Transcript 부신피질호르몬의 종류
오승준 부신피질 호르몬이란? 부신피질호르몬제제와 올바른 사용 부신피질호르몬제제 사용시 문제점 부신피질 호르몬이란? 부신피질호르몬제제와 올바른 사용 부신피질호르몬제제 사용시 문제점 15% Zona glomerulosa: Aldosterone 75% Zona fasciculata: Cortisol 10% Zona reticularis: Sex steroid Cell types Vessels Compound E Sep 21, 1948 The first injection of compound E for rheumatoid arthritis Cortisone Nobel Prize in 1950 Charles H. Slocumb (left) Howard F. Polley Edward c. Kendall Philip S. Hench A Famous Sufferer of Addison’s Disease John Kennedy was sick from age 13 on. In 1930, when he was 13, he developed abdominal pain. By 1934 he was sent to the Mayo Clinic where they diagnosed colitis or it was called colitis. By 1940 his back started hurting him, by 1944 he had his first back operation, by 1947 he was officially diagnosed as having Addison's Disease. John F. Kennedy Steroid Biosynthesis Source: LDL cholesterol ACTH increase the number of LDL receptors Daily secretion of cortisol 15 ~ 30 mg LDL Cholesterol 부신피질호르몬의 종류 1. Glucocorticoid(당류코르티코이드) Cortisol: 15 – 30 mg/day 2. Mineralocorticoid(염류코르티코이드) Aldosterone: 50 – 250 g/day 3. Adrenal androgen(안드로젠) 15 – 30 mg/day Dehydroepiandrosterone (DHEA) DHEAS 일중변동 (Circadian rhythm) JCEM 94:1548-1554, 2009 Steroid Transport Unbound form (free cortisol) Less than 5% of circulating cortisol Hypersecretion of corsitol: urine free cortisol Bound form Cortisol binding globulin (CBG): high affinity ○ CBG is reduced in inflammation site ○ CBG increased in high-estrogen state (preg., pill) ○ Synthetic steroid bind less to CBG Albumin: low affinity Synthetic glucocorticoid: low affinity to CBG Mechanism of cellular cortisol action Liver, Adipose tissue Kidney Cortisol 11β-HSD2 Cortisone Cortisol Glucocorticoid receptor 11β-HSD1 Cortisone Effect 글루코코르티코이드 기능 대사에 관한 작용 - glycogen metabolism - gluconeogenesis - peripheral glucose utilization - lipid metabolism 면역계에 대한 작용: 항염증작용 근골격계에 대한 작용 기타 작용 Immune-adrenal axis Leukocytosis - release from BM - Inhibition of egress through the capillary wall Anti-pyretic action - Inhibition of IL-1 Suppress cell-mediate immunity Effects on Skeletal System - Deplete the protein matrix of the vertebral column (trabecular bone) Effects on Liver - Fatty acid mobilization by activation of cellular lipase Effects on Glucose Metabolism - Antagonizing action of insulin Inhibition of insulin secretion Inhibition of peripheral glucose uptake Promote gluconeogenesis 합성 글루코코르티코이드를 장기 투여할 때 나타나는 부작용 부신피질 호르몬이란? 부신피질호르몬제제와 올바른 사용 부신피질호르몬제제 사용시 문제점 의인성 쿠싱증후군을 일으키는 요인 Formulation of steroid Pharmacokinetics Affinity for the GR Biologic potency Duration of action 합성 스테로이드의 특징 Affinity for CBG Affinity for GR 국소 스테로이드 사용시 주의 Topical Steroid + Disruption of skin integrity Inhaled steroid + Anti-fungal agent Issues affecting withdrawal from steroid therapy The possibility of suppression of the HPA axis The possibility of worsening of the underlying disease Steroid withdrawal syndrome Corticosteroid Products Relative biologic potencies of synthetic steroids Steroid Anti-inflammatory Action Hypothalamic-Pituitary -Adrenal Suppression Salt Retention Cortisol 1 1 1 Prednisolone 3 4 0.75 Methylprednisolone 6.2 4 0.5 Fludrocortisone 12 12 125 5 4 0 26 17 0 Triamcinolone Dexamethasone PDL vs. methylprednisolone Prednisolone Methylprednisolone Potency 4 5 Mode of administration oral oral, parenteral Action duration intermediate Intermediate or long PDL 60 mg/d for 4 days PDL 50 mg/d for 2 days 14 days PDL 40 mg/d for 2 days PDL 30 mg/d for 2 days PDL 10 mg/d for 2 days PDL 20 mg/d for 2 days 부신피질 호르몬이란? 부신피질호르몬제제와 올바른 사용 부신피질호르몬제제 사용시 문제점 단기간 스테로이드 사용시 문제점 Hypothalamic-pituitary-adrenal (HPA) axis suppression Hyperglycemia Gastrointestinal effects Psychiatric effects HPA axis 억제 2차성 부신기능저하증 장기간 스테로이드 치료를 받는 일반 인구의 1%가 해당 70세 이상 인구에서는 2.5%가 해당 원인 약제 스테로이드 (가장 흔함) 항진균제: ketoconazole > itraconazole, fluconazole 수면제: etomidate 항암제: sunitinib 스테로이드제제 치료전 고려사항 얼마나 사용할 것인가? 1~3주: 안전 장기간 사용할 것이라면 alternative day therapy 고려 약제의 형태 Topical > Systemic 전신 스테로이드 제제일 경우 mineralocorticoid activity가 있으면 안된다. 사용전 동반질관의 고려 사항 당뇨병 골다공증 소화성 궤양: gastritis, esophagitis 결핵 또는 만성 감염증 고혈압, 심혈관질환 심리학적 문제점 스테로이드에 의한 부신기능 억제 기전 Negative feedback control of the HPA axis 관여하는 요인 기간: 3 주 이내 사용에서는 대부분 안전 용량: PDL 50 mg 이면 HPA axis 억제 고용량 스테로이드를 단기간 자주 사용하는 경우 안전하지 않다. 저용량 스테로이드를 장기간 사용하는 경우 HPA axis 억제는 사례별로 다름. 부신억제에서 회복되는 기간? 일반적으로 6~9 개월 돌아오는 순서 CRH 분비: 수주내 회복 ACTH 분비 Cortisol 분비 부신기능저하의 증상 일차성 부신기능저하증 (Addison’s syndrome) 과 유사 Anorexia Nausea Weight loss Arthralgia Lethargy Skin desquamation Postural dizziness 부신 기능을 평가하기 위한 방법 CRH stimulation test Insulin induced hypoglycemic stimulation test Rapid ACTH stimulation test 1 μg ACTH (corticotropin) IV 정상반응 ○ 주사 30 분 뒤 혈청 코르티솔 25 μg/dL 이상 증가. ○ 기저치로부터 9 μg/dL 이상 상승 250 μg ACTH (corticotropin) IV 스테로이드 중지시 요령 수주에 걸쳐 생리적 요구량에 해당되는 용량으로 감량 (PDL 7.5 mg/day) 2-4 주 간격으로 환자의 상태를 보면서 1mg 씩 감량 (PDL) Hydrocortisone 20mg/day로 교체 10mg/day가 될때까지 매주 2.5mg/day씩 감량 2-3 개월 뒤 HPAaxis 평가를 위한 신속 ACTH 자극검사 Normal 스테로이드 완전 중지 Duration of Glucocorticoid Treatment Dose (mg PDL /day) ≥ 7.5 mg ≤ 3 wks Can stop Reduce rapidly (2.5 mg every 3-4 d ays) Then 5-7.5 mg Can stop Reduce by 1 mg ev ery 2-4 wks < 5 mg Can stop >3 wks or Convert 5 mg pred to HC 20 mg and Then ↓ by 2.5 mg/wk to 10 mg for 2-3 mo Reduce by 1 mg ev ery 2-4 wks Rapid ACTH test If pass, withdraw If fail, continue Alternative-day steroid therapy How to minimize the Cushingoid effects Single dose of intermediate-acting steroid in the morning, every other day 3 Consideration Transition schedules that allow the patient to adjust gradually. Supplementary NSAID: minimize the patient’s Sx Many Sx may occur during the off day ○ May represent relative adrenal insufficiency Withdrawal of steroid following long-term use The dosage is gradually reduced Finally discontinued after a replacement dosage has been reached (5 to 7.5 mg PDL) Check the pituitary-adrenal axis before discontinuing steroid Especially, long term use 생리적 스테로이드 보충 Drug-Induced Hyperglycemia Textbook of Diabetes 4th Edition GLUCOCORTICOIDS: Insulin antagonistic hormones Liver promote gluconeogenesis Muscle & adipose tissue antagonize uptake and utilization of insulin Pancreas inhibitory effect on insulin release and stimulation of glucagon secretion Typical Pattern of Steroid Diabetes Elevated glucose after meals Decrease to normal glucose overnight Hyperglycemia Management Decision Making Short term drug use? Long term drug use? Is this new hyperglycemia/diabetes? Do they have pre existing diabetes? What is their current control? What is their current therapy? ○ Orals- non sulfonylurea vs. sulfonylurea ○ Insulin- premix vs. basal/bolus insulin Treatment Algorithm for Steroid-induced Hyperglycemia <216 mg/dL 216-306mg/dL >306mg/dL <144 mg/dL Textbook of Diabetes 4th Edition Oral Diabetes Medications In general minimal benefits Long acting agents like glyburide and glimiperide will have minimal effect on post prandial hyperglycemia and increase risk of fasting hypoglycemia. The use of rapid-acting drugs such as repaglinide, nateglinide, and acarbose all make physiological sense but in clinical practice often are ineffective. INSULIN Most effective Peak action of the insulin needs to correspond to the post absorptive state - the primary affect of steroids is on glucose disposal following the meal. Rapid acting analog insulin before the meals Cautious use of long acting insulin Ratio prandial:basal 70:30 요약 스테로이드 치료 전 당뇨병, 위궤양, 감염증 등 의 동반질환 유무 점검 스테로이드 제제의 종류, 용량, 사용기간을 고려 해야 한다. 사용 기간은 1~3 주 이내의 경우 안전하다. 선택한 제제가 염류코르티코이드 활성도가 높 지 않아야 한다. 장기간 사용 또는 부신기능저하 증세가 있을 경 우 신속 ACTH 자극 검사가 필요하다.