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門診處方討論 藥 師 鄭 育 凌 1 2 病史 • This p’t is 38 y/o female,在95年 1/31看診新陳代謝科 • 診斷:庫興氏症候群、 高血壓、 失眠 • 檢查:血液中cortisol濃度偏高,且收集24小時尿液 ,可 測得cortisol值遠大於正常人。做腦部CT-scan 發現病患在腦下垂體有corticotropic adenoma故 給予ketoconazole 1# TID治療 3 Introduction : Cushing's syndrome is a hormonal disorder caused by prolonged exposure of the body's tissues to high levels of the hormone cortisol. Sometimes called "hypercortisolism“ 1. • • • • 2. • • • Causes: 主要分成2種 ACTH independent— exogenous iatrogenic: administration of corticosteroids Adrenal adenoma Micronodular hyperplasia Macronodular hyperplasia ACTH dependent— endogenous Pituitary ACTH-secreting adenoma Ectopic ACTH Ectopic CRH 4 • • • • • • • • • • • Signs and symptoms moon facies, facial plethora supraclavicular fat pads buffalo hump truncal obesity purple striae proximal muscle weakness easy bruising weight gain, hirsutism in children, growth retardation Hypertension, osteopenia, diabetes mellitus impaired immune function may occur. 5 Fig1 Pathophysiology of Cushing's Disease 6 Fig2 7 Fig3 8 Fig4 9 Differential Diagnosis 篩檢: plasma cortisol 24-Hour Urinary Free Cortisol Level:＞100µg/dl/24hr 診斷: low-dose dexamethasone suppression test(LDDST): 11pm dexamethasone 1mg, serum cortisol >10µg/dl 鑑別 high-dose dexamethasone suppression test: dexamethasone 2mg q6h 連續48小時 血漿中的ACTH濃度: CRH Stimulation Test 17-hydroxycorticosteroid、17-ketosteroid(17-KS)、 testosetrone、estradiol。 10 造影 : x-rays, CT scan, MRI Treatment Reducing corticosteroid use Surgery: transsphenoidal surgery, adrenalectomy Radiation therapy • Hormone replacement →may require glucocorticoid replacement to avoid adrenal insufficiency Medical therapy:主要分四大類 11 Drug therapy Synthesis inhibitors & glucocorticoid antagonists 一.Adrenal enzyme inhibitors: Ketoconazole(NizoralR) : is the most popular and effective of these agents for long-term use and usually is the agent of choice Dosage:200-400mg PO bid/tid Mechanism of action: Imidazole broad-spectrum antifungal agent that acts on several of the P450 enzymes, including the first step in cortisol synthesis, cholesterol side-chain cleavage, and conversion of 11-deoxycortisol to cortisol. 12 Adverse effects: headache,sedation,nausea,irregular menses, decreased libido, impotence, gynecomastia,and elevated liver function Precaution: avoided administer antacid,anticholinergics, or H2 blockers at least 2h after taking ketoconazole Metyrapone Dosage:1 g/d PO divided qid; increase gradually , not to exceed 4.5 g/d blocks 11-ß-hydroxylase activity,the final step in cortisol synthesis. 13 Aminoglutethimide(Cytadren), Dosage:250 mg PO bid initially; increase to 2 g qid inhibits the synthesis of cortisol, aldosterone and sex hormones Adverse effects : somnolence, headache, a generalized pruritic rash, hypothyroidism, and goiter. In rare cases, it may cause bone marrow suppression Trilostane Dosage:200-1000mg/day inhibits3ß-hydroxysteroid dehydrogenase It is not a first-choice agent because it is a weak inhibitor of steroidogenesis 14 Etomidate imidazole-derivative anesthetic agent block 11ß- hydroxylase use is limited by the intravenous route: 0.3 mg/kg/h 二.Glucocorticoid blocking agents Mifepristone (RU486) Dosage:20mg/kg/day antiprogestational agent, anti-glucocorticoid effects. an investigational basis for treatment of Cushing syndrome 15 三. Centrally active drugs include bromocriptine, cyproheptadine, valproic acid, and octreotide. decrease CRH or ACTH release Currently, use of these agents is investigational 四.adrenolytic agent Mitotane(o,p’-DDD ,LysodrenR) inhibiting 11ß-hydroxylase and cholesterol side-chain cleavage enzymes. This drug also leads to mitochondrial destruction and necrosis of adrenocortical cells in the zona fasciculata and reticularis Is expensive and is limited by adverse gastrointestinal and neurologic effects, including nausea, diarrhea, dizziness, and ataxia 16 Reference • Ilias I, Torpy DJ, Pacak K, et al: Cushing's syndrome due to ectopic corticotropin secretion: twenty years' experience at the National Institutes of Health. J Clin Endocrinol Metab 2005 Aug; 90(8): 4955-62[Medline]. • Mark S.Cooper etc. NEJM 2003;348:727-34 • Wiebke Arlt etc. Lancet 2003; 361: 1881-93 • DIAGNOSTIC TESTING FOR CUSHING'S SYNDROME By Dr. James Findling, December, 2003 • Cushing's Disease Clinical Manifestations and Diagnostic Evaluation-september 1,2000-American family physician • Adapted with permission from Orth DN. Cushing's syndrome. N Engl J Med 1995;332:791-803 [Published erratum appears in N Engl J Med 1995; 332:1527]. 17