Fig. 35. - Dog after vascular nephritis produced by arsenic: a, Before caffeine; b, eight minutes after caffeine; c, twenty-two minutes after caffeine. I, Drops of urine. II, Volume of kidney. III, General arterial pressure (from Pearce, Hill, and Eisenbrey).

These experiments, with many others of a like nature, seem to indicate that the diuresis of caffeine is not at all through a circulatory action, but is due to a direct action of the caffeine on the cells of the renal tubules. (See also under Diuretics.) But whether the action is stimulation of the tubule cells or interference with reabsorption, or both, has not been finally determined.

In caffeine diuresis there is increased excretion of certain substances that are known to be excreted by the tubule cells, as urinary pigment and creatinin. Salant and Ringer (1912) find the latter increased 100 per cent. or more in rabbits.

As with other diuretics, the more water there is in the body, the more readily is diuresis produced. V. E. Henderson has shown that when the body is poor in water, caffeine fails as an excitant to secretion, though it brings about the usual dilatation of the renal arterioles. But caffeine is strongly diuretic, for Rafael found that 7 1/2 grains of caffeine with 1000 c.c. of water in a day increased his urine 42 per cent. over that from 1000 c.c. of water without the caffeine.

It is of interest that caffeine increases peristalsis in the ureters, for this alone during a short experimental period may favor the urine flow.

Toxicology

As coffee and tea are employed so extensively as beverages, mild caffeine poisoning is usually seen from the use of these, rather than from the medicinal use of caffeine.

Acute Poisoning

(a) When a moderate overdose of caffeine is taken, as two or three times the accustomed amount of coffee or tea, the brain and cord become overactive, and there are increased reflex irritability, increased motor activity, and impairment of the mental power because ideas follow one another so rapidly as to prevent concentration of thought. The patient cannot concentrate his attention, and is excitable, restless, and unable to sit quietly. His arm and leg muscles or face muscles may twitch, and he may feel gastric discomfort, with oppression about the heart and palpitation. His breathing may be deep, but oppressive.

The treatment consists of rest, with bromides or other central sedatives. Sollmann and Pilcher found that alcohol increased the toxicity of poisonous amounts of caffeine, though caffeine does not increase the toxicity of alcohol.

(b) With marked toxic doses there may be vomiting, convulsions, weak and irregular heart, low arterial pressure, and collapse. Death takes place usually from failure of the heart muscle, but may be due to exhaustion of the respiratory center. One case of death was reported by Allard in 1904, and the author has seen two probable instances in cardiac cases. One of our own students took two teaspoonfuls of pure citrated caffeine instead of effervescing citrated caffeine. He went into collapse and later vomited several times. He was very anxious and nervous, and his heart remained weak and irritable, so that he could not leave his bed for seventeen days. He continued to be excessively nervous, and suffered from insomnia for many months.

The treatment of severe poisoning is that for collapse. Especially necessary is absolute repose. Because of the exhaustion of the centers, drugs are contraindicated. Saline irrigations may be of use to promote elimination by the kidneys.

Chronic poisoning is a state reached by excessive daily ingestion of tea or coffee. It is prone to show in digestive disturbances, cardiac neuroses, nervousness, insomnia, and morning headache, relieved by coffee. Asthenopia, amblyopia, nystagmus, ataxia, and increased reflexes are reported.

Therapeutics

1. As a central stimulant to counteract the depression of the respiratory, cerebral, and spinal centers, and the loss of tone of the muscles in collapse, especially that resulting from narcotic drugs, as chloral, morphine, alcohol, or ether.

2. As a respiratory stimulant in edema of the lungs and depression of the respiration.

3. As a stimulant or tonic in convalescence from acute dis-ease, as after influenza or pneumonia, in nervous exhaustion, in conditions of mental and physical weariness, and in depressed states of the mind.

4. As a diuretic in dropsy or in any condition in which increased urination is desired. In inflammatory conditions of the kidneys the effect depends upon the amount of kidney tissue that is still functional.

5. Perhaps as an emergency heart stimulant.

6. In the night dyspnea of heart cases. Christian found that a dose at bedtime was followed by better breathing and sleep.

It is frequently given with drugs like acetanilid and phenac-etin, because of an erroneous idea that it will prevent the depression that these sometimes cause. But the studies of Hale in the laboratory of Public Health and Hygiene at Washington have shown that the toxicity of acetanilid and antipyrine are increased by caffeine. As a matter of fact, many of the cases of acute acetanilid poisoning have occurred from mixtures which contained caffeine. (See Antipyretics.)

In the employment of caffeine in therapeutics, three things must always be borne in mind, viz.: (1) It strongly stimulates the cerebral cortex, so that a few doses may result in an excitable nervous condition, with alert mind and complete inability to sleep, at a time when an inactive mind and sleep may be the greatest necessities of the patient. What Mackenzie says of the treatment of heart disease is especially to be noted, viz.: "Whatever the form the heart failure may assume, sleep is essential. It may be taken as an axiom that if the patient does not get sufficient sleep he will never get well." (2) It stimulates the perceptions, and so may increase a patient's suffering and the appreciation of his sick condition; in very sick patients a condition of apathy is better. (3) Its dose is uncertain, as there is a great difference in individual susceptibility to the drug, and the tea and coffee habits establish varying degrees of tolerance. It is a well-known fact that one person will sleep well and experience no discomfort after several cups of tea or coffee, while another may be kept awake or have palpitation of the heart from one cup. A cup of coffee contains from 1 to 2 grains of caffeine; therefore 5 grains of citrated caffeine every four hours, as I have seen prescribed, would equal a cup of strong coffee every four hours all day and perhaps for several days. This would be a large amount for one who is healthy, even if not especially susceptible to caffeine; and it is a poisonous quantity for one who is sick and is susceptible. Powerful remedies to which persons show marked variations in susceptibility should have very little employment in medicine, because one cannot calculate in advance the probable dose that will give the desired effect. Moreover, tea and coffee are so much used that caffeine has often lost its influence to a greater or less degree. These three things, then, must be remembered:

1. Caffeine promotes wakefulness and nervousness.

2. It increases the perceptions.

3. Its dose is uncertain, because of marked variations in individual susceptibility.

From large doses in cases of myocarditis Taylor reports nausea, vomiting, headache, restlessness, and insomnia.

Administration

Ordinarily, coffee or tea may be employed, or the citrated caffeine given in 1 -grain tablet triturates. In collapse, hot strong coffee may be given by mouth or by rectum; or the salicylate or benzoate of sodium with caffeine may be given hypodermatically.