Chloroform (chloroformum), Chc13, is a non-inflammable, volatile liquid, which is about 1 1/2 times as heavy as water, boils at 141° F., and has a burning, strikingly sweetish taste. It mixes freely with alcohol, ether, and the oils, and dissolves to the extent of about 0.5 per cent. in water (U. S. P.). Moore and Roaf found it to be soluble to the extent of 0.95 per cent. in water, and to the extent of 4 per cent. in blood-serum, and their work indicated that this extra solubility in serum was due to the formation of a loose protein compound.

On long standing, or if exposed to sunlight or a flame, chloroform may decompose, with the formation of free hydrochloric acid, or the poisonous carbonyl chloride (Cocl2), or free chlorine, which is very irritating. Alcohol acts as a preservative, as the chloroform does not undergo decomposition so long as there is any alcohol present to be oxidized. Hence the Pharmacopoeia specifies that 0.6-1 per cent. of alcohol shall be present.

Preparations And Doses

Chloroform, 5 minims (0.3 c.c.). Water (1/2 per cent.), 4 drams (15 c.c.). Spirit (6 per cent.), 30 minims (2 c.c.). Liniment - (chloroform, 30 per cent., soap liniment, 70 per cent.).

Pharmacologic Action

Chloroform is a general protoplasmic poison of considerable destructive power. If concentrated, it will cause the death of tissues with which it comes in contact; and even when dilute, as in the blood, it can readily produce degenerative changes in various organs of the body. This striking property seems to be common to various hydrocarbons which contain chlorine.

Microorganisms

Chloroform is antiseptic, and even in such a dilute solution as "chloroform water" (1/2 per cent. in strength) will retard putrefaction and fermentation, as in urine.

Local

It is less volatile than ether, so is less cooling to the skin, and its tendency is rather to irritate than to soothe. If it is dropped on the face from a chloroform inhaler and prevented from ready evaporation, it will make a decided burn. In liniments, if evaporation is prevented by covering with flannel or oiled silk, it is counterirritant.

Alimentary Tract

Undiluted, it is very irritating to throat and stomach; but its official preparations, being very dilute, are sweet to the taste and pleasant carminatives. They are also soothing to the stomach and antemetic It is said that the activity of rennet and pepsin is promoted by solutions of less than 0.5 per cent. strength, and retarded by strong solutions.

Heart

In perfusing an isolated heart, the addition of a small amount of chloroform results in a momentary strengthening, followed very quickly by muscular weakness, the heart soon becoming dilated and the beats small and ineffective. The drug is a strong poison to cardiac muscle. Sherrington and Sowton found that in a perfusion fluid a strength of 0.05 per cent. of chloroform was sufficient regularly to arrest the heart, but that restoration would take place on returning to pure saline. That is, when the osmotic pressure of chloroform in the cardiac cells is below a certain limit, the heart beats again. If too strong chloroform is used, the heart cannot dissociate itself from the chloroform and death ensues.

Levy and Lewis, experimenting with cats, found that light anesthesia, i. e., with the tension of chloroform vapor in the inspired air between 0.5 and 1.5 per cent., regularly produced irregularities in the action of the ventricle, of the types described under "Digitalis" as due to excessive irritability. They observed paroxysmal tachycardia (of ventricular origin), premature ventricular contractions, and ventricular fibrillation. The increase of the vapor tension to 2 per cent. was regularly followed by the disappearance of the irregularity. Levy considers this due to muscle weakening and dilatation which he considers protective against fibrillation. With the low-tension vapor, a small intravenous of epinephrine hydrochloride produced the worst form of irritability, viz., ventricular fibrillation, which usually means immediate death; with the higher tension vapor a small intravenous of epinephrine produced the irregularities which had been observed to result from the low percentages of chloroform alone.

Of considerable importance in anesthesia is the finding of Cushny and Edmunds that the heart may be dilated and very weak before there is any noteworthy change in its rate.

Arteries

The vasoconstrictor center, after a primary irritation, is depressed. Bayliss, who has done much work in inhibition, thinks that the vasoconstrictor center is changed by chloroform so that afferent impulses which normally result in vasoconstriction, now result in vasodilatation. (See Sherrington's theory under Strychnine.)

In some cases the destructive action results in fatty degeneration of the heart, the cardiac ganglia, and even the arteries. This is particularly likely to be the case after the prolonged administration of chloroform for anesthesia, or the repetition of its administration as an anesthetic within a day or two. In anesthesia, death sometimes takes place from collapse, due to depression of the heart and arterial muscles or to ventricular fibrillation. In the early stages of the anesthesia, before the patient is fully anesthetized, death may be due to powerful reflex stimulation of the vagus and vasoconstrictor centers, the latter causing abnormal peripheral resistance against a weakened heart. Muehlberg and Kramer, by the injection of a few minims of chloroform into the carotid artery or jugular vein of laboratory animals, obtained intense stimulation of the vagus and vaso-contrictpr centers with heart failure.

Respiratory

There is a decided depression of the respiratory center, preceded by a very short period of stimulation. In some cases respiratory paralysis is the cause of death, and in experiments with the much diluted vapor the respiration regularly ceases before the heart; but the heart is too weak to permit resuscitation. In the throat and bronchi, if the vapor is properly diluted, it is not irritating and may even be soothing, so that cough or bronchial irritation may be less after the anesthesia than before (Bennett).

Nervous System

The effects are practically those of ether, the cerebral and spinal depression, however, following more rapidly and from a much smaller amount of drug. The highest intellectual functions are depressed first, then, in succession, the emotional and motor, the cerebellar, the spinal, and finally the medullary. By removing the pia from a portion of the cord to exclude that portion from the action of the drug, Bernstein tried to find the exact site of action of chloroform. On lightly anesthetizing the animal he found that on irritating the afferent nerves whose cells were in the excluded area reflexes could be obtained involving motor cells in the chloroformized parts of the cord, i. e., the motor cells where not paralyzed. But on irritating the afferent nerves whose fibers passed through the chloroformized part of the cord, there was no motor response at all. Therefore, he concluded, the action of chloroform must be on the first synapse or the intermediate neuron of the afferent system, the same structure, probably, that is excited by strychnine. (See Fig. 37.) With larger amounts of chloroform the motor cells or their synapses are also paralyzed.

Eye

In complete anesthesia the pupil is rather contracted, and of about 1.5 to 3 mm. in diameter, i. e., two-thirds the diameter of the ether pupil.

Elimination is chiefly by the lungs and is rapid. Traces are also found in the urine; also in milk and fetal blood.

Kidneys

Figures as to the occurrence of albuminuria after ether and chloroform vary considerably with the different writers. After 41 ether anesthesias Babaci and Bebi noted albuminuria in 35 per cent.; while after 54 chloroform anesthesias, albuminuria occurred in only 18 per cent., i. e., ether proved twice as likely to produce albuminuria as chloroform. On following up their observations with experiments on dogs, guinea-pigs, and rabbits, these investigators found that though ether more readily causes a passing or functional albuminuria, chloroform is more prone to produce destructive changes, i. e., fatty degeneration and permanent inflammatory lesions. Hence chloroform, though less prone to produce albuminuria, is more dangerous to the kidneys than ether.

Metabolism

Chloroform tends to produce fatty changes in various organs, in the following order of extent and frequency: liver, kidneys, spleen, heart, arteries and cardiac ganglia, and perhaps the lungs.

The main effects on metabolism are due to the marked destructive changes in the liver leading to necrosis. There is a decrease in the storage of glycogen, and, as a consequence, an increase of sugar in the blood. In the urine there is increase in phosphates, chlorides, sulphates, and total nitrogen, the ammonia nitrogen being increased while the urea is decreased. The urine sometimes contains sugar, acetone, and allied bodies, and cystin, leucin, or tyrosin. These effects are evidences of increased destructive metabolism with incomplete oxidation.

Therapeutics Of Chloroform, Aside From Its Use As Anesthetic

Externally. - (1) In liniments, as a rubefacient for muscular, joint, and neuralgic pains. (2) On cotton in a decayed tooth for toothache.

Internally

(1) As a mild and pleasant carminative in flatulence or colic - the water or spirit. (2) As an antemetic in refractory cases of vomiting - one dram of the water every hour. (3) As antihysteric and cerebral sedative - the spirit.

The Chloroform habit is not uncommon, the sweet taste and narcotic action making the drug a rather pleasant dose. In some cases it is rubbed into the gums. The effects of the habit are similar to those of the chloral habit. (See Chloral Hydrate.)