Metyrosine and Catecholamine Biosynthesis

Catecholamine Biosynthesis Inhibitors

• Metyrosine (Demser) is a competitive inhibitor of enzyme tyrosine hydroxylase (TH) in catecholamine (CA) biosynthesis.
• Metyrosine is more effective than inhibitors of other enzymes involved in CA biosynthesis.
• Structurally, metyrosine differs from tyrosine only in the presence of an α-methyl group.
• The (L) isomer of metyrosine possesses the inhibitory activity.

Clinical Use of Metyrosine

• Metyrosine is used orally in dosages ranging from 1 to 4 g/day, primarily for preoperative management of pheochromocytoma.
• It reduces the frequency and severity of hypertensive episodes by significantly lowering CA production (35%–80%).
• The drug is polar (log P ≈ 0.73) and excreted mainly unchanged in the urine.

Side Effects and Precautions

• Sedation is the most common side effect of metyrosine.
• Crystalluria is a potential serious side effect, which can be minimized by maintaining a daily urine volume of more than 2 L.

Other Inhibitors of CA Synthesis

• α-Methyl-m-tyrosine is used in the treatment of shock, and differs structurally from metyrosine only in the presence of m-OH instead of p-OH.
• Inhibitors of CA synthesis have limited clinical utility due to nonspecific inhibition of all CAs and resulting side effects.

Inhibitors of Aromatic Amino Acid Decarboxylase (AADC)

• Carbidopa is an example of an AADC inhibitor, which is used to inhibit the metabolism of L-DOPA in the treatment of Parkinson disease.

Reserpine

• Reserpine is an indole alkaloid obtained from the root of Rauwolfia serpentina.
• It depletes the vesicle storage of NE in sympathetic neurons in PNS, neurons of the CNS, and E in the adrenal medulla.
• Reserpine also depletes the storage of serotonin and DA in their respective neurons in the brain.
• It binds tightly with and blocks VMAT, which transports NE and other biogenic amines from the cytoplasm into the storage vesicles.