Tyrosine hydroxlase

Dopa decarboxylase

Dopa decarboxylase

20% PNMT 80%

Biosintesis dan metabolisme katekolamin

Biosintesa dan metabolisme cathecolamin
Biosintesa & metabolisme cathecolamin
 definisi

• Suatu tumor jarang , berasal dari sel chromaffin ,

yang mensekresi katekolamin
• Tumor diluar kelenjar adrenal disebut extra
adrenal pheochromocytoma atau paragangliomas
• Peningkatan sekresi katekolamin yang berlebihan,
dapat mempresipitasi terjadinya hipertensi yang
mengancam jiwa dan cardiac arrythmia
 insidensi

• Terjadi pada 0,05 – 0,2% penderita hipertensi

• 90% bersifat sporadis dan jinak

• 10% merupakan bagian dari sindroma familial, seperti

(multiple endocrine neoplasia )MEN 2A dan 2B,
Neurofibromatosis (von Recklinghausen disease), dan
von Hippel lindau (VHL) disease
• laki-laki = wanita

• Usia antara dekade 3 dan 5 kehidupan

• Dapat terjadi pada semua ras , jarang pada ras kulit hitam

• 10% terjadi pada anak-anak

• 50% soliter intra adrenal

• 25% bilateral

• 25% extra adrenal

 Mortalitas / morbiditas
Cardiovascular morbidity :

• Hypertension (paling sering )

• Cardiac arrythmia ( atrial / ventricular fibrilasi

• Myocarditis

• Tanda dan gejala myocardial infarction

• Dilated cardiomyopathy

• Pulmonary edema

Komplikasi Neurologis

• Hipertensi krisis  encephalopathy

• Stroke infark / emboli / PIS

 Signs and Symptoms of Pheochromocytoma*

Symptoms Signs
Headaches ++++ Hypertension ++++
Palpitations +++ Tachycardia or reflex bradycardia +++
Sweating +++
Anxiety/nervousness ++ Postural hypotension +++
Tremulousness ++ Hypertension, paroxysmal ++
Nausea/emesis ++
Pain in chest/abdomen++ Weight loss ++
Pallor ++
Weakness/fatigue ++ Hypermetabolism ++
Dizziness + Fasting hyperglycemia ++
Heat intolerance + Tremor ++
Paresthesias + Increased respiratory rate ++
Constipation +
Dyspnea + Decreased gastrointestinal motility ++
Visual disturbances + Psychosis (rare) +
Seizures, grand mal + Flushing, paroxysmal (rare) +

From Plouin PE et al.[53]

*Incidence: ++++, 76% to 100%; +++, 51% to 75%; ++, 26% to 50%; +, 1% to
25%.
 Medications That May Cause Physiologically Mediated
False-Positive Elevations of
Plasma and Urinary Catecholamines or Metanephrines

Catecholamines Metanephrines
NE E NMN MN
Tricyclic antidepressants
 Amitriptyline (Elavil), imipramine (Topfranil), nortriptyline (Aventyl) +++ − +++ −
α-Blockers (nonselective)
 Phenoxybenzamine (Dibenzyline) +++ − +++ −
α-Blockers (α1-selective)
 Doxazosin (Cardura), terazosin (Hytrin), prazosin (Minipress) + − − −
β-Blockers
 Atenolol (Tenormin), metoprolol (Lopressor), propranolol (Inderal), labetalol (Normadyne)*+ + + +
Calcium channel antagonists
 Nifedipine (Procardia), amlodipine (Norvasc), diltiazem (Cardizem), verapamil (Calan) + + − −
Vasodilators
 Hydralazine (Apresoline), isosorbide (Isordil, Dilatrate), minoxidil (Loniten) + − Unknown
Monoamine oxidase inhibitors
 Phenelzine (Nardil), tranylcypromine (Parnate), selegiline (Eldepryl) − − +++ +++
Sympathomimetics
 Ephedrine, pseudoephedrine (Sudafed), amphetamines, albuterol (Proventil) ++ ++ ++ ++
Stimulants
 Caffeine (coffee*, tea), nicotine (tobacco), theophylline ++ ++ Unknown
Miscellaneous
 Levodopa, carbidopa (Sinemet)* ++ − Unknown
 Cocaine ++ ++ Unknown

E, Epinephrine; MN, metanephrine; NE, norepinephrine; NMN, normetanephrine; +++, substantial increase; ++, moderate increase;
+, mild increase if any; −, little or no increase.
Clinical Setting Symptoms
Pheochromocytoma multisystem crisis Hypertension and/or hypotension, (PMC)
multiple organ failure, temperature of 40° C,
encephalopathy

Cardiovascular Collapse
Hypertensive crisis
Upon induction of anesthesia
Medication-induced or other
mechanisms

Shock or profound hypotension

Acute heart failure
Myocardial infarction
Arrhythmia
Cardiomyopathy
Myocarditis
Dissecting aortic aneurysm
Limb ischemia, digital necrosis or gangrene

Pulmonary Acute pulmonary edema

Adult respiratory distress syndrome
Abdominal Abdominal bleeding
Paralytic ileus
Acute intestinal obstruction
Severe enterocolitis and peritonitis
Colon perforation
Bowel ischemia plus generalized peritonitis
Mesenteric vascular occlusion
Acute pancreatitis
Cholecystitis
Megacolon

Neurologic Hemiplegia
Limb weakness
Renal Acute renal failure
Acute pyelonephritis
Severe hematuria
Metabolic Diabetic ketoacidosis
Lactic acidosis

Adapted from Brouwers FM, Lenders JW, Eisenhofer G, Pacak K:

Pheochromocytoma as an endocrine emergency, Rev Endocr Metab Disord 4:121–128, 2003.
 anamnesa
Gejala klasik :

• Hypertensi • Weakness
• Headache • Anxiety
• Diaphoresis • Epigastric pain
• Palpitation • Flank pain
• Tremor • Constipation
4 karakteristik terpenuhi
• Nausea • strongly
Weightsuggestive
loss
 Pemeriksaan fisik

• Hypertension (50% • Neurofibromas

paroxysmal)
• Cafe au lait spot
• Hypotensi postural
• Tachyarrythmias
• Retinopathy hypertensi
• Pulmonary edema
• Weight loss
• Cardiomyopathy
• Pallor
• ileus
• Fever
• Tremor
 laboratorium

• Hyperglycemia

• Hypercalcemia

• erythrocytosis
 ORALLY ADMINISTERED DRUGS USED TO
TREAT PHEOCHROMOCYTOMA

Drug Dosage, mg/day[*] Initial (maximum) Side Effects

α-ADRENERGIC BLOCKING AGENTS
Phenoxybenzamine 20[†] (100)[†] Postural hypotension, tachycardia, miosis, nasal
congestion, diarrhea, inhibition of ejaculation, fatigue
Prazosin 1 (20)[‡] First-dose effect, dizziness, drowsiness, headache, fatigue,
palpitations, nausea
Terazosin 1 (20)[†] First-dose effect, asthenia, blurred vision, dizziness, nasal
congestion, nausea, peripheral edema, palpitations, somnolence
Doxazosin 1 (20) First-dose effect, orthostasis, peripheral edema, fatigue,
somnolence
COMBINED α- AND β-ADRENERGIC BLOCKING AGENT
Labetalol 200[†] (1200)[†] Dizziness, fatigue, nausea, nasal congestion, impotence

CALCIUM CHANNEL BLOCKERS

Nicardipine sustained release 30[†] (120)[†] Edema, dizziness, headache, flushing, nausea, dyspepsia

CATECHOLAMINE SYNTHESIS INHIBITOR

α-Methyl-ρ-L-tyrosine ( 1000[‡] (4000)[‡] Sedation, diarrhea, anxiety, nightmares, crystalluria, Metyrosine)
galactorrhea, extrapyramidal symptom

* Given once daily unless otherwise indicated.

† Given in two doses daily.
‡ Given in three or four doses daily.
INTRAVENOUSLY ADMINISTERED DRUGS USED
TO TREAT PHEOCHROMOCYTOMA

Agent Dosage Range

FOR HYPERTENSION
Phentolamine 1 mg IV test dose, then 2- to 5-mg IV boluses as needed or continuous infusion
Nitroprusside Infusion rates of 2 μg/kg of body weight per minute are suggested as safe, while rates
greater than 4 μg/kg per minute may lead to cyanide toxicity within 3 hours. Doses exceeding
10 μg/kg per minute are rarely required and the maximal dose should not exceed 800 μg/min
Nicardipine Initiate therapy at 5.0 mg/hr and the infusion rate may be increased by 2.5 mg/hr every
15 minutes up to a maximum of 15.0 mg/hr
FOR CARDIAC ARRHYTHMIA
Lidocaine can be given every 5 to 10 minutes if needed up to a maximum of 3 mg/kg. Loading is
followed by a maintenance infusion of 2 to 4 mg/min (30 to 50 μg/kg per minute) adjusted for effect
and settings of altered metabolism (e.g., heart failure, liver congestion) and as guided by blood level
monitoring.
Esmolol An initial loading dose of 0.5 mg/kg is infused over a minute duration, followed by a
maintenance infusion of 0.05 mg/kg per minute for the next 4 minutes. Depending on the desired
ventricular response, the maintenance infusion may then be continued at 0.05 mg/kg per minute or
increased stepwise (e.g., by 0.1 mg/kg per minute increments to a maximum of 0.2 mg/kg per minute) with
each step being maintained for ≥4 minutes.
IV, Intravenous.
 Pemeriksaan Laboratorium
• Plasma metanephrine

(sensitifitas 96%, spesitifisitas 85% )

• Katekolamin dan metanephrine pada urine 24 jam
( sensitifitas 87,5%, spesitifisitas 99,7%)
• Kreatinin, total katekolamin , vanillylmandelic acid (VMA)
dan metanephrin pada urine 24 jam
 Test provokative / supresi

• Test provokative kadang2 diperlukan

menggunakan histamin, tyramine , glucagon, dan
metoclopropamide
• Test supresi menggunakan phentolamin dan
clonidin
• Pemeriksaan kadar Chromogranin A (sensitifitas
83%, spesitifisitas 96%)
 Biochemical Tests: Summary
SEN SPEC
Ucatechols 83% 88%
Utotal metanephrines 76% 94%
Ucatechols+metaneph 90% 98%
UVMA 63% 94%
Plasma catecholamines 85% 80%
Plasma metanephrines 99% 89%
 Test pencitraan

• MRI lebih superior dibanding CT Scan (sensitifitas 100%)

• CT Scan abdomen 85-95% akurat bila lesi > 1cm

• Scanning dengan Iodine 131 labeled

metaiodobenzylgunadine (MIBG) , bila biokimia (+) MRI
dan CT scan (-)
• Somatostatin receptor analog indium – 111 ( 111 in)

• Positron emission tomography (PET) scanning

• MR spectroscopy
 Patologi Anatomi

• Berat bervariasi antara 2 – 3 kg, rata2 100 gr

( kelenjar adrenal normal 4-6 gr.)
• Tumor ini mempunyai kapsul, banyak vaskular,
berwarna merah kecoklatan bila dibelah
• Gambaran PA ; zellballen, fine granular
basophilic / esinophilic cytoplasm.nukleus bulat
atau oval dengan banyak nukleoli
 staging

• 10% malignant

• Faktor penduga malignant adalah ukuran tumor

yang besar, DNA ploidy pattern ( aneuploidy,
tetraploidy)
• Metastase tersering tulang, hati , KGB
 Tujuan persiapAN preoperatif

• Menormalkan Tekanan darah

• Mengisi cairan tubuh penderita

• Memulihkan fungsi jantung

Ke 3 nya sangat penting dan harus tercapai

sebelum tindakan operasi
 Persiapan preoperatif

• Obat2an penurun darah tinggi

• Makanan bergaram atau cairan infus intravena

• Persiapan operasi yang cukup , kurang lebih 2

minggu
 Tatalaksana Operasi
• Pilihan terbaik adalah operasi pengangkatan tumor

• Surgical mortality : 2-3%

• Pergunakan arterial line,CVP line, cardiac monitor,Swan-Ganz

catheter

• Berikan steroid stress dose untuk reseksi bilateral

• Laparascopic adrenalectomy untuk lesi < 8 cm

• Bila pheochromocytoma intraadrenal : angkat seluruh kelenjar

adrenal

• Jika malignan : reseksi tumor sebanyak mungkin

 Preoperative pilihan 1
• Alpha blocker ( phenoxybenzamin ) 7 – 10 hari

• Pemberian larutan NaCL isotonik untuk

meningkatkan volume darah
• Intake bebas garam

• Pemberian beta blocker diberikan setelah

pemberian alfa blocker yang adekwat untuk
mengontrol takhikardia
• Berikan alfa dan beta blocker pada pagi hari
menjelang operasi
 Pre operasi pilihan ke 2

• 3 hari pre operasi penderita dirawat di ICU

• Semua pengobatan termasuk beta bloker dihentikan

• Pasang arterial kateter hubungkan dengan tekanan

darah secara kontinyu
• Urapidil (10-15 mg/jam ) IV .

• Sore hari sebelum operasi diberikan magnesium

sulfat 1 gr/jam , target pre operasi tekanan darah <
140/90 mmHg, HR < 100 x /mnt
• Pemberian cairan Nacl/ Ringer lactate sesuai
panduan CVP 10-13 cm H2o
• Monitor aritmia dan takhikardia
 Intra operatif

• Obat2 premedikasi Midazolam 0,15 mg/KgBB IM

• Induksi fentanyl 300 g/kgBB dan propofol 200 mg

• Bolus MgSo4 4 g IV sebelum intubasi, dilanjutkan

dengan 1,5 g/jam drip
• Maintenance fentanyl 0,5 g/kgBB/jamj

• Maintenance urapidil 10 mg/jam dan MgSo4 1,5

g/jam
 Intra operatif2

• Phentolamine IV(alpha adrenergik antagonis kerja

cepat) digunakan untuk mengontrol TD
• Beta bloker IV kerja cepat spt Esmolol juga
digunakan untuk mengontrol takhikardia dan
takhiaritmia
• Sebelum reseksi tumor ditambahkan bolus
urapidil 15 mg dan MgSo4 2 gr
• Infus fentanyl dinaikkan sampai 1 g/kgBB/jam

• Bila vena tumor sdh di klamp , hentikan urapidil

dan MgSo4
 Post operasi

• Pasien tetap di ICU untuk monitor tekanan darah

tanpa anti hipertensi sampai 5 hari
• Komplikasi terpenting adalah

• hipertensi efek residual tumor,

• hipotensi  efek alfa blocker preoperatif

• Hipoglikemia kadar insulin meningkat, lipolisis

dan glukoneogenesis menurun
 Follow up rawat inap

• Periksa plasma free metanephrin 2 minggu post

operasi
• Pemantauan perbaikan hipertensi dan komplikasi
lainnya
 Follow up rawat jalan

• Pemeriksaan plasma free metanephrin tiap tahun

selama 5 tahun berturut turut
• Pemantauan tekanan darah

• 5 years survival rate

• kasus non malignancy > 95%
• kasus malignancy < 50%
 Alpa bloker

Phenoxybenzamine Hydrochloride
• Dosis : 2 X 10 mg po naikkan 10 mg sampai dosis optimum (range : 20-
40 mg bid/tid)

Doxazosin mesylate (Cardura)

• Dosis : 4 X 1 mg naikan 2 mg sampai dosis maksimal ( tidak melebihi 4
X 8 mg)

Phentolamine mesylate (Regitine)

• Dosis : 5-15 mg IV, untuk intraoperatif

Urapidil
• Dosis : 10-15 mg/jam
 Betablocker

Propanolol Hydrochloride (Inderal)

• Sebagai adjunctive therapy, tidak cocok untuk
hipertensi emergensi
• 1-3 mg IV untuk mengontrol takikardia

• Untuk metastasis pheochromocytoma : 30 mg

dosis terbagi

Atenolol (tenormin) 4 X 50 mg,naikkan 100 mg prn

 Tyrosine kinase inhibitors

Mertyrosyne ( denser )
• Fungsi untuk menghambat sintesa katekolamnin

• Dosis 250 mg PO qid

• Dinaikkan 250-500 mg qd prn (tak boleh lebih 4 gr qd,

monitor simptom dan eksresi katekoamin
 Pheo: Unresectable, Malignant

 -blockade
 Selective 1-blockers (Prazosin, Terazosin, Doxazosin)
1st line as less side-effects
 Phenoxybenzamine: more complete -blockade
 -blocker
 CCB, ACE-I, etc.
 Nuclear Medicine Rx:
 Hi dose 131I-MIBG or 111indium-octreotide depending on
MIBG scan or octreoscan pick-up
 Sensitize tumor with Carboplatin + 5-FU
 Pheo & Pregnancy
 Diagnosis with 24h urine collections and MRI
 No stimulation tests, no MIBG if pregnant
 1st & 2nd trimester (< 24 weeks):
 Phenoxybenzamine + blocker prep
 Resect tumor ASAP laprascopically
 3rd trimester:
 Phenoxybenzamine + blocker prep
 When fetus large enough: cesarian section followed by
tumor resection
TERIMA KASIH