Medicines for cell damage. To correct the regulatory effects on cells, preparations of hormones, neurotransmitters , cyclic nucleotides, etc. are used. Methods and schemes for their use are different depending on the nature of the damage and the pathological process that develops in connection with this. Medicines for cell damage The use of medicines for various diseases and pathological processes can be accompanied by significant changes in pharmacokinetics (absorption, distribution in organs and tissues, metabolism and excretion) and pharmacodynamics (effects and mechanisms of action). These circumstances require ongoing monitoring of the nature and severity of the action of drugs and, if necessary, correction or change in the schemes of their use.
The most common causes of changes in the pharmacokinetics and pharmacodynamics of drugs in the event of cell damage are disorders of drug conversions during metabolic reactions ( biotransformation ) or as a result of combination with various chemical groups and molecules (conjugation). For example, a decrease in the activity of enzymes in microsomes of cells, in particular in the liver, in which many drugs are transformed and inactivated, may be accompanied by an increase in the duration or severity of the effect of drugs. Disruption of drug conversions in damaged cells can lead to various consequences: • the formation of compounds of high toxic activity (for example, phenetidine from phenacetin); • a change in the nature of the action of drugs (for example, the metabolite of the antidepressant iprazine – isoniazid has anti-tuberculosis activity); • accumulation (cumulation) of the drug in organs and tissues. A significant factor influencing the effects of drugs is a change in the reactive properties of cells damaged as a result of a disease or pathological process. Thus, the effects of respiratory analeptics ( lobeline , tsitito -on) that appear on a background of normal breathing or moderate hypoxia recess and rapid breathing, are significantly reduced with the growth of the degree of hypoxia. Moreover, the use of high doses of these agents at the stages preceding clinical death often causes depression of the respiratory center. Repeated use of drugs in conditions of cell damage in various pathological processes and diseases can cause: • increased sensitivity to drugs (sensitization); • acceleration of addiction to the drug (tolerance); • the formation of conditions characterized by a pronounced or even irresistible desire to re-use the given drug (drug dependence); • development of severe conditions as a result of taking medications (drug intolerance). Some drugs only work on altered or damaged cells (for example, cardiac glycosides are most effective in conditions of heart failure; antipyretics have a more pronounced effect in fever). This is due to the fact that the action of these and some other means is mainly associated with the suppression of the links of pathogenesis that are formed in a given disease or pathological process. For example, in heart failure, Ca2 + transport to cardiomyocytes is impaired . Under these conditions, cardiac glycosides, inhibiting the activity of Na +, K + – ATPase , prevent the release of Ca2 + from cells, which promotes the activation of actomyosin interaction and, as a consequence, an increase in the contractile function of myocytes . Acetylsalicylic acid (aspirin) inhibits or blocks the development of fever by decreasing or suppressing the activity of cyclooxygenase (increased in fever). As a result, aspirin reduces the formation of Pg group E ( PgE ), which is one of the mediators of the development of a febrile reaction.
Mefenamic acid ( ponstan ) (t1 / 2 3 h) is slowly absorbed from the small intestine and excreted mainly in the form of metabolites in the urine and feces. It is used for mild to moderate pain, not accompanied by severe inflammation, such as muscle, dental, post-traumatic and headache, as well as for dysmenorrhea and menorrhagia associated with uterine dysfunction. The main adverse reactions include diarrhea, upper abdominal discomfort, development of peptic ulcers, and hemolytic anemia. Elderly people who take mefenamic acid can develop neoliguric renal failure, especially with dehydration caused by, for example, diarrhea. Avoid prescribing mefenamic acid or treat it only with close supervision of the patient.
Popliteal artery compression syndrome is a rare cause of intermittent claudication (IC). This syndrome occurs with some anatomical configuration options and attachment of the medial head of the gastrocnemius muscle, which can compress the popliteal artery. The popliteal muscle can also press on the popliteal artery and cause this syndrome. In about 30% of patients, compression of the popliteal artery is observed on both limbs. This syndrome should be suspected in young athletes with intermittent claudication (IC). In most cases, men get sick. The consequences of this condition can be thrombosis of the popliteal artery, embolism, or the formation of aneurysms. Peripheral pulses may be normal without provoking tests. Walking, repeated flexion-extension of the ankle, or foot movement can lead to a weakening or disappearance of the pulse on the foot in patients with compression of the popliteal artery and a decrease in the ankle- brachial index (ABI). Imaging studies, such as duplex ultrasound, CT, MRA, or conventional angiography, are performed on the patient at rest and with repeated flexions of the ankle and are ordered to confirm the diagnosis. MRI and CT scans can also ut help assess the anatomical features of the gastrocnemius muscle and the popliteal artery. Treatment of the popliteal artery syndrome involves releasing it. This can lead to the need to separate and fix the medial head of the gastrocnemius muscle elsewhere. Occasionally, popliteal artery bypass grafting is performed if occlusion is present.
Iron supplements (iron salts or multivitamin tablets containing iron) can cause serious poisoning. Poison Control Centers register more than 4,000 children with acute iron poisoning every year. The latter is one of the ten substances that cause acute poisoning in children under the age of 5 years. Iron supplements are available over the counter and come in bottles of 250 in large candy-like tablets. In addition, parents usually do not see them as a potential threat to their children. Clinic of iron poisoning There are four phases of iron poisoning: (1) Symptoms from the gastrointestinal tract. Within 30-60 minutes after taking the drug, vomiting (possibly with blood), colicky abdominal pain, diarrhea (blood is characteristic) appear . Iron directly affects the gastrointestinal tract, in particular the lining of the stomach and small intestine (with the appearance of hemorrhages). (2) After 3-4 hours, the condition stabilizes, lasting up to 48 hours. This phase is characterized by latent and clinically not detected changes. There are no signs of dysfunction of the central nervous system. (3) Circulatory shock develops after 48 hours. Shock is caused by loss of blood and fluid through the gastrointestinal tract, increased capillary permeability and loss of vascular tone, which are the result of the direct action of iron. Secondary coagulopathy may develop . Shock occurs due to a pronounced deficiency of intravascular fluid and the body’s inability to cope with it. (4) Late onset: (a) Cicatricial changes in the stomach wall develop within 2-6 weeks. Since iron directly acts on the gastrointestinal tract tissue, the healing process can be accompanied by the development of cicatricial deformity and stenosis of both the pyloric area and the small intestine. (b) Rarely, liver necrosis may develop as a result of direct liver damage.
Treatment of poisoning with iron preparations (1) It is necessary to assess the potential risk to the child’s life: (a) It should be considered that the number of tablets missing in the vial has been swallowed by the child. (b) The toxic dose is determined based on the total amount of iron as a chemical element in the tablets swallowed. (c) The toxic dose in mg / kg is calculated based on the weight of the child. A dose of less than 20 mg / kg is associated with minimal risk, 20-60 mg / kg – requires the appointment of ipecacuana syrup and re-assessment of the child’s condition while maintaining abdominal pain and signs of gastrointestinal bleeding. At a dose of more than 60 mg / kg, you should consult a doctor. [In all cases of poisoning consult a doctor]. (2) All children with gastrointestinal changes and CNS dysfunctions should be evaluated. The examination is also carried out in those cases when the taken dose of the drug is conventionally non-toxic (due to the errors made in the calculations and the possibility of poisoning with other drugs). (3) All boys and girls who have taken large doses of iron supplements should be examined by a doctor, as suicidal attempts are possible at this age. (4) In 4-6 hours after poisoning, it is necessary to determine the iron content in the blood serum. By this time, the victim should be given emetics and laxatives (activated charcoal is not effective): (a) If the iron content does not exceed 300 μg% (53.5 μmol / l), then the poisoning does not pose a threat to health. (b) The concentration of iron in serum from 300 to 500 μg% (53.5-89.2 μmol / L), exceeds the iron-binding capacity of the blood and – in the presence of symptoms of poisoning – should determine the tactics of treatment. (c) An iron concentration greater than 500 μg% (89.2 μmol / L) is toxic. (5) Abdominal fluoroscopy can help diagnose because iron tablets are radiopaque . (6) At high iron concentrations, it is recommended to administer deferoxamine intravenously , which chelates with iron. The drug is administered slowly, at 15 mg / kg / hour. The onset of action of the drug is judged by the appearance of a pinkish tint of urine due to the formation of a chelate complex with iron. The introduction of deferoxamine is stopped when the iron concentration decreases to 300 μg% and below.
Intravenous immunoglobulin for urticaria The effectiveness of treatment with intravenous immunoglobulins varies from long-term remission to slight temporary improvement. The response to treatment is fast. The optimal dose and number of infusions have yet to be determined. Only a few cases and small studies have been reported. Methotrexate for urticaria Methotrexate may be recommended for resistant cases of urticaria. In isolated cases and small studies, improvement was recorded, which occurs within 1-2 weeks . since taking methotrexate . Since serious side effects are possible and frequent monitoring is necessary, methotrexate is used only in resistant cases, when all alternative drugs have proved ineffective. A reasonable starting dose of methotrexate is 10-15 mg per week or 2.5 mg 2 times a day for 3 consecutive days of the week. Urticaria Treatment without medication and its prevention to help reduce itching cool showers, warm baths with oats ( Aveeno ), cooling lotion with menthol (Lotion Sarna ) and local lotions pramoxine ( Itch -X). Avoid factors that increase itching (aspirin, alcohol, tight or coarse woolen clothing).
Pericardial effusion, pericarditis after myocardial infarction
a) Pericardial effusion after myocardial infarction. The presence of fluid in the pericardial cavity is usually diagnosed during echocardiography . The incidence of pericardial effusion will vary depending on the method used and the criteria and experience of the specialist. Especially sensitive methods, such as MRI, can detect epicardial effusion in 70% of patients with STEMI. The appearance of effusion is most typical for patients with anterior STEMI localization and for extensive MI, as well as in the presence of CHF symptoms. In most cases, the accumulation of effusion during STEMI does not lead to hemodynamic impairment. However, occasionally, tamponade may develop, usually with rupture of the walls of the ventricle or with hemorrhagic pericarditis. The rate of reabsorption of postinfarction pericardial effusion is rather low (the complete disappearance of the effusion may take several months). An effusion does not necessarily indicate the presence of pericarditis; the effusion can develop simultaneously with pericarditis, but in most cases it is not accompanied by other signs of pericarditis.
b) Pericarditis after myocardial infarction. Pericarditis can cause pain both in the early period, for example, on the first day, and in the late period – 6 weeks after the development of STEMI. Pericardial pain can be mistaken for postinfarction angina, recurrent MI, or both. An important distinguishing feature is the irradiation of pain to the area of the trapezius muscle, which is a pathognomonic symptom of pericarditis and rarely occurs with pain of ischemic genesis. Transmural MI, by definition extending to the surface of the epicardium, typically causes localized inflammation of the pericardium. Acute fibrinous pericarditis ( pericarditis epistenocardica ) often develops with transmural MI , but most patients do not have any symptoms of this process. In patients with transmural MI, a transient pericardial friction murmur is relatively common during the first 48 hours, but pain and ECG changes do not always appear. Pericardial friction murmur correlates with greater damage and more pronounced hemodynamic disturbances. With pericarditis, discomfort is usually felt with a deep breath; to reduce discomfort, you can recommend the patient to sit down and bend slightly forward. It should be noted that the use of anticoagulants undoubtedly increases the risk of hemorrhagic pericarditis in the early stages of STEMI; however, this complication is not observed so often to speak of contraindications to the appointment of heparin and FLT when detecting pericardial friction murmur. However, when diagnosing pericardial effusion based on ECG changes, anticoagulants should generally be abandoned. In patients for whom the continuation or initiation of anticoagulant therapy is extremely important (for example, with catheterization or subsequent coronary angioplasty ), for the prevention of tamponade, it is necessary to monitor the clotting parameters and pay attention to the clinical manifestations. There are known cases of compression of the pericardium at a later date due to anticoagulant-induced hemopericardium . In the treatment of pericardial discomfort aspirin used usually at higher doses than those routinely administered after MI – 650 mg per os every 4 or 6 hours. The prescription of NSAIDs and steroids should be avoided, since such drugs negatively affect the formation of postinfarction scar.
When cells are activated by various stimuli, such as microbial products and various inflammatory mediators, the arachidonic acid contained in the membrane, under the action of enzymes, forms prostaglandins and leukotrienes . These biologically active lipid mediators transmit intracellular and extracellular signals to trigger various biological processes, including inflammation and hemostasis. Arachidonic acid is a 20-carbon polyunsaturated fatty acid (5,8,11,14-eicosatetraenoic acid) found in foods or converted from the essential fatty acid linoleic acid . Arachidonic acid is not found in the cell in a free state, but is usually esterified into membrane phospholipids. Mechanical, chemical and physical stimuli (for example, C5a) release arachidonic acid from membrane phospholipids under the action of cellular phospholipases , mainly phospholipase A2. Biochemical signals are involved in the activation of phospholipase A2, including an increase in the content of cytoplasmic Ca2 + and the activation of various kinases in response to external stimuli. Eicosanoids (metabolites of arachidonic acid) are synthesized by two main classes of enzymes: cyclooxygenases (COX) (producing prostaglandins) and lipoxygenases (producing leukotrienes and lipoxins ). Eicosanoids bind to G-protein-coupled receptors on a variety of cell types and can actually mediate every phase of the inflammatory response.
a) Prostaglandins. Prostaglandins (PGs) are produced by mast cells, macrophages, endothelial cells and many other cell types and are implicated in local and systemic inflammatory responses. Prostaglandins are formed under the action of two COX: constitutively expressed COX-1 and an inducible COX-2 enzyme. Prostaglandins are divided into groups according to structural properties and are coded by a letter (PGD, PGE, PGF, PGG, PGH, etc.) and a subscript (for example, 1, 2), which indicates double bonds in their structure. The most important among them in inflammatory reactions are PGE2, PGD2, PGF2a, PGI2 and thromboxane A2, each of which is formed by the action of a specific enzyme on a precursor during signal transduction. Some of these enzymes restrict tissue proliferation. For example, platelets contain the enzyme thromboxane synthetase and the main product of these cells is thromboxane A2, a potential platelet aggregator and vasoconstrictor. Thromboxane A2 is unstable and is quickly converted to an inactive form – thromboxane B2. In the vascular endothelium, thromboxane synthetase is absent, but prostacyclin synthetase is present , which leads to the formation of PGI2 ( prostacyclin ) and its stable end product PGFla . PGI2 is a vasodilator and a potential inhibitor of platelet aggregation, which also markedly increases the permeability and chemotactic effects of other mediators. An imbalance of thromboxane and PGI2 is observed in the early stages of thrombus formation in coronary and cerebral blood vessels. PGD2 is the major mast cell prostaglandin. Together with the widespread PGE2, it induces vasodilation and increases the permeability of postcapillary venules , thus enhancing the formation of edema. PGF2ot stimulates the contraction of the smooth muscles of the uterus, bronchial tree and small arterioles. PGD2 is a chemoattractant for neutrophils. Prostaglandins have a local effect and are also involved in the pathogenesis of pain and fever in inflammation. PGE2 has a hyperalgesic effect and makes the skin hypersensitive to pain, for example, with intradermal injections of quasi-optimal concentrations of histamine and bradykinin . In infections, it is involved in the development of cytokine-induced fever.