Arginine (Monograph)

Drug class: Pituitary Function
VA class: DX900
CAS number: 1119-34-2

Medically reviewed by Drugs.com on Mar 24, 2025. Written by ASHP.

Introduction

Arginine hydrochloride, the synthetic monohydrochloride salt of the dibasic, essential amino acid arginine, is used to evaluate pituitary growth hormone reserve.

Uses for Arginine

Growth Hormone Reserve Test

Arginine hydrochloride is administered by IV infusion to evaluate pituitary growth hormone reserve in patients with known or suspected growth hormone deficiency. The drug may be used as an aid to the detection of growth hormone deficiency in conditions such as panhypopituitarism, pituitary dwarfism, chromophobe adenoma, postsurgical craniopharyngioma, hypophysectomy, pituitary trauma, and in problems with growth and stature. The drug may also be used in the evaluation of pituitary function in gigantism and acromegaly.

Evaluation of growth hormone reserve should not be made on the basis of a single provocative test; additional tests using arginine or other methods should be performed after a 1-day period. A false-positive response to arginine hydrochloride, indicating pituitary deficiency, occurs in about 20–32% of patients with normal pituitary function and a false-negative response occurs in about 27% of pituitary-deficient patients. Despite these diagnostic inaccuracies, arginine hydrochloride is a more reliable diagnostic indicator of growth hormone reserve than is glucagon or vasopressin. Diagnostic tests for growth hormone reserve employing a combination of propranolol and glucagon reportedly exhibit reliability similar to arginine hydrochloride, while a combination of levodopa and propranolol has shown greater reliability than arginine. The insulin hypoglycemia test for growth hormone reserve generally provides the most reliable results, but is often considered a less desirable diagnostic aid than arginine because the resultant hypoglycemia is poorly tolerated by many patients. Arginine hydrochloride may be used to confirm or refute the results of these other diagnostic agents.

Acute Hyperammonemia

Arginine hydrochloride is used with sodium phenylacetate and sodium benzoate as an essential component of adjunctive IV therapy for acute hyperammonemia and associated encephalopathy in patients with disorders (i.e., deficiencies in enzymes) of the urea cycle. Urea cycle disorders can result from decreased activity of N-acetylglutamate synthase (NAGS), carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), or arginase. Arginine hydrochloride is administered to restore arginine blood concentrations in patients with CPS, OTC, ASS, or ASL deficiency and help prevent protein catabolism. In patients with ASS and ASL deficiencies, larger dosages (see Acute Hyperammonemia under Dosage and Administration: Dosage) of arginine hydrochloride are administered to promote incorporation of ammonia into citrulline and argininosuccinate, providing alternative pathways for elimination of waste nitrogen. Some experts state that high-dose arginine hydrochloride is effective in reducing plasma ammonia concentrations in patients with ASS (citrullinemia) and ASL (argininosuccinic aciduria) deficiency, and such therapy alone may be sufficient in patients with ASL deficiency. Arginine hydrochloride should not be administered in patients with arginase deficiency. Because infants with hyperammonemia suspected of having a urea cycle disorder (except for arginase deficiency) are usually arginine deficient, and infants with ASS or ASL deficiency usually respond favorably to arginine administration, IV arginine hydrochloride also should be given to hyperammonemic infants with a suspected urea cycle disorder pending specific diagnosis.

Acute symptomatic hyperammonemia can rapidly result in brain damage or death if uncontrolled, and should be treated as a life-threatening emergency. Prompt use of all therapies to reduce serum ammonia levels is essential, and may include dialysis (preferably hemodialysis) to remove a large burden of ammonia, caloric supplementation (to reverse catabolism and reduce protein turnover), and restriction of dietary protein. Management of hyperammonemia secondary to inborn errors of metabolism should be undertaken in coordination with medical personnel familiar with such diseases, and usually requires health care facilities able to provide multidisciplinary treatment (e.g., hemodialysis, nutritional management, medical support). (For further information on treatment of acute hyperammonemia associated with urea cycle disorders, see Sodium Phenylacetate and Sodium Benzoate 40:10.)

Nutritional Supplementation

Oral^{† [off-label]} arginine hydrochloride has also been used as a nutritional supplement^{† [off-label]}, in addition to low protein diets, in patients with dibasicaminoaciduria and argininosuccinic aciduria, and in one patient with hyperornithinemia, hyperammonemia, and homocitrullinuria. Some clinicians have recommended that arginine hydrochloride be used parenterally during total parenteral nutrition therapy as a nutritional supplement.

Metabolic Alkalosis

Because of its high chloride content, IV arginine hydrochloride has been recommended by some clinicians as a systemic acidifier for the management of extreme metabolic alkalosis^{† [off-label]}; however, use of the drug for metabolic alkalosis should not preclude the use of IV sodium chloride and/or potassium chloride.

Other Uses

Arginine hydrochloride has been administered orally^{† [off-label]} to cystic fibrosis patients as a detergent and emulsifier to correct malabsorption and steatorrhea syndromes and by inhalation as a mucolytic, but controlled clinical studies have shown that the drug provided no benefit in these conditions.

Arginine has been used IV as an adjunct in the symptomatic management of severe encephalopathies associated with elevated blood ammonia concentrations and concomitant hepatic failure^{† [off-label]}. Controlled clinical studies indicate, however, that the drug is of no value in reducing blood ammonia concentrations or in improving clinical status in patients with hepatic encephalopathy and its use for this purpose is no longer approved by the US Food and Drug Administration.

Arginine Dosage and Administration

Administration

Arginine hydrochloride is administered by IV infusion via an indwelling needle or soft catheter into the antecubital or other suitable vein. Because of its hypertonicity, the injection should only be injected IV.

For use in acute hyperammonemia, 10% arginine hydrochloride should be administered through a central IV line. The drug may be mixed in the same infusion container with sodium phenylacetate and sodium benzoate; however, other infusion solutions and drug products should not be admixed with the drugs.

Arginine hydrochloride injection should be inverted and inspected visually prior to administration to ensure that the solution is clear. The manufacturer states that warming the injection prior to use is not necessary, but solutions that are not clear or containers lacking a vacuum should be discarded.

Dosage

Growth Hormone Reserve Test

The arginine hydrochloride test for growth hormone reserve should be performed in the morning, after a normal night of sleep and an overnight fast; the fast and bedrest should be continued during the test. To produce more accurate results in adolescent male patients with suspected constitutional delay, 5 mg of diethylstilbestrol (no longer commercially available in the US) has been given twice daily for 2–3 days prior to the test; the value of estrogen pretreatment in the routine testing of growth hormone reserve has not been conclusively determined. Because growth hormone concentrations fluctuate spontaneously in response to stress and exercise, apprehension and distress should be minimized before and during test procedures to avoid invalidation of test results. Blood samples should be taken by venipuncture from the contralateral arm 30 minutes prior to, and immediately before, beginning the arginine infusion and at 30-minute intervals for 2.5 hours thereafter. Blood samples should be promptly centrifuged and stored at -20°C until assayed.

For the growth hormone reserve test, a 100 mg/mL solution of arginine hydrochloride should be infused IV at a constant rate (preferably with the aid of an infusion pump) over 30 minutes; in adults, 30 g of arginine hydrochloride is administered and in children, a dose of 500 mg/kg is administered. Inadequate dosage or prolongation of the infusion period may diminish the stimulus to the pituitary and nullify the test; for this reason, oral administration of arginine is ineffective. As a modification of the above procedure, a 0.075–0.1 unit/kg dose of regular insulin injection may be administered IV 60 minutes after beginning the arginine infusion; blood samples are taken as previously indicated.

In patients with normal pituitary function, plasma growth hormone concentrations of 10–30 ng/mL usually occur 60 minutes after starting the arginine infusion. Some clinicians require, as a criterion for diagnosis of normal pituitary growth hormone reserve, plasma growth hormone concentrations of 7 ng/mL or greater, with arginine-induced plasma concentrations of growth hormone elevated at least 5 ng/mL or double those of basal concentrations. Gigantism or acromegaly may be reflected by an inability to respond to arginine stimulation. Plasma growth hormone concentrations of 4 ng/mL or less may indicate pituitary growth hormone deficiency. When the arginine and insulin hypoglycemia tests are combined, growth hormone deficiency may be suspected if a 50% decrease in fasting glucose concentrations occurs and plasma growth hormone concentrations do not exceed 7 ng/mL. Arginine-induced elevation of growth hormone concentrations may be greater in women than in men and greater in pregnant than in nonpregnant women. Response to arginine may be blunted in obese patients and those with hypothyroidism. Estrogens and estrogen-progestin combinations may elevate growth hormone concentrations. (See Drug Interactions.)

Acute Hyperammonemia

For the treatment of acute hyperammonemia in patients with urea cycle disorders (i.e., deficiency in carbamyl phosphate synthetase [CPS], ornithine transcarbamylase [OTC], argininosuccinate synthetase [ASS], argininosuccinate lyase [ASL]), arginine hydrochloride is administered concomitantly with sodium phenylacetate and sodium benzoate. The dosage of arginine hydrochloride depends on the specific enzyme deficiency. In pediatric or adult patients with CPS or OTC deficiency, the recommended arginine hydrochloride dosage (regardless of body weight) is 200 mg/kg administered by IV infusion over 90–120 minutes as a loading dose, followed by maintenance infusions of 200 mg/kg per 24 hours. Pediatric or adult patients with ASS or ASL deficiency should receive an arginine hydrochloride loading dose of 600 mg/kg administered by IV infusion over 90–120 minutes and maintenance infusions of 600 mg/kg per 24 hours (regardless of body weight).

Pending specific diagnosis, infants with a suspected urea cycle disorder should receive an arginine hydrochloride loading dose of 600 mg/kg by IV infusion over 90 minutes, followed by maintenance infusions of 600 mg/kg per 24 hours. If ASS and ASL deficiencies are excluded, dosage of arginine hydrochloride should be decreased to 200 mg/kg per 24 hours. Patients suspected of having ASS deficiency should initially receive the loading doses of arginine hydrochloride (600 mg/kg) and sodium phenylacetate and sodium benzoate at a decreased rate of administration (i.e., administered over 6 hours). If the diagnosis of ASS deficiency is confirmed, the loading doses should be administered over 90 minutes.

Metabolic Alkalosis

Arginine hydrochloride has been administered IV for the management of severe metabolic alkalosis^†. Dosage (in grams) can be estimated by multiplying the desired decrease in plasma bicarbonate concentration (mEq/L) by the patient’s weight (in kg) and dividing this by 9.6.

Cautions for Arginine

Adverse Effects

Arginine hydrochloride has a low order of toxicity; however, IV infusion of the drug, especially if administered too rapidly, may produce flushing, nausea, vomiting, numbness, headache, and local venous irritation. Leakage of IV solutions of arginine hydrochloride into the surrounding tissue may cause necrosis and superficial phlebitis.

Abdominal pain and bloating have been reported following oral administration of arginine hydrochloride, and inhalation of a 5% solution of the drug by ultrasonic nebulizer has resulted in intense coughing.

Decreased platelet count in one patient and exacerbation of acrocyanosis in another patient have been reported during arginine therapy. Exacerbation of sickle cell anemia, and elevations of BUN and serum creatine and creatinine may occur.

An allergic reaction, characterized by macular rash with redness and swelling of the hands and face, that subsided rapidly following discontinuance of the drug and administration of diphenhydramine, has been reported in one patient. Nasal obstruction and discharge, choking, sweating, and increased pulse rate have also been reported during IV arginine administration and may have represented an allergic reaction to the drug.

Precautions and Contraindications

The manufacturer recommends that arginine hydrochloride not be used in patients with allergic tendencies and that antihistamines be available for use if an allergic reaction occurs.

Because of its high chloride content (0.475 mEq/mL), arginine hydrochloride injection may be hazardous in patients with electrolyte imbalance, particularly hyperchloremic acidosis. Arginine may alter the ratio of extracellular-to-intracellular potassium and elevated plasma potassium concentrations may result following administration of arginine in patients with renal impairment. Administration of the drug has been associated with life-threatening hyperkalemia in patients with renal failure since excretion of potassium is decreased in these patients. Arginine should be used cautiously in patients with renal disease or anuria.

When used for acute hyperammonemia, administration of high arginine hydrochloride dosages may cause hyperchloremic metabolic acidosis; therefore, plasma chloride and bicarbonate concentrations should be monitored and simultaneous administration of appropriate amounts of bicarbonate may be required.

Because arginine contains a high content of metabolizable nitrogen, the temporary effect of a high nitrogen load on the kidneys should be evaluated before the drug is used.

Arginine hydrochloride is ineffective for treatment of hyperammonemia caused by organic acidemias, and should not be used in such a disorder. Arginine hydrochloride is contraindicated in patients with urea cycle disorder who have arginase deficiency.

Drug Interactions

Estrogens and estrogen-progestin combination oral contraceptives may elevate growth hormone response, and reduce glucagon and insulin response to arginine. Reduction of arginine-induced growth hormone response by medroxyprogesterone acetate and of insulin response by norethindrone has also been reported.

Plasma insulin concentrations following arginine stimulation may be further elevated by thiazide diuretics, xylitol, and aminophylline. The latter 2 drugs may also reduce glucagon response to arginine.

Long-term administration of sulfonylurea oral antidiabetic agents may suppress plasma glucagon response to arginine. In one study, phenytoin reduced the plasma insulin response to arginine when glucose intolerant patients were given a glucose load.

Severe, potentially fatal, hyperkalemia has occurred following arginine hydrochloride therapy for metabolic alkalosis in several patients with severe hepatic disease who had recently received spironolactone. Severe hyperkalemia, requiring treatment, developed within several hours after initiating arginine therapy; spironolactone had been discontinued 2–3 days prior to initiation of arginine. Death occurred in one patient subsequent to ventricular tachycardia and asystole despite attempts to decrease serum potassium concentrations and treat cardiac abnormalities. Severe hyperkalemia in these patients probably resulted from an arginine-induced extracellular shift of potassium from cells, impaired hepatic metabolism of arginine, and/or a spironolactone-induced decrease in renal excretion of the ion; spironolactone’s effect on potassium persists for several days following discontinuance of the drug. Patients receiving a potassium-sparing diuretic are at increased risk of arginine-induced hyperkalemia, and therefore combined use of the drugs should be avoided.

Pharmacology

Arginine, like other dibasic amino acids, stimulates pituitary release of growth hormone and prolactin, and pancreatic release of glucagon and insulin. The mechanism(s) of action of arginine is not clear, but it appears to be independent of adrenergic control and of changes in blood glucose concentrations. Arginine’s stimulation of pituitary growth hormone and prolactin release probably originates in the hypothalamus. As compared to patients with normal pituitary function, patients with impaired pituitary function have lower or no increases in plasma concentrations of growth hormone after arginine administration.

Arginine is an essential amino acid in the urea cycle of patients with deficiency of the enzymes N-acetylglutamate synthase (NAGS), carbamyl phosphate synthetase (CPS), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), or argininosuccinate lyase (ASL). Administration of arginine hydrochloride in patients with such disorders restores blood arginine concentrations and helps to prevent protein catabolism. IV infusion of larger dosages (see Acute Hyperammonemia under Dosage and Administration: Dosage) in patients with ASS or ASL deficiency promotes incorporation of ammonia into citrulline and argininosuccinate. These intermediate urea cycle products are less toxic and more easily excreted in the urine than ammonia, and provide an alternative pathway for elimination of waste nitrogen.

Arginine increases blood glucose concentrations. This effect may be direct; the amount of glucose released from the liver is reported to be directly related to the quantity of amino acid infused. Glycogenolysis and gluconeogenesis may also be mediated by stimulation of glucagon release by arginine.

Serum gastrin concentrations are elevated by arginine. The drug competitively inhibits renal tubular reabsorption and thus increases urinary excretion of protein, including albumin, light chains of immunoglobulin, and β₂ microglobulins.

Arginine Pharmacokinetics

Absorption

Normal basal plasma concentrations of arginine are usually about 2 µmol/mL. Following IV infusion of 30 g of the drug over a 30-minute period in adults, peak plasma arginine concentrations of approximately 8 µmol/mL are reached 20–30 minutes after beginning the infusion and plasma concentrations remain above 4 µmol/mL for about 1 hour. Following IV infusion of 30 g of arginine over a 30-minute period in adults, the drug induces peak elevations in serum gastrin concentrations after 10–20 minutes, in blood glucose concentrations after 20 minutes, in plasma insulin concentrations after 20–30 minutes, in plasma glucagon concentrations after 30–45 minutes, in prolactin serum concentrations after 45 minutes, and in plasma growth hormone concentrations after 1–2 hours. Following oral administration, arginine hydrochloride is well absorbed from the GI tract, reaching peak plasma concentrations after about 2 hours.

Distribution

Following IV administration of arginine to pregnant women, low concentrations of the drug have been detected in the fetus.

Elimination

Arginine hydrochloride is incorporated into many biochemical pathways. The amino acid is metabolized in the liver, via hydrolytic cleavage of the guanidino group by arginase, to ornithine and urea. Ornithine potentially enters many anabolic and metabolic pathways, including the citric acid cycle, and may ultimately be used in the production of glucose via the phosphoenolpyruvate system. Arginine is filtered at the glomerulus and is almost completely reabsorbed by the renal tubules.

Chemistry and Stability

Chemistry

Arginine hydrochloride is the synthetic monohydrochloride salt of the dibasic, essential amino acid l-arginine. The drug occurs as white crystals or a crystalline powder and is soluble in water and slightly soluble in hot alcohol. The 10% injection of arginine hydrochloride is hypertonic (950 mOsm/L), has a pH of 5–6.5, and contains 0.475 mEq of chloride per mL.

Stability

Arginine hydrochloride injection should be stored at room temperature (25°C) and exposure to excessive heat should be avoided; solutions that have been frozen should be discarded. Arginine hydrochloride injection should not be used if the solution is not clear or if stored in containers that lack a vacuum.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.