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

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)

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, glyco

lysis, glycogenolysis, and gluconeogenesis.• EPI-secreting pheochromocytoma; more frequently show e

pisodic 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

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 +

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

Arterioles

    Coronary α1, α2; ß2 Constriction +; dilations ++ Angina

    Skin and mucosa α1, α2 Constriction +++ Pallor

    Skeletal muscle α ; ß2 Constriction ++; dilations ++ Hypertension

    Cerebral α 1 Constriction (slight) Stroke

    Pulmonary α1; ß2 Constriction +; dilations ++ Edema

    Abdominal viscera α1; ß2 Constriction +++; dilations + E.g. Bowel ischemia

    Salivary glands α1,α 2 Constriction +++

    Renal α1,α2; ß1, ß2 Constriction +++; dilations + Renal failure

Veins (systemic) α1, α 2; ß2 Constriction ++; dilations ++ Orthostatic hypotension

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 α 1 Contraction (usually) +    Secretion α 2 Inhibition ConstipationGallbladder and ducts ß2 Relaxation + Gallstones

Kidney    Renin secretion α1; ß2 Decrease +; increase ++Urinary bladder    Detrusor ß2 Relaxation (usually) + Urinary retention

    Trigone and sphincter α 1 Contraction ++ Urinary retention

Ureter    Motility and tone α 1 Increase

Uterus α1; ß2 Pregnant: contraction; relaxation

Nonpregnant: relaxationSex 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,

glycosuriaß2 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 synthesisPosterior pituitary

ß1 Antidiuretic hormone secretion Decreased diuresis

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 preoperativelyBlood 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

α-Aderenoceptor antagonists• Phenoxybenzamine; irreversible, noncompetitive, α-adrenoceptor blocke

r. 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 ac

hieved 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

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

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

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

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 ra

rely cause extrapylamidal signs

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