Biosintesis dan metabolisme katekolamin

80%20%

Tyrosine hydroxlase

Dopa decarboxylase

Dopa decarboxylase

PNMT

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

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

Mortalitas / morbiditas

Symptoms SignsHeadaches ++++ 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%.

Signs and Symptoms of Pheochromocytoma*

Catecholamines MetanephrinesNE 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.

Medications That May Cause Physiologically MediatedFalse-Positive Elevations of

Plasma and Urinary Catecholamines or Metanephrines

Clinical Setting SymptomsPheochromocytoma 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 weaknessRenal 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

• Hypertensi

• Headache

• Diaphoresis

• Palpitation

• Tremor

• Nausea

• Weakness

• Anxiety

• Epigastric pain

• Flank pain

• Constipation

• Weight loss

Gejala klasik :

4 karakteristik terpenuhi strongly suggestive

Pemeriksaan fisik

• Hypertension (50% paroxysmal)

• Hypotensi postural

• Retinopathy hypertensi

• Weight loss

• Pallor

• Fever

• Tremor

• Neurofibromas

• Cafe au lait spot

• Tachyarrythmias

• Pulmonary edema

• Cardiomyopathy

• ileus

laboratorium

• Hyperglycemia

• Hypercalcemia

• erythrocytosis

ORALLY ADMINISTERED DRUGS USED TO TREAT PHEOCHROMOCYTOMA

Drug Dosage, mg/day[*] Initial (maximum) Side Effectsα-ADRENERGIC BLOCKING AGENTSPhenoxybenzamine 20[†] (100)[†] Postural hypotension, tachycardia, miosis, nasal

congestion, diarrhea, inhibition of ejaculation, fatiguePrazosin 1 (20)[‡] First-dose effect, dizziness, drowsiness, headache, fatigue,

palpitations, nauseaTerazosin 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 AGENTLabetalol 200[†] (1200)[†] Dizziness, fatigue, nausea, nasal congestion, impotence

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

CATECHOLAMINE SYNTHESIS INHIBITORα-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 RangeFOR HYPERTENSIONPhentolamine 1 mg IV test dose, then 2- to 5-mg IV boluses as needed or continuous infusionNitroprusside 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 ARRHYTHMIALidocaine 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 kadang2 diperlukan menggunakan histamin, tyramine , glucagon, dan metoclopropamide

• Test supresi menggunakan phentolamin dan clonidin

• Pemeriksaan kadar Chromogranin A (sensitifitas 83%, spesitifisitas 96%)

Test provokative / supresi

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