Lithium 用於 Graves Disease

主講人 :郭人瑚指導藥師：張美琪

99/7/29

Question

Patient History

ObjectiveFamily history of thyroid diseaseThyroid Gr1-2 diffuse firm goiter, combine

Graves diseasePalpitation, proximal muscle weakness , m

enstral cycle : irregular, stool passage increased, soft loose stool

Drug profile

980728 980803 980810 980817 980914 981012 981109 981109 981223 990208 990406 990505

peptidine 1 ＃ TID

propanolol 1 ＃ TID

bisoprolol 0.5 ＃QD

0.5 ＃BID

1#BID

methimazole 2#TID 2#TID 3#TID

cetirizine 1#HS 1#HS

PTU 2#BID 2#TID

3#QID

alprazolamXR 1#HS

diphenidol 1#QID

lithium 1#QD

使用 Propanolol 耐受性不佳→ Bisprolol

使用 Methimazole 會癢→PTU

HR 一直很快

Lab DataThyroglbulin: 519.2ng/ml [<50ng/ml]TRab: (+) 61.79% [(-) <15%]

3. 68 3. 19 3. 482. 81

3. 56

6. 97

5. 35

-1

1

3

5

7

9

TSH

FT4

Free-T4 正常值 0.73-2.01ug/dL TSH 正常值 0.35-4.94ulU/ml

檢驗值

Outline

何謂 Graves Disease

臨床表徵及診斷

治療

What is Graves’ Disease?

Disease in which the immune system attacks the thyroid gland, causing the thyroid gland to react by making too much thyroid hormone.

The over-activity of a thyroid gland is referred to as hyperthyroidism.

Graves Disease

Causes of Graves’ Disease

Genetic tendencies of the immune system to attack itself

Stress

Symptoms

Diagnosed

Diagnose

TSH ↓ ＆ FT4↑ ＆RAIU 瀰慢性

TRAb (+)

Treatment

Anti-thyroid drugs

Make it harder for the thyroid gland to create hormones by decreasing the thyroid gland’s ability to use iodine

Radio active iodine: iodine 131 Impairs thyroid cells, thereby reducing the

amount of thyroid hormone produced Surgery

Removal of the majority of the thyroid gland

Treatment

主要藥物治療Antithyroid drugs

methimazole propylthiouracil

Treatment

輔助治療 -β-blockerLithiumGlucocorticoids

inhibit peripheral T4 to T3 conversion and, reduce thyroid secretion. They have been used in patients with severe hyperthyroidism and thyroid storm, although their efficacy is not well demonstrated

Lithium 用於 Graves Disease 的治療

機轉 : 作用機轉相似於碘 Lithium acts by inhibiting T4 and T3 release from t

he thyroid and possibly also by inhibiting their synthesis.

優點不影響甲狀腺碘的攝取停藥後不會加重甲狀腺機能亢進放射碘治療或手術前後的準備和輔助治療。

Evidence

MicromedexFDA Approval: Adult, no; Pediatric, noEfficacy: Adult, Evidence is inconclusiveRecommendation: Adult, Class IIIStrength of Evidence: Adult, Category B

Impact of lithium on efficacy of radioactive iodine therapy for Graves' disease: a cohort study on cure rate, time to cure, and frequency of increased serum thyroxine after antithyroid drug withdrawal.

Patients: 651 patients with newly diagnosed Graves' disease Intervention: 298 patients RAI plus lithium (900 mg/day for 12 day) 353 patients RAI alone Results: (1)cure rate : RAI plus lithium (91.0%) vs RAI alone 85.0% (P = 0.030) (2) RAI plus lithium were cured more rapidly (median 60 day) than those treated with RAI alone (median 90 day, P = 0.000). (3) Treatment with lithium prevented the serum free T(4) increase after methimazole withdrawal and RAI therapy.

J Clin Endocrinol Metab. 2010 Jan;95(1):201-8.

Use of lithium in the treatment of thyrotoxicosis

Patients: 13 名等候以放射性碘或施手術的病人 ( 對 Antithyroid drugs 治療有不良反應或對此藥療效不佳 )

Dosage : 500-1500 mg/day 血清中濃度 0.63 mmol/L Results:

有八名病患對 lithium 治療反應滿意 , 且均在 1-2 星期內 FT4 減少了 40% 或以上。

4 名在治療 3-5 星期內獲得效果 , 一名對 lithium 治療反應緩慢

Conclusions: 如果病人不能接受 thionamides 類的治療或對 thionamides 類的治

療沒有療效反應 , 低劑量的鋰治療是控制甲狀腺機能亢進的另一個安全有效的治療方式

Hong Kong Med J 2006;12:254-9

Comparison of Radioiodine with Radioiodine plusLithium in the Treatment of Graves’ Hyperthyroidism*

Patients: 110 patients with newly diagnosed, untreated Graves’ disease,

age more than 20 yr, recent onset of hyperthyroidism (≦6 months), and nonsevere or absent Graves’ ophthalmopathy

Dosage : 900 mg/day for 6 days starting on the day of radioiodine adm

inistration

Results: Goiters shrank in both groups (P<0.0001), more effectively an

d promptly (P < 0.0005) in the radioiodine-plus-lithium group.

Journal of Clinical Endocrinology and Metabolism JCE & M² 1999 Vol. 84, No. 2

Successful outcome with methimazole and lithium combination therapy for propylthiouracil-induced hepatotoxicity.

49-year-old man with severe thyrotoxicosis and propylthiouracil-induced hepatotoxicity , indices of liver function continued to increase despite discontinuation of propylthiouracil treatment. Adjunctive therapy with methimazole and lithium Conclusion ： Adjunctive therapy with methimazole and lith

ium is synergistic in promptly achieving a euthyroid state.

Endocr Pract. 1998 Jul-Aug;4(4):197-200.

The Use of Lithium Carbonate in the Preoparation for Definitive Therapy in Hyperthyroid Patients

Patients: 6 patients

Methods : in 5 patients with Graves’ diseaseand in 1 patient with toxic multinodular goiter because of side effects of thionamide in 5

patients and ineffectiveness of antithyroid medication in the remaining patient.

Results: All 6 patients had a benign course following treatment without thyr

oid storm. No adverse effects or complications of lithium carbonate were observed.

Conclusions: This report shows that lithium carbonate can be safely used preo

peratively or prior to radioiodide therapy in circumstances where antithyroid medications are contraindicated and are ineffective in obtaining an euthyroid status.

Med Princ Pract 2008;17:167-170

注意事項

Lithium 血中濃度 Trough : 服用藥物 8-12 小時後 , 早上給藥前 治療範圍：

0.60~1.20 meq/L 警示範圍： 1.20-1.50 meq/L Toxic ： Over 1.50 meq/L

血清濃度超過 1.5 meq/L— 產生運動失調、震顫、下 瀉、衰 弱、鎮定、嘔吐 超過 2.5 meq/L—

舞蹈狀、迷惑、痙攣、意識下降、增加肌腱反射、嗜睡、肌肉高張液體、不醒人事，腎臟毒性

超過 2.5 meq/L— 昏迷，也有可死亡。

注意事項

其它影響甲狀腺功能Amiodarone - due to amiodarone’s high iodi

ne content

Conclusion

In patients who develop serious side-effects due to thionamides or who do not respond to these drugs, lithium therapy can be used as an effective interim measure before undertaking definitive therapy.

Hong Kong Med J 2006;12:254-9

Reference

Endocrinol Metab Clin North Am - 01-JUN-2009; 38(2): 355-71

J Clin Endocrinol Metab. 2010 Jan;95(1):201-8. Micromedex ,Up toDate , MD consult, CMAJ

Hong Kong Med J 2006;12:254-9 Adapted from Weetman AP: Graves disease. N Engl J Med

2000;343:1236–1248. AACE Thyroid Guidelines, Endocr Pract. 2002;8(No. 6) 46

1• Endocr Pract. 1998 Jul-Aug;4(4):197-200.

Propranolol (1)10mg/tab,  (2)40mg/tab, 

Bisoprolol

25mg/tab非心臟選擇性 (β1+β2- Receptor ) 具心臟選擇性 (β1 Receptor)

短效型 20-80 mg PO tid; 1-2 mg IV q4-8h 長效型 2.5-20mg qd; max: 40mg/day

Cardiovascular: Bradyarrhythmia, Hypotension

Dermatologic: Dermatitis, Pruritus, Urticaria

Gastrointestinal: Nausea, Vomiting

Neurologic: Fatigue, Insomnia, Paresthesia

Psychiatric: Depression, Psychotic disorder

Respiratory: Dyspnea

Cardiovascular: Bradyarrhythmia (9%), Cold extremities, Hypotension

Gastrointestinal: Diarrhea (4%), Indigestion, Nausea (2%), Vomiting (2%)

Musculoskeletal: Arthralgia (3%)

Neurologic: Dizziness (10%), Headache (11%)

Psychiatric: Dyssomnia (8%-10%)

Respiratory: Cough (3%), Dyspnea (2%), Pharyngitis (2%), Rhinitis (4%), Sinusitis (2%), Upper respiratory infection (5%)

Other: Fatigue (8%)

Propylthiouracil (PTU)

Methimazole

Protein Binding 75 ~ 80 % 0

T 1/2 (h) 1 ~ 2 6 ~ 13

Initial Dose 300 ~ 400mg /day, 分 3~4 次服用

15 mg (mild); 30 to 40 mg (moderately severe); 60 mg (severe) ORALLY per day

Maintenance Dose 100~150 mg/ day 5~ 15 mg /day

Neonates 5~ 10 mg/ kg/day 0.5 ~ 1 mg/ kg/day

Transplacental passage

Low Higher

Levels in breast milk

Low Higher