Metyrosine and Catecholamine Biosynthesis

Study Notes

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.

Description

Learn about the role of metyrosine in inhibiting catecholamine biosynthesis, particularly its effects on enzymes involved in the production of epinephrine and norepinephrine. Understand how metyrosine is a more effective competitive inhibitor compared to other agents.