acromegaly • Treatment – Transsphenoidal surgery • Primary therapy – Successful in 90% of patients – Radiation • Adjunctive therapy in some patients • Slow onset of action • May result in panhypopituitarism – Medical therapy • Most patients require post-surgical adjuvant • Also used for unresectable tumors • Does not typically shrink tumor Acromegaly—Somatostatin Analogs • Bind somatostatin receptor • Adverse effects & mimics somatostatin – Nausea/abdominal pain action; inhibits GH – Diarrhea production – Gallstones/sludge/ – Octreotide (Sandostatin®) – Lanreotide (Somatuline®) – Pasireotide (Signifor®) • High affinity binding to somatostatin receptor • Inhibits ACTH secretion pancreatitis – HypER or hypOglycemia • ↓ insulin & glucagon • hypERglycemia more common – – – – – Bradycardia Rash/pruritus Alopecia Anemia QTc prolongation Acromegaly—Somatostatin Analogs IGF Research 2011;21:129 Acromegaly—Somatostatin Analogs • Octreotide – SubQ duration 6-12 hours • TID dosing – IM depot • Q4 weeks – Hepatic metabolism • ~1/3 excreted in urine unchanged – t½ ~2 hours • Lanreotide – IM, subQ Q4 weeks – Metabolized in GI tract after biliary excretion – t½ ~23-36 days • Pasireotide (Signifor®) – IM Q4 weeks – Primarily biliary elimination as unchanged drug Acromegaly—Somatostatin Analogs (SSA) • Mechanism of action • Pasireotide* (Signifor®) – Bind somatostatin receptor • Mimics somatostatin, inhibits GH production – 30-40X binding vs octreotide, lanreotide • Octreotide (Sandostatin®) • Lanreotide (Somatuline®) • SSA adverse effects – Primarily GI • Nausea, abdominal pain • Diarrhea, constipation • Gallstones/sludge, pancreatitis – Hyperglycemia • ↑ with pasireotide – QTc prolongation * Better outcomes vs octreotide in RCT; IGF Research 2011;21:129 J Clin Endocrinol Metab 2014;99:791 Acromegaly—GH Receptor Antagonist IGF Research 2011;21:129 Acromegaly—GH Receptor Antagonist • Pegvisomant (Somavert®) – Binds GH receptor • Similar structure to GH; binds without activation – Competitive antagonist – Blocks GH binding—dose dependent receptor occupation – Adverse events • • • • Diarrhea Nausea Rare hepatoxicity; reversible Lipohypertrophy • PK – t½ ~6 days – SubQ • Loading dose • Daily injections • Interferes with GH assays – OVERestimates GH levels • Normalizes IGF-1 Somatostatin Analog vs GH Receptor Antagonist • Somatostatin analogs – – – – – – GH/IGF-1 normalized ~50% Induce tumor shrinkage Improve co-morbidities Decrease mortality Good safety profile Convenient (monthly) & cost effective • GH receptor antagonist – Safe & more effective vs SSA • IGF-1 normalized >95% – Little to no change in tumor size – Improves cardiac & respiratory co-morbidities – Combination with SSA can reduce PEGV dose Acromegaly—Dopamine Agonists • Cabergoline, bromocriptine – Ergot derivatives – Bind D2 receptors on GHproducing cells • Decreases GH production – ~15% efficacy – Adverse events • Nausea/vomiting – Chemoreceptor trigger zone (CTZ) binding • • • • Orthostatic hypotension Headache Fatigue Psych issues • Cabergoline PK – Hepatic metabolism • Hydrolysis – t½ ~ 63-69 hours • Extensive distribution • Bromocriptine PK – Extensive hepatic metabolism • CYP3A4 – t½ ~ 3-5 hours • High protein binding VASOPRESSIN Vasopressin Action • Antidiuretic action – Collecting ducts of the kidney • Vasopressin – Binds V2 receptors on the cell surface of tubular cells – Initiates intracellular cascade – Results in generation aquaporin-2 Arginine Vasopressin Deficiency (AVP-D) • Decrease in ADH – Cannot concentrate urine • Presentation – – – – Polyuria Nocturia Polydipsia Hypernatremia if access to free water impaired, or decreased thirst response • Treatment goals – Replace fluid losses & decrease nocturia & urine output Arginine vasopressin resistance (AVP-R) = ↓ renal response to ADH AVP-D • Decreased vasopressin (ADH) – Cannot concentrate urine • Presentation – – – – Polyuria >50mL/kg/day Nocturia Polydipsia Hypernatremia if: • Access to free water impaired • Decreased thirst response • Treatment goals – Replace fluid losses – Decrease nocturia – Decrease urine output AVP-D Treatment—AVP Analog • Desmopressin AKA (DDAVP®) – Increases cAMP in renal tubular cells • Increases permeability – Decreased urine volume – Increased urine osmolality – Dosed at bedtime to reduce nocturia – Adverse events • Rhinitis with intranasal • Hyponatremia risk – PK • IV/IM/SQ/IN/PO – Inj ~ 10X potent vs IN – IN 10-40X potent vs PO » 0.1mg tab ~5µg spray • Duration 4-6 hours • t½ ~3 hours – Renal excretion AVP-D Treatment—Other • AVP-DEpendent – Increase ADH response • Chlorpropamide • Carbamazepine – NSAIDs (primarily indomethacin) • Inhibits renal prostaglandin synthesis – Increases ability to concentrate urine » Renal prostglandins are ADH antagonists • AVP-INdependent – Hydrochlorothiazide (HCTZ) • 1st line in AVP-R; also effective in AVP-D • Volume depletion from HCTZ – Causes increase in proximal sodium & water reabsorption – Decreases water delivery to collecting tubules (ADH sensitive) Syndrome of Inappropriate ADH—SIADH • Vasopressin excess – Signs & symptoms • Opposite of central DI • Rapid Na+ decreases can result in cerebral edema • ↓Na+ may be tolerated if decline gradual • Causes – – – – – Tumor Reset osmostat Pulmonary infections Ectopic ADH production Drugs • Hyponatremia – > 130 mEq/L • Asymptomatic – 120 – 125 mEq/L • Lethargy • Confusion • Weakness – <120 mEq/L • Seizures • Coma • Death • Treat underlying cause SIADH Diagnosis • Diagnosis – Hyponatremia & hypoosmolality • High Uosm – > 100 mOsm/kg) • Urine Na+ – > 20 mEq/L – Euvolemia – Normal plasma pH – Normal renal, adrenal & thyroid SIADH Treatment—↑ Serum Na+ • Fluid restriction – < 800 mL/day • Increase solute intake – Salt tablets, urea • ± loop diuretic • IV hypertonic (3%) NaCl only if Na+ very low – Don’t correct too quickly • Risk of cerebral pontine myelinolysis • <0.5 mEq/L/hr -OR• <12 mEq per 24 hours • Vasopressin (V2) receptor antagonist • Tolvaptan, conivaptan – Selective aquaresis; excrete free water • Demeclocycline & lithium; not commonly used – Act on collecting tubules to decrease response to ADH & increase water excretion Drug—Induced SIADH Mnemonic • Vasopressin – Vincristine – Vinblastine – Vasopressin/desmopressin • Primary – Phenothiazines • Cause – Carbamazepine – Cyclophosphamide – Chlorpropamide • Of – Oxytocin (high dose) • SIADH – SSRIs • iN – Nicotine • MosT – MAO inhibitors – Tricyclic antidepressants PROLACTIN Prolactin Regulation Costanzo LS. Physiology, 5th Ed. W.B. Saunders Company, 2014 Hyperprolactinemia • Prolactin (PRL) – Stimulation • TRH • Estrogen • Dopamine antagonists – Inhibition • Dopamine – Effect • Stimulates milk production CMAJ 2003;169:575 Hyperprolactinemia • Causes • Signs/symptoms – Pregnancy – Primary hypothyroid – Prescriptions • Dopamine antagonists – Phenothiazines – Metoclopramide • Prolactin stimulators – – – – Benzodiazepines Tricyclic antidepressants Opioids H2 blockers – Prolactinoma – Women • • • • • Irregular menses Amenorrhea Galactorrhea Mood swings Weight gain – Men • • • • Decreased libido Hypogonadism Gynecomastia Erectile dysfunction Dopamine Agonists…yep, same drugs • Cabergoline, bromocriptine – Ergot derivatives – Binds D2 receptors • Prolactin under hypothalamic inhibitory control (dopamine) – Adverse events • Nausea/vomiting – Chemoreceptor trigger zone (CTZ) binding • • • • Orthostatic hypotension Headache Fatigue Psych issues • Cabergoline PK – Hepatic metabolism • Hydrolysis – t½ ~ 63-69 hours • Extensive distribution • Bromocriptine PK – Extensive hepatic metabolism • CYP3A4 – t½ ~ 3-5 hours LUTEINIZING HORMONE & FOLLICLE STIMULATING HORMONE LH/FSH • Luteinizing hormone (LH) – Stimulation • Gonadotropin Releasing Hormone (GnRH) • Estradiol (Follicular Phase) • Clomiphene – Inhibition • Estradiol (children) • Testosterone – Effects • Ovulation, maintains corpus luteum • Testosterone production (men) • Follicle stimulating hormone (FSH) – Stimulation • GnRH • Menopause/ovarian disorders • Clomiphene – Inhibition • Estradiol (children) • Inhibin (men) – Effects • Follicle stimulation • Estrogen & progesterone • Sex binding hormone globulin (men) LH/FSH Deficiency • Signs/symptoms – Female • Decreased libido, axillary and pubic hair, vaginal lubrication, infertility, vasomotor instability – Male • Infertility, decreased facial hair, impotence, decreased hematocrit • Treatment – Female • Estrogen replacement – Hormone therapy – Oral contraceptives • Clomiphene – Stimulate ovulation – Male • Testosterone – IM, patch, gel PANHYPOPITUITARISM Hypopituitarism • Pathophysiology – Underactive pituitary gland • Signs/symptoms – Present with features of specific hormone deficiency • Decreased growth hormone – Fatigue • Decreased FSH/LH – Decreased libido, impotence, decreased menstruation, decreased pubic hair, change in sexual function • ACTH deficiency – Non-specific fatigue, weakness, apathy – No hypokalemia, salt cravings, or hyperpigmentation • Decreased TSH – Similar to central hypothyroidism, usually no goiter • Arginine vasopressin deficiency (AVP-D) – Polyuria, nocturia, polydipsia, hypernatremia Hypopituitarism • Treatment – Resolve underlying cause & replace deficient hormones; doses based on individual needs • • • • • • Glucocorticoid replacement GH replacement Estrogen/progesterone replacement (♀) Testosterone replacement (♂) Thyroid replacement Desmopressin for AVP deficiency ADRENAL DISORDERS Hypothalamic/Pituitary Hormones Adrenal Physiology • Adrenal medulla – Catecholamines • Norepinephrine • Epinephrine • Dopamine • Adrenal cortex – Steroid hormones • Zona glomerulosa – Mineralocorticoids » Aldosterone • Sodium & fluid balance • Zona fasciculata – Glucocorticoids » Cortisol • Carbohydrate & protein metabolism • Antiinflammatory • Zona reticularis – Sex hormones » Secondary source Costanzo LS. Physiology, 5th Ed. W.B. Saunders Company, 2014 Adrenal Hormones • Adrenal androgens – Dehydroepiandrosterone (DHEA) & androstenedione • Cortisol – Stimulates gluconeogenesis – Suppresses inflammatory & immune responses – Increases vascular responsiveness to catecholamines • Aldosterone – Increases renal Na+ reabsorption – Increases K+, H+ secretion Adrenal Hormones • Cortisol – – – – Stimulates gluconeogenesis Suppresses inflammatory & immune responses Increases vascular responsiveness to catecholamines Stressor response • Actions – Maintain CV function – BP regulation – CHO metabolism » Hepatic glucose regulation – Immune function » ¯ inflammation » Immune suppression – Deficiency • ¯ response to stressors • Rapid deterioration – Organ damage ®shock/coma/death Adrenal Hormones • Aldosterone – Mineralocorticoid • Water/sodium balance • Increases renal Na+ reabsorption • Increases K+, H+ secretion – Deficiency • Inability to maintain BP – Over-excretion of Na+ • Hyperkalemia ADRENAL INSUFFICIENCY HPA Axis • Hypothalamic pituitary adrenal feedback loop Adrenal Insufficiency • Primary (Addison’s) – Damaged adrenal glands • Auto-immune ~ 80% • Secondary – ¯ CRH (hypothalamus) • Mineralocorticoid production maintained – ¯ ACTH (pituitary) • Mineralocorticoid production maintained Nat Rev Neph 2010;6:117 Adrenal Insufficiency—Chronic Features • Weakness, fatigue • Gastrointestinal symptoms – N/V & pain; diarrhea & constipation may alternate • Weight loss/anorexia • Psychiatric – Depression, apathy – Psychosis – Memory impairment • ¯ BP • Myalgia, arthralgia • Amenorrhea • Auricular calcifications – Males • Lab findings – Hyponatremia • ~75% – Hypoglycemia • More common in secondary – Normocytic anemia Adrenal Insufficiency—1° vs 2° • 1° • 2° – Hyperpigmentation • Most – Orthostasis, syncope – Hyperkalemia • Hyperchloremic acidosis – Salt craving – Hypoglycemia • Mild, occasional – Hyperpigmentation • None – Orthostasis, hypotension • Uncommon – Hyperkalemia • None – Salt craving • None – Hypoglycemia • More severe, common Adrenal Insufficiency—Treatment • Hydrocortisone/prednisone • Fludrocortisone – Glucocorticoid replacement • Some mineralocorticoid action – Adverse effects • Hypertension, hyperglycemia, fluid retention, osteoporosis, impaired immune function – Adverse effects primarily related to over-replacement – Mineralocorticoid replacement • Some glucocorticoid action • ↑ K+ & H+ secretion in distal tubule • Na+ & H2O retention – Adverse effects • Hypertension, hyperglycemia, fluid retention, osteoporosis, impaired immune function – Sodium & fluid retention are desired effects Adrenal Insufficiency—Treatment • Maintenance – Glucocorticoid • Hydrocortisone (HCT) traditional choice – 10mg QAM; 5mg @ 1800 • Prednisone – 5mg QAM – Mineralocorticoid • Primary only • Fludrocortisone – 100µg QAM • Minor illness • ­ HCT 2X-3X • Continue fludrocortisone 100µg QAM • Moderate stress dosing – Minor procedure • HCT 100mg IV Adrenal Crisis—Pathophysiology • Precipitating event – Illness/stress • Infection & injury common – Non-adherence • Stress (non) response – Non-responsive to catecholamines • Vasodilation & capillary leak • Cannot maintain BP • Eventual circulatory collapse – Hypoglycemia • Cannot maintain fasting BG • No hepatic response to hypoglycemia – Difficult to reverse without cortisol replacement Adrenal Crisis—Clinical Presentation • Hypovolemia & hypotension – Unresponsive to fluids/pressors • Abdominal pain – Vomiting • 1° disease only – Hyperkalemia – Hyponatremia • Neurologic deficits – – – – – HA Confusion Seizure Lethargic Unresponsive • Hypoglycemia – > in 2°; may be refractory to D50 Adrenal Crisis—Treatment • Fluids – NS 2−3L • Over first few hours – D5/NS if hypoglycemia • Glucocorticoid – HCT 100mg bolus • 50mg IV Q6 OR • 200mg/24hr infusion • Treat precipitating illness • Taper/discontinue IV steroids – Clinical improvement – Discontinue NS • Give 100µg fludrocortisone prior to DC drip (1∘) • Initiate replacement glucocorticoids Equipotent Steroid Dosing Steroid EQ Dose (mg) Glucocorticoid activity (antiinflammatory) Mineralocorticoid activity Dosage Forms 25 20 0.8 1 2 1 PO PO, inj, top Methylprednisolone Prednisolone Prednisone Triamcinolone 4 5 5 4 5 4 4 5 0 1 1 0 Fludrocortisone -- 10 125 PO, inj, top PO PO PO, inj, top, nasal, inh*, opth PO 0.6 0.75 25 30 0 0 Inj, top PO, inj, top, opth Short-acting (t½ 8–12h) Cortisone Hydrocortisone Intermediate (t½ 18–36h) Long-acting (t½ 36–54h) Betamethasone Dexamethasone Attridge, Miller, Moote, Ryan 2012. Internal Medicine: A Guide to Clinical Therapeutics 1st ed. McGraw-Hill HYPERCORTISOLISM Cushing’s Syndrome • Cortisol – Stimulation • Adrenocorticotropic hormone • Release is pulsatile & diurnal – Higher AM vs. PM levels • Stress – Inhibition • Glucocorticoid concentration – Pituitary & adrenal level • Etiologies – Adrenal neoplasm • Adenoma • Carcinoma – Excess pituitary ACTH • aka “Cushing’s Disease” • Pituitary microadenoma – Excess ectopic ACTH – Iatrogenic (most common) • Long term glucocorticoid therapy Cushing’s Syndrome—Presentation • Obesity – Truncal obesity – Buffalo hump – Moon face • • • • • • • Red face Hypertension Hirsutism Muscle weakness Bruising Striae Acne • Psychiatric disorders • Amenorrhea • Osteoporosis Glucocorticoids—Adverse Effects Adverse Effect Incidence Onset Comments Fragile skin, 3% (in arthritis Variable purpura, striae patients) Most common in elderly® dose/duration dependent, striae Fat redistribution Variable Buffalo hump, ­ abdominal fat, thin extremities, muscle wasting, moon face Cushingoid appearance Common w/­ 2 months dose/duration ­ incidence w/­ doses; ~25% of patients taking > 7.5mg pred EQ/QD X 6 mo (Ann Rheum Dis 2009;68:1119) Euphoria/ psychosis 5% 1-2 weeks Rare with doses < 20mg pred EQ/day; typically resolves ~week after DC Cataracts Variable ³1 year Typically bilateral; risk is dose/duration related Osteoporosis Variable Variable Dose/duration dependent; bone loss greatest in 1st 6 mo; fracture rate up to 25% with long term tx Hyperglycemia ~100% Immediate Dose dependent Neutrophilia* ~100% 4-6 hours Average CBC changes after 40mg pred EQ® WBC ↑ 4X103 cells/mm3, lymphocytes ↓70%, monocytes ↓90%, no left shift (J Clin Invest 1968;47:249) Adrenal suppression Dose/duration > 3 weeks dependent (low dose) Months ¯ risk < 7.5-20mg pred EQ/day < 3 weeks (J Clin Invest 1964;43:1824; N Engl J Med 2003;348:727) Steroid Biosynthesis Cushing’s Syndrome—Treatment • Osilodrostat (Isturisa®) – Unable to have pituitary surgery – No disease resolution after surgery • Mechanism – Blocks 11β-hydroxylase • Oral therapy – Before initiating therapy • Fix hypokalemia & hypomagnesemia • Baseline ECG (repeat after 1 week) – 2mg BID initially, titrate Q2 weeks Cushing’s Syndrome—Treatment • Osilodrostat – Adverse effects • Adrenal insufficiency (dose related) – Anorexia, fatigue, nausea, vomiting, electrolyte abnormalities • Androgenic effects – Increased testosterone » Hirsutism, hypertrichosis, acne • Mineralocorticoid effects – Hypokalemia, hypertension, edema • QT prolongation – Concentration dependent, unknown mechanism Cushing’s Syndrome—Treatment • Ketoconazole – CYP450 enzyme inhibitor • • • • Blocks side chain cleavage 11β-hydroxylase 17𝛼-hydroxylase 17, 20 lyase – ↓ cortisol, aldosterone & testosterone – Adverse effects ketoconazole N-deacetyl ketoconazole • ***Hepatic injury*** • GI effects • Effects related to decreased steroid production – Drug interactions • P450 substrates Cushing’s Syndrome—Treatment • Mitotane (Lysodren®) – Cytotoxic—suppresses ACTH secretion • ↓ cortisol synthesis – Adverse effects • N/V/D, tiredness – U.S. Boxed Warning • Discontinue mitotane temporarily with onset of shock or severe trauma • Administer appropriate steroids • Cyproheptadine – 1st generation antihistamine (H1) & serotonin blocker • Decreases ACTH secretion; mechanism unclear – Only 30% efficacy • Metyrapone (Metopirone®) – Approved as diagnostic agent for ACTH dependent adrenal insufficiency; limited availability – Cushing’s is unlabeled use – Inhibits 11-hydroxylase • ↓synthesis of cortisol – Adverse effects • N/V, hypotension, dizziness & sedation – Primarily in those with adrenal insufficiency vs. Cushing’s – Drug interactions • Weak CYP2A6 inhibitor; weak CYP3A4 inducer Cushing’s Syndrome—Treatment • Pasireotide (Signifor®) yes…same drug – Somatostatin analog • High affinity binding to somatostatin receptor— inhibits ACTH secretion – Adverse effects • HA, fatigue, hyperglycemia & DM, GI effects, increased prothrombin time, QTc prolongation – Drug interactions • QTc prolonging drugs – Primarily biliary elimination as unchanged drug • Mifepristone – Blocks cortisol effects at glucocorticoid receptor • Used to decrease hyperglycemia in hypercortisol states; long-term therapy effects unknown – Adverse effects • Edema, HTN, fatigue, HA, dizziness, hypokalemia, nausea, vomiting, anorexia, diarrhea, arthralgias, QTc prolongation, abortifacient – Drug interactions • Corticosteroids, cyclosporine, strong CYP3A4 inducers, QTcprolonging drugs Cortisol Biosynthesis & Blockade Nat Clin Prac & Metab 2008;4:560 HYPERALDOSTERONISM Aldosterone Regulation • Renal arterial BP – RAAS • • • • • ➜ renin ➜ angiotensinogen ➜angiotensin I ➜ angiotensin II ➜ aldosterone synthesis – Extracellular K+ • Low K+ inhibits aldosterone secretion – Aldosterone • Na+, H2O retention – Increased BP • Cardiac remodeling Aldosterone Antagonists • Spironolactone (Aldactone®) – Mineralocorticoid receptor blocker – Also blocks androgen receptors • Gynecomastia – Hyperkalemia • Eplerenone (Inspra™) – Selective mineralocorticoid receptor blocker • No gynecomastia – Hyperkalemia • Aldosterone blockade – Inhibit Na+ reabsorption – Inhibit K+ excretion • Monitor K+ & renal function – Not recommended • Creatinine > 2.5mg/dL • Clearance < 30 mL/min • Serum K+ > 5.0 mEq/L – C/I in pregnancy PHEOCHROMOCYTOMA Pheochromocytoma • Signs/symptoms – PHEo • Palpitations • Headache • Episodal sweating • Achieve hemodynamic stability – IV fluids (NS) – Control blood pressure • α-blockade for BP control – Elevated catecholamine levels » α-mediated vasoconstriction • Target <120/80mmHg – Systolic >90mmHg – Maintain volume • Liberal Na+ intake • IV fluids Pheochromocytoma Treatment • α-blockade – Phenoxybenzamine • Traditional drug of choice • Typically 1—2 weeks prior to surgery • Non-selective, irreversible (non-competitive blockade) – Postural hypotension » Reflex tachycardia – Nasal congestion – Fatigue – Sexual dysfunction » Retrograde ejaculation • Titrate to BP control Pheochromocytoma Treatment • Selective α-1 blockers – Prazosin, terazosin, doxazosin – Alternatives for long-term therapy – Incomplete alpha blockade • β-blocker – Only if still tachycardic after α-block – Do NOT initiate before α-blockade • Results in unopposed α-stimulation Summary—Pituitary Disorders • GH deficiency – GH replacement • GH excess—acromegaly – Dopamine agonists • Vasopressin deficiency (AVP-D; AVP-R) – Desmopressin (DDAVP) – Other miscellaneous agents that increase response • SIADH – Fix cause – Increase serum Na+ • Hyperprolactinemia – Dopamine agonists • LH/FSH deficiencies – Replace estrogen/progesterone ♀; testosterone ♂ Summary—Adrenal Disorders • Adrenal insufficiency – Glucocorticoid replacement • Hydrocortisone (HCT)— 10mg QAM; 5mg @ 1800 – Mineralocorticoid replacement if needed • Fludrocortisone—100µg QAM • Hyperaldosteronism – Spironolactone – Eplerenone • Pheocromocytoma – α-blockade to control BP; β-blocker if needed • Cushing’s Syndrome – – – – – – – Osilodrostat Ketoconazole Cyproheptadine Mitotane Metyrapone Pasireotide Mifepristone