Journal Club 2008.6.27. Masahiro Masuzawa APPROACH TO THE PATIENT

1. Journal Club 2008.6.27. Masahiro Masuzawa APPROACH TO THE PATIENT Preoperative Management of the Pheochromocytoma Patient Karel Pacak 2007 The Journal of Clinical Endocrinology & Metabolism 92(11): 4069-4079

3. Pheochromocytoma as Catecholamine Excess and Storm • Most extraadrenal pheochromocytoma; NE dominant • Adrenal pheochromocytoma; either NE and EPI • MEN type 2, NF type 1; dominant EPI • Average NE content 1,770,000pg/g tissue( 53% of its release each day) • Average EPI content 3,801,000pg/g tissue( 5% of its release each day) • 1000 times or more catecholamine release occur after direct tumor stimulation • 15-20%, plasma or urine catecholamine are within normal limits • Produce other vasoactive substances( NPY, adrenomedullin, and ANP)

4. Catecholamines and Adrenoceptors • EPI; more potent effect on β2-aderenoceptors than NE • NE; more potent β1-adrenoceptors than EPI • EPI; more potent α-adrenoceptors than NE • EPI; stimulate lipolysis, ketogenesis, thermogenesis, glycolysis, glycogenolysis, and gluconeogenesis. • EPI-secreting pheochromocytoma; more frequently show episodic symptom and sign( palpitation, light-headedness or syncope, anxiety, and hyperglycemia) • NE-secreting pheochromocytoma; continuous symptoms and signs( hypertension, sweating, headache) • Desensitization; (1) internalization of receptors (2) decrease binding affinity

5. Signs Symptoms Hypertension ++++ Headaches ++++     Sustained hypertension ++ Palpitations ++++     Paroxysmal hypertension ++ Anxiety/nervousness +++ Postural hypotension + Tremulousness ++ Tachycardia or reflex bradycardia +++ Weakness, fatigue ++ Excessive sweating ++++ Nausea/vomiting + Pallor ++ Pain in chest/abdomen + Flushing + Dizziness or faintness + Weight loss + Paresthesias + Fasting hyperglycemia ++ Constipation (rarely diarrhea) + Decreased gastrointestinal motility + Visual disturbances + Increased respiratory rate +

6. Effector organs Receptor type Responses Most relevant clinical manifestations Eye     Radial muscle, iris α1 Contraction (mydriasis) ++ Blurry vision     Ciliary muscle ß2 Relaxation for far vision + Heart     SA node ß1, ß2 Increase in heart rate ++ Palpitations, angina     Atria ß1, ß2 Increase in contractility and conduction velocity ++ Palpitations, angina     AV node ß1, ß2 Increase in automaticity and conduction velocity +++ Palpitations, angina     His-Purkinje system ß1, ß2 Increase in automaticity and conduction velocity +++ Palpitations, angina     Ventricles ß1, ß2 Increase in contractility, conduction velocity, automaticity, and rate of idioventricular pacemakers +++ Palpitations, angina

7. Arterioles     Coronary α1, α2; ß2 Constriction +; dilations ++ Angina     Skin and mucosa α1, α2 Constriction +++ Pallor     Skeletal muscle α ; ß2 Constriction ++; dilations ++ Hypertension     Cerebral α1 Constriction (slight) Stroke     Pulmonary α1; ß2 Constriction +; dilations ++ Edema     Abdominal viscera α1; ß2 Constriction +++; dilations + E.g. Bowel ischemia     Salivary glands α1,α2 Constriction +++     Renal α1,α2; ß1, ß2 Constriction +++; dilations + Renal failure Veins (systemic) α1, α2; ß2 Constriction ++; dilations ++ Orthostatic hypotension

8. Lung     Tracheal and bronchial muscle ß2 Relaxation +     Bronchial glands α1; ß2 Decreased secretion; increased secretion Stomach     Motility and tone α1,α2;ß2 Decrease (usually) + Early satiety, discomfort     Sphincters α1 Contraction (usually) + Intestine     Motility and tone α1, α2;ß1, ß2 Decrease + Constipation, ileus     Sphincters α1 Contraction (usually) +     Secretion α2 Inhibition Constipation Gallbladder and ducts ß2 Relaxation + Gallstones Kidney     Renin secretion α1; ß2 Decrease +; increase ++ Urinary bladder     Detrusor ß2 Relaxation (usually) + Urinary retention     Trigone and sphincter α1 Contraction ++ Urinary retention Ureter     Motility and tone α1 Increase

9. Uterus α1; ß2 Pregnant: contraction; relaxation Nonpregnant: relaxation Sex organs, male α1 Ejaculation ++ Skin     Pilomotor muscles α1 Contraction ++     Sweat glands α1 Localized secretion + Sweating Spleen capsule α1; ß2 Contraction +++; relaxation + Skeletal muscle ß2 Increased contractility; glycogenolysis; K+ uptake Hyperglycemia, glycosuria Pancreas     Acini Decreased secretion +     Islets (ß cells) α2 Decreased secretion +++ Hyperglycemia, glycosuria ß2 Increased secretion + Hypoglycemia Fat cells α2; ß1,ß2 Lipolysis +++ (thermogenesis) Feeling warm Salivary glands α1 K+ and water secretion + ß Amylase secretion + Lacrimal glands α Secretion + Lacrimation Pineal gland ß Melatonin synthesis Posterior pituitary ß1 Antidiuretic hormone secretion Decreased diuresis

10. Current Views on Preoperative Blockade Main goal • normalize blood pressure, heart rate and function of other organs • Restore volume depletion • Prevent a patient from surgery-induced catecholamine storm and its consequences on the cardiovascular system • Adrenergic blockade usually started 7-14 d preoperatively Blood pressure; about 130/80mmHg while sitting, about 100mmHg while standing( not less than 80/45mmHg) Heart rate; about 60-70bpm while sitting, 70-80bpm while standing

11. α-Aderenoceptor antagonists • Phenoxybenzamine; irreversible, noncompetitive, α-adrenoceptor blocker. long-lasting Initial dose 10mg twice a day. Total daily dose 1mg/kg. hypotension in the first 24 h after tumor removal. expensive. • Competitive and short acting α-adrenoceptor blocker; titration can be achieved more quickly with much less side effect( no reflex tachycardia, less post-operative hypotension) (1)Prazocin; 2-5mg two or three times a day (2)Terazosin; 2-5mg per day (3)Doxazosin 2-8mg per day Should be given in the morning before surgery Goldstein et al. Preoperative complication; 65% without α-adrenoceptor blockade 3% with α-adrenoceptor blockade

12. β-aderenoceptor antagonists • Need when catecholamine- or α-adrenoceptor blocker-induced tachyarrhythmia occurs • Should never be used in the absence of an α-adrenoceptor blocker (1)Atenolol; 12.5-25mg two or three times a day (2)Metoprolol; 25-50mg three or four times a day (3)Propranol 20-80mg one to three times a day

13. Combined α-and β-adrenoceptor antagonists • It should not be used as the primary choice for blockade • Labetalol; fixed ratio α-to β-antagonistic activity is about 1:7 • α-to β-antagonistic activity should be at least 4:1 to achieve adequate hypertensive effect • Labetalol; reduces the uptake of 131I-metaiodobenzylguanidine( MIBG) • Needs to be stopped about 2 wk before 131I- MIBG scintigraphy

14. Calcium channel blockers • These drug block NE-mediated calcium infux into vascular smooth muscle Controlling hypertension and tachyarrhythmia • Do not cause hypotension or orthostatic hypotension during normotensive period • May prevent catecholamine-associated coronary spasm (1)Amlodipine; 10-20mg (2)Nicardipine 60-90mg (3)Nifedipine 30-90mg (4)Verapamil 180-540mg

15. Catecholamine Synthesis Inhibitor α-Methyl-L-tyrosine or metyrosin( Demser) • Competitively inhibit tyrosine hydroxylase Maximum effect after about 3 d of treatment dose: 250mg orally every 8 to 12 h Increased by 250 to 500mg every 2 to 3 d Total dose of 1.5 to 2.0 g per day • Crosses the blood-brain barrier Sadation, depression, anxiety, galactorrhea, and rarely cause extrapylamidal signs

16. Drug class Relevant clinical uses ß-Adrenergic blockers1 May be used to treat conditions that result from catecholamine excess (e.g. hypertension, cardiomyopathy, heart failure, panic attacks, migraine, tachycardia and cardiac dysrhythmias) Dopamine D2 receptor antagonists Control of nausea, vomiting, psychosis, hot flashes and for tranquilizing effect Tricyclic antidepressants Treatment of insomnia, neuropathic pain, nocturnal enuresis in children, headaches, depression (rarely) Other antidepressants (serotonin and NE reuptake inhibitors) Depression, anxiety, panic attacks, antiobesity agents Monoamine oxidase inhibitors Non-selective agents rarely used as antidepressants (due to ''cheese effect''). Sympathomimetics1 Control of low blood pressure during surgical anesthesia; decongestants; antiobesity agents Chemotherapeutic agents1 Antineoplastic actions; treatment of malignant pheochromocytoma Opiate analgesics1 Induction of surgical anesthesia Neuromuscular blocking agents1 Induction of surgical anesthesia Peptide and steroid hormones1 Diagnostic testing