Arginine

L-arginine is a conditionally essential amino acid obtained from the diet and synthesized endogenously from citrulline. It is the substrate for nitric oxide synthase and a precursor of urea, ornithine, creatine, polyamines and agmatine.

The only FDA-approved arginine drug product is arginine hydrochloride injection 10% (R-Gene 10), for intravenous use. No FDA-approved oral arginine drug product exists; oral L-arginine is otherwise sold as a dietary supplement.

R-Gene 10 (arginine hydrochloride injection) is FDA-labeled as an intravenous stimulant of pituitary growth hormone release, for use as a diagnostic aid when measuring pituitary growth hormone reserve.

There is no FDA-labeled indication or dose for oral L-arginine. Prescribers use compounded oral preparations when they determine a patient-specific need; dosing is individualized by the prescriber.

Nitric oxide synthase converts L-arginine to nitric oxide and citrulline; nitric oxide activates soluble guanylate cyclase, raising cGMP and relaxing vascular smooth muscle. Arginase converts arginine to ornithine and urea in the urea cycle. Arginine decarboxylase yields agmatine, and peptidyl-arginine deiminases convert protein arginine residues to citrulline.

Given intravenously, arginine stimulates release of growth hormone, prolactin, insulin and glucagon. This secretagogue response is the basis of the labeled diagnostic use.

Oral absorption occurs in the small intestine by cationic amino acid transporters. Oral bioavailability is low and variable, roughly 20% in pharmacokinetic studies, because of extensive first-pass metabolism by intestinal and hepatic arginase. Peak plasma concentrations occur about 1 hour after an oral dose.

The plasma half-life is about 1 to 2 hours. Arginine is metabolized mainly by arginase and nitric oxide synthase; it is filtered by the kidney and largely reabsorbed, with urinary loss rising at high plasma concentrations.

• Hypersensitivity to arginine or any component of the preparation. R-Gene 10 labeling also contraindicates use in patients with highly allergic tendencies.
• Avoid after a recent or acute myocardial infarction (see Warnings & Precautions).

• Post-myocardial infarction: a randomized trial of oral L-arginine added to standard care after acute myocardial infarction was stopped early because of excess deaths in the arginine group. Avoid after recent MI.
• Hyperkalemia: arginine shifts potassium out of cells; life-threatening hyperkalemia has been reported with arginine hydrochloride, particularly in renal or hepatic impairment.
• Acid–base: arginine hydrochloride carries a chloride load and can cause hyperchloremic metabolic acidosis. Pediatric overdosage of the injection has caused cerebral edema and death.
• Hypotension: additive vasodilation with nitrates, PDE5 inhibitors and antihypertensives.
• Herpes simplex: arginine supports herpesvirus replication in vitro; use caution in patients with frequent recurrences.
• Glucose: arginine stimulates insulin and glucagon release; monitor glucose in patients with diabetes.

• Nitrates and riociguat: additive hypotension; avoid unless the prescriber determines otherwise.
• PDE5 inhibitors, alpha-blockers and antihypertensives: additive blood-pressure lowering.
• Potassium-sparing diuretics, ACE inhibitors, ARBs and potassium supplements: increased risk of hyperkalemia.
• Insulin and other antidiabetic agents: possible changes in glucose; monitor.
• Anticoagulants and antiplatelets: a theoretical additive effect on platelet function; monitor in combination.

Oral: nausea, abdominal pain or cramping, bloating and diarrhea are reported, mostly dose-related. Hypotension, flushing and headache can occur. Hypersensitivity, including airway reactions, is uncommon.

Intravenous (arginine hydrochloride): flushing, nausea, vomiting, headache, numbness, local irritation and extravasation injury at the infusion site, hyperkalemia and metabolic acidosis.

Arginine is a normal dietary amino acid, but the safety of supplemental or compounded doses in pregnancy has not been established, and animal reproduction studies of R-Gene 10 have not been conducted. Use in pregnancy is at the prescriber's discretion after weighing risk and benefit.

Arginine is a normal component of human milk. The effect of supplemental maternal doses on the breastfed infant has not been studied.

Blood pressure and symptoms of hypotension, especially with vasodilators or antihypertensives. Serum potassium and renal function in renal or hepatic impairment or with potassium-raising drugs. Blood glucose in patients with diabetes. Gastrointestinal tolerance.

• R-Gene 10 (arginine hydrochloride injection) Prescribing Information, Pfizer.
• Natural Medicines Comprehensive Database, L-Arginine monograph.
• Goodman & Gilman's The Pharmacological Basis of Therapeutics, McGraw Hill.