Doses

Doses (from the Greek dosis-portion, dose), any definite quantities of medicinal substances or preparations prescribed to a patient for use. The dose is indicated to the patient verbally by the physician or in writing in a prescription. Already more than 3,000 years ago, physicians in Egypt, when prescribing medications, precisely indicated the quantities thereof per dose; in the most ancient Indian and Chinese manuscripts, indications have been found of physicians' ability to dose medicinal substances prescribed to patients. As medical knowledge developed, more and more attention was paid to the question of the magnitude of doses needed for treatment, and it became increasingly clear that determining the dose represents a very difficult and responsible task, since the magnitude of the dose depends not only on the strength but often also on the nature of the action of the agent used. One must not give too little medication for it to exert the necessary therapeutic effect; but on the other hand, the dose must not be too large to avoid causing poisoning in the patient, and practically, in order to select the correct therapeutic dose, certain systems for administering medicinal substances were created. A method proposed for determining doses by the Ghent surgeon Bourggraeve and called dosimetry or the dosimetric system was well-known and is still used in Belgium, Holland, Italy, Spain, and France. According to this method, certain medications representing active principles as purely as possible (alkaloids and salts) are prescribed to the patient in strictly sequentially ascending doses. Starting for potent substances from 0.0005 or for some from 0.001, and for weaker substances from 0.01, the dose is successively increased until the medication causes in the patient what are called physiological effects; then the increase in doses is stopped, and the dose found for this case and this patient is taken as the sought therapeutic dose. The use of medications in very large doses, as was especially regularly practiced by physicians of the 18th century according to the views of Stahl and his followers, convinced many of the unquestionable harm of excessive doses and prompted physicians to use smaller ones. In this case, Hahnemann (see) fell into another extreme, attaching special and exclusive value for therapy to infinitely small, so-called infinitesimal doses. Hahnemann admitted depending on the magnitude of the dose a twofold action of medications on the organism—'primary' (therapeutic) and 'secondary', always opposite to the primary; the 'primary' action appears the more clearly, the smaller the dose used; with large doses, only the 'secondary' action develops. Hahnemann's views on 'infinitesimal' doses met with a critical attitude even among his closest followers, and at present the majority of homeopaths in treatment use no more than the sixth dilution (see Homeopathy).-To the question of the specificity of small doses, clinically approached in 1925 by the famous Berlin surgeon Professor A. Bier (Bier), guided by the Arndt-Schulz law (see) and explaining the effect of medications under such conditions by their irritating action. Experimentally, the question of minimal doses was resolved by N. P. Kravkov in connection with the oligodynamic phenomena first indicated by Naegeli, and in connection with the extraordinary sensitivity of the protoplasm of living cells of the organism. To explain the action of infinitely small doses, Kravkov resorted to the hypothesis of the decay of the atom into electrons. This view, however, met with severe criticism from various sides. The question of the significance of the magnitude of substances taken for action was more broadly illuminated by Lagovsky, who came to the conclusion that 'between the dose and the strength of action of a poison there is a regularity expressed in the fact that to the increase and decrease of the dose a certain number of times corresponds the same change in the strength of action of the poison'. This refutes the so-called 'Juckuff's law', according to which the increase in the strength of action of a poison is not proportional to the increase in the dose but proceeds much faster than the latter, i.e., with a doubling of the dose, the action increases not twofold but 11, 14, 15, 30, 50 times, since the dose acting on the cell (resp. on the organism) proves to be the excess amount of poison remaining free after the expenditure of a certain amount of poison to overcome the resistance which each living cell (resp. organism) possesses in relation to the destructive action of the poison.-When considering the strength of action of medicinal substances depending on the dose, the significance of the concentration in which a particular dose of a substance is introduced comes to the fore. It has been experimentally proven that the degree of dilution of a poison has a tremendous influence on the strength of its action: the action is strengthened at high concentrations, weakened at lower ones, consequently a smaller dose of a substance but in a more concentrated form can cause an action that is not obtained from the same dose or a somewhat larger one but introduced in a less concentrated form. Straub pointed out that in the absorption of poison by cells, the absolute amount of substance plays a role, however noting that at higher concentrations of the substance, its absorption by cells proceeds more quickly, at lower concentrations-more slowly. Since an increase in the speed of action of medicinal substances usually leads to an intensification of their action, to regulate the strength of action, with increased speed, the dose must be reduced.-The dosage of medicinal substances is also reflected in the combined use of two or several substances. In such a case, if substances are taken in significant concentrations, their action can be summed up and cause a toxic effect, whereas the same substances, taken in lower concentrations, influence each other quite differently: one reduces the strength of the other. With an increase in temperature, the dose of medicinal substances should also be reduced (Blagoveshchensky) in sick persons and in experimental animals, if one wants to maintain the strength of action of the medicinal preparation only at a certain level. Thus, in dosing medicinal substances, it is necessary to take into account a number of conditions, in many cases extremely complex and not easily determinable. Therefore, the regulation of doses cannot be regarded as something absolutely precise; meanwhile, practical medicine thanks to many years and innumerable observations and tests of the action of various doses of medicinal substances and preparations has always striven and for most medications has been able to establish so-called therapeutic doses prescribed to adult patients. The limits within which the magnitude of therapeutic doses fluctuates for each substance are relatively wide and begin with those magnitudes at which in healthy or sick persons certain phenomena characteristic of the action of this particular substance appear. In contrast to those doses which due to their insignificance have no effect and are called indifferent, the initial active doses received a special name—physiological. If the applied dose causes poisoning phenomena, it is called toxic (dosis toxica). In some cases, with special indications, such doses are nevertheless used for treatment. Doses of medicinal substances that cause death when introduced into the organism are called lethal or fatal (dosis letalis). Therapeutic doses border on the one hand with indifferent doses, and on the other hand directly reach the magnitude of toxic doses. Initial therapeutic doses cause weak action—not sharp, slow and often therapeutically incomplete. To obtain complete or average action in treatment, larger doses than the initial ones are already necessary; the picture of the effect of this agent is then clearly, distinctly expressed in certain changes in the organism corresponding to the action of the substance taken, but not going beyond the limits of physiological phenomena. Such doses are called therapeutic medicinal or average (dosis medicinalis, s. media). It must be remembered that many medications are used for different therapeutic effects (calomel—as a laxative and antiseptic, quinine—against malaria and as a cardiac, etc.) and therefore the same remedy can have several average doses depending on its purpose. Since knowledge of average doses is very important for a physician treating a patient, some pharmacopoeias, for example the American and English, listing and characterizing the principal modern therapeutic substances, indicate for each its average therapeutic dose without defining the limiting boundaries of dosage. Most modern pharmacopoeias, however, do not mention average doses at all; only in relation to poisonous and potent medicinal substances do they introduce indications of so-called 'higher doses' (dosis maxima). Higher doses were first given in 1827 in the fourth Prussian pharmacopoeia. The compilers of this pharmacopoeia write in its preface: 'For the means usually called heroic, we establish higher doses. However, we know very well that a physician in prescribing medications cannot be bound by any dose. Often, however, it happens that due to a mistake a larger dose may be indicated in the prescription than the physician himself would want to prescribe. If the physician has prescribed a larger dose than is in the pharmacopoeia, the pharmacist should prepare the medication only in the case where an exclamation mark stands opposite the dose in the prescription, from which the pharmacist will see that the larger dose was prescribed intentionally'.

This is where the 'maximum D.' are placed among therapeutic doses and given an orientation-preventative significance: the physician, in the list of 'maximum D.', has a certain basis for determining the size of doses, and in case of an error in dosage, the possible danger to the patient is prevented by the pharmacy staff based on the indications of 'maximum D.'. Such assignment of a list of 'maximum D.' is still preserved by the pharmacopoeias. The French pharmacopoeia provides a list of 'maximum D.' for potent and poisonous substances, but this list does not have the character of a mandatory government prescription, but is given only for information. The Swedish Ph. indicates only single maximum doses, while most Ph. provide single (pro dosi) and daily (pro die) 'maximum doses' and establish mandatory rules that physicians must follow when prescribing poisonous and potent substances, and pharmacy staff when preparing and dispensing medications with such substances. The German Ph. states that the rules for dosing poisonous substances are mandatory to follow when prescribing prescriptions not only for oral administration of the medication, but also when prescribing substances for eye drops, inhalations, subcutaneous injections, enemas, and suppositories. The Austrian Ph. emphasizes the mandatory nature of the rules on 'maximum doses' of poisonous substances not only when administered internally, but also when used externally, if the substances are absorbed. The Belgian Ph. considers 'maximum doses' mandatory when prescribing medications orally per os or per rectum. The Swiss Ph. additionally also for subcutaneous and intravenous injections, and the Dutch Ph.-and for injections into the genitourinary apparatus. The Soviet FUP, regulating the maximum single doses of poisonous and potent medicinal substances for adults, in general does not limit the application of the indicated D. to any particular methods of administration and only in a few cases specifically highlights maximum D. for subcutaneous and intravenous injection, and also determines the D. of some substances used for the purpose of inducing emetic action. Similar to the German Ph., the Soviet Ph. in its rules provides for the procedure for preparing and dispensing medications containing poisonous and potent substances, if such are prescribed in a D. exceeding that indicated in the pharmacopoeial list, without the special markings established in such cases by the physician on the prescription. Consequently, while having a general type, the pharmacopoeial rules on 'maximum D.' in different countries differ in details. The magnitudes of the 'maximum D.' themselves, established by different pharmacopoeias for the same substances, often also differ, as can be seen from the following comparisons: the maximum single dose of chloral hydrate according to the Soviet FUP-2.0, according to the Dutch Ph.-1.0, according to the German-already 3.0, and according to the French-even 4.0. The daily D. of chloral hydrate differ even more: according to the Dutch Ph.-4.0, according to the Soviet and German-6.0, and according to the French-12.0. Caffein pro dosi according to the Austrian Ph.-0.2, according to the Soviet and German'-0.5; D. per day according to the Austrian-0.6, according to the Soviet and German-1.5. Sublimate according to the Dutch Ph.-0.01 pro dosi, according to the Soviet-0.02, and according to the Austrian-0.03. Ordinary tincture of opium-according to the Soviet FUP pro dosi-1.0, according to the German-1.5, according to the French-2.0; pro die according to the Soviet Ph.-3.0, according to the German-5.0,according to the French-6.0 etc. The compilers of various pharmacopoeias apparently regarded the magnitudes of 'maximum D.' differently even for the same preparations. Some authors sought to be as cautious as possible with dosing poisonous and potent substances, while others tried to establish the highest therapeutic D. that could be used more or less safely, well knowing the approximate value of maximum D. and taking into account that even moderate therapeutic doses can cause poisoning phenomena, since in the action of drugs not only the magnitude of D. plays a role, but also the mass of other conditions under which medicinal substances are introduced. When compiling the pharmacopoeial (F VII) table of maximum D. of poisonous and potent medicinal substances, it was considered best to set narrower limits of dosages, so as to more strictly protect the health of patients. Guided by the magnitudes of maximum doses indicated in FVII, the physician can more or less correctly determine the average therapeutic D., if from the maximum D. of a poisonous substance he takes for ordinary cases of treating patients one third, and from the maximum doses of potent substances-one third or half. In regard to D. of poisonous and potent substances not mentioned in F VII, but used for treatment, one is guided by the indications of foreign pharmacopoeias or specialized literature. The table of 'maximum doses' contained in FVII contains the following instructions. 1. The maximum D. of poisonous and potent medicinal substances, indicated in the list, are calculated for adult people 25 years of age. For those not yet mature and for children, maximum D. are reduced depending on age approximately as follows: for young people 18 years- ¹/₄ of the dose for adults, 14 years-¹/₂, for children 7 years-¹/₃, 6 years-¹/₄, 4 years-¹/₆. ^{2 years}-¹/₈ of 1 year-¹/₁₂, up to 1 year-¹/₂₄-¹/₁₂ of the dose for adults. 2. Maximum D. are reduced to ¹/₃ and ¹/₂ of the dose for adults also for persons who have passed the 60-year age. 3. If a poisonous or potent medicinal substance is prescribed in a prescription in a D. exceeding that indicated in the list, and moreover not in writing and without an exclamation mark, then 'the head of the pharmacy or his deputy are obliged to contact the physician verbally (can by telephone) or in writing (in a sealed envelope) and only after receiving the answer to dispense the prescribed medication in the corresponding dosage. In case of being unable to communicate with the physician for any reason, the head of the pharmacy or his deputy dispense the prescribed substance in half of the D., which is indicated in the list as maximum. As for these rules, the third does not require additional explanations, since a similar rule of the Prussian Ph. has been analyzed above and its significance has been clarified; the indications contained in points 1 and 2 are observed by physicians when prescribing all medicinal substances, and not only potent and poisonous ones, since the effect of medicinal substances on the body always depends on the ratio between the magnitude of the prescribed D. and the magnitude of the patient's body, which changes depending on age. In general, the larger the animal, and in particular the human being, the greater amount they tolerate of the introduced medication and the greater therapeutic D. must be given to obtain the necessary therapeutic effect. Such dependence of the action of a drug on the magnitude of the animal is understandable, since a given number of molecules of the medicinal substance is distributed in the body of a large animal (resp. human) over a larger number of units of receptive protoplasm, as a result of which the therapeutic D., correctly chosen for a large adult person, usually turns out to be excessive for a teenager and fatal for a small child. Therefore, physicians began to use the age criterion when choosing D. for patients. The initial magnitude in such a method of determining D. is the average therapeutic D., prescribed to a 25-year-old adult man with an average weight of about 65 kg. Based on this D., the calculation is performed as indicated in the mentioned rules 1 and 2 of F VII. Approximately in the same way, Juncker and Gaubius proposed to perform the calculation: if the D. for an adult person (25 years) is taken as a unit, then to a child up to 1 year one must give ¹/₁₂ of this D., up to 2 years-¹/₃, up to 3 years-¹/_{4. D° for 4 years-¹/6, up to 7 years-¹/2 and for 14 years-²/3- Cauteraux somewhat changed Gaubius's table, proposing such dosing: up to 1 year-¹/12, from 1 year to 3 years-¹/4, from 3 y. to 7 years-¹/3, from 7 y. to 14 years-¹/2 and from 14 years to 20 years-²/3- The senile age, when the body's forces fade and resistance falls, both named authors to some extent liken to childhood in dosing medications, however stipulating that such a position has frequent exceptions. English physicians usually use for calculating D. the simple formula proposed by Young, in which the numerator is the number of years of the patient, and the denominator is the same number of years, but with 12 added, so that if the patient is 12 years old, then for him the magnitude of the dose is determined from the fraction ¹²/12+12 = ¹/2, i.e. equal to half that given to an adult. According to Fonsagrive, 13 is added to the denominator instead of 12. When calculating D., according to Young or according to Fonsagrive, the magnitudes of doses approximately coincide in size with the D. indicated by Gaubius.}

Dosing by age is very common in practice, but requires constant adjustment, since subjects of the same age often vary greatly in size; this is especially often the case with people of the same age but different sexes; prescribing the same dose in such cases is clearly irrational. One cannot also administer the same dose of a drug to two children, for example, of seven years of age, if one weighs 28 kg and the other 18 kg, since the fact that the same dose has a different strength of effect on animals of different weight is proven both by practice and through experimental research. To be most precise in dosing poisons in scientific research, pharmacologists have turned to calculating the dose of a drug per unit of weight of the animal, usually taking 1 kg as such a unit. Thus, in addition to the method of determining the size of a drug dose by age, a second method of dosing was introduced - by weight. The starting point for justifying such a method is the fact that in connection with the weight of the animal there is a more or less constant amount of blood (1/3 of the entire animal), and a given dose of drug, after being absorbed, is diluted by the blood and, at a certain concentration, acts on the receptive elements of the organism with the same force in different subjects, if the same ratio is maintained between the amount of elements affected by the drug and the concentration of the drug solution. Guided by this principle, Bouchard developed an experimental method for determining doses for newly introduced medicinal substances. According to this system, first the so-called toxic equivalent is determined, i.e., the amount of substance that kills 1 kg of body weight with rapid and uniform intravenous administration of the substance to the animal, and then only with great caution, starting to prescribe doses 200-100-20 times smaller, they proceed to determine the therapeutic equivalent, i.e., the dose needed for the therapeutic effect, and therefore the average therapeutic dose. The method of determining the dose of a drug by weight has taken a very firm place in laboratory research work on animals and in veterinary practice, because in these cases the age factor often cannot play any significant role, and on the other hand also because the weight of animals of the same species is very different if the individuals belong to different varieties, and therefore only weight, not age, can serve as the basis for dosing. In Volume VII there is a list of the highest single doses of potent medicinal substances for adult domestic animals. The list is compiled by weight. In the treatment of humans, however, determining doses by weight has not become widespread, mainly because of the inconvenience of weighing every patient as soon as it is necessary to determine the size of their drug dose. In addition, it often happens that when dosing, one cannot attach decisive importance to weight, for example, in general obesity, in large tumors (fibromas, lipomas, myomas, fibromyomas), in dropsy, when a huge amount of transudates accumulates in the body, in large exudative effusions, in pregnancy, in overfilling of the stomach and intestines, etc. In all these cases, the patient's weight increases significantly either due to tissues or fluids that do not play a significant role in diluting the drug taken by the patient, or due to the mass of food that only temporarily increases body weight. If, in addition, one takes into account that the effect of a drug is often different in children and adults due to differences in the degree of development, for example, of the nervous system or due to differences in the function of the endocrine apparatus, if one also considers cases of idiosyncrasy to medicinal substances, then the general rule of dosing per 1 kg of weight also turns out to be very conditional and difficult in practice, and it becomes understandable why the method of determining drugs by age is still used in medicine, despite the obvious shortcomings of such a method. The dose per administration (pro dosi) is called a single dose, and the total amount of drug taken per day or within 24 hours is called the daily dose (pro die). As with the first, the doctor must always keep this latter dose in mind when prescribing a drug, so that on the one hand the effect of the drug is not insufficient, and on the other hand it is not excessive. If the doctor finds it necessary to give the full average dose (dosis plena), which is usually due per administration, in some cases divided into small portions, then each such part is called a divided dose (dosis refracta). When establishing the sizes of single doses of medicinal substances for general effect on the body, one always has in mind how much of the drug is absorbed from a given dose; this amount of drug is essentially the active dose. This value must be taken into account when prescribing the average single dose in order to establish the concentration of the substance in the blood and therefore the dose of the drug acting on the body. If a drug is given for a long time, its effect also depends on the rate of excretion of the drug from the body, and the larger the dose that can be administered, the faster the substance is excreted from the body. The question of the rate of excretion is also connected with the question of the cumulative properties of medicinal substances. If a drug has cumulative properties, its dosing is limited so that poisoning does not occur in the patient. And in this case, as in all others, attention is paid to the total amount of medicinal substance taken (dosis totalis), mostly establishing the limiting boundaries empirically. The choice of routes for introducing drugs into the body affects the size of the doses administered to the patient, since depending on the route of administration, the rate of penetration of the drug into the blood (and therefore the speed and intensity of the effect) varies, since different parts of the body have different absorptive capacities. Experimentally and empirically, the following dosing of drugs has been established depending on the method of their administration: if the oral dose for an adult is taken as one unit, then for intravenous administration, it is generally considered quite sufficient to have 1/4-1/3 of the same dose; for intra-intestinal (enema) administration-1/2-1; for percutaneous-3-6. These figures are approximate and can be decreased or increased depending on a number of conditions. In relation to many medicinal substances regularly taken by patients, the body develops a habit, due to which it is necessary to increase the dose to obtain the desired degree of effect; before stopping the use of such drugs, patients take them, gradually reducing the single doses, in order to gradually wean the body from the drug being taken. When creating artificial immunity, a substance is given in gradually increasing amounts. Conversely, in cases of anaphylaxis or idiosyncrasy to certain drugs, very small doses of these substances are prescribed so that poisoning does not occur. Features of the sexual life of the body are also often a reason for changing the dosing of drugs. During menstruation, pregnancy, menopause, some drugs are given in smaller amounts than in normal periods of life. The different intensity of the patient's disease state is also an indicator for decreasing or increasing the dose; in cases of extreme weakness and exhaustion of the body, one must be especially careful with drug doses so as not to exceed the body's tolerance. The significance of temperature fluctuations in patients when determining the size of the dose has already been mentioned earlier; here it can only be pointed out that a high temperature to a certain degree characterizes the special intensity of the pathological process, therefore temperature fluctuations are always taken into account when establishing the size of the dose of a medicinal substance for a patient. The dose may be decreased or increased also depending on the time of day when the patient takes the drug. In the morning on an empty stomach, substances taken orally are absorbed faster than after lunch, when the food masses and liquids in the stomach prevent the drug from coming into contact with the mucous membrane and thus prevent rapid absorption. Therefore, when administering drugs to a patient on an empty stomach, the dose should be smaller than when taking the drug after lunch. The time of taking the drug also plays an essential role in another respect: hypnotic substances act faster and stronger if they are taken at night, i.e., before the usual time of falling asleep. The speed and strength of the effect of a drug also depend on the form in which the substance is introduced into the body. Alcohol tinctures are absorbed faster than aqueous infusions or decoctions; solutions of medicinal substances are absorbed faster than the same substances taken in powder form, etc.

Therefore, when determining the D. for a patient, it is also necessary to consider the strength of the drug's action depending on the form in which the drug is administered to the patient. Atmospheric and climatic peculiarities and fluctuations always affect the tone of the nervous system, the somatic and psychic activity of organisms, the conditions of blood circulation, absorption, combustion, breakdown, and excretion of drugs, as well as the intensity of the pathological process and the course of the disease in the patient, i.e., on a whole series of conditions that are always taken into account when determining the magnitude of the D. At present, when prescribing medicinal substances by prescription in the USSR, as in most European states and in the U.S.A., the magnitude of the D. is expressed in units of weight of the decimal, or French system, conventionally denoting gram-1.0, its tenth-0.1, hundredth-0.01, thousandth-0.001, etc., i.e., without adding the long word 'gram'. Previously, in our pharmacies, the exclusively empirical, so-called Nuremberg pharmacy weight (see Weight), pondus medicinale Norinbergense, was used, which was abolished for pharmacies in 1899, but was still applied for a long time after that in prescriptions by tradition by old physicians. The majority of modern pharmacopoeias require that the D. of prescribed medicinal ingredients be dispensed from pharmacies only by weight, and not by volume measure; only in England and the U.S.A. can liquid medicinal substances be prescribed in volume units. However, we have to prescribe liquid medicines for practical reasons in volume measures, significantly deviating in such cases from the precise determination of the magnitude of the administered D. Liquid medicines are prescribed to be taken by drops or by spoons, glasses, tumblers, cups, and sometimes even bottles. The magnitude of the prescribed doses in these cases naturally varies, since the utensils used for measuring the dose are far from always of the same capacity: a vodka bottle (1/40 of a state bucket) holds 615 cm³ of distilled water, and a wine bottle holds about 650 cm³; a glass-180-220 cm³; a cup-90-150 cm³; a tumbler-30-50 cm³; a tablespoon (metallic)-15 cm³, and a wooden one-20-35 cm³; a dessert spoon-8-10 cm³; a teaspoon-4-5 cm³. The weight of a drop of distilled water is considered equal to 0.05 g, and of ordinary water-0.06 g, but it should be said that the weight of a drop depends on very many conditions and therefore for various medicinal substances is subject to extremely wide variations and dosing by drops can in practice lead to a number of complications. To more precisely determine the magnitude of a dose by volume, special utensils are used-drop dispensers (see) and measuring glass cups; on the walls of the latter are markings indicating volumes of 5-10-15-20 cm³.-The concept of D. from medicinal therapy has been transferred to all other methods of treatment-serotherapy, roentgentherapy, radiotherapy, heliotherapy, hydrotherapy, balneotherapy, and other branches of physiotherapy, where the corresponding dosage is indicated.