Action and mechanism

Acetylsalicylic acid belongs to the group of nonsteroidal anti-inflammatory drugs (NSAIDs). The analgesic effect of acetylsalicylic acid is exerted peripherally due to the inhibition of prostaglandin synthesis, which prevents the stimulation of pain receptors by bradykinin and other substances. Central effects on the hypothalamus are also possible in pain relief.
The antipyretic effect appears to be due to the inhibition of prostaglandin synthesis, although the nuclei of the hypothalamus have a significant role in the control of these peripheral mechanisms.
Acetylsalicylic acid inhibits the formation of thromboxane A2 by acetylating platelet cyclooxygenase. This antiplatelet effect is irreversible for the lifespan of the platelets.
Caffeine is pharmacologically similar to other xanthines such as theobromine and theophylline. Caffeine stimulates the central nervous system by antagonizing adenosine receptors.

Instructions

- [PAIN]: Symptomatic relief of mild to moderate pain, [HEADACHE], [TOOTHACHE], [DYSMENORRHEA], [MUSCLE CONTRACTURE], [LUMBAR PAIN].

- [FEVER]: Febrile states.

Posology

- Adults, oral: 500 mg dose of acetylsalicylic acid (1 tablet) every 4-6 hours. Do not exceed 4 g of acetylsalicylic acid (eight tablets) in 24 hours.
If the pain persists for more than 5 days, the fever for more than 3 days, or if symptoms worsen or other symptoms appear, the clinical situation should be evaluated.
-Children: Do not use on children under 16 years of age.

- Patients with renal or hepatic impairment: reduce the dose (see precautions section).

Dosage in renal insufficiency

* ClCr < 10 ml/min: Not recommended.

Posology

IN LIVER FAILURE
* Severe: Not recommended.

Guidelines for proper administration

Take the medication with food or milk, especially if you experience digestive discomfort.

Contraindications

Acetylsalicylic acid should not be administered in the following cases:

- Patients with active, chronic or recurrent [PEPTIC ULCER], [ACUTE GASTRITIS]: may cause a worsening of the disease or exacerbation of gastric bleeding or recurrence of gastrointestinal lesions.

- Patients with [ASTHMA]: there is a higher risk of bronchospastic hypersensitivity reactions.

- Patients with a history of [SALICYLATE ALLERGY], to any of the components of this specialty, [NSAID ALLERGY] or to tartrazine (cross-reaction).

- Patients with [XANTHINE ALLERGY] (aminophylline, theophylline,...) may also be sensitive to caffeine.

- Patients with diseases that present with [COAGULATION DISORDERS], mainly [HEMOPHILIA] or [HYPOPROTHROMBINEMIA].

- Concomitant therapy with oral anticoagulants.

- Patients with nasal [NASAL POLYPS] associated with asthma that are induced or exacerbated by acetylsalicylic acid.
-Children under 16 years of age, since in these cases the intake of acetylsalicylic acid has been associated with Reye's syndrome.

Precautions

- [DIABETES]: High doses of acetylsalicylic acid can cause alterations in blood glucose levels. Caffeine can raise blood glucose levels, so this should be taken into account in diabetic patients.

- [GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY]: risk of hemolytic anemia with high doses of ASA.

- Alcohol: Alcohol should not be ingested as it increases the adverse gastrointestinal effects of acetylsalicylic acid and is a triggering factor in the chronic irritation caused by it. The use of acetylsalicylic acid in patients who regularly consume alcohol (three or more alcoholic drinks - beer, wine, liquor, etc.) should be avoided.
- per day) can cause gastric bleeding.

- [RENAL INSUFFICIENCY]: Acetylsalicylic acid and its metabolites are primarily excreted in the urine. Additionally, patients with renal insufficiency have a higher risk of developing renal toxicity.

- [HEPATIC INSUFFICIENCY]: Salicylates are metabolized in the liver. Hepatic cirrhosis and severe hepatic insufficiency are associated with a higher risk of adverse renal effects and hemorrhage, respectively.

- Due to its caffeine content, it should be administered with caution in patients with severe heart disease, cardiac arrhythmia, due to the risk of tachycardia and extrasystoles, hyperthyroidism, and anxiety. In these patients, do not administer more than 100 mg/day of caffeine.

- Medications containing acetylsalicylic acid should not be given to children, particularly those under 16 years of age and adolescents suffering from viral illnesses with or without fever, without consulting a doctor or pharmacist. Some viral illnesses, especially influenza A, influenza B, and chickenpox, carry a risk of Reye's syndrome. The risk of developing this syndrome increases with the concurrent use of acetylsalicylic acid; however, no causal relationship between them has been established. In some children, acetylsalicylic acid may be, among other factors, a trigger for Reye's syndrome. If persistent vomiting or lethargy occurs, this could be a symptom of Reye's syndrome, and treatment should be discontinued immediately.

Advice to the patient

Take the medication with food, especially if you experience digestive discomfort. If you take a tablet, remain upright for at least 15 minutes to prevent the medication from damaging your esophagus.

- Do not drink alcoholic beverages, as alcohol increases the adverse gastrointestinal effects of acetylsalicylic acid.

It is advisable to discontinue its administration one week before surgical procedures. The administration of acetylsalicylic acid should be avoided before or after a tooth extraction or surgical procedure.

Keep the medicine out of the reach of children. Aspirin poisoning is common in children.

- Store the medication in a dry place. Humidity can decrease the effectiveness of the medication.

Special warnings

- If the pain persists for more than 10 days, the fever for more than 3 days, or if symptoms worsen or other symptoms appear, the clinical situation should be evaluated.

- Do not administer systematically as a preventative measure against possible discomfort caused by vaccinations.

- Advise the patient that during prolonged treatment with acetylsalicylic acid, monitor for possible signs of coagulation disorders (skin spots, bleeding gums, black stools).

- Acetylsalicylic acid can interfere with some analytical tests.

Interactions

- Acetazolamide. Aspirin has been shown to increase acetazolamide levels by up to 80-200%, probably due to displacement from plasma protein binding. There is a risk of toxicity, so administration should be avoided. In addition, acetazolamide may cause systemic acidosis, which could delay the elimination of salicylates. Although no cases of this interaction have been reported with other carbonic anhydrase inhibitors, it cannot be ruled out.

- Urinary acidifiers (ascorbic acid, ammonium chloride, methionine) or urinary alkalinizers (absorbable antacids). Aspirin (ASA) is a weak acid whose elimination in urine depends on urinary pH. Drugs that decrease pH will decrease renal elimination, while those that increase pH will lead to increased elimination.

- Tiludronic acid. A pharmacokinetic interaction has been detected, as aspirin may decrease the bioavailability of tiludronate by up to 50% when taken within one hour of tiludronate. It is recommended to separate the administration of these medications by at least 2 hours.

- Valproic acid. There have been cases of increased valproate levels associated with the administration of aspirin. The interaction could be due to competition between the two drugs for the same renal elimination mechanism. A dosage adjustment may be necessary.

- NSAIDs. The combined administration of aspirin with other NSAIDs, including coxibs, may increase the risk of peptic ulcer and gastric bleeding. Furthermore, aspirin has been shown to reduce plasma levels of other NSAIDs, particularly those with an arylpropionic structure such as ibuprofen.
-Aliskiren. Possible reduction of the antihypertensive effect of aliskiren (NSAIDs act on the renin-angiotensin system). In patients with impaired renal function (dehydrated or elderly), deterioration of renal function may be precipitated (possible acute renal failure, usually reversible). Caution, especially in the elderly, monitoring the antihypertensive effect and renal function.

- Antacids. Antacids may delay and decrease the absorption of aspirin. In addition, absorbable antacids may increase the elimination of aspirin.

- Antiplatelet agents. Clopidogrel and ticlopidine may potentiate the antiplatelet effects of aspirin. Dipyridamole, on the other hand, has been shown in pharmacokinetic studies to increase Cmax and AUC by 31.5% and 37%, respectively, probably due to inhibition of metabolism, with the consequent risk of toxicity. In the case of prasugrel, concomitant administration is indicated, since the efficacy and safety of prasugrel were studied in patients receiving aspirin.

- Oral anticoagulants. Aspirin (ASA) has been shown to potentiate the effects of anticoagulants such as acenocoumarol, with the consequent risk of bleeding, especially gastric bleeding. This interaction could be due to the hypoprothrombinemic effects of ASA at high doses (more than 3 g) or to the inhibition of platelet aggregation. Administering single doses of ASA does not appear to pose a significant risk. However, it is advisable to avoid this combination in patients treated with ASA for long periods, using salicylates or other NSAIDs without antiplatelet effects instead, and if this is not possible, to exercise extreme caution and monitor the INR.

- Antiulcer drugs. Pharmacokinetic studies have shown that the increase in gastric pH produced by H2 antihistamines or proton pump inhibitors could increase the absorption of aspirin, with the possible risk of toxicity. In patients receiving high doses of aspirin, a reduction in dosage may be necessary.

- Barbiturates. ASA could increase barbiturate concentrations, with the consequent risk of poisoning.

- Beta-blockers. Administration of aspirin at high doses, exceeding 2 g, has resulted in a decrease in the antihypertensive effects of beta-blockers. Although the cause is unknown, it is probably due to the inhibition of prostaglandin synthesis, which appear to mediate the antihypertensive effects of beta-blockers. Therefore, it is recommended to avoid high-dose aspirin in patients treated with a beta-blocker.

- Cyclosporine. NSAIDs may increase cyclosporine nephrotoxicity. Periodic evaluation of renal function is recommended, especially in the elderly.

- Corticosteroids. There is an increased risk of damage to the gastric mucosa. Furthermore, it appears that corticosteroids may reduce plasma levels of aspirin, although the mechanism is unclear. However, it is believed that this could be due to an increase in glomerular filtration and a decrease in tubular reabsorption. For its part, aspirin may displace corticosteroids from their protein binding sites, leading to toxic effects.

- Digoxin. Aspirin may increase digoxin levels, increasing the risk of toxicity. A dosage adjustment may be necessary.

- Diuretics. Several trials have shown that aspirin may slightly reduce the diuretic effects of drugs such as furosemide, and the natriuretic effects of spironolactone. Furthermore, the occurrence of acute renal failure may be more frequent, especially in dehydrated patients treated with thiazide diuretics.

- Ototoxic drugs. Aspirin may increase the ototoxicity of drugs such as aminoglycosides, cisplatin, erythromycin, furosemide, or vancomycin, especially at high doses.

- Phenytoin. At high doses, aspirin may displace phenytoin from its protein-binding sites, leading to toxic effects. However, symptoms of this interaction are uncommon, as free phenytoin is redistributed in tissues, decreasing its plasma concentrations. Patient monitoring is recommended.

- Griseofulvin. Griseofulvin may significantly decrease the absorption of ASA, so it is recommended to avoid this combination.

- Heparin. Numerous cases have been described in which the administration of heparin with aspirin resulted in potentiation of the anticoagulant effects, with an increased risk of bleeding. Although heparin has been combined with aspirin to reduce mortality associated with postoperative thromboembolism, the risk should be assessed in each patient, and their coagulation parameters should be monitored.

- Ibuprofen. Experimental data suggest that ibuprofen may inhibit the effect of
Low doses of aspirin have been shown to affect platelet aggregation when administered concomitantly. However, there is no clinical evidence, and it is unlikely that there will be a relevant effect with the occasional use of ibuprofen.

- ACE inhibitors. Studies have shown that NSAIDs at doses above 1 g have an antagonistic effect on ACE inhibitors, probably due to the inhibition of prostaglandin synthesis, which has vasodilatory effects. Regular blood pressure monitoring is recommended.

- SSRIs. There is a higher risk of bleeding in general, and gastric bleeding in particular, so it is recommended to avoid this combination.

- Lithium. Aspirin may decrease lithium clearance, increasing the risk of toxicity. A dosage adjustment may be necessary.

- Methotrexate. Numerous cases have been described in which the administration of aspirin potentiated the effects of methotrexate. These effects could be due to the displacement of methotrexate from its protein-binding sites by aspirin, or to decreased renal clearance due to inhibition of tubular secretion. This effect is especially important in elderly patients with renal impairment. Extreme caution is advised due to the risk of severe pancytopenia.

- Nitroglycerin. Pharmacokinetic studies have shown that aspirin (ASA) may increase plasma nitroglycerin levels by up to 54%, possibly due to decreased hepatic blood flow and nitroglycerin metabolism. Conversely, prolonged aspirin treatment resulted in increased nitroglycerin requirements for the same effect, perhaps due to decreased production of vasodilatory prostaglandins. Patient monitoring is recommended.

- Pentazocine. One case of reversible renal toxicity from aspirin with the addition of pentazocine has been reported. Evaluation of the patient's renal function is recommended.

- Sulfonylureas. Administration of high doses of aspirin (AAS), above 2 g, may potentiate the hypoglycemic effects of sulfonylureas. The mechanism is unknown, but aspirin may displace sulfonylureas from their plasma protein binding sites, while also potentially reducing the renal elimination of some of them, such as chlorpropamide. Blood glucose monitoring is recommended, especially at the start and end of aspirin treatment, adjusting the sulfonylurea dosage if necessary.

- Uricosuric agents. Aspirin (ASA) has uricosuric effects at high doses, above 3 g, but at low doses, it has been shown to antagonize the effects of probenecid or sulfinpyrazone. Furthermore, uricosuric agents may decrease the elimination of ASA. This can lead to an accumulation of uric acid and ASA. Therefore, this combination should be avoided.

- Verapamil. Cases of potentiation of the antiplatelet effects of aspirin by verapamil have been described. Patient monitoring is recommended.

- Zafirlukast. Pharmacokinetic studies have shown that aspirin may increase zafirlukast levels by up to 45%, with a potential risk of toxicity. Patient monitoring is recommended.

- Zidovudine. Plasma concentrations of zidovudine can be increased by competitively inhibiting glucuronidation or by directly inhibiting microsomal metabolism.
It can affect the liver, potentially reaching toxic levels. Caution should be exercised. It also increases the toxicity of acetylsalicylic acid.

- Food. Pharmacokinetic studies have shown that administering aspirin after meals can reduce absorption by up to 50%. Therefore, if rapid effects are desired, it is advisable to administer aspirin on an empty stomach. However, administration with food reduces the risk of gastric irritation.

- Ethyl alcohol. There is an increased risk of gastric damage, so it is recommended to avoid alcohol consumption, especially in the 8-10 hours after a dose of aspirin. Patients who consume more than three alcoholic drinks daily should avoid using aspirin and replace it with another NSAID.

Pregnancy

Acetylsalicylic acid: FDA Pregnancy Category D. Animal studies with salicylates have shown teratogenic and embryocidal effects. Salicylates rapidly cross the placenta. Controlled studies with acetylsalicylic acid (ASA) in humans have not demonstrated teratogenicity. Chronic use of high doses of salicylates during the third trimester may prolong gestation, which could lead to fetal injury or death due to decreased placental function, and increase the risk of maternal antenatal hemorrhage. The use of salicylates, especially ASA, during the last two weeks of pregnancy may increase the risk of fetal or neonatal hemorrhage. Regular or excessive use during the final stage of pregnancy could theoretically lead to premature closure of the fetal ductus arteriosus, and also increase the risk of stillbirth or neonatal death (possibly due to antenatal hemorrhage, premature closure of the ductus arteriosus, and low birth weight); however, this was not observed in studies with therapeutic doses. Chronic treatment with high doses of salicylates during the final stages of pregnancy can prolong and complicate labor and increase the risk of maternal or fetal hemorrhage. The use of aspirin (analgesic doses) is only acceptable when safer therapeutic alternatives are unavailable; chronic use or high doses are not recommended, especially during the third trimester.
Caffeine: FDA Category C.

Lactation

Acetylsalicylic acid, as well as other salicylates, is excreted in breast milk in small amounts. There is a potential risk of effects on platelet function in the newborn, although these have not been reported with the use of aspirin. It is generally recommended that breastfeeding be discontinued in nursing mothers on long-term and/or high-dose therapy; however, some experts believe that occasional single doses do not appear to pose a significant risk to the infant.
Caffeine is excreted in small amounts in breast milk.

Children

Contraindicated in children under 16 years of age because the use of acetylsalicylic acid has been linked to Reye's syndrome, a rare but serious disease.

Seniors

The elderly may be more sensitive to the toxic effects of acetylsalicylic acid, probably due to decreased kidney function.

Adverse reactions

The adverse effects of acetylsalicylic acid, in most cases, are a consequence of its pharmacological mechanism of action and primarily affect the digestive system. 5-7% of patients experience some type of adverse effect.
The most characteristic adverse effects are:

- Gastrointestinal: Frequent (19%): [NAUSEA], [DYSPEPSIA], [VOMITING], [GASTRIC ULCER], [DUODENAL ULCER]. Less frequently, [GASTROINTESTINAL HEMORRHAGE] ([MELENA], [HEMATEMESIS]).

- Dermatological/Hypersensitivity: [URTICARIA], [EXANTHEMATOUS ERUPTIONS], [ANGIOEDEMA], [RHINITIS], paroxysmal [BRONCHOSPASM], and severe [DYSPNEA]. [EXCESSIVE SWEATING] (with high doses). Anaphylactic or anaphylactoid reactions may occur in patients with a history of hypersensitivity to acetylsalicylic acid and other nonsteroidal anti-inflammatory drugs. This could also occur in patients who have not previously shown hypersensitivity to these drugs.

- Hepatic: Infrequent (<1%): reversible hepatotoxicity (particularly in patients with juvenile arthritis, systemic lupus erythematosus, rheumatic fever, and a history of liver impairment), alteration of liver function parameters. Very rarely, Reye's syndrome (in children under 16 years of age) with very serious consequences.

- Central nervous system: With high doses, [DIZZINESS], [HEADACHE], [CONFUSION], [NERVOUSNESS], [ANXIETY].

- Otorhinolaryngological: [TINNITUS], [DEAFNESS] (with high doses).

- Renal: [RENAL INSUFFICIENCY] and acute [INTERSTITIAL NEPHRITIS] (with high doses).

- Blood disorders: [HYPOPROTHROMBINEMIA] (at high doses), [LEUKOPENIA], [THROMBOCYTOPENIA] and prolongation of bleeding time and [ANEMIA].
Treatment should be discontinued immediately if the patient experiences any episodes of deafness, tinnitus, or dizziness.
Due to the presence of caffeine in the preparation, adverse reactions may occur as a result of CNS stimulation, with symptoms such as nervousness, restlessness, or mild gastrointestinal irritation. These adverse effects depend on individual sensitivity to caffeine and the daily dose. Vegetatively labile individuals may react even to low doses of caffeine with insomnia, restlessness, tachycardia, and possibly gastrointestinal discomfort.

Overdose

Symptoms: The symptoms of salicism include nausea, vomiting, ringing in the ears, deafness, sweating, vasodilation and hyperventilation, headache, blurred vision, and occasionally diarrhea.
These are signs of an overdose. Most of these reactions are caused by the direct effect of the compound. However, vasodilation and sweating are the result of an accelerated metabolism.
Acid-base imbalances are common, which can influence salicylate toxicity by altering their distribution between plasma and tissues. Stimulation of respiration leads to hyperventilation and respiratory alkalosis. Impaired oxidative phosphorylation results in metabolic acidosis.
In salicylate poisoning, both symptoms occur to some degree, but the metabolic component tends to predominate in children up to 4 years old, while in older children and adults respiratory alkalosis is more common.
Neurological disorders, such as confusion, delirium, seizures, and coma, are signs of acute poisoning. Signs of salicylate poisoning appear when plasma salicylate concentrations exceed 300 mg/L. Supportive measures are needed for adults with plasma salicylate concentrations above 500 mg/L and for children when concentrations exceed 300 mg/L.
Treatment: There is no antidote for salicylate poisoning. In the case of a suspected overdose, the patient should be kept under observation for at least 24 hours, as symptoms and blood salicylate levels may not be evident for several hours. Overdose is treated with gastric lavage, forced alkaline diuresis, and supportive therapy. Restoration of acid-base balance, along with hemodialysis, may be necessary in acute cases.
Symptoms that appear in case of caffeine overdose are a result of excessive stimulation of the CNS (insomnia, restlessness, vomiting, convulsions and symptoms of excitation) and gastrointestinal irritation (nausea, vomiting, diarrhea, abdominal pain).

- It is recommended to administer acetylsalicylic acid after meals.
- It is advisable to avoid consuming alcoholic beverages during treatment.
- You should notify your doctor of symptoms such as heartburn, abdominal pain, unexplained general weakness, cold sweats, dizziness, low blood pressure, bloody vomiting, or black stools.
- If the patient is going to undergo a tooth extraction or other type of surgery, treatment should be suspended 5-7 days before the procedure.
- It is advisable to avoid using chewable tablets for 7 days after tooth extractions, tonsillectomies or oral cavity surgery.
- If pain and/or fever persist after 10 and 3 days respectively of treatment, it is advisable to see a doctor.
- Do not use on children and adolescents under 16 years of age.