Camphor

Camphor, Camphora (C VII), a ketone of bicyclic terpene, having the following structural formula: C₁₀H₁₆O. White crystalline substance, of granular-fibrous fracture, with characteristic odor. Melts at 175°, boils at 204°, sublimes even at ordinary temperature. C. is little soluble in water (1:840), well in 90% alcohol (1:1), easily in ether, chloroform, fats, and essential oils. When triturated with phenol, menthol, chloral hydrate, forms thick liquids. Natural, so-called Japanese (otherwise laurel) C. rotates the plane of polarization to the right. It is obtained by distillation with water from the wood and leaves of the camphor tree - Cinnamomum Camphora, seu Lauras Camphora L. (family Lauraceae). The camphor tree grows and is cultivated in southeastern Asia, mainly in southern Japan and on the island of Formosa; it is also cultivated in climatically corresponding areas of Africa and America. The final purification of C. is carried out by sublimation. In some essential oils (e.g. in Tanacetum vulgare) there is the levorotatory isomer of C. At present C. is also obtained synthetically from the bicyclic hydrocarbon pinene contained in turpentine. Synthetic C. represents a racemic, optically inactive form. According to experimental data, all three isomers of C. in chemically pure form are pharmacologically very similar, but to this day only the natural dextrorotatory C. remains official; synthetic camphora is used mainly for technical purposes.

Locally on the skin and mucous membranes C. produces a moderately irritating effect, causing hyperemia, and with prolonged exposure - inflammation. Hyperemia is accompanied by a sensation of burning, more intensely expressed when C. acts on mucous membranes. Small concentrations of C. initially cause a sensation of cold, which is explained by the excitation of specific nerve endings, since the skin temperature in this case is even increased due to hyperemia. Following the phenomena of irritation, C. gives a certain analgesia. C. has a burning taste and, by irritating the oral mucosa, causes salivation. Small doses, moderately irritating the gastric mucosa, cause a sensation of internal warmth. The appearing hyperemia of the skin in this case apparently has a reflex nature. Moderate irritation of the gastric mucosa by C. gives reason to use small doses of it in dyspepsia. Large doses can cause reflex vomiting. C. has disinfectant properties, but in strength it is far inferior to the phenol group. In solution C. leukocytes lose their ability to move. C. is well absorbed by mucous membranes in general and by the intestinal in particular; however, its concentration in the blood when taken per os does not reach a high level due to the relatively rapid neutralization of C. in the body. Only a negligible part of C. is excreted unchanged through the lungs (camphor odor of exhaled air after taking large doses), while the larger part of it is rapidly oxidized in the so-called camphorol C₁₀H₁₆O₂ (otherwise - oxycamphora), easily excreted by the kidneys in the form of pharmacologically inactive camphor-glucuronic acid; some part of camphora is apparently excreted in the form of uramido-camphor-glucuronic acid.

With resorptive effect C. excites the central nervous system. Excitation of higher psychic centers after taking therapeutic doses of C. is revealed by psycho-physical tests according to the method of Kraepelin (W. Stross); however, in terms of the strength of such action C. is inferior to caffeine. The insignificance of C.'s action on psychic centers is manifested in the fact that when therapeutic doses are prescribed with the aim of exciting the vital centers of the medulla oblongata, there are no undesirable side symptoms (insomnia, etc.) from the higher centers of the brain. Toxic doses of C., in addition to the phenomena of cortical excitation (delirium, motor excitement, epileptiform convulsions of cortical origin), also cause certain symptoms of depression of higher centers (confusion and loss of consciousness). In the medulla oblongata, the excitatory effect of C. manifests itself mainly on the respiratory center, and the depth of breathing especially increases. The sensitivity of the respiratory center to CO₂ under the influence of C. increases. Less pronounced is the excitatory effect of C. on the vasomotor center. An increase in blood pressure due to the effect of C. on the vasomotor center was observed on chloralized animals (Levin). However, this pressor effect of C. is insignificant and is observed far from in all cases. The excitatory effect of C. on the centers of the spinal cord is expressed in a certain increase in reflexes, but this excitation does not reach high degrees, and convulsions are not produced by camphora in decapitated animals as a rule. The excitation of spinal cord centers controlling the secretion of sweat glands explains the sweating caused by camphora. Some clinicians attribute to camphora anti-aphrodisiac properties, considering that camphora has the ability to depress the corresponding centers of the spinal cord. Such an action of camphora is doubtful. Of particular interest in view of its significance for clinic is the question of the effect of C. on the heart; despite numerous experimental works and frequent use of C. in clinic as a cardiac remedy, this question cannot be considered resolved. In experiments with the effect of C. on the healthy heart, both in situ and isolated, it is very difficult to detect the excitatory and generally positive effect of this remedy. Small concentrations do not have any noticeable effect on the heart, while when using stronger solutions of C., a depressing, although easily reversible, effect is manifested. However, in experiments on the isolated frog heart within certain, although narrow, limits, concentrations can be found that cause an increase in the amplitude of contractions along with a slight decrease in rhythm. More distinctly expressed is the excitatory effect of C. when tested on hearts whose activity is reduced. For example, a frog heart stopped by muscarin or poisoned by chloral hydrate can be excited by weak, usually completely ineffective concentrations of C., which at the same time causes acceleration of rhythm and increase in contractions (positive chrono- and inotropic action). On the basis of the antagonism between C. and chloral hydrate, it is believed that the characteristic property of C. in relation to the heart is the ability to excite autonomous neuromuscular nodes, promoting the occurrence of impulses in them. This effect of C. is especially manifested in those cases when the frog heart does not work optimally and the occurrence of impulses is reduced. Conductivity and excitability of the healthy heart C. depresses; positive in relation to conductivity (dromotropic) effect is manifested only on frog hearts depressed by preliminary poisoning. The pronounced property of C. to eliminate depression caused by certain poisons gave Wieland (H. Wieland) reason to express the idea that such an action of C. is based on its high capillary activity (surface activity), thanks to which C. displaces toxic substances from the surface of protoplasm. C. also has an excitatory effect on weakened hearts of some warm-blooded animals (rats), however on isolated hearts of higher mammals (rabbit, cat) the excitatory effect of C. is manifested less definitely. It is more noticeable in the period after the action, called by Kravkov the stage of poison elimination. Even more rarely do researchers note the excitatory effect of C. on the hearts of warm-blooded animals in situ. According to Wilson and Harrison (Wilson, Harrison), C. in therapeutic doses does not increase the minute volume of blood in healthy dogs. The question of the effect of C. on the so-called fibrillation-atrial flutter and ventricular flutter is controversial. Some authors (Gottlieb, Seligmann) with the help of C. managed to prevent or even eliminate ventricular flutter caused by electric current. On this basis, camphora is sometimes prescribed by clinicians in atrial fibrillation. However, other researchers and in particular the expert in this field Winterberg (H. Winterberg) deny the favorable effect of camphora on fibrillation (flutter) of the atrium. When evaluating the therapeutic value of C. as a cardiac remedy, it is necessary to take into account that C. dilates the coronary vessels (Likhacheva) and, by increasing the nutrition of the heart, increases its performance. The vasodilating effect of C. apparently depends on the direct relaxing effect on the muscular wall of the vessels; in addition to the coronary vessels, it is also manifested to some extent on the other vessels. Other smooth muscles also relax under the influence of camphora. The daily experience of clinicians teaches that the injection of C. improves the breathing, pulse, and general condition of weak patients. The excitatory effect of C. on the respiratory center is beyond doubt, and the improvement in breathing undoubtedly has a favorable effect on the general condition of the patient. However, there are no clinical observations registered by instrumental methods on the basis of which one could undoubtedly assert that there is a direct excitatory effect of C. on the circulatory apparatus. The absence of such data can be explained by the rapidity of the action of C.

Then the exciting action of Camphor on the heart and vasomotor center, as can be judged from the above experimental data, does not differ in great strength and manifests itself only with a certain state of depression. But on the other hand, Camphor as an exciting agent is valuable for its low toxicity. While the usual therapeutic dose is 0.1-0.2, symptoms of poisoning, but not yet dangerous to life, have been described only with a single dose of 2.0. It is difficult to specify the lethal dose for humans; a case has been noted where poisoning of an adult with 15.0 Camphor ended in recovery. Poisoning in humans manifests as redness of the face, headache, dizziness, a desire to move; then comes psychic excitement: hallucinations, delirium, and finally loss of consciousness and epileptiform convulsions. The rapid neutralization of Camphor in the body allows for its repeated application after relatively short intervals. When analyzing the therapeutic effect of subcutaneous injections of Camphor, one must also take into account those reflexes that arise as a result of its local irritating action and which can cause excitation of the vital centers of the medulla oblongata. Some authoritative researchers (Cushny) generally doubt the resorptive effect of therapeutic doses of Camphor and reduce the therapeutic effect of an injection of Camphor to such a reflexive influence. Large doses of Camphor have been proposed as a specific agent for lobar pneumonia. Indeed, with respect to some cultures of pneumococcus, Camphor proved to possess fairly high bactericidal properties, and in a number of experiments, injection of Camphor produced an unquestionable therapeutic effect on experimental pneumonia in animals. However, it turned out that the sensitivity to Camphor of different cultures of the same pneumococcus varies within very wide limits, which probably explains the inconsistency of Camphor's action in both experimental and clinical pneumonia. The expectorant properties attributed to Camphor, which give reason to use it in bronchitis, can be explained by its action on the bronchial mucosa when excreted through the lungs. Like other aromatic compounds, Camphor possesses some antipyretic effect; however, due to the weakness of such an effect, Camphor is not currently used as an antipyretic. Preparations of Camphor are widely used as local irritants. Preparations. I. For oral administration. 1. With amphora trita, powder, for the preparation of which pieces of Camphor are moistened with a small amount of alcohol or ether and triturated in a mortar. The powder is not sifted through a sieve and is prepared only in a small supply. Due to its volatility, it is dispensed in waxed or paraffined paper. Orally 0.1-0.2 several times a day. 2. Camphora monobromata (bromocamphor), C₁₀H₁₅OVr, colorless prismatic crystals or needles with a weak camphor odor. Almost insoluble in water, soluble in 8.25 parts alcohol, very easily soluble in ether, chloroform, and fatty oils. Melting point 74-76°; boils at about 279°. Due to its bromine content, it is prescribed mainly in cases where a calming effect of Camphor is expected, e.g., in painful erections during gonorrhea and in painful urination (due to cystitis), as well as in cardiac neuroses. Doses: 0.1-0.5 several times a day. 3. Vinum camphoratum (2%) 1-2 teaspoons. II. For external use (in neuralgic, rheumatic and other pains). 1. Unguentum camphoratum (Ph. VII), 20% camphor ointment on lard and wax. 2. Spiritus camphoratus (Ph. VII), camphor spirit: 10 parts camphor, 70 parts wine alcohol (90%) and 20 parts water. 3. Oleum camphoratum (Ph. VII), camphor oil for external use, 10% solution of Camphor in sunflower oil. 4. Linimentum ammonio-camphoratum, Linimentum camphoratum - volatile camphor ointment, consisting of 3 parts Olei camphorati, 1 part Olei Sesami, 1 part Ammonii caustici soluti; a white ointment of a rather thick consistency. 5. Linimentum saponato-camphoratum liquidum, s. Spiritus saponato-camphoratus (liquid opodeldoc), a mixture of Spiritus camphorati (60 parts), Spiritus saponati (175 parts), Ammonii caustici soluti (12 parts) with the addition of Olei Thymi (1 part) and Olei Rosmarini (2 parts). The last two preparations, formerly official, were not included in Ph. VII. Camphor is included in many other external remedies, such as camphor-chloroform-vazogen (see Vazogen). III. For subcutaneous injection: Oleum camphoratum sterilisatum (Ph. VII), 20% solution of Camphor in almond (<&VII) or other (sesame, olive) vegetable oil, 1-2 cm³ under the skin. Some have recommended camphor oil for intravenous injections in the amount of 0.5-1 cm³, and supposedly there is no danger of embolism; however, unfortunate cases have been observed with this method of administration. For intravenous administration, a solution of Camphor in ether (0.2 : 0.5) has also been proposed. More common is the intravenous administration of a saturated Camphor (0.142%) physiological solution, which can be prepared as follows: Spiritus camphorati 3.5; Spiritus vini 2.0; Aq. destillatae ad. 10.0; M. D. ad vitrum sterilis.; administer intravenously in 1 liter of physiological solution (cloudiness disappears on shaking). The disadvantage of the camphor physiological solution is the need to introduce a large amount of fluid into the vein. Due to the low solubility of camphor in water and the poor absorption of oil solutions (sometimes oil depots are formed), several soluble preparations replacing Camphor have been proposed. These include: 1. Camphogen «Ingelheim», 2% solution of Camphor in a mixture of aqueous solutions of 25% acetdiethylamide and 15% sodium salicylate; 1-2 cm³ intravenously, subcutaneously, intramuscularly. 2. Campher-Losung «H b s k s t», 10-20% solution of synthetic⁴ Camphor in diethylene; subcutaneously and intramuscularly 1-2 cm³. 3. Camphochol (Riedel), a compound of Camphor with apocholic acid (C_MH_S8O₂ + C₁₀H₁₈O), containing 28% Camphor; a white crystalline powder. Insoluble in water, easily soluble in weak alkalis, in particular in the alkaline contents of the intestine. Tablets of 0.1 orally several times a day. 4. Cadechol (Boehringer, Ingelheim), a compound of Camphor with choleic acid (C₂₄H₄₀O₄)₂ C₁₀H₁₆O, a white crystalline powder containing 15% Camphor. Insoluble in water, but soluble in weak alkalis; tablets of 0.1 orally several times a day. 5. Hexeton, a synthetic isomer of Camphor (methylisopropyl-cyclohexenone), soluble in water with the addition of sodium salicylate (see Hexeton). Acts on respiration and circulation more strongly than Camphor. A drug replacing camphor is also cardiazol (see). Derivatives of Camphor include: 1. Camphoric acid, C₈H₁₄(COOH)₂, colorless crystals, soluble in 150 parts cold water, in 8 parts hot water, and well in alcohol and ether. Acts on the respiratory center like Camphor, differing only in less toxicity. Unlike Camphor, camphoric acid is credited with the ability to suppress sweating, which is why it is prescribed against night sweats in consumptives (1.0-2.0 pro dosi before meals). Such action has not received experimental confirmation. Camphoric acid is also used locally as a weak disinfectant and astringent in catarrhs of mucous membranes (1-2% solutions). 2. Oxycamphora (Paraoxycamphora), C₁₀H₁₅OOH, otherwise camphorol, a white crystalline powder, well soluble in water. It has a greater exciting effect on the heart than camphor and, unlike it, does not excite but calms the respiratory center. Used orally 0.5-1.0 two to three times a day for shortness of breath due to tuberculosis, emphysema, and heart defects. Due to the instability of aqueous solutions, a 50% alcoholic solution, so-called oxaphor, is usually used, 30 drops per dose.