DOXAZOSIN 用在PHEOCHROMOCYTOMA

( 嗜鉻細胞瘤 , 如 : 腎上腺髓質瘤 ) 的治療評估

99.05.28

主講人 : 謝曉瑩 藥師

指導藥師 : 張秀玲 藥師

Question

Question

Patient History

63歲，男性 Past history suspect adhesion ileus Diadetes Mellitus , type 2 Hypertention Chronic Kidney Disease Suspected malignant pheochromocytoma with

 multiple para-aortic lymph nodes and liver metastasis.Complicated with fluctuated blood pressure, peripheral vessel and bowel ischemia episodes

0

2

4

6

8

10

12

Lab Data

Creatinine

(1.1-1.5mg/dL)

0

500

1000

1500

2000

2500

2008/11/6 2009/1/5 2010/3/22

Norepinephrine

(11.1-85.5mcg/day)

1213.95

2028.27 1835.6

2

9.8

4.1

5.7

Drug Profile

Propranolol 10mg/tab

Amlodipine 5mg/tab

Iososrbide mononitrate 60mg/CRtab

Doxazosin 4mg/tab

Sennoside A+B

Insulin aspart

Insulin glargine

98/10/0598/06/2598/05/0498/02/1198/01/0697/12/2497/11/24

1# BID

1# QD

1# BID

2# BID

1#QID

1# QD

•BP=132/95 , HR=108•Increase Doxazosin dose to 2# bid

for pheochromocytoma management.•Increase Indera 1# to qid

for palpitation and blood pressure treatment.

1# BID

Pheochromocytoma

Diagonsis Treatment Conclusion

Pheochromocytoma Phaeochromocytomas(PHEOs) are catecholamine-producin

neuroendocrine tumours arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia.

Pheochromocytoma is characterized by hypertension which is typically paroximal, but may be persistent.

About 0.6% of all

hypertensive patients were due to pheochromocytoma. 1

The diagnosis of pheochromocytomas depends mainly upon thedemonstration of catecholamine excess by 24-h urinarycatecholamines and metanephrines or plasma metanephrines.

Pheochromocytoma

α-blocker β-blocker Vasodilator CCBs

PHENOXYBENZAMINE HYDROCHLORIDE  Adults (initial): 10 mg orally twice daily; titrate to maintenance; may increase dose every other day to 20 to 40 mg orally 2 to 3 times dailyPediatrics: 1 to 2 mg/kg/day orally in divided doses

PHENTOLAMINE MESYLATE  Adults: 1 to 5 mg boluses IV (maximum dose 15 mg) Pediatrics: 0.05 to 0.1 mg/kg/dose IV

DOXAZOSIN  

LABETALOL HYDROCHLORIDE   Adults: 2 mg/minute IV infusion OR 20 mg every 10 minutes IV to maximum of 80 mg every 10 minutes (maximum cumulative dose 300 mg/24 hours)

PROPRANOLOL HYDROCHLORIDE   Adults: 10 mg orally 3 times daily initially, increase dose as necessary to maximum of 80 mg 3 times daily Pediatrics: 1 to 2 mg/kg orally twice daily (maximum 15 mg/kg/day)

ESMOLOL HYDROCHLORIDE

SODIUM NITROPRUSSIDE Adults (Following initial phentolamine therapy): 0.3 to 0.5 mcg/kg/minute IV; increase in increments of 0.5 mcg/kg/minute to desired effect (range 0.5 to 10 mcg/kg/minute)Pediatrics (Following initial phentolamine therapy): 0.3 to 0.5 mcg/kg/minute IV; increase in increments of 0.5 mcg/kg/minute to desired effect (range 0.5 to 10 mcg/kg/minute)

NIFEDIPINE   Adults: 10 to 20 mg orally 3 times daily OR 30 to 60 mg orally once daily

Selective alpha1-blocking agents, such as prazosin,

terazosin, and doxazosin, are altermative medications when

long-term therapy is required for metastatic pheochromocytoma.

Treatment

Negative side-effects might be tachycardia, orthostatic 　hypotension, gastrointestinal problems or swelling of 　 nasal mucosa due to effective a-blockage.

BBs should be added, as needed, to control tachycardia and arrhythmia. 8

CCBs may also be advantageous as secondary or tertiary agents because they attenuate the pressor response to norepinephrine and can prevent catecholamine-induced coronary spasm8

Treatment

Calcium channel blockers have been used alone or with selective a1-receptor blockers to successfully control BP and symptoms in patients with PHEO14

Hypertensive crises are controlled with nitroprusside, nitroglycerine, phentolamine or urapidile.13

MICROMEDEX β-blocker僅能用於已經在使用 α-blocker控制的病患，因為若單獨使用 β-blocker時，會對骨骼肌血管 β-mediated vasodilatation產生結抗作用而造成血壓之增高。通常 β-blocker的使用時機，是在已使用 α-blocker控制的病患發生心搏過速時，此時可使用propranolol 10mg 一天三至四次 11

Monotherapy with doxazosin was effective in 8 of 12 patients (66.7%), and combined therapy with a beta-blocker was effective in 11 of 12 patients (91.7%).

In patients with pheochromocytoma, doxazosin (1 to 2 milligrams (mg) initially, increasing to a dose of 2 to16 mg daily) alone or in combination with a beta-blocker is effective for controlling blood pressure and heart rate before and during surgery.

Pheochromocytoma

FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence favors efficacy Recommendation: Adult, Class IIb Strength of Evidence: Adult, Category B

Conclusion α-blockers仍舊是最廣泛被使用的降壓藥，一般常用

phenoxybenzamine，但是其會增加 catecholamines 和metanephrine的合成，使得心跳加快 .7

Despite adverse side effects, phenoxybenzamine has been widely used for the preoperative management of patients with pheochromocytoma. Doxazosin (2-16 mg/day) was as effective as phenoxybenzamine in controlling arterial pressure and heart rate before and during surgery, but doxazosin, a specific a 1-adrenoceptor antagonist, caused fewer undesirable side effects both before and after surgery. 6

Pheochromocytomas with mild or moderate level of blood pressure are indicative of the use of doxazosin mosylate .8

Conclusion Once a phaeochromocytoma is located, complications during

surgery need to be kept to a minimum by appropriate preoperative medical treatment. The major aim of medical pretreatment is to prevent catecholamine induced, serious, and potentially life-threatening complications during surgery, including hypertensive crises, cardiac arrhythmias, pulmonary oedema, and cardiac ischaemia.12

Should substantial rises in blood pressure still take place during surgery, these can be controlled by bolus or by continuous infusion of phentolamine, sodium nitroprusside, or a shortacting calcium antagonist (eg, nicardipine); tachyarrhythmias can be treated by infusion of a shortacting -adrenoceptor blocker (eg, esmolol). 12

Conclusion Selective postsynaptica1-receptor antagonists, such as

prazosin, terazosin, and doxazosin, have a shorter duration of action, permitting more rapid adjustment of dosage and a reduced duration of postoperative hypotension.

1. Graham JB. Pheochromocytoma and hypertension; An analysis of 207 cases. Int Surg 1951;92:105-21.

2. Y-C Kuo, M-Y Yen, Y-F Yang, et al. Pheochromocytoma with acute manifestation at the emergency department: a case report. J Taiwan Emerg Med 2002; 4:129-135.

3. Walther MM, Keiser HR, Linehan WM. Pheochromocytoma: evaluation, diagnosis, and treatment. World J Urol 1999;17:35-9.

4. Sheng-Wen Cheng, Ying-Hock Teng, Chao-Hsin Wu, Chen-Kuo Chu, Lee-Min Wang. Pheochromocytoma Presenting as a Cutaneous Manifestation: A Case Report. J Taiwan Emerg Med 2008;10:87-90

5. Jia-Hwia Wang. Pheochromocytoma. JTUA 20:75-8, 20096. Prys-Roberts C, Farndon JR. Efficacy and safety of doxazosin for perioperative

management of patients with pheochromocytoma. World J Surg. 2002 Aug;26(8):1037-42. Epub 2002 Jun 19.

7. Case Discussion 內科繼續教育8. Pan DL, Li HZ, Ji ZG, Zeng ZP. [Effects of doxazosin mosylate and

phenoxybenzamine in preoperative volume expansion of pheochromocytoma: a comparative study in 38 cases] . Zhonghua Yi Xue Za Zhi. 2005 Jun 1;85(20):1403-5.

9. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS MEDICAL GUIDELINES FOR CLINICAL PRACTICE FOR THE DIAGNOSIS AND TREATMENT OF HYPERTENSION AACE Hypertension Guidelines, Endocr Pract. 2006;12

10. Neuroendocrine Tumors. Practice Guidelines in Oncology – v.1.2010

Reference

Reference

11. Chung-Yin Wu, Eric Chen, Gien-Wen Chio. Severe Hypertension Induced by Pheochromocytoma: A Case Report and Review of Literature. J Emerg Crit Care Med. Vol.10, No.3, 1999

12. Jacques W M Lenders, Graeme Eisenhofer, Massimo Mannelli, Karel Pacak. Phaeochromocytoma. www.thelancet.com Vol 366 August 20, 2005

13. Nicole Reischa, Mariola Peczkowskab, Andrzej Januszewiczb and Hartmut P.H. Neumannc. Pheochromocytoma: presentation, diagnosis and treatment. 2332 Journal of Hypertension 2006, Vol 24 No 12

14. Asterios Karagiannis, Dimitri P Mikhailidis1, Vasilios G Athyros and Faidon Harsoulis. Pheochromocytoma: an update on genetics and management. Endocrine-Related Cancer (2007) 14 935–956