STUDY - Technical - New Dacian's Medicine
Principles
of Drug Therapy (7)
Translation Draft
I've reached the toxicity of the primary pharmacological activity of the drugs and I'm going to start with cytotoxic reactions. Understanding so-called idiosyncratic reactions has been greatly improved by recognizing that many of these are due to irreversible binding of the drug or its metabolites to tissue macromolecules through covalent bonds. Some carcinogenic substances, such as alkylants, combine directly with DNA. Usually, covalent bonds occur only after metabolic activation of the drug, through the formation of reactive metabolites. This activation usually occurs in the microsomemal oxidative system with mixed function, the enzyme system responsible for the metabolism of many drugs.
During the metabolism of the drug, reactive metabolites may covalently bind to tissue macromolecules, causing damage to connective tissue. Due to the reactivity of these metabolites, covalent bonds often occur near their place of formation. Characteristically, that is the liver, but the oxidative system with mixed function is found in other tissues. An example of this type of drug adverse reaction is hepatotoxicity associated with isoniazide. This drug is metabolized mainly by acetilation to acetilizoniaside, which is then hydrolyzed to acetylsalicylic.
Subsequent metabolism of acetylsalicylics by the mixed-function oxidase system leads to the release of reactive metabolites, which covalently bind to liver macromolecules, causing hepatic necrosis. The administration of drugs that increase the activity of the microsomemal oxidative system with mixed function (e.g. phenobarbital or rifampicin) concomitantly with isoniazide is associated with increased production of reactive metabolites, the formation of a large number of covalent bonds and a higher risk of liver damage. hepatic necrosis produced by acetaminophen overdose is also determined by reactive metabolites. Under normal conditions, these metabolites are purified by combining with hepatic glutathione.
When glutathione is depleted, metabolites bind to liver proteins, causing damage to hepatocytes. Liver necrosis produced by the ingestion of acetaminophen can be prevented, or at least attenuated, by the administration of substances such as N-acetylcysteine, which reduces the binding of electrophilian metabolites to liver proteins. The risk of hepatic necrosis is increased in patients receiving phenobarbital-type drugs, which increase the rate of drug metabolism and production of toxic metabolites. It is likely, although it has not yet been demonstrated, that other idiosyncratic reactions are caused by the covalent binding of reactive metabolites to tissue macromolecules, with direct cytotoxic effect or by initiating an immune response.
Now, about the immune mechanisms. Most pharmacological agents have a low immunogenicity because they are small molecules with molecular weight below 2000. Stimulating the synthesis of antibodies or sensitizing lymphocytes under the action of a medicine or its metabolite usually requires in vivo activation and covalent binding of proteins, carbohydrates or nucleic acids. Stimulating the synthesis of antibodies under the action of a drug can mediate tissue damage through one or more mechanisms, Antibodies can attack the drug when it is attached to a cell through a covalent bond, producing cell destruction. This mechanism occurs in penicillin-induced hemolytic anaemia.
Drug antibody-antigen complexes can be passively absorbed on the surface of a cell, which is then destroyed by activating the complement (this mechanism occurs in quinine and quinidine-induced thrombocytopenia). Their active drugs or metabolites can cause damage to the host tissues, making it antigenic and stimulating the synthesis of autoantibodies. for example, hydralamide and procainamide can chemically alter the nuclear content, stimulating the formation of antinuclear antibodies and occasionally causing lupus erythematosus. The synthesis of autoantibodies can be stimulated by drugs that neither interact with host antigens nor bear resemblance to host tissue (for example, alpha-methyldopa frequently stimulates the formation of antibodies to host erythrocytes, although the drug itself does not attach to erythrocytes nor has structural similarities to the antigenic determinants on the surface of the erythrocytes).
Drug-induced erythrocytic aplasia is based on an immunological reaction to drugs. The formation of erythrocytes in bone marrow cultures may be inhibited by phenytoin and purified IgG obtained from a patient with pure erythrocytic aplasia due to phenytoin. Serum disease is caused by the storage of circulating antibody-drug complexes on the surface of the endothelium. Activation of the complement occurs, chemotactic factors are generated locally and an inflammatory response develops at the site of fixation of these complexes. Arthralgia, hives, lymphadenopathy, glomerulonephritis or cerebritis may occur.
Currently, penicillin is the most common cause of serum disease. Many drugs, in particular antimicrobial agents, induce the synthesis of IgE, which attaches to the membranes of mastocytes. Contact with a medicinal antigen initiates a number of biochemical phenomena inside the mastocyte, resulting in the release of mediators that can produce hives, wheezing, rhinorrhea, congestion and occasionally hypotension (characteristic of anaphylaxis). Medications can also stimulate the immune-mediated cellular response. Topically administered substances may interact with the sulfhydryl or amino groups in the skin and react with sensitised lymphocytes, producing the rash characteristic of contact dermatitis. Other types of rash may also occur as a result of the interaction between serum factors, medications and sensitizing lymphocytes. The role of lymphocytes activated by the drug in immune mechanisms responsible for visceral tissue destruction is not known.
And, there's something else to be presented about the toxicity associated with genetically determined enzyme defects. In porphyria, drugs that stimulate the activity of enzymes located before the deficient enzyme in the path of biosynthesis of porphyrins can increase the amount of porphyrin precursors, which accumulate proximal to the deficient enzyme. patients with glucoso-6-phosphate dehydrogenase (G6PD) deficiency develop hemolytic anaemia when taking primaquine and a number of other medicines that do not cause hemolysis in patients who have adequate amounts of this enzyme.
Let's get to the diagnosis now! The manifestations of drug-induced diseases usually resemble those of other diseases and a given set of manifestations can be produced by different drugs. Recognition of the role of a medicinal product or medicinal products in a disease depends on the assessment of possible adverse reactions to medicinal products in any disease, the identification of a temporal link between the administration of the medicinal product and the occurrence of the disease, as well as the similarity with the manifestations frequently caused by certain drugs. Numerous associations have been described between certain medicines and specific reactions, but there is always a "first case" for a new combination and any medicinal product should be suspected as the cause of an adverse effect when the clinical framework is suggestive. Disease related to a pharmacological action of the drug is often more easily recognized than that of an immunological nature or by other mechanisms.
For example, side effects such as cardiac arrhythmias in patients receiving digital, hypoglycaemia in those receiving insulin, and bleeding in patients receiving anticoagulants may be more easily related to the administration of these medicines, as opposed to symptoms such as fever or rash that can be caused by many medications or other factors. Once an adverse reaction is suspected, discontinuation of the incriminated medicinal product followed by the disappearance of the adverse reaction is presumptive evidence of the medical condition produced by the medicinal product. Decisive evidence can be provided by the cautious reintroduction of the drug and the observation of the recurrence of the reaction. This is only necessary if confirmation is useful for subsequent treatment of the patient and if the manoeuvre does not involve excessive risk. In the case of adverse reactions dependent on the concentration of the drug, the dose decrease may be followed by the disappearance of the reactions, and the increase in the dose may lead to their recurrence. When an allergic reaction is suspected, re-administration of the drug may be risky, as anaphylactic shock may occur.
Re-administration is not indicated under these conditions, unless alternative medicines are not available and treatment is absolutely necessary. If the patient receives more than one medication when an adverse reaction is suspected, the medicines most likely in their production can be commonly identified. All medicines should be discontinued immediately or, if not possible, they may be discontinued one at a time, starting with the most suspected adverse reactions, and the patient should be monitored for improvement in symptomatology. The time taken to eliminate adverse effects dependent on the concentration of the drug depends on the period of time during which the concentration falls below the level associated with adverse effects and this in turn depends on the initial blood concentration and the rate of elimination or metabolism of the drug.
Side effects of long-half-life drugs, such as phenobarbital, disappear over a long period of time. Drugs recognised as producing a number of side effects are in quite large numbers and are inserted into well-documented tables (even if some are less well known), focusing on those that are harmful enough to be considered.
These tables are used to suggest the drug that most likely causes an adverse reaction, and the absence of a drug in these tables does not exclude the possibility of its involvement in that adverse reaction. Serum antibodies have been identified in some people with drug allergies, involving figurative blood elements such as agranulocytosis, hemolytic anaemia and thrombocytopenia. For example, both quinine and quinidine may produce platelet aggregation in vitro in the presence of complement and serum from a patient who developed thrombocytopenia after taking one of these drugs. It is important for diagnosis to obtain from the patient a history of the therapy followed.
Attention should be directed both to non-prescription medicines and to prescription medicines. Each medicine may be responsible for side effects and adverse interactions may occur between prescription and non-prescription. In addition, it is common for patients to be under the care of several doctors, so patients may be recommended medicines with synergistic, analogue, cumulative or opposite effect if doctors are not informed about the history of medicines given to the patient. Before prescribing any medication, each doctor should be informed of the medicines the patient has received, at least for the last 30 days.
One source of exposure to an additional drug, commonly omitted, is topical therapy (for example, a patient who blames symptoms associated with bronchospasm may omit the fact that he is using a beta blocker for ophthalmic use, unless asked to do so). Often there is a history of adverse reactions to the patient's medications. As such patients are a predisposition for drug-induced conditions, anamnesis in this regard is an additional precaution for prescribing medicines. Patients with biochemical abnormalities such as erythrocytic G6PD deficiency may be identified.
Most patients with G6PD deficiency are black or come from the Mediterranean area. Drug-induced hemolytic seizures can be avoided by testing enzyme activity before taking medicines that can cause the reaction. Similarly, patients with abnormal serum levels of pseudocolinesterase may experience prolonged apnea when receiving succinylcholine.
I will complete this post with some general comments. No drug is completely free of side effects, and a side effect in one patient may be the desired pharmacological effect for another patient. Current drug regulations allow doctors to have considerable confidence in the purity, bioavailability and effectiveness of the medicines they prescribe. However, doctors should weigh the potential toxicity well in relation to the possible benefits. Thus, the toxicity that would be accepted in the case of an effective neoplastic agent is not allowed in oral contraceptives.
Due to the small number of treated patients required in premarketing studies, rare adverse reactions cannot be identified, so the primary responsibility for identifying and reporting these effects lies with the clinician by using national variants of adverse reaction reporting systems. The publication of a recently identified adverse reaction may, in a short time, stimulate the reporting of similar reactions that were not previously recognised. Prevention of adverse reactions to medicines implies, first of all, a high index of suspicion that the appearance of a new sign or symptom may be related to the drug.
Reducing the dose or discontinuing the suspected medication usually clarifies the problem of toxic reactions dependent on the concentration of the drug. Physicians should be well aware of the usual side effects of the medicines they use, and when they have doubts consult the literature.
Ready for this job, and. Next time I will address a particularly interesting topic from the point of view of classical medicine "extrapolated" in the new medicine, that related to the physiology and pharmacology of the vegetative nervous system.
I've reached the toxicity of the primary pharmacological activity of the drugs and I'm going to start with cytotoxic reactions. Understanding so-called idiosyncratic reactions has been greatly improved by recognizing that many of these are due to irreversible binding of the drug or its metabolites to tissue macromolecules through covalent bonds. Some carcinogenic substances, such as alkylants, combine directly with DNA. Usually, covalent bonds occur only after metabolic activation of the drug, through the formation of reactive metabolites. This activation usually occurs in the microsomemal oxidative system with mixed function, the enzyme system responsible for the metabolism of many drugs.
During the metabolism of the drug, reactive metabolites may covalently bind to tissue macromolecules, causing damage to connective tissue. Due to the reactivity of these metabolites, covalent bonds often occur near their place of formation. Characteristically, that is the liver, but the oxidative system with mixed function is found in other tissues. An example of this type of drug adverse reaction is hepatotoxicity associated with isoniazide. This drug is metabolized mainly by acetilation to acetilizoniaside, which is then hydrolyzed to acetylsalicylic.
Subsequent metabolism of acetylsalicylics by the mixed-function oxidase system leads to the release of reactive metabolites, which covalently bind to liver macromolecules, causing hepatic necrosis. The administration of drugs that increase the activity of the microsomemal oxidative system with mixed function (e.g. phenobarbital or rifampicin) concomitantly with isoniazide is associated with increased production of reactive metabolites, the formation of a large number of covalent bonds and a higher risk of liver damage. hepatic necrosis produced by acetaminophen overdose is also determined by reactive metabolites. Under normal conditions, these metabolites are purified by combining with hepatic glutathione.
When glutathione is depleted, metabolites bind to liver proteins, causing damage to hepatocytes. Liver necrosis produced by the ingestion of acetaminophen can be prevented, or at least attenuated, by the administration of substances such as N-acetylcysteine, which reduces the binding of electrophilian metabolites to liver proteins. The risk of hepatic necrosis is increased in patients receiving phenobarbital-type drugs, which increase the rate of drug metabolism and production of toxic metabolites. It is likely, although it has not yet been demonstrated, that other idiosyncratic reactions are caused by the covalent binding of reactive metabolites to tissue macromolecules, with direct cytotoxic effect or by initiating an immune response.
Now, about the immune mechanisms. Most pharmacological agents have a low immunogenicity because they are small molecules with molecular weight below 2000. Stimulating the synthesis of antibodies or sensitizing lymphocytes under the action of a medicine or its metabolite usually requires in vivo activation and covalent binding of proteins, carbohydrates or nucleic acids. Stimulating the synthesis of antibodies under the action of a drug can mediate tissue damage through one or more mechanisms, Antibodies can attack the drug when it is attached to a cell through a covalent bond, producing cell destruction. This mechanism occurs in penicillin-induced hemolytic anaemia.
Drug antibody-antigen complexes can be passively absorbed on the surface of a cell, which is then destroyed by activating the complement (this mechanism occurs in quinine and quinidine-induced thrombocytopenia). Their active drugs or metabolites can cause damage to the host tissues, making it antigenic and stimulating the synthesis of autoantibodies. for example, hydralamide and procainamide can chemically alter the nuclear content, stimulating the formation of antinuclear antibodies and occasionally causing lupus erythematosus. The synthesis of autoantibodies can be stimulated by drugs that neither interact with host antigens nor bear resemblance to host tissue (for example, alpha-methyldopa frequently stimulates the formation of antibodies to host erythrocytes, although the drug itself does not attach to erythrocytes nor has structural similarities to the antigenic determinants on the surface of the erythrocytes).
Drug-induced erythrocytic aplasia is based on an immunological reaction to drugs. The formation of erythrocytes in bone marrow cultures may be inhibited by phenytoin and purified IgG obtained from a patient with pure erythrocytic aplasia due to phenytoin. Serum disease is caused by the storage of circulating antibody-drug complexes on the surface of the endothelium. Activation of the complement occurs, chemotactic factors are generated locally and an inflammatory response develops at the site of fixation of these complexes. Arthralgia, hives, lymphadenopathy, glomerulonephritis or cerebritis may occur.
Currently, penicillin is the most common cause of serum disease. Many drugs, in particular antimicrobial agents, induce the synthesis of IgE, which attaches to the membranes of mastocytes. Contact with a medicinal antigen initiates a number of biochemical phenomena inside the mastocyte, resulting in the release of mediators that can produce hives, wheezing, rhinorrhea, congestion and occasionally hypotension (characteristic of anaphylaxis). Medications can also stimulate the immune-mediated cellular response. Topically administered substances may interact with the sulfhydryl or amino groups in the skin and react with sensitised lymphocytes, producing the rash characteristic of contact dermatitis. Other types of rash may also occur as a result of the interaction between serum factors, medications and sensitizing lymphocytes. The role of lymphocytes activated by the drug in immune mechanisms responsible for visceral tissue destruction is not known.
And, there's something else to be presented about the toxicity associated with genetically determined enzyme defects. In porphyria, drugs that stimulate the activity of enzymes located before the deficient enzyme in the path of biosynthesis of porphyrins can increase the amount of porphyrin precursors, which accumulate proximal to the deficient enzyme. patients with glucoso-6-phosphate dehydrogenase (G6PD) deficiency develop hemolytic anaemia when taking primaquine and a number of other medicines that do not cause hemolysis in patients who have adequate amounts of this enzyme.
Let's get to the diagnosis now! The manifestations of drug-induced diseases usually resemble those of other diseases and a given set of manifestations can be produced by different drugs. Recognition of the role of a medicinal product or medicinal products in a disease depends on the assessment of possible adverse reactions to medicinal products in any disease, the identification of a temporal link between the administration of the medicinal product and the occurrence of the disease, as well as the similarity with the manifestations frequently caused by certain drugs. Numerous associations have been described between certain medicines and specific reactions, but there is always a "first case" for a new combination and any medicinal product should be suspected as the cause of an adverse effect when the clinical framework is suggestive. Disease related to a pharmacological action of the drug is often more easily recognized than that of an immunological nature or by other mechanisms.
For example, side effects such as cardiac arrhythmias in patients receiving digital, hypoglycaemia in those receiving insulin, and bleeding in patients receiving anticoagulants may be more easily related to the administration of these medicines, as opposed to symptoms such as fever or rash that can be caused by many medications or other factors. Once an adverse reaction is suspected, discontinuation of the incriminated medicinal product followed by the disappearance of the adverse reaction is presumptive evidence of the medical condition produced by the medicinal product. Decisive evidence can be provided by the cautious reintroduction of the drug and the observation of the recurrence of the reaction. This is only necessary if confirmation is useful for subsequent treatment of the patient and if the manoeuvre does not involve excessive risk. In the case of adverse reactions dependent on the concentration of the drug, the dose decrease may be followed by the disappearance of the reactions, and the increase in the dose may lead to their recurrence. When an allergic reaction is suspected, re-administration of the drug may be risky, as anaphylactic shock may occur.
Re-administration is not indicated under these conditions, unless alternative medicines are not available and treatment is absolutely necessary. If the patient receives more than one medication when an adverse reaction is suspected, the medicines most likely in their production can be commonly identified. All medicines should be discontinued immediately or, if not possible, they may be discontinued one at a time, starting with the most suspected adverse reactions, and the patient should be monitored for improvement in symptomatology. The time taken to eliminate adverse effects dependent on the concentration of the drug depends on the period of time during which the concentration falls below the level associated with adverse effects and this in turn depends on the initial blood concentration and the rate of elimination or metabolism of the drug.
Side effects of long-half-life drugs, such as phenobarbital, disappear over a long period of time. Drugs recognised as producing a number of side effects are in quite large numbers and are inserted into well-documented tables (even if some are less well known), focusing on those that are harmful enough to be considered.
These tables are used to suggest the drug that most likely causes an adverse reaction, and the absence of a drug in these tables does not exclude the possibility of its involvement in that adverse reaction. Serum antibodies have been identified in some people with drug allergies, involving figurative blood elements such as agranulocytosis, hemolytic anaemia and thrombocytopenia. For example, both quinine and quinidine may produce platelet aggregation in vitro in the presence of complement and serum from a patient who developed thrombocytopenia after taking one of these drugs. It is important for diagnosis to obtain from the patient a history of the therapy followed.
Attention should be directed both to non-prescription medicines and to prescription medicines. Each medicine may be responsible for side effects and adverse interactions may occur between prescription and non-prescription. In addition, it is common for patients to be under the care of several doctors, so patients may be recommended medicines with synergistic, analogue, cumulative or opposite effect if doctors are not informed about the history of medicines given to the patient. Before prescribing any medication, each doctor should be informed of the medicines the patient has received, at least for the last 30 days.
One source of exposure to an additional drug, commonly omitted, is topical therapy (for example, a patient who blames symptoms associated with bronchospasm may omit the fact that he is using a beta blocker for ophthalmic use, unless asked to do so). Often there is a history of adverse reactions to the patient's medications. As such patients are a predisposition for drug-induced conditions, anamnesis in this regard is an additional precaution for prescribing medicines. Patients with biochemical abnormalities such as erythrocytic G6PD deficiency may be identified.
Most patients with G6PD deficiency are black or come from the Mediterranean area. Drug-induced hemolytic seizures can be avoided by testing enzyme activity before taking medicines that can cause the reaction. Similarly, patients with abnormal serum levels of pseudocolinesterase may experience prolonged apnea when receiving succinylcholine.
I will complete this post with some general comments. No drug is completely free of side effects, and a side effect in one patient may be the desired pharmacological effect for another patient. Current drug regulations allow doctors to have considerable confidence in the purity, bioavailability and effectiveness of the medicines they prescribe. However, doctors should weigh the potential toxicity well in relation to the possible benefits. Thus, the toxicity that would be accepted in the case of an effective neoplastic agent is not allowed in oral contraceptives.
Due to the small number of treated patients required in premarketing studies, rare adverse reactions cannot be identified, so the primary responsibility for identifying and reporting these effects lies with the clinician by using national variants of adverse reaction reporting systems. The publication of a recently identified adverse reaction may, in a short time, stimulate the reporting of similar reactions that were not previously recognised. Prevention of adverse reactions to medicines implies, first of all, a high index of suspicion that the appearance of a new sign or symptom may be related to the drug.
Reducing the dose or discontinuing the suspected medication usually clarifies the problem of toxic reactions dependent on the concentration of the drug. Physicians should be well aware of the usual side effects of the medicines they use, and when they have doubts consult the literature.
Ready for this job, and. Next time I will address a particularly interesting topic from the point of view of classical medicine "extrapolated" in the new medicine, that related to the physiology and pharmacology of the vegetative nervous system.
Don't forget the feast of
St. Nicholas!
Happy birthday to everyone
who celebrates their name today! Don't forget to make wishes!
St. Nicholas is not only the one who has the twig with him for
the naughty ones, but he is also the one who fulfills his
desires... And, of course, Love, Gratitude and Understanding!
Dorin, Merticaru