Metyrosine - Approved Drug for Pheochromocytoma

Overview:

Pheochromocytoma is a rare tumor that can result in high blood pressure. Metyrosine is used to treat the symptoms of pheochromocytoma. It functions by preventing some neurotransmitters that are linked to the disease from developing. The United States Food and Drug Administration (FDA) approved Metyrosine to manage pheochromocytoma on 25th April 2008.

Drug Group:

Metyrosine is a member of the tyrosine hydroxylase inhibitor and antihypertensive medication group. It is used to treat hypertension or elevated blood pressure, which is triggered by pheochromocytoma. It is an adrenal gland noncancerous tumor.

Dosages:

For oral dosage form (capsules):

• Adults and Children 12 Years of Age and Older: 1000 milligrams to 3000 milligrams (1 to 3 grams) daily, divided into four doses.

For Patients:

What Is Pheochromocytoma?

Excessive levels of adrenaline and noradrenaline hormones are produced by a rare tumor called pheochromocytoma, which grows in the adrenal glands. Along with other symptoms, these hormones can cause severe hypertension and an accelerated heartbeat. Anxiety, sweating, and headaches are common symptoms of the illness. Blood and urine tests, imaging, and even genetic screening are used to diagnose. The main course of treatment is surgical tumor removal. The adrenal gland disease is usually not malignant; however, early discovery and treatment are essential for managing potentially fatal consequences.

What Is the Management of Pheochromocytoma?

• Pheochromocytoma management requires a multidisciplinary approach, frequently involving endocrinologists, surgeons, and other specialists working together. The main objective of the management is controlling and returning the adrenal tumor's excessive catecholamine output to normal.

• Alpha-adrenergic inhibition with drugs such as Phenoxybenzamine is part of the immediate preoperative therapy to avoid hypertensive crises during surgery. After alpha blockade is established, beta-adrenergic blockers may be added to treat tachycardia and other symptoms associated with beta-adrenergic blockade.

• The final course of treatment is still surgical tumor excision, usually with an adrenalectomy. When possible, minimally invasive techniques like robotic or laparoscopic surgery are frequently preferred.

• Medical management becomes essential when surgery is not recommended or when there is a metastatic illness. Long-term alpha-adrenergic blockade with Doxazosin or Phenoxybenzamine aims to stabilize blood pressure and manage symptoms. If necessary, beta-blockers may also be continued.

• Following surgery, careful monitoring of heart rate, blood pressure, and catecholamine levels is necessary. Patients should also be made aware of the significance of taking their medications as prescribed and how to spot symptoms of catecholamine excess.

• Frequent evaluations, such as imaging identification of metastases or recurrence. For hereditary pheochromocytomas, genetic testing may be taken into consideration.

• Pheochromocytoma management necessitates a customized strategy based on unique patient characteristics, focusing on striking a balance between long-term monitoring, pharmacological control, and surgical intervention to guarantee the best possible results.

How Does Metyrosine Work?

Tyrosine hydroxylase is inhibited by Metyrosine, which prevents tyrosine from being converted to L-DOPA (Levodopa), an essential step in manufacturing dopamine. It is helpful in disorders like pheochromocytoma, which is marked by excessive dopamine production, as it lowers dopamine levels by obstructing this process. This uncommon tumor causes increased noradrenaline and adrenaline secretion. Metyrosine aids in the control of symptoms like hypertension. Hypotension and drowsiness from lowered catecholamine levels are possible adverse effects. To balance adverse effects and therapeutic efficacy, regular monitoring is crucial.

How Should the Drug Be Taken?

• The drug is taken orally. It is essential to adhere to the recommended dosage and timing. To keep the medicine levels in the body constant, try taking medication every day simultaneously.

• Metyrosine taken with food can lessen the possibility of an upset stomach. However, a doctor's advice is regarded in this regard.

• Take the missed dose as soon as the patient remembers it, but do not take two doses at once if the next planned dose is close.

• It is crucial to inform the healthcare practitioner about the medical history and any other medications or supplements the patients are taking, as these medications may interact with specific foods, medications, or conditions. Watch out for any adverse effects or changes to the course of therapy; routine check-ups are vital.

• Only change the dosage independently after first talking to a healthcare provider. Contact the doctor immediately if the patient has serious side effects or questions regarding the drug.

What Are the Benefits of Using Metyrosine for Pheochromocytoma?

• Metyrosine is used to manage symptoms of pheochromocytoma, a rare tumor that can lead to excessive release of adrenaline and noradrenaline. By inhibiting the enzyme tyrosine hydroxylase, Metyrosine reduces the production of these stress hormones and thus helps control high blood pressure, palpitations, and other related symptoms.

• The medication is particularly beneficial in preparing patients for surgical removal of the tumor, as it helps to stabilize blood pressure during the procedure. Additionally, Metyrosine can be employed as a long-term treatment for those who are not candidates for surgery or as an adjunctive therapy alongside other interventions.

• However, it is essential to note that Metyrosine may have side effects, including fatigue, depression, and gastrointestinal issues. Close monitoring by healthcare professionals is crucial to adjust the dosage and manage potential adverse reactions.

• Metyrosine plays a vital role in alleviating symptoms and optimizing conditions for individuals with pheochromocytoma, offering a multifaceted approach to the management of this rare and challenging condition.

What Must the Patient Inform the Doctor Before Taking Metyrosine?

• Medical history, particularly pheochromocytoma or cancers of the adrenal glands.

• Pharmaceutical allergies, particularly to Metyrosine or related substances.

• Present prescription and over-the-counter medications, along with herbal supplements.

• Pregnancy or a plan to become pregnant, as the consequences on fetuses are not well-known.

• It is unknown if Metyrosine passes through breast milk.

• Any past mental illness or depressive history.

• Any planned surgeries, as the medication may need to be adjusted.

• Concerns about blood pressure because Metyrosine can alter blood pressure.

• Liver or kidney issues, so dosage modifications might be required.

What Are the Side Effects of Using Metyrosine?

• Dizziness.

• Nausea.

• Vomiting.

• Diarrhea.

• Fatigue.

• Headache.

• Blurred vision.

• Mental/mood changes.

For Doctors:

Description:

Metyrosine, a tyrosine 3-monooxygenase inhibitor, is used to treat pheochromocytoma patients who have excessive sympathetic activation. An extra methyl group is added to position 2 of L-tyrosine to create alpha-methyl-L-tyrosine, an L-tyrosine derivative—an inhibitor of the tyrosine 3-monooxygenase enzyme, which in turn inhibits the production of catecholamines. Metyrosine is used to manage the symptoms of hyper-sympathetic stimulation in pheochromocytoma patients. It functions as an inhibitor of tyrosine 3-monooxygenase and an antihypertensive. It is a non-proteinogenic L-alpha amino acid and a derivative of L-tyrosine.

Therapeutic Uses of Metyrosine:

• Metyrosine is mainly employed in the treatment of pheochromocytoma by preventing the synthesis of catecholamines.

• Additionally, patients with carcinoid syndrome disorder marked by an excess of serotonin and other bioactive substances are treated with it as an adjunctive therapy.

• The drug may help control symptoms, including tachycardia, hypertension, and excessive perspiration, that come with these illnesses.

• Tyrosine hydroxylase, an enzyme required for the synthesis of catecholamines such as dopamine, norepinephrine, and epinephrine, is blocked by Metyrosine. By reducing the overproduction of these neurotransmitters, this pharmaceutical action helps treat symptoms and enhances the patient's quality of life.

• The medication may also be used in experimental settings to investigate its potential in disorders associated with excessive catecholamine release or dysregulation of dopamine.

Dosage Forms and Strengths:

Metyrosine typically comes in capsule form. Common strengths include 250 mg and 500 mg capsules.

Dosages and Administration:

For adults and children 12 years of age and older, the first recommended dosage of Metyrosine capsules is 250 milligrams taken orally four times daily. This can be raised daily by 250 to 500 mg, with a maximum of 4 grams per day in separate doses. Metyrosine capsules should be consumed for a minimum of five to seven days.

The dosage must be changed in hypertensive patients to control blood pressure and clinical symptoms. The dosage of Metyrosine for patients with normotension should be changed to reduce Vanillylmandelic acid or urine metanephrine levels by at least fifty percent. If Metyrosine cannot provide adequate control, an alpha-blocker, like Phenoxybenzamine, should be added.

Indications:

• Medical Use: The main reason that Metyrosine is recommended is to treat specific medical disorders.

• Neurological Disorders: By lowering catecholamine production, Metyrosine is approved for treating pheochromocytoma, an uncommon tumor that affects the adrenal glands.

• Control of Symptoms: Metyrosine can reduce the signs and symptoms of pheochromocytoma, including palpitations, sweating, and hypertension (high blood pressure).

• Adrenal Gland Regulation: Metyrosine obstructs the tyrosine hydroxylase enzyme, which prevents the adrenal glands from producing hormones and neurotransmitters.

• Preoperative Preparation: Metyrosine is often used before surgery to prepare patients with pheochromocytomas for a more secure and regulated process.

• Off-label Uses: Metyrosine might occasionally be administered off-label for various conditions, but this has to be done under a doctor's supervision.

• Dosing management: Achieving therapeutic results while limiting side effects requires careful dosing and titration.

• Monitoring: During Metyrosine treatment, it is crucial to regularly measure blood pressure, heart rate, and other vital parameters.

Contraindications:

• Hypersensitivity: Avoid patients who have a Metyrosine allergy.

• Pheochromocytoma: In individuals with this adrenal tumor, contraindications apply.

• Severe Liver Disease: Due to possible hepatic impact, caution is necessary.

• Restrictors Interaction: Requires caution when combined with monoamine oxidase inhibitors.

• Cardiovascular Problems: Should be used carefully in patients who have heart problems.

• Pregnancy and Nursing: Due to the risks associated with pregnancy and nursing, caution should be kept.

• Hypotension: This could make low blood pressure worse.

• Renal Impairment: Modify dosage for individuals with reduced renal function.

• Psychiatric Disorders: Possible aggravation of psychological problems.

Precautions and Warnings:

It should be used with caution by people who have problems with their adrenal glands, heart problems, or mental health conditions. Fatigue, mood swings, and dizziness are possible adverse effects. It may affect blood pressure when combined with drugs such as MAO inhibitors. Before using, nursing or pregnant people should speak with their doctor. It is vital to assess liver, kidney, and blood pressure functions regularly. Report any strange symptoms right away. It is critical to follow the dosage instructions.

What Are the Adverse Reactions of Metyrosine?

• Hypotension.

• Sedation.

• Diarrhea.

• Nausea.

• Confusion.

• Severe allergic reactions.

• Liver problems.

Pharmacological Aspects of Metyrosine

Mechanism of Action:

Tyrosine hydroxylase, the enzyme that catalyzes the initial transformation in catecholamine biosynthesis, which is the change of tyrosine into dihydroxyphenylalanine (DOPA), is inhibited by Metyrosine. Blockade of tyrosine hydroxylase activity reduces endogenous levels of catecholamines and their production because the first step is also the rate-limiting stage. As a result, the body's stores of catecholamines dopamine, adrenaline, and noradrenaline are reduced. This is typically indicated by a decrease in the excretion of catecholamines and their metabolites in the urine. Lower blood pressure is one of the main effects of catecholamine deficiency.

Pharmacodynamics:

One to four grams of Metyrosine per day have been shown to reduce the amount of catecholamines that are biosynthesized (by total excretion of catecholamines and their metabolites, vanillylmandelic acid, and metanephrine) in patients with pheochromocytoma, who produce excessive amounts of norepinephrine and epinephrine. The maximum biochemical impact happens typically in two to three days, and three to four days after stopping Metyrosine, the urine concentration of catecholamines and their metabolites usually returns to pretreatment levels. When Metyrosine is used to treat pheochromocytoma, the majority of patients report less frequent and severe hypertension episodes, along with the accompanying headache, nausea, perspiration, and tachycardia. Blood pressure gradually drops in patients who react to Metyrosine therapy over the first two days of treatment; following withdrawal, blood pressure typically rises to pretreatment levels in two to three days.

Pharmacokinetics:

Metyrosine modifies catecholamine production and is utilized in the treatment of pheochromocytoma. When taken orally, it is metabolized by the liver to produce inactive metabolites. Absorption varies and is influenced by diet. Within two to four hours, plasma levels reach their peak. Its half-life for elimination is between two and four hours. With very little unaltered drug excretion, Metyrosine is mainly eliminated through the kidneys. Renal impairment may require dosage modifications. Although its safety profile is generally good, there is a chance of experiencing adverse effects such as orthostatic hypotension and mental problems. Keeping an eye on plasma levels helps maximize the effectiveness of treatment. Comprehending the pharmacokinetics of Metyrosine is imperative for its secure and efficient administration in medical environments.

Drug Interactions:

Serious Interactions:

• Lofexidine.

• Metoclopramide intranasal.

• Olopatadine intranasal.

• Ropeginterferon alfa 2b.

Monitor closely for these drugs:

• Carbidopa.

• Clonidine.

• Daridorexant.

• Difelikefalin.

• Midazolam intranasal.

• Stiripentol.

• Xipamide.

Minor reactions:

• Agrimony.

• Brimonidine.

• Chlorpromazine.

• Cornsilk.

• Fluphenazine.

• Forskolin.

• Haloperidol.

• Maitake.

• Octacosanol.

• Perphenazine.

• Prochlorperazine.

• Promazine.

• Promethazine.

• Reishi.

• Shepherd's purse.

• Thioridazine.

• Tizanidine.

• Trifluoperazine.

Use in Specific Populations:

• Pregnancy: During pregnancy, Metyrosine should only be administered when necessary. Surgery is the only proven treatment for pheochromocytomas. However, in women who are over twenty-four weeks pregnant, tumor accessibility issues may cause a delay in the procedure.

• Lactation: Care should be taken when giving Metyrosine to a nursing mother because many medications are excreted in human milk. The drug's pharmacology may negatively affect the nursing infant, and its low molecular weight may make passage to breast milk possible.

• Pediatrics: Adult patients with pheochromocytoma are treated with Metyrosine primarily. A medical expert should assess whether to utilize it in pediatrics based on the particular circumstances.

• Geriatrics: No particular data evaluating the usage of Metyrosine in older adults compared to that of other age groups is available.

Clinical Studies:

The clinical studies looked at how different medications affect patients undergoing surgery for pheochromocytoma, a tumor that can cause high blood pressure. They examined the use of Metyrosine (which reduces the production of certain chemicals), prazosin, and phenoxybenzamine (which block the effects of these chemicals) before surgery. The results showed that using Metyrosine before surgery helped control blood pressure during the operation, reducing the need for additional medications. Patients who did not receive any medication had higher blood pressure during surgery, and two of them unfortunately died due to a severe increase in blood pressure.