Belladonna
BELLADONNA (from the Ital. bella donna, "beautiful lady," the berries having been used as a cosmetic), the roots and leaves of Atropa belladonna, or deadly nightshade (q.v.), widely used in medicine on account of the alkaloids which they contain. Of these the more important are atropine (or atropia), hyoscyamine, hyoscine and belladonine; atropine is the most important, occurring as the malate to the extent of about 0.47% in the leaves, and from 0.6 to 0.25% in the roots.
Atropine, C17H23NO3, was discovered in 1833 by P.L. Geiger and Hesse and by Mein in the tissues of Atropa belladonna, from which it may be extracted by means of chloroform. By crystallization from alcohol it is obtained as colourless needles, melting at 115°. Hydrolysis with hydrochloric acid or baryta water gives tropic acid and tropine; on the other hand, by boiling equimolecular quantities of these substances with dilute hydrochloric acid, atropine is reformed. Since both these substances have been synthesized (see Tropine), the artificial formation of atropine is accomplished. Atropine is optically inactive; hyoscyamine, possibly a physical isomer, which yields atropine when heated to 108.6°, is laevorotatory.
Medicine. - The official doses of atropine are from 1/200 to 1/100 grain, and the sulphate, which is in general use in medicine, has a similar dose. It is highly important to observe that the official doses of the various pharmacopoeias may with safety be greatly exceeded in practice. They are based on the experimental toxic, as distinguished from lethal dose. A toxic dose causes unpleasant symptoms, but in certain cases, such as this, it may require very many times a toxic dose to produce the lethal effect. In other words, whilst one-fiftieth of a grain may cause unpleasant symptoms, it may need more than a grain to kill. So valuable are certain of the properties of atropine that it is often desirable to give doses of one-twentieth or one-tenth of a grain; but these will never be ventured upon by the practitioner who is ignorant of the great interval between the minimum toxic and the minimum lethal dose. It actually needs twenty to thirty grains of atropine to kill a rabbit: the animal is, however, somewhat exceptional in this regard. The most valuable preparations of this potent drug are the liquor atropinae sulphatis, which is a 1% solution, and the lamella - for insertion within the conjunctival sac - which contains one five-thousandth part of a grain of the alkaloid.
Pharmacology. - When rubbed into the skin with such substances as alcohol or glycerine, which are absorbed, atropine is carried through the epidermis with them, and in this manner - or when simply applied to a raw surface - it paralyses the terminals of the pain-conducting sensory nerves. It acts similarly, though less markedly, upon the nerves which determine the secretion of the perspiration, and is therefore a local anaesthetic or anodyne and an anhidrotic. Being rapidly absorbed into the blood, it exercises a long and highly important series of actions on nearly every part and function of the nervous system. Perhaps its most remarkable action is that upon the terminals of nearly all the secretory nerves in the body. This causes the entire skin to become dry - as in the case of the local action above mentioned; and it arrests the secretion of saliva and mucus in the mouth and throat, causing these parts to become very dry and to feel very uncomfortable. This latter result is due to paralysis of the chorda tympani nerve, which is mainly responsible for the salivary secretion. Certain nerve fibres from the sympathetic nervous system, which can also cause the secretion of a (specially viscous) saliva, are entirely unaffected by atropine. A curious parallel to this occurs in its action on the eye. There is much uncertainty as to the influence of atropine on the secretions of the stomach, intestines, liver, pancreas and kidneys, and it is not possible to make any definite statement, save that in all probability the activities of the nerves innervating the gland-cells in these organs are reduced, though they are certainly not arrested, as in the other cases. The secretion of mucus by the bronchi and trachea is greatly reduced and their muscular tissue is paralysed - a fact of which much use is made in practical medicine. The secretion of milk, if occurring in the mammary gland, is much diminished or entirely arrested. Given internally, atropine does not exert any appreciable sedative action upon the nerves of pain.
The action of atropine on the motor nerves is equally important. Those that go to the voluntary muscles are depressed only by very large and dangerous doses. The drug appears to have no influence upon the contractile cells that constitute muscle-fibre, any more than it has directly upon the secretory cells that constitute any gland. But moderate doses of atropine markedly paralyse the terminals of the nerves that go to involuntary muscles, whether the action of those nerves be motor or inhibitory. In the intestine, for instance, are layers of muscle-fibre which are constantly being inhibited or kept under check by the splanchnic nerves. These are paralysed by atropine, and intestinal peristalsis is consequently made more active, the muscles being released from nervous control. The motor nerves of the arteries, of the bladder and rectal sphincters, and also of the bronchi, are paralysed by atropine, but the nervous arrangements of those organs are highly complex and until they are further unravelled by physiologists, pharmacology will be unable to give much information which might be of great value in the employment of atropine. The action upon the vaso-motor system is, however, fairly clear. Whether effected entirely by action on the nerve terminals, or by an additional influence upon the vaso-motor centre in the medulla oblongata, atropine certainly causes extreme dilatation of the blood-vessels, so much so that the skin becomes flushed and there may appear, after large doses, an erythematous rash, which must be carefully distinguished, in cases of supposed belladonna poisoning, from that of scarlet fever: more especially as the temperature may be elevated and the pulse is very rapid in both conditions. But whilst the characteristic action of atropine is to dilate the blood-vessels, its first action is to stimulate the vaso-motor centre - thereby causing temporary contraction of the vessels - and to increase the rapidity of the heart's action, so that the blood-pressure rapidly rises. Though transient, this action is so certain, marked and rapid, as to make the subcutaneous injection of atropine invaluable in certain conditions. The respiratory centre is similarly stimulated, so that atropine must be regarded as a temporary but efficient respiratory and cardiac stimulant.
Toxic doses of atropine - and therefore of belladonna - raise the temperature several degrees. The action is probably nervous, but in the present state of our knowledge regarding the control of the temperature by the nervous system, it cannot be further defined. In small therapeutic and in small toxic doses atropine stimulates the motor apparatus of the spinal cord, just as it stimulates the centres in the medulla oblongata. This is indeed, as Sir Thomas Fraser has pointed out, "a strychnine action." In large toxic and in lethal doses the activity of the spinal cord is lowered.
No less important than any of the above is the action of atropine on the cerebrum. This has long been a debated matter, but it may now be stated, with considerable certainty, that the higher centres are incoordinately stimulated, a state closely resembling that of delirium tremens being induced. In cases of poisoning the delirium may last for many hours or even days. Thereafter a more or less sleepy state supervenes, but it is not the case that atropine ever causes genuine coma. The stuporose condition is the result of exhaustion after the long period of cerebral excitement. It is to be noted that children, who are particularly susceptible to the influence of certain of the other potent alkaloids, such as morphine and strychnine, will take relatively large doses of atropine without ill-effect.
The action of atropine on the eye is of high theoretical and practical importance. The drug affects only the involuntary muscles of the eye, just as it affects only the involuntary or non-striated portion of the oesophagus. The result of its instillation into the eye - and the same occurs when the atropine has been absorbed elsewhere - is rapidly to cause wide dilatation of the pupil. This can be experimentally shown - by the method of exclusion - to be caused by a paralysis of the terminals of the third cranial nerve in the sphincter pupillae of the iris. The action of atropine in dilating the pupil is also aided by a stimulation of the fibres from the sympathetic nervous system, which innervate the remaining muscle of the iris - the dilator pupillae. As a result of the extreme pupillary dilatation, the tension of the eyeball is greatly raised. The sight of many an eye has been destroyed by the use of atropine - in ignorance of this action on the intra-ocular tension - in cases of incipient glaucoma. The use of atropine is absolutely contra-indicated in any case where the intra-ocular tension already is, or threatens to become, unduly high. This warning applies notably to those - usually women - who are accustomed indiscriminately to use belladonna or atropine in order to give greater brilliancy to their eyes. The fourth ocular result of administering atropine is the production of a slight but definite degree of local anaesthesia of the eyeball. It follows from the above that a patient who is definitely under the influence of atropine will display rapid pulse, dilated pupils, a dry skin and a sense of discomfort, due to dryness of the mouth and throat.
Therapeutics. - The external uses of the drug are mainly analgesic. The liniment or plaster of belladonna will relieve many forms of local pain. Generally speaking, it may be laid down that atropine is more likely than iodine to relieve a pain of quite superficial origin; and conversely. Totally to be reprobated is the use, in order to relieve pain, of belladonna or any other application which affects the skin, in cases where the surgeon may later be required to operate. In such cases, it is necessary to use such anodyne measures as will not interfere with the subsequent demands that may be made of the skin, i.e. that it be aseptic and in a condition so sound that it is able to undertake the process of healing itself after the operation has been performed. Atropine is universally and constantly used in ophthalmic practice in order to dilate the pupil for examination of the retina by the ophthalmoscope, or in cases where the inflamed iris threatens to form adhesions to neighbouring parts. The drug is often replaced in ophthalmology by homatropine - an alkaloid prepared from tropine - which acts similarly to atropine but has the advantage of allowing the ocular changes to pass away in a much shorter time. The anhidrotic action of atropine is largely employed in controlling the night-sweats so characteristic of pulmonary tuberculosis, small doses of the solution of the sulphate being given at night.
The uses of atropine in cardiac affections are still obscure and dubious. It can only be laid down that the drug is a valuable though temporary stimulant in emergencies, and that its use as a plaster or internally often relieves cardiac pain. Recollection of the extraordinary complexity of the problems which are involved in the whole question of pain of cardiac origin will emphasize the extreme vagueness of the above assertion. Professor Schäfer recommended the use of atropine prior to the administration of a general anaesthetic, in cases where the action of the vagus nerve upon the heart is to be dreaded; and there is little doubt of the value of this precaution, which has no attendant disadvantages, in all such cases. Atropine is often of value as an antidote, as in poisoning by pilocarpine, muscarine (mushroom poisoning), prussic acid, etc.
Omitting numerous minor applications of this drug, we may pass to two therapeutic uses which are of unquestionable utility. In cases of whooping-cough or any other condition in which there is spasmodic action of the muscular fibre in the bronchi - a definition which includes nearly every form of asthma and many cases of bronchitis - atropine is an almost invaluable drug. Not only does it relieve the spasm, but it lessens the amount of secretion - often dangerously excessive - which is often associated with it. The relief of symptoms in whooping-cough is sharply to be distinguished from any influence on the course of the disease, since the drug does not abbreviate its duration by a single day. In treating an actual and present attack of asthma, it is advisable to give the standardized tincture of belladonna - unless expense is no consideration, in which case atropine may itself be used - in doses of twenty minims every quarter of an hour as long as no evil effects appear. Relief is thereby constantly obtained. Smaller doses of the drug should be given three times a day between the attacks.
The nocturnal enuresis or urinary incontinence of children and of adults is frequently relieved by this drug. The excellent toleration of atropine displayed by children must be remembered, and if its use is "pushed" a cure may almost always be expected.
Toxicology. - The symptoms of poisoning by belladonna or atropine are dealt with above. The essential point here to be added is that death takes place from combined cardiac and respiratory failure. This fact is, of course, the key to treatment. This consists in the use of emetics or the stomach-pump, with lime-water, which decomposes the alkaloid. These measures are, however, usually rendered nugatory by the very rapid absorption of the alkaloid. Death is to be averted by such measures as will keep the heart and lungs in action until the drug has been excreted by the kidneys. Inject stimulants subcutaneously; give coffee - hot and strong - by the mouth and rectum, or use large doses of caffeine citrate; and employ artificial respiration. Do not employ such physiological antagonists as pilocarpine or morphine, for the lethal actions of all these drugs exhibit not mutual antagonism but coincidence.
Note - this article incorporates content from Encyclopaedia Britannica, Eleventh Edition, (1910-1911)
