Acetylsalicylic acid + Dipyridamole (Acidum acetylsalicylicum + Dipyridamolum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Antiaggregants

NSAIDs - Salicylic acid derivatives

Included in the formulation
  • AgrenoX®
    capsules inwards 
    Boehringer Ingelheim International GmbH     Germany
    • АТХ:

    B.01.A.C   Inhibitors of platelet aggregation (excluding heparin)

    Pharmacodynamics:

    Acetylsalicylic acid inactivates the enzyme cyclooxygenase in thrombocytes and thus prevents the formation of thromboxane A2, a powerful inducer of platelet aggregation and vasoconstriction.

    Dipyridamole inhibits the capture of adenosine in erythrocytes, platelets and endothelial cells in vivo and in vitro; inhibition reaches a maximum of 80% and in therapeutic concentrations (0.5-2 μg / ml) is dose-dependent. As a consequence, there is a local increase in the concentration of adenosine, which acts on the A2-receptor platelets, stimulating platelet adenylate cyclase, and, thus, increases the level of platelet c-AMP.

    Dipyridamole inhibits PDE in various tissues. As long as the inhibition of c-AMP-PDE is weak, the therapeutic concentrations inhibit c-HMP-PDE and, consequently, promote the increase in c-HMF under the action of RFEV (a relaxing factor released from the endothelium identified as NO).

    Adenosine has a vasodilating effect, which is one of the mechanisms by which dipyridamole causes vasodilation.

    Dipyridamole stimulates biosynthesis and release of prostacyclin by endothelium.

    Dipyridamole reduces the thrombogenicity of subendothelial structures, increasing the concentration of the protective mediator 13-GODE (13-hydroxyoctadecadienoic acid).

    Thus, in response to various stimulants, for example, TAF, collagen and adenosine diphosphate, aggregation of platelets is suppressed. Reduction of platelet aggregation leads to normalization of adenosine consumption by platelets.

    If acetylsalicylic acid inhibits only aggregation of platelets, then dipyridamole further inhibits the activation and adhesion of platelets. Therefore, a combination of these two drugs can be expected to have an additional effect.

    Pharmacokinetics:

    There was no pharmacokinetic interaction between dipyridamole in the form of sustained release and acetylsalicylic acid. Pharmacokinetics of the drug, respectively, is a mapping of the pharmacokinetics of its components.

    Acetylsalicylic acid

    Acetylsalicylic acid is rapidly and completely absorbed. Cmax in plasma after taking a daily dose of 50 mg of acetylsalicylic acid in the drug (25 mg twice a day) is observed after 30 minutes, and Cmax in the plasma at an equilibrium state is 319 ng / ml (range 175-463 ng / ml). Cmax salicylic acid in the plasma is achieved in 60-90 minutes.

    30-40% of the dose of acetylsalicylic acid undergoes primary metabolism with cleavage to salicylic acid, which is the main pathway of metabolism.

    Acetylsalicylic acid binds poorly to plasma proteins, and its apparent Vd small (10 liters). Metabolite of acetylsalicylic acid - salicylic acid - largely associated with plasma proteins, but binding depends on the concentration (non-linearly). At low concentrations (<100 μg / ml), about 90% of salicylic acid is bound to albumin. Salicylic acid is well distributed in all tissues and body fluids, including the central nervous system, breast milk and fetal tissues.

    Acetylsalicylic acid is rapidly metabolized by the action of nonspecific esterases in the liver and to a lesser extent in the stomach to salicylic acid, followed by the formation of hydroxyhippuric acid as a result of the reaction with glycine.

    Half-Elimination (half-life) Acetylsalicylic acid is 15-20 minutes; half-elimination period (half-life) the main metabolite (salicylic acid), which is 2-3 hours, can increase to 5-18 hours at high doses (> 3 g) due to saturation of the enzyme.

    About 90% of acetylsalicylic acid is excreted in the form of metabolites through the kidneys.

    In severe disorders of kidney function (glomerular filtration rate less than 10 ml per minute), acetylsalicylic acid should not be prescribed.

    An increase in duration was reported half-elimination (half-life) 2-3 times in patients with kidney disease.

    Dipyridamole

    Absolute bioavailability is about 70%. Since at the "primary passage" about 1/3 of the dose administered is removed, we can assume almost or complete absorption of dipyridamole after taking the drug.

    Cmax dipyridamole in plasma after taking a daily dose of 400 mg (200 mg twice a day) are observed 2-3 hours after taking the drug. Medium Cmax at an equilibrium state of 1.98 μg / ml (range 1.01-3.99 μg / ml), and the concentration between doses is 0.53 μg / ml (range 0.18-1.01 μg / ml).

    The intake of food has no effect on the pharmacokinetics of dipyridamole.

    Due to its high lipophilicity, dipyridamole distributed in many organs.

    In animals dipyridamole mainly distributed in the liver, as well as in the lungs, kidneys, spleen and heart.

    The rapid phase of the distribution observed with intravenous administration can not be determined by oral administration.

    Apparent Vd in the central compartment (Vfrom) is about 5 liters (similar to the volume of the plasma). Apparent Vd at an equilibrium state is about 100 liters, reflecting the distribution in different compartments.

    The drug does not penetrate the blood-brain barrier in a significant amount.

    Penetration of the drug through the placental barrier is very low.

    In one case, breast milk was found to contain an amount of 1/17 of its concentration in the plasma.

    The binding of dipyridamole with proteins is about 97-99%, mainly it binds to the α1-acid glycoprotein and albumin.

    With repeated administration of a dose, no appreciable cumulation of the drug is observed.

    The metabolism of dipyridamole occurs in the liver. Dipyridamole is mainly metabolized by conjugation with glucuronic acid to form mainly monoglycuronide and only small amounts of diglucuronide.In plasma, about 80% of the total amount is present in the form of the starting compound and 20% of the total amount in the form of monoglycuronide. The pharmacodynamic activity of dipyridamole glucuronides is significantly lower than that of dipyridamole.

    Half-Elimination (half-life) the initial phase for oral administration, as for intravenous administration, is about 40 minutes.

    Excretion of the drug unchanged through the kidneys is negligible (<0.5%). Excretion of the metabolite glucuronide in the urine is low (5%), metabolites are mainly (about 95%) excreted through bile with feces, while intestinal-hepatic recirculation is observed. The total clearance is about 250 ml per minute, the average residence time in the body is about 11 hours, determined on the basis of its own average residence time in the body of about 6.4 hours and an average suction time of 4.6 hours.

    In patients with hepatic insufficiency, there was no change in plasma dipyridamole concentrations, but an increase in the concentration of glucuronides with low pharmacodynamic activity was noted. Therefore, correction of the dose of dipyridamole is necessary only in the case of clinically confirmed decompensation of liver function.

    Indications:

    Secondary prophylaxis of ischemic stroke, proceeding as a thrombosis, and transient ischemic attacks.

    ICD-10

    VI.G40-G47.G45   Transitory transient cerebral ischemic attacks [attacks] and related syndromes

    IX.I60-I69.I63   Cerebral infarction

    IX.I60-I69.I66.9   Occlusion and stenosis of the cerebral artery, unspecified

    IX.I60-I69.I69   Effects of cerebrovascular disease

    IX.I70-I79.I74   Embolism and thrombosis of the arteries

    Contraindications:

    Peptic ulcer of the stomach or duodenum in the phase of exacerbation or with a tendency to bleeding, pregnancy (III trimester), age to 18 years, hypersensitivity to any component of the drug or to salicylates.

    Carefully:

    Along with other properties dipyridamole has a vasodilating effect. The drug should be administered with caution to patients with severe ischemic heart disease (including with unstable angina and recently suffered myocardial infarction, as well as with difficulty in ejection of blood from the left ventricle or instability of hemodynamics (for example, in decompensated heart failure).

    Since one of the components of the drug is acetylsalicylic acid, the drug should be used with caution in patients with bronchial asthma, allergic rhinitis, nasal polyposis, chronic or recurrent ulcers of the stomach or duodenum, with impaired renal or hepatic function or with deficiency of glucose-6-phosphate dehydrogenase, with increased sensitivity to non-steroidal anti-inflammatory drugs.

    Pregnancy and lactation:

    Action category for the fetus by Food and Drug Administration (US Food and Drug Administration) - D.

    Data on the safety of the use of dipyridamole and acetylsalicylic acid in low doses during pregnancy in humans is not enough. In preclinical studies, no adverse effects were identified.

    Dipyridamole and salicylates are excreted in breast milk.

    The drug can be taken in the I and II trimesters of pregnancy or during lactation only if the benefit to the mother exceeds the potential risk to the fetus (child). The drug is contraindicated in the III trimester of pregnancy.

    Dosing and Administration:

    The recommended dose is 1 capsule containing 25 mg of acetylsalicylic acid and 200 mg of dipyridamole, 2 times a day.

    Usually take 1 capsule in the morning and 1 capsule in the evening, regardless of food intake.

    Capsules should be swallowed whole, without chewing, with a glass of water.

    Side effects:

    There have been reports of hypersensitivity reactions (rash, hives, severe bronchospasm and angioedema) with respect to dipyridamole and acetylsalicylic acid.

    In very rare cases, after taking acetylsalicylic acid, there may be a decrease in the number of platelets (thrombocytopenia). There were also reports of individual cases of thrombocytopenia observed with dipyridamole treatment.

    Hemorrhages on the skin, such as bruising, bruising, ecchymosis and bruising, can occur when the drug is used.

    The undesirable effects of dipyridamole in therapeutic doses are usually mild and transient. When treated with dipyridamole, vomiting, diarrhea and symptoms such as dizziness, nausea, headache, migraine-like headache (especially at the beginning of treatment) and myalgia were noted. These symptoms usually disappear with prolonged use of the drug.

    As a consequence of the vasodilating effect of dipyridamole, arterial hypotension, hot flashes and tachycardia can occur. Symptoms of coronary heart disease worsened.The syndrome of coronary stealing (when doses more than 225 mg per day).

    Acetylsalicylic acid increases the time of bleeding, and after the administration of dipyridamole in very rare cases, increased bleeding during and after surgery.

    When taking acetylsalicylic acid, epigastric pain may occur, nausea and vomiting, a stomach or duodenal ulcer and an erosive gastritis, which can lead to serious gastrointestinal bleeding.

    As a result of latent bleeding, especially when taking acetylsalicylic acid for a long period of time, iron deficiency anemia may develop.

    Overdose:

    Symptoms: due to the ratio of doses of dipyridamole and acetylsalicylic acid in case of drug overdose, the symptoms and symptoms of an overdose of dipyridamole are likely to prevail.

    Experience with respect to an overdose of dipyridamole is limited due to a small number of observations. Presumably, such symptoms as a feeling of heat, hot flashes, increased sweating, nervous state, weakness, dizziness and symptoms of angina pectoris should be observed.A sharp drop in blood pressure and tachycardia may occur.

    Symptoms of a minor acute overdose of acetylsalicylic acid are hyperventilation, ringing in the ears, nausea, vomiting, visual and hearing impairment, dizziness and blurred vision.

    Dizziness and ringing in the ears, especially in patients of senile age, may be symptoms of an overdose.

    Treatment: spend symptomatic therapy, gastric lavage. The introduction of xanthine derivatives (eg, aminophylline) can neutralize the hemodynamic effects of an overdose of dipyridamole.

    Because dipyridamole widely distributed in tissues and basically eliminated by the liver, it is not excreted in hemodialysis.

    Interaction:

    When using dipyridamole in combination with acetylsalicylic acid or with warfarin, precautions for these drugs should be taken into account.

    Acetylsalicylic acid can enhance the effect of anticoagulants (for example, coumarin and heparin derivatives), drugs that inhibit platelet aggregation (clopidogrel, ticlopidine),valproic acid and increase the risk of side effects from the gastrointestinal tract when used simultaneously with non-steroidal anti-inflammatory drugs or with corticosteroids, as well as with the systematic use of ethanol.

    The combined use of dipyridamole and acetylsalicylic acid does not increase the frequency of bleeding.

    Selective serotonin reuptake inhibitors may increase the risk of bleeding.

    Dipyridamole increases the concentration of adenosine in the plasma and enhances its cardiovascular effects. It is necessary to take into account the need to correct the dose of adenosine.

    With the combined use of dipyridamole and warfarin, the frequency and severity of bleeding was no more than when only one warfarin was administered.

    Dipyridamole can enhance the antihypertensive effect of drugs that lower blood pressure and reverse the anticholinesterase effect, reducing the effect of cholinesterase inhibitors, and, as a consequence, cause a worsening of the course of the malignant myasthenia gravis.

    The effect of hypoglycemic drugs and toxicity of methotrexate may be enhanced when combined with acetylsalicylic acid.

    Acetylsalicylic acid can reduce the natriuretic effect of spironolactone and inhibit the effect of uricosuric medicines (eg, probenecid, sulfinpyrazone).

    Simultaneous administration of ibuprofen (but not other non-steroidal anti-inflammatory drugs or paracetamol) in patients with an increased risk of cardiovascular disease may limit the beneficial effect of acetylsalicylic acid on the cardiovascular system.

    Caution is advised to prescribe the drug to patients who receive treatment with drugs that increase the risk of bleeding (platelet aggregation inhibitors / clopidogrel, ticlopidine) or selective serotonin reuptake inhibitors.

    Special instructions:

    Clinical experience suggests that patients receiving dipyridamole and who also requires a pharmacological stress test with intravenous administration of dipyridamole, should stop taking medications containing dipyridamole, 24 hours before the test. Otherwise, the sensitivity of the test may be impaired.

    In patients with malignant myasthenia after a change in the dose of dipyridamole, correction of the main therapy may be required.

    In a small number of cases, it was shown that unconjugated dipyridamole in varying degrees, is built into gallstones (up to 70% of the dry weight of the stone). All patients were senile. They had ascending cholangitis, and they received dipyridamole for many years. Evidence that dipyridamole was the initiating factor in the formation of gallstones, is not available. Probably, the presence of dipyridamole in gallstones can be explained by the bacterial deglucuronization of conjugated dipyridamole in bile.

    In addition to other properties, dipyridamole acts as a vasodilator. The drug should be used with caution in individuals with severe coronary artery disease, including unstable angina, and those who have recently had myocardial infarction with an obstruction of outflow from the left ventricle, with unstable hemodynamics (eg, decompensated heart failure).

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