Ascorbic acid, Acetylsalicylic acid

Pharmacological properties

acetylsalicylic acid belongs to the group of NSAIDs, it has analgesic, antipyretic and anti-inflammatory effects. The mechanism of action of acetylsalicylic acid is the irreversible inactivation of the enzyme cog, which plays an important role in the synthesis of prostaglandins.

When taken orally in doses of 0.3–1 g, acetylsalicylic acid is used to reduce the severity of pain and conditions accompanied by fever, such as a cold, to reduce body temperature and reduce pain in joints and muscles.

Acetylsalicylic acid inhibits platelet aggregation by blocking the synthesis of thromboxane A₂.

The water-soluble vitamin ascorbic acid is part of the bodys defense system against oxygen radicals and other oxidizing agents of endogenous and exogenous origin, which play a special role in inflammatory processes and the functioning of white blood cells.

The results of in vitro and ex vivo studies have shown that ascorbic acid has a positive effect on the leukocyte immune response in humans.

Ascorbic acid is necessary for the synthesis of intracellular substances (mucopolysaccharides), which simultaneously with collagen fibers are responsible for the integrity of the walls of the capillaries and thus reduce the permeability of blood vessels.

Adding ascorbic acid to acetylsalicylic acid reduces digestive tract damage and oxidative stress. These benefits are probably the result of an improved tolerance profile for the combination of acetylsalicylic acid with ascorbic acid compared to acetylsalicylic acid, which is used alone.

Pharmacokinetics After oral administration, acetylsalicylic acid is rapidly and completely absorbed in the digestive tract. During and after absorption, it is transformed into the main active metabolite - salicylic acid. C_max Acetylsalicylic acid in blood plasma is reached after 10–20 minutes, salicylates - after 20–120 minutes, respectively.

Acetylsalicylic and salicylic acids completely bind to plasma proteins and are rapidly distributed in the body. Salicylic acid passes through the placenta and into breast milk.

Salicylic acid is metabolized in the liver. Metabolites of salicylic acid are salicylic uric acid, salicylphenol glucuronide, salicylacyl glucuronide, gentisic acid and gentisine uric acid.

The kinetics of excretion of salicylic acid is dose-dependent, since metabolism is limited by the activity of liver enzymes. T_½ depends on the dose and increases from 2-3 hours when used in low doses up to 15 hours - when used in high doses.

Salicylic acid and its metabolites are excreted primarily from the body by the kidneys.

Following oral administration, ascorbic acid is absorbed in the intestines by Na⁺-dependent active transport system, most actively in the proximal intestine. Absorption is disproportionate to the dose. With an increase in the daily oral dose of ascorbic acid, its concentration in blood plasma and other body fluids does not increase proportionally, but tends to approach the upper limit.

Ascorbic acid is filtered by the glomerular system of the kidneys and reabsorbed by the proximal tubules under the action of active Na⁺-dependent process. The main metabolites are excreted in the urine in the form of oxalates and diketogulonic acid.

Indications

Minor or moderate pain, such as a headache, toothache, intermittent pain in women, pain symptoms associated with a cold (e.g. headache, sore throat, pain in the limbs).

Fever.

Application

Aspirin® C is taken orally after a meal. effervescent tablets are dissolved in a glass of water immediately before administration. the dose of the drug is calculated by acetylsalicylic acid.

Aspirin^® C can not be taken for longer than 3-5 days without consulting a doctor.

Adults and children over the age of 15 years. 1-2 effervescent tablets as a single dose. Repeated intake is possible after 4-8 hours. The maximum daily dose should not exceed 10 tablets (4 g).

Warning. For patients with concomitant impaired liver or kidney function, the dose of the drug should be reduced or the interval between doses should be increased.

Contraindications

Hypersensitivity to acetylsalicylic acid, other salicylates, ascorbic acid or any component of the drug. BA, caused by the use of salicylates or other NSAIDs in history. acute gastrointestinal ulcers. hemorrhagic diathesis. severe kidney disease; severe renal failure. urolithiasis disease. severe liver failure. severe heart failure. tendency to thrombosis, thrombophlebitis. diabetes. combination with methotrexate at a dosage of ≥15 mg / week (see interactions).

Side effects

Gastrointestinal disorders: dyspepsia, epigastric pain and abdominal pain, heartburn, diarrhea, nausea, vomiting, stomach cramps; in some cases - inflammation of the gastrointestinal tract, erosive and ulcerative lesions of the gastrointestinal tract, which in rare cases can lead to gastrointestinal bleeding and perforation with appropriate laboratory and clinical manifestations; rarely, transient liver failure with an increase in liver transaminases.

Blood system and lymphatic system. Due to the antiplatelet effect on platelets, acetylsalicylic acid can increase the risk of bleeding. The following bleeding was observed: perioperative bleeding, hematomas, bleeding from the organs of the genitourinary system, nosebleeds, bleeding from the gums; rarely or very rarely - serious bleeding, such as gastrointestinal bleeding and cerebral hemorrhages (especially in patients with uncontrolled hypertension and / or with the simultaneous use of anticoagulants), which in some cases can potentially be life-threatening.

Bleeding can lead to acute and chronic posthemorrhagic anemia / iron deficiency anemia (due to the so-called latent microbleeding) with corresponding laboratory manifestations and clinical symptoms, such as asthenia, pale skin, hypoperfusion. In patients with severe glucose-6-phosphate dehydrogenase deficiency, hemolysis and the development of hemolytic anemia have been reported.

Immune system: in patients with individual hypersensitivity to salicylates, allergic reactions may develop, including symptoms such as rash, urticaria, itching, eczema, rhinitis, nasal congestion, decreased blood pressure. Severe hypersensitivity reactions have been very rarely observed, including anaphylactic shock, angioedema, and non-cardiogenic pulmonary edema.

In patients with AD, it is possible to increase the incidence of bronchospasm, allergic reactions from mild to moderate, which potentially affect the skin, respiratory system, gastrointestinal tract and cardiovascular system.

Nervous system: headache, dizziness, hearing impairment; ringing in the ears and confusion, which may indicate an overdose. Sleep disturbances.

Others: sensation of heat.

With prolonged use in high doses, the following are possible: damage to the glomerular apparatus of the kidneys, the formation of urate and / or oxalate calculi in the kidneys and urinary tract, renal failure; damage to the insular apparatus of the pancreas (hyperglycemia, glucosuria) and impaired glycogen synthesis up to the development of diabetes mellitus; myocardial dystrophy; thrombocytosis, hyperprothrombinemia, erythrocytopenia, neutrophilic leukocytosis, hemolytic anemia; decreased capillary permeability (possibly worsening tissue trophism, increased blood pressure), in patients with glucose-6-phosphate dehydrogenase deficiency, can cause erythrocyte hemolysis; oral dysbiosis; metabolic imbalance of zinc, copper.

special instructions

The drug is used with caution in case of hypersensitivity to analgesic, anti-inflammatory, anti-rheumatic drugs, as well as for allergies to other substances; a history of gastrointestinal ulcers, including a history of chronic or recurrent peptic ulcer or a history of gastrointestinal bleeding; simultaneous use of anticoagulants; impaired renal function or circulatory disorders (for example, renal vascular disease, congestive heart failure, dehydration, massive surgery, sepsis, or significant blood loss), since acetylsalicylic acid can further increase the risk of kidney damage and lead to a medical history of; impaired liver function.

In patients with allergic complications, including AD, allergic rhinitis, urticaria, pruritus, swelling and polyposis of the nasal mucosa, as well as in combination with chronic respiratory infections and in patients with hypersensitivity to NSAIDs during treatment with the drug, development bronchospasm, asthma attack or other hypersensitivity reactions.

Due to its suppression effect on platelet aggregation, which lasts up to several days after the use of acetylsalicylic acid, the drug can increase the tendency to bleed during and after surgery (including minor operations, such as tooth extraction).

When acetylsalicylic acid is used in low doses, uric acid excretion may be reduced. This can lead to gout in patients who have decreased uric acid excretion.

In patients with glucose-6-phosphate dehydrogenase deficiency, acetylsalicylic acid can cause hemolysis or hemolytic anemia. Factors that increase the risk of hemolysis are, for example, the use of high doses, fever, or acute infections.

Prolonged use of analgesics can lead to headaches.

Frequent use of pain medications can cause a temporary disruption of the kidneys with a risk of developing renal failure (analgesic nephropathy). The risk is especially high when several different analgesics are used simultaneously.

1 Effervescent Aspirin Tablet^® C contains 466.4 mg of sodium, which should be considered for patients on a sodium-restricted diet.

In patients prone to calcium-oxalate nephrolithiasis, or with kidney stone disease that recurs, ascorbic acid should be used with caution.

When taking the drug in high doses and prolonged treatment, it is necessary to monitor renal function and blood pressure, as well as pancreatic function. Use the drug with caution in patients with a history of mild to moderate renal disease. Since ascorbic acid increases iron absorption, its use in high doses can be dangerous for patients with hemochromatosis, thalassemia, polycythemia, leukemia and sideroblastic anemia. Patients with a high iron content in the body should use the drug in minimal doses.

Simultaneous administration of the drug with alkaline drink, fruit or vegetable juices reduces the absorption of ascorbic acid. Also, the absorption of ascorbic acid may be impaired with intestinal dyskinesia, enteritis and achilia. Ascorbic acid as a reducing agent can affect the results of laboratory tests, for example, in determining the blood glucose, bilirubin, transaminase activity, lactate dehydrogenase, etc. Since ascorbic acid has a mild stimulating effect, the drug is not recommended to be taken at the end of the day.Prolonged use of ascorbic acid in high doses can accelerate its own metabolism, which is why paradoxical hypovitaminosis is likely to occur after discontinuation of treatment. Do not exceed recommended dose. It should not be used simultaneously with other drugs containing acetylsalicylic acid and vitamin C. With caution, it is necessary to use the drug with polycythemia, leukemia. Can be false negative results of a study of the presence of occult blood in the feces.

During pregnancy and breastfeeding. Pregnancy. The drug can be used during pregnancy only when other drugs are ineffective and only after assessing the risk / benefit ratio.

Inhibition of prostaglandin synthesis may adversely affect pregnancy and / or fetal / intrauterine development. Available epidemiological studies indicate a risk of miscarriage and fetal malformations after the use of prostaglandin synthesis inhibitors in early pregnancy. The risk increases depending on the dose increase and the duration of therapy. According to available data, the relationship between the intake of acetylsalicylic acid and an increased risk of miscarriage has not been confirmed.

Available epidemiological data on the occurrence of malformations are not consistent, however, an increased risk of gastroschisis cannot be excluded with the use of acetylsalicylic acid. The results of a prospective study of the effect in early pregnancy (1–4 months) involving approximately 14,800 female – child couples do not indicate any association with an increased risk of malformations.

Animal studies indicate reproductive toxicity.

In the I and II trimester of pregnancy, preparations containing acetylsalicylic acid should not be prescribed without a clear clinical need. In women who are suspected to be pregnant, or in the first and second trimester of pregnancy, the dose of drugs containing acetylsalicylic acid should be as low as possible, and the duration of treatment as short as possible.

In the III trimester of pregnancy, all prostaglandin synthesis inhibitors can affect the fetus as follows:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• impaired renal function with possible subsequent development of renal failure with oligohydramnios.

At the end of pregnancy, prostaglandin synthesis inhibitors can affect a woman and a fetus in this way:

• the possibility of prolonging bleeding time, an antiplatelet effect that can occur even after very low doses;
• inhibition of uterine contractions, which can lead to a delay or increase in the duration of labor.

Considering the above, acetylsalicylic acid is contraindicated in the III trimester of pregnancy.

Fertility. There is some evidence that drugs that suppress the synthesis of prostaglandins can impair reproductive function in women due to the effect on ovulation. This phenomenon is reversible and disappears after discontinuation of treatment.

Lactation. Salicylates and their metabolites penetrate into breast milk in a small amount. Therefore, their use is possible during lactation. But due to the fact that ascorbic acid is present in the composition of the drug, one should refrain from taking the drug during breast-feeding, since ascorbic acid passes into breast milk.

Children. The drug is used in children aged 15 years. Do not use drugs containing acetylsalicylic acid for children with acute respiratory viral infections, which is accompanied or not accompanied by an increase in body temperature without consulting a doctor.In some viral diseases, especially influenza A, B and chickenpox, there is a risk of developing Reyes syndrome, which is a very rare but life-threatening condition that requires emergency medical attention. The risk may be increased if acetylsalicylic acid is used as a concomitant drug, but a causal relationship has not been proven in this case. If these conditions are accompanied by prolonged vomiting, this may be a sign of Reyes syndrome.

The ability to influence the reaction rate when driving vehicles and working with other mechanisms. Not marked.

Interactions

Contraindicated combinations. the use of methotrexate in doses of ≥15 mg / week increases the hematological toxicity of methotrexate (decrease in renal clearance of methotrexate with anti-inflammatory agents and displacement of methotrexate with salicylates due to plasma proteins).

Combinations to be used with caution. When methotrexate is used in doses of 15 mg / week, the hematological toxicity of methotrexate is increased (decreased renal clearance of methotrexate by anti-inflammatory agents and displacement of methotrexate with salicylates due to blood plasma proteins). The simultaneous use of ibuprofen prevents the irreversible inhibition of platelets by acetylsalicylic acid. Ibuprofen treatment of patients with an increased risk of cardiovascular disease may limit the cardioprotective effect of acetylsalicylic acid.

With the simultaneous use of salicylates in high doses with NSAIDs (as a result of synergism), the risk of ulcers and gastrointestinal bleeding increases. With the simultaneous use of the drug Aspirin^® C and anticoagulants increase the risk of bleeding.

The simultaneous use with uricosuric agents, such as benzobromaron, probenecid, decreases uric acid excretion (due to competition in the excretion of uric acid by the renal tubules).

With simultaneous use with digoxin, the concentration of the latter in blood plasma increases due to a decrease in renal excretion.

With the simultaneous use of acetylsalicylic acid in high doses and oral antidiabetic drugs of the sulfonylurea or insulin derivative group, the hypoglycemic effect of the latter is enhanced due to the hypoglycemic effect of acetylsalicylic acid and the displacement of sulfonylurea associated with blood plasma proteins.

Diuretics in combination with high doses of acetylsalicylic acid reduce glomerular filtration due to a decrease in prostaglandin synthesis in the kidneys.

Systemic corticosteroids (excluding hydrocortisone, which is used for replacement therapy for Addisons disease) during the treatment with corticosteroids reduce the level of salicylates in the blood and increase the risk of overdose after treatment, and also increases the risk of gastrointestinal bleeding.

ACE inhibitors in combination with high doses of acetylsalicylic acid cause a decrease in glomerular filtration due to inhibition of vasodilating prostaglandins and a decrease in the hypotensive effect.

Selective serotonin reuptake inhibitors: increased risk of bleeding from the upper gastrointestinal tract due to possible synergism.

With simultaneous use with valproic acid, acetylsalicylic acid displaces it from its connection with blood plasma proteins, increasing the toxicity of the latter.

Ethyl alcohol contributes to damage to the gastrointestinal mucosa and prolongs bleeding time due to the synergism of acetylsalicylic acid and alcohol.

Ascorbic acid reduces the toxicity of sulfonamide drugs, reduces the effects of heparin and indirect anticoagulants, promotes the absorption of iron, increases the absorption of penicillin, ethinyl estradiol, aluminum (must be taken into account when used with antacids containing aluminum); enhances the side effects of salicylates (risk of crystalluria). Preparations of the quinoline series, calcium chloride, salicylates, GCS with prolonged use reduce the reserves of vitamin C in the body. With the simultaneous use of ascorbic acid reduces the chronotropic effect of isoprenaline; in high doses - increases the excretion of mexiletine by the kidneys. Barbiturates and primidone increase urinary excretion of ascorbic acid. Ascorbic acid reduces the therapeutic effect of antipsychotics (phenothiazine derivatives), tubular reabsorption of amphetamine and tricyclic antidepressants. Reception of ascorbic acid along with deferoxamine increases tissue toxicity of iron, especially in the heart muscle, which can lead to decompensation of blood circulation. Ascorbic acid can be taken 2 hours after injection of deferoxamine. In high doses, ascorbic acid affects the absorption of vitamin B₁₂. Ascorbic acid enhances the excretion of oxalates in the urine, thus increasing the risk of the formation of oxalate calculi.

Overdose

Overdose of salicylates is possible due to chronic intoxication, which arose as a result of prolonged therapy (use at a dose of 100 mg / kg / day for more than 2 days can cause toxic effects), as well as acute intoxication, which can be life-threatening (overdose), and the reasons for which may be, for example, accidental use by children or unforeseen overdose.

Chronic salicylate poisoning can be hidden, since its signs are nonspecific. Moderate chronic intoxication caused by salicylates, or salicylism is noted, as a rule, only after repeated administration in high doses.

Symptoms Dizziness, ringing in the ears, deafness, hyperhidrosis, nausea and vomiting, headache, confusion. These symptoms can be controlled by dose reduction. Tinnitus can be noted with a concentration of salicylates in blood plasma of 150-300 μg / ml. More serious adverse reactions are detected at a concentration of salicylates in blood plasma of 300 μg / ml.

Acute intoxication is evidenced by a pronounced change in the acid-base balance, which depends on the age of the patient and the severity of intoxication. In children, the most characteristic manifestation is metabolic acidosis. The severity of the condition cannot be estimated only on the basis of the concentration of salicylates in blood plasma. The absorption of acetylsalicylic acid may be slowed due to a delay in gastric release, the formation of calculi in the stomach, or when the preparation is administered in the form of enteric-coated tablets.

Due to complex pathophysiological effects, the signs and symptoms of salicylate poisoning can be:

Mild to moderate intoxication - tachypnea, hyperpnoea, respiratory alkalosis. Sweating, nausea, and vomiting.

Moderate to severe intoxication - respiratory alkalosis, which is accompanied by compensatory metabolic acidosis, hyperpyrexia. From the respiratory system: from hyperpnea, non-cardiogenic pulmonary edema to respiratory arrest and asphyxiation. From the cardiovascular system: from arrhythmia, arterial hypotension to cardiac arrest. There is also dehydration, oliguria to renal failure; impaired glucose metabolism, ketosis; gastrointestinal bleeding; hematological changes - from platelet depression to coagulopathy.From the side of the nervous system: toxic encephalopathy and central nervous system depression, manifested in the form of drowsiness, depression of consciousness up to the development of coma and seizures.

On the part of laboratory and other indicators: alkalemia, alkaluria, acidemia, aciduria, changes in blood pressure, changes in the ECG, hypokalemia, hypernatremia, hyponatremia, changes in kidney function, hyperglycemia, hypoglycemia (especially in children). Elevated levels of ketone bodies, hypoprothrombinemia.

Overdose of ascorbic acid. Ascorbic acid is a water-soluble vitamin, its excess is excreted in the urine.

Acute and chronic overdose caused by ascorbic acid has been reported in the literature. In patients with glucose-6-phosphate dehydrogenase deficiency, an overdose of ascorbic acid can cause oxidative hemolysis, DIC, and a significant increase in the level of oxalates in blood serum and urine. It has been established that elevated levels of oxalates lead to calcium deposition in patients on dialysis. In addition, there are several reports that high doses of vitamin C, both for oral and intravenous use, can provoke the formation of calcium-oxalate calculi in the kidneys, the development of calcium-oxalate crystalluria in patients with increased crystallization of salts, the development of tubulointerstitial nephropathy as well as acute renal failure due to stone formation in the kidneys.

With prolonged use of vitamin C in high doses, inhibition of the function of the insular apparatus of the pancreas is possible, which requires monitoring the state of the latter.

High doses of vitamin C can lead to vomiting, nausea, or diarrhea, which disappear after withdrawal.

Treatment of intoxication caused by an overdose of acetylsalicylic acid is determined by the severity, clinical symptoms and is provided by standard methods that are used in case of poisoning (gastric lavage, use of activated charcoal, forced diuresis). All measures should be aimed at accelerating the elimination of the drug and restoring the electrolyte and acid-base balance. Depending on the state of acid-base balance and electrolyte balance, infusion administration of electrolyte solutions is carried out. In severe poisoning, hemodialysis is indicated.

Storage conditions

At a temperature not exceeding 25 ° C.