The official ones are antipyrine, acetanilid, and acet-phenet-idin. Some of the quinoline derivatives, among the so-called coal-tar drugs, have been employed largely as antipyretics (kairin, thallin, etc.), but have been discarded in favor of more certain remedies.

Antipyrina, antipyrine, phenyl-dimethyl-pyrazolon, is freely soluble in water and alcohol, and has a slightly bitter taste. It is a body closely resembling the alkaloids, and is precipitated by tannic acid, alkalies, and some other alkaloidal pre-cipitants. With calomel it forms a poisonous compound. With spirit of nitrous ether or other nitrites it gives a deep-green color (iso-nitroso-antipyrine); with ferric salts a deep red; with chloral hydrate, naphthol, phenol, and sodium salicylate it liquefies; with caffeine, quinine, and some other alkaloids it forms soluble double salts. Dose, 4 grains (0.25 gm.). For local application it is employed in 5 to 25 per cent. aqueous solution. Close relatives are pyramidon, dimethyl-dimethyl-amino-pyrazolon, and sali-pyrine, antipyrine salicylate.

The Analgesic Antipyretics 86

Acetanilidum, acetanilid, phen-acetamide, C6H5.NH.Ch3co, has a slightly biting taste, and is soluble in 190 parts of water and in 3.4 of alcohol. Its solubility in water is increased by acids and decreased by alkalies. Dose, 4 grains (0.25 gm.).

Close relatives of acetanilid are exalgine, methyl-acetanilid, and salophen, acetanilid-salicylic acid.

Acet-phenetidinum, C6H4.Oc2h5.NH.Ch3co, more familarly known under the proprietary name "phenacetin," is a derivative of phenol. It is soluble in 1310 parts of water and 15 of alcohol, and is almost tasteless. The chemic formula shows that phenacetin might properly be called oxyethyl-acetanilid, but it is not a direct derivative of acetanilid, and may better be placed in a separate group with other phenetidin compounds. It is not readily soluble in water. Dose, 5 grains (0.3 gm.). The other phenetidin compounds worthy of note are lactophenin, a lactic-acid derivative; malakin, a salicylic-acid derivative; and apolysin and citrophen, the mono- and tri-phenetidin citric acids.

Pharmacologic Action

These drugs all reduce temperature in the same way, are all analgesic, are all nerve sedatives, and are all antiseptic. This antiseptic action is mild, but is the same in kind as that of the phenol group of antiseptics, to which they are closely related chemically. Their antipyretic action is powerful, as exhibited in the reduction of temperature in the infectious fevers. Their analgesic action is chiefly shown in headache and nerve and muscle pains.

Locally, antipyrine differs from the others in that a 10 to 25 per cent. solution applied to a mucous membrane acts mildly like cocaine, inducing vasoconstriction with shrinkage of the membrane and the checking of small hemorrhages, and lessening pain. Acetanilid is slightly irritant locally, and phenacetin is bland.

The Antipyretic Effect

It seems probable that in many cases hyperthermy or fever is a protective reaction on the part of the body, and in these cases moderate degrees of fever require ho antipyretic treatment. There are some cases, however, in which even mild degrees of fever seem disadvantageous, and others in which the protective fever reaction overshoots the mark and produces a high and dangerous body temperature, and it is in these that antipyretic measures are indicated. Hektoen believes that fever is an indication that foreign protein is being broken down.

In fever the temperature may be reduced either by lessened production of heat or by increased output of heat, or by both. The tendency of the body is to keep itself at a normal temperature. If the body is too warm, there is a dilatation of cutaneous blood-vessels and an outpouring of sweat, so that the body will undergo heat loss by - (1) Radiation and convection of heat, more heated blood from the interior being brought to the surface; and (2) the evaporation of sweat. At the same time there is a tendency to lessened muscular activity with diminished heat production. This combination of lessened heat production and greater heat dissipation tends to bring the overheated body to a normal temperature.

If, on the contrary, the body is too cool, there is stimulus to greater muscular activity, the muscular act of shivering takes place, sweating stops, and the cutaneous vessels are contracted. So there are greater heat production and lessened heat dissipation, and the too cool body becomes warmed.

This heat production and heat-dissipation are, to a certain extent, under the control of some central structures spoken of collectively as the heat-regulating centers, the function of which is to keep the body temperature normal. There are probably thermogenic centers governing the production of heat, and thermolytic centers governing the dissipation of heat, and it is believed that they are situated in the corpus striatum and optic thalamus. Barbour and Wing have shown that heat applied directly in these regions results in body cooling, and cold results in body warming. Any variations from the normal affect these centers; and they at once send out impulses which influence the mechanisms for the production or the dissipation of heat, as may be needed.

In active muscular exercise much heat is produced; but through the heat-regulating mechanism heat dissipation is increased to correspond, so that the temperature scarcely rises, and if it does, is soon restored to normal. The extra loss of heat is brought about by dilatation of the cutaneous vessels and sweating.

But in some of the infectious fevers that have been studied the heat production has been found very little increased, and the hyperthermy to be due to the failure of the heat-dissipating mechanisms to do their work. For example, in one case of malaria Liebermeister estimated the increase in heat production during the hot stage to be 21 to 24 per cent., much less than the increase during active exercise; but during the malarial chill, owing to the muscular activity of vigorous shivering, the heat production rose 147 per cent. At the same time, owing to the constriction of the cutaneous vessels, the mechanisms for heat dissipation were in abeyance. It would seem in such cases that the fever results from the failure of the heat-regulating centers to make the heat loss keep pace with the heat production. Whether or not the toxins of the disease affect the center directly is still a question.