Pheochromocytoma is a rare type of tumor that develops in the adrenal glands and causes an overproduction of hormones like adrenaline and noradrenaline. This hormonal surge often results in symptoms such as high blood pressure, headaches, sweating, rapid heart rate, and anxiety, which can mimic more common conditions but pose significant risks if left untreated. (24)
The risk of life-threatening consequences necessitates the effective management of pheochromocytoma. While surgery is often the definitive treatment, medications play a key role in controlling symptoms and stabilizing patients beforehand or when surgery is not an option.
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Understanding Pheochromocytoma
Pheochromocytoma is a rare tumor that arises from chromaffin cells within the adrenal medulla, the inner part of the adrenal glands. These cells produce catecholamines, including adrenaline and noradrenaline – hormones that regulate the body's stress response.
Although pheochromocytomas are most commonly found in the adrenal glands, they can also develop in chromaffin tissue outside the adrenal glands. When this happens, the tumors are called paragangliomas.
Pheochromocytomas are relatively rare, occurring in approximately 2 to 8 people per million annually. They are usually diagnosed in adults between the ages of 30 and 50 but can also occur in children (21). While most pheochromocytomas are benign, about 10% may become malignant (cancerous) and travel to other parts of the body outside of the adrenal glands.
Pheochromocytoma Risk Factors
Approximately 35% of pheochromocytomas are linked to genetic mutations. Individuals with a family or personal history of hereditary syndromes like multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau (VHL) disease, and neurofibromatosis type 1 (NF1) are at a higher risk of developing pheochromocytoma.
Pheochromocytoma Symptoms
Pheochromocytoma symptoms are often episodic and can include:
- Sustained or episodic high blood pressure (hypertension)
- Severe headaches
- Excessive sweating
- Palpitations
- Pale skin
- Anxiety
- Abdominal pain
- Nausea
- Weight loss
Diagnosing Pheochromocytoma
Diagnostic testing begins with biochemical testing to measure plasma or urinary fractionated metanephrines (metabolites of catecholamines). Elevated plasma or urinary metanephrines suggest pheochromocytoma. (10)
The tumor is then located using imaging studies, such as computed tomography (CT) or magnetic resonance imaging (MRI) (10).
Functional imaging, such as metaiodobenzylguanidine (MIBG) or positron emission tomography (PET) scans, are used when metastatic disease is suspected (10).
The Role of Medications in Managing Pheochromocytoma
The preferred treatment for pheochromocytoma is surgery. Without preoperative preparation, surgical mortality rates are high due to catecholamine surges that cause lethal hypertensive crises, arrhythmias, and multi-organ failure (8). Preoperative medical management reduces these risks, translating to surgical mortality rates of less than 2-3%.
Preoperative medical treatment is started at least 7-14 days before surgery to control catecholamine-induced symptoms, stabilize the patient's blood pressure and heart rate, and prevent surgical complications.
Cardiovascular preoperative targets include:
- Blood pressure < 130/80 millimeters of mercury (mmHg) or less while sitting, and systolic blood pressure around 100 mmHg when standing
- Heart rate 60-70 beats per minute (bpm) when sitting and 70-80 bpm when standing
Per the Endocrine Society's medical guidelines, the following medications are recommended for treating pheochromocytoma:
Alpha-Blockers
Alpha-blockers are used as first-line pharmaceutical intervention to induce adrenergic blockade. These medications work by preventing catecholamines from binding to alpha-adrenergic receptors. This helps prevent vasoconstriction (tightening/narrowing of blood vessels) and relax blood vessels to lower blood pressure. (1)
Common agents used include (8):
- Phenoxybenzamine
- Prazosin
- Terazosin
- Doxazosin
Beta-Blockers
After adequate alpha blockade, beta-blockers are introduced to control heart rate (9). They prevent tachycardia (rapid heart rate) caused by catecholamine surges and treat reflex tachycardia often induced by alpha-blockers.
These medications block beta-adrenergic receptors to slow heart rate and reduce the heart's workload (3).
Beta-blockers should never be used on their own without successful alpha blockade, as this could lead to unopposed alpha-receptor stimulation, worsen hypertension, and cause hypertensive crisis (9).
Examples include (8):
- Propranolol
- Atenolol
- Metoprolol
Calcium Channel Blockers (CCBs)
CCBs are sometimes used with alpha-blockers in patients who require additional blood pressure control or as an alternative to alpha-blocking agents for patients who experience side effects (9).
CCBs reduce vasoconstriction and control hypertension and tachycardia by preventing norepinephrine-mediated calcium influx in vascular smooth muscle (9).
Common examples include (8):
- Nifedipine
- Nicardipine
- Amlodipine
Metyrosine
Metyrosine is a catecholamine synthesis inhibitor. It works by inhibiting tyrosine hydroxylase, the enzyme involved in the first step of catecholamine synthesis, thereby reducing the overall production of catecholamines. (8)
Combining metyrosine with an alpha-blocker can lead to better blood pressure control and less blood loss during surgery (8). Because metyrosine is expensive, cost may be a limiting factor to its use. However, it can be beneficial for patients with difficult-to-control symptoms, high catecholamine levels, or metastatic and inoperable pheochromocytomas (9).
Monitoring and Adjusting Treatment
Regular assessment of blood pressure and heart rate during treatment helps ensure that the medications are achieving their desired effects. For commonly used medications, dosing ranges typically include:
- Phenoxybenzamine: 10 mg once or twice daily, titrated as needed by increments of 10-20 mg/day every 2-3 days to a max dose of 1 mg/kg/day (9)
- Propranolol: 10 mg 3-4 times daily, increased as needed to max dose of 200 mg/day (8)
- Nifedipine: 10 mg 3 times daily, increasing as necessary to a max dose of 120 mg/day (8)
- Metyrosine: 250 mg every 8-12 hours, titrated by 250-500 mg/day every 2-3 days as needed to a max dose of 4 g/day (average range 1.5-2 g/day) (8, 9)
In addition to monitoring blood pressure and heart rate, healthcare providers will also screen for potential side effects associated with these medications. Doctors can modify the dose or use alternative agents to manage side effects if they occur. Common side effects for each class include:
- Alpha-Blockers: orthostatic hypotension (a drop in blood pressure upon standing), reflex tachycardia, dizziness, fatigue, and sexual dysfunction (1, 9)
- Beta-Blockers: fatigue, bradycardia (slow heart rate), dizziness, nausea, insomnia (difficulty sleeping), and dry mouth (3)
- Calcium Channel Blockers: peripheral edema (swelling of the legs), headache, flushing, and dizziness (17)
- Metyrosine: sedation, diarrhea, movement disorders, and changes in mental status (18)
Long-Term Management and Follow-Up
In cases where pheochromocytoma cannot be surgically removed, usually due to size or metastasis, alternative treatment options may be considered:
- Embolization involves blocking the blood supply to the tumor, which can help reduce its size and hormone production.
- Radiation therapy uses beams of energy to destroy cancer cells and shrink tumors.
- Chemotherapy uses drugs to stop cancer cell growth and may be used to treat malignant pheochromocytomas.
- Targeted therapies are used in metastatic pheochromocytoma. These therapies use drugs, such as tyrosine kinase inhibitors, to target specific molecular pathways involved in tumor growth to attack cancer cells.
These therapies can be used in conjunction with long-term palliative alpha- and beta-adrenergic blockade for symptom management.
Long-term follow-up is required regardless of the course of treatment. After surgical resection of pheochromocytoma, long-term follow-up is essential to ensure complete recovery and monitor for recurrence, which can occur in up to 6.5-16.5% of patients. The Endocrine Society recommends lifelong blood pressure monitoring and annual biochemical testing to detect signs of tumor recurrence or metastasis. (16)
FAQs and Common Concerns
Can Pheochromocytoma Be Managed Without Surgery?
Yes, pheochromocytoma can be managed without surgery in cases where the tumor is inoperable, or the patient is not a surgical candidate. Alternative treatment options to surgery include medications for symptom control, radiation therapy, chemotherapy, ablation therapy, embolization therapy, and targeted therapy (22).
What Are the Risks of Not Treating Pheochromocytoma?
Without treatment, pheochromocytoma can lead to life-threatening complications such as hypertensive crisis. This is a dangerous rise in blood pressure to 180/120 mmHg or above that increases the risk of heart attack, stroke, and organ damage.
Can Medications Cure Pheochromocytoma?
No, medications cannot cure pheochromocytoma. They manage symptoms by controlling blood pressure and heart rate but do not eliminate the tumor. Complete surgical removal of the tumor is the preferred definitive treatment for pheochromocytoma.
Are There Natural Alternatives to Medications?
There are no proven natural alternatives to medications for managing pheochromocytoma. Medical guidelines emphasize the importance of evidence-based treatments like alpha- and beta-blockers to prevent serious complications. Natural therapies are not recommended as a substitute for pharmacological management.
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Key Takeaways
- Medications play a vital role in treating pheochromocytoma, particularly in the preoperative period, where symptom management and blood pressure control are essential for improving surgical outcomes and reducing complications. By stabilizing the effects of excess catecholamines, medications help prevent hypertensive crises and cardiovascular events, ensuring a safer surgical experience for patients.
- The preoperative adrenergic blockade algorithm begins with alpha-blockers to control blood pressure.
- Once adequate alpha blockade is achieved, beta-blockers are introduced to manage heart rate and prevent tachyarrhythmias.
- If additional blood pressure control is needed, calcium channel blockers and catecholamine synthesis inhibitors can be added.
- Patients should be encouraged to take a multidisciplinary approach to their treatment, working closely with their healthcare team, including endocrinologists, surgeons, cardiologists, and primary care physicians, to discuss all available treatment options. This collaborative effort ensures comprehensive management of pheochromocytoma and increases the chances of successful treatment.
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