Poisoning

There are a number of reported cases of poisoning from its ingestion by mouth, with intense irritation of the esophagus and stomach, vomiting, diarrhea, coma, and collapse. The kidneys are also irritated, as shown by albuminuria, bloody urine, or suppression. The urine may contain albumin and formic acid. The chemic antidote for the stomach is ammonia, well diluted, and followed by demulcents, such as bland oils, mucilaginous drinks, starch water, milk, and white of eggs. Collapse is treated in the usual way.

4Nh3 +

6Hcoh

=

N4(Ch2)6 +

6H2O

Ammonia

Formaldehyd

Hexamethylenamine

Water

Hexamethylenamine, N4(Ch2)6, known also as urotropine, cystogen, formin, etc., is an artificial alkaloid made by combining 6 molecules of Hcoh with 4 of ammonia. It occurs in crystals which are soluble in 1.2 parts of water and in 10 parts of alcohol. It is incompatible with acids and salts of acid reaction, and with mercuric chloride.

Hexamethylenamine has no local action. A 50 per cent. solution is non-irritant (Burnam). In the acid gastric juice formaldehyd is liberated and may be irritating. It is rapidly absorbed, has no essential systemic action, and appears in the urine in a few minutes. If the kidneys are diseased its excretion is greatly retarded, a fact which explains the "urotropin test" for kidney function. It has been found in the ear discharge in a case of middle-ear disease, and in the milk, bile, pancreatic juice, blood, saliva, synovial fluid, nasal and bronchial secretions, pleural effusions, and cerebrospinal fluid of human beings. It is not essentially diuretic, and has no power to dissolve uric-acid calculi. It came into use as a urinary disinfectant, its value depending on its ability to liberate formaldehyd. This it tends to do in acid fluids.

Jordan (1911) gave 10 grains (0.7 gm.) three times a day, and found that when the urine was alkaline or of low acidity, there was no germicidal effect. When the urine was alkaline, he could obtain the effect by administering acid sodium phosphate to acidify the urine; and when the urine was acid, he could lessen the effect by administering potassium citrate. Sollmann (1908) found that in alkaline urine it developed antiseptic properties, i. e., formaldehyd in antiseptic amounts, only after one and a half hours. In ammoniacal urine formaldehyd cannot exist, as it has great chemic affinity for ammonia. When formaldehyd is present, the urine will reduce Fehling's solution.

At Johns Hopkins Hospital hexamethylenamine was found to lessen greatly the number of typhoid bacilli in the urine of typhoid patients, though not to render the urine completely germ free. In pyelitis and in cystitis it is disinfectant, though in Bacillus coli infections and in gonorrhea it has sometimes failed completely to clear the urine. L'Esperance found formaldehyd present in the urine in 52 per cent. of cases taking hexamethylenamine. Burnam (1912) tested the urines of some of Howard A. Kelly's cases after they were given hexamethylenamine. Of 10 cases taking 5 to 10 grains (0.3-0.7 gm.) three times a day, only 2 showed formaldehyd; some others gave the reaction when the dose was increased to 20 to 30 grains (1.3-2 gm.) every four or six hours; and some gave no reaction, even after a dose of 100 grains (6.7 gm.). He found it in some cases with alkaline urine, and failed to get it in some with acid urine. In some patients the concentration in the urine reached as high as 1: 5000. Levy and Strauss obtained similar results and found this strength antiseptic, but not germicidal, except to the typhoid bacillus.

The use of hexamethylenamine in therapeutics depends solely on its power to liberate formaldehyd. Its appearance in a secretion does not, therefore, indicate its antiseptic value in that secretion, for when it does not liberate formaldehyd its antiseptic effect is very slight.

Burnam (1912) tested the secretions other than urine in certain cases of Dr. Howard A. Kelly. The following are his results from Hehner's test, which reacts very delicately to both hexamethylenamine and formaldehyd. (The urine was the only secretion that was positive with Burnam's test, which reacts with formaldehyd in amounts above 1:150,000, but not with hexamethylenamine.)

1. The Bile

In 10 cases of biliary fistula, 60 grains (4 gm.) a day gave only a faint test, though bile containing as much as 1: 50,000 gives a sharp reaction.

2. The Saliva

Only faint traces.

3. Sputum

In three cases of bronchitis, absolutely none of the drug present.

4. Cerebrospinal Fluid

In one case getting 15 grains (1 gm.) every three hours for twenty-four hours, 4 c.c. of the spinal fluid showed mere traces.

In all these fluids the drug, either hexamethylenamine or formaldehyd, was not present in amounts above 1:150,000, and therefore was absolutely without antiseptic value. Hanzlik (1910) showed that there was no formaldehyd set free in the saliva, and Fullerton points out that Sollmann's demonstration of the time required for the development of formaldehyd in alkaline liquids would forbid its formation in any free-running secretion. It is to be noted that formaldehyd in the urine may lessen the heat test for albumin and the test for indican, and may give Fehling's reaction.

Untoward Effects

In acid urine it sometimes so increases the acidity as to make the urine irritating, or sets free enough formaldehyd to do this; and marked vesical pain, frequent burning micturition, bloody urine, and defoliation of the bladder mucous membrane have been reported. The kidneys are also irritated at times, though Richardson (1899) showed that in the presence of an existing nephritis there was no increase in albumin or casts. Coleman (1903) reported the following untoward sequelae: irritation of stomach, diarrhea, and abdominal pain; irritation of kidneys and bladder, with hematuria and hemoglobinuria; headache, ringing in ears; and a skin rash like that of measles. Crowe reports that of 95 cases getting an average dosage of 75 grains (5 gm.) a day, 7 developed painful micturition and hematuria. He has noted also skin rashes, acute catarrh of mucous membranes, and gastric irritation. Frothingham (1909) reported that very large doses could be given to guinea-pigs without toxicity, though their stomachs were prone to become ulcerated and to bleed. He sometimes got necrosis at the site of a hypodermatic injection of the drug. Burnam says that a 50 per cent. solution is not irritant locally.

Therapeutics And Administration

From the above it is seen that there is no question of the frequent value of hexamethylena-mine as a disinfectant in the urinary tract. For this purpose it is given in amounts of 5 to 20 grains (0.3-1.3 gm.) three times a day with large quantities of water to favor elimination by the kidneys. If the urine is alkaline, it may be acidified by acid sodium phosphate, but this must not be given at the same hour as the drug, as they are chemically incompatible.

As proved by an overwhelming amount of experimental data, outside the urinary tract hexamethylenamine has no therapeutic value whatever. Even in the urinary tract the drug rarely produces enough formaldehyd to render the urine completely destructive to bacteria.