INTRODUCTION:

Aspirin is a Non-Steroidal Anti-inflammatory drug (NSAID). Aspirin is used to reduce fever and treat pain or inflammation caused by many conditions such as headache, toothache, back pain, arthritis, menstrual cramps, or minor injury¹. The FDA warns consumers that all OTC Analgesics (Pain relievers) should be taken carefully to avoid serious problems that may occur with improper usage². Many patients are unaware that over-the-counter (OTC) analgesics can cause potentially serious adverse effects when used in combination with other common medications such as anticoagulants, corticosteroids, or antihypertensive agents³.

Received on 15.03.2015 Modified on 20.03.2015

Research J. Pharm. and Tech. 8(5): May, 2015; Page 580-586

DOI: 10.5958/0974-360X.2015.00097.9

The patients, who are on concomitant ibuprofen, anticoagulant, corticosteroid, or Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitors (SSRI) therapy, can be treated with Acetaminophen an effective alternative to NSAIDs to treat pain or fever^1,4.

Aspirin is a salicylate drug and it is also known as acetylsalicylic acid (ASA). It is one of the most important medicines required in basic health system⁵. It is listed as Essential Medicines in the World health organization’s List. It is one of the most widely used medicines in the world about 40,000 tons of it, used every year. Generally used as pain killer⁶. Pain is a irritating sensation that can adversely affect all areas of a person's life, including comfort, thought, sleep, emotion, and normal daily activity. Chronic, untreated pain can interfere quality of life and social functioning and disrupt employment⁷. The pain sensation produced by composite phenomena that involve physical perception as well as the emotional reaction to the perception. Physiologic variables (e.g., tissue injury) and psychological variables (e.g., anxiety) influence a person's response to pain. The pain perception is the net effect of complicated interactions of ascending and descending neural pathways with biochemical and electrochemical processes⁸.

As an antipyretic, aspirin decrease body temperature but does not affect normal body temperature. It resets the hypothalamic thermostat through inhibiting the prostaglandins (PG) production in the hypothalamus. Anti-inflammatory action of aspirin is also result due to inhibition of PG synthesis. It has also antiplatelet action.by inhibiting the production of thromboxane. Aspirin has also therapeutic effect if it is being used as long term at low doses to prevent heart attack, strokes and blood clot. Also, low doses of aspirin may be given immediately after a heart attack to reduce the risk of another heart attack or of the death of cardiac tissue⁹.

Background of aspirin

The active ingredient of aspirin was first discovered from the bark of the willow tree in 1763 by Edward Stone of Wadham College, University of Oxford. He had discovered salicylic acid, the active metabolite of aspirin. Aspirin was first synthesized by Felix Hoffmann, a chemist with the German company Bayer in 1897¹⁰.

Aspirin belongs to class of Nonsteroidal anti-inflammatory drugs (NSAID) and these drugs are assumed to exert their analgesic effects by inhibiting prostaglandin synthesis in the periphery; however, this probably is an oversimplified view of their action. The main side effects of aspirin are gastrointestinal ulcers, stomach bleeding, and ringing in the ears, especially with higher doses. In children and adolescents, aspirin is not recommended for flu-like symptoms or viral illnesses, because of the risk of Reye's syndrome. Aspirin is part of a group of medications called nonsteroidal anti-inflammatory drugs (NSAIDs), but differs from most other NSAIDs in the mechanism of action. Though it and others with similar structure, called the salicylates, have similar effects (antipyretic, anti-inflammatory, analgesic) to the other NSAIDs and inhibit the same enzyme cyclooxygenase (COX), aspirin does so in an irreversible manner and, unlike others, affects more the COX-1 variant than the COX-2 variant of the enzyme⁹.

Table 2: Major interaction of aspirin with other drugs

Drug combination	Interaction	Effective Measures
Aspirin and Ibuprofen	Ibuprofen may reduce the effectiveness of aspirin, increase the risk of developing gastrointestinal ulcers and bleeding.	Dose adjustment or frequent monitoring.
Asprin and Tenofovir	Aspirin potentiate the effect of Tenofovir on kidney risk.	Require dose adjustment or more frequent monitoring. Physicians should be consulted in case of symptoms including nausea, vomiting, loss of appetite, increased or decreased urination, sudden weight gain or weight loss, fluid retention, swelling, shortness of breath, muscle cramps, tiredness, weakness, dizziness, confusion, and irregular heart rhythm.
Aspirin and Acetazolamide	Cause ringing in ears, headache, nausea, vomiting, dizziness, confusion, hallucinations, rapid breathing, fever, seizure (convulsions), or coma	Need dose adjustment or special tests to safely use both medications.
Aspirin and Anisindion	Increase the risk of bleeding	Need dose adjustment based on prothrombin time or International Normalized Ratio (INR)
Aspirin and Apixaban	Increase the risk of bleeding, including severe and sometimes fatal hemorrhage	Seek immediate medical attention in case of unusual bleeding or bruising.
Aspirin and Leflunomide	Increase the risk of liver damage.	Avoid or limit the use of alcohol while being treated with these medications. Need dose adjustment or more frequent monitoring.
Aspirin and Ardeparin	Increase the risk of bleeding complications.	Need dose adjustment.
Aspirin and Fondaparinus	Increase the risk of bleeding complications.	Need dose adjustment. Physicians should be consulted in case of unusual bleeding or bruising, swelling, vomiting, blood in your urine or stools, headache, dizziness, or weakness during treatment with these medications.
Aspirin and Tacrolimus	Kidney problems	Physicians should be consulted in case of symptoms including nausea, vomiting, loss of appetite, increased or decreased urination, sudden weight gain or weight loss, fluid retention, swelling, shortness of breath, muscle cramps, tiredness, weakness, dizziness, confusion, and irregular heart rhythm.
Aspirin and Tenofavir	Increase the risk of kidney problems.	Require dose adjustment or more frequent monitoring to safely use both medications. Physicians should be consulted in case of symptoms including nausea, vomiting, loss of appetite, increased or decreased urination, sudden weight gain or weight loss, fluid retention, swelling, shortness of breath, muscle cramps, tiredness, weakness, dizziness, confusion, and irregular heart rhythm.
Aspirin and Botulism immune globlin	Increase the risk of kidney problems.	Need dose adjustment. Physicians should be consulted in case of symptoms including nausea, vomiting, loss of appetite, increased or decreased urination, sudden weight gain or weight loss, fluid retention, swelling, shortness of breath, muscle cramps, tiredness, weakness, dizziness, confusion, and irregular heart rhythm.
Aspirin and Iodine I 131 tositumomab	May increase the risk of bleeding.	Need immediate medical attention if experience any unusual bleeding or bruising, or have other signs and symptoms of bleeding such as dizziness; lightheadedness; red or black, tarry stools; coughing up or vomiting fresh or dried blood that looks like coffee grounds; severe headache; and weakness.
Aspirin and Sodium biphosphate / sodium phosphate	Bowel cleansing with sodium biphosphate can cause kidney failure.	Need a dose adjustment or special tests to safely use both medications. Use sodium biphosphate exactly as prescribed by doctor, and drink plenty of clear fluids before, during, and after the cleansing process to keep yourself hydrated.
Aspirin and Cabozantinib	Increase the risk of bleeding	Take appropriate precautions. Monitoring closely for any potential complications.
Aspirin and Cidofavir	It may cause kidney damage	If receiving aspirin, may need to wait at least seven days after last dose before start treatment with cidofovir.
Aspirin and Warferin	Increase the risk of bleeding	Need dose adjustment based on prothrombin time or International Normalized Ratio (INR)
Aspirin and Dalteprin	Increase the risk of bleeding complications.	May need a dose adjustment or more frequent monitoring to safely use both medications.
Aspirin and Danaparoid	Increase the risk of bleeding complications.	May need a dose adjustment or more frequent monitoring to safely use both medications.
Aspirin and Ponatinib	May increase the risk of bleeding and sometimes fatal hemorrhage.	Take appropriate precautions and monitoring closely for any potential complications.
Aspirin and Ketorolac	Ketorolac is not recommended with aspirin which may cause nausea, vomiting, stomach pain, drowsiness, black or bloody stools, coughing up blood.	Do not use any other over-the-counter cold, allergy, or pain medication without the consult of physician.
Aspirin and Enoxaparin	Increase the risk of bleeding	Need dose adjustment based on prothrombin time or International Normalized Ratio (INR)
Aspirin and Methazolamide	May cause ringing in ears, headache, nausea, vomiting, dizziness, confusion, hallucinations, rapid breathing, fever, seizure (convulsions), or coma.	May need a dose adjustment or special tests to safely take both medications.
Aspirin and Methotrexate	May increase the effects of methotrexate which may cause nausea, vomiting, diarrhea, sore throat, chills, fever, rash, unusual bruising or bleeding, pale skin, dark urine, swelling of the extremities, or shortness of breath.	You may need a dose adjustment or special test if you take both medications.
Aspirin and Omacetaxine	Increase the risk of bleeding	Take appropriate precautions and monitoring is required closely for any potential complications. Seek immediate medical attention if experience any unusual bleeding or bruising,
Aspirin and Ramucirumab	May cause bleeding and gastrointestinal perforation aspirin may increase the risk	should seek immediate medical attention if you experience any unusual bleeding or bruising, or have other signs and symptoms of bleeding such as dizziness; lightheadedness; red or black, tarry stools; coughing up or vomiting fresh or dried blood that looks like coffee grounds; severe headache; and weakness.
Aspirin and Rogarafenib	May increase the risk of bleeding.	Seek immediate medical attention if experience any unusual bleeding or bruising, or have other signs and symptoms of bleeding such as dizziness; lightheadedness; red or black, tarry stools; coughing up or vomiting fresh or dried blood that looks like coffee grounds; severe headache; and weakness.
Aspirin and Rivaroxaban	Increase the risk of bleeding, including severe and sometimes fatal hemorrhage.	Seek immediate medical attention if experience any unusual bleeding or bruising, or have other signs and symptoms of bleeding such as dizziness; lightheadedness; red or black, tarry stools; coughing up or vomiting fresh or dried blood.
Aspirin and Drotrecogin alfa	Increase the risk of bleeding complications.	Take appropriate precautions and is monitor closely for any potential complications.
Aspirin and Ibritumomab	May increase the risk of bleeding, ibritumomab alone has been associated with severe and sometimes fatal hemorrhage.	Seek immediate medical attention.

Table 3: Moderate interaction of aspirin with other drugs

Drug combination	Interaction	Effective Measures
Aspirin and Hydrocortisone	Reduce the effects of aspirin.	May need a dose adjustment or more frequent monitoring to safely use both medications.
Aspirin and Methylprednisolon	Make aspirin less effective.	May need a dose adjustment or special tests while taking these medications.
Aspirin and Urokinase	Increase the risk of bleeding	May need a dose adjustment or special tests to safely use both medications
Aspirin and Abciximab	Increase the risk of bleeding	May need a dose adjustment in addition to special tests to safely use both medications.
Aspirin and Zafirlukast	Aspirin may increase the effects of zafirlukast.	May need a dose adjustment or special test to safely use both medications.
Aspirin and Salicylamide	May increase the risk of developing gastrointestinal ulcers and bleeding.	May need a dose adjustment.
Aspirin and Aluminum hydroxide	May decrease the effects of aspirin.	May need a dose adjustment or special test to safely use both medications.
Aspirin and Calcium carbonate	May decrease the effects of aspirin.	If your doctor does prescribe May need a dose adjustment or special test to safely use both medications.
Aspirin and Zoledronic acid	If taking by mouth may increase risk of developing gastrointestinal ulcers and bleeding. If receive by IV infusion may have an increased risk of kidney problems.	May need a dose adjustment or more frequent monitoring.
Aspirin and Argatroban	Using aspirin with argatroban can cause you to bleed more easily.	may need a dose adjustment in addition to testing of your prothrombin time or International Normalized Ratio (INR)
Aspirin and Nifedipine	The combination may cause your blood pressure to increase.	You may need a dose adjustment or your blood pressure checked more often. Also, if you are already taking the combination and stop taking aspirin, your blood pressure may decrease.
Aspirin and Naproxan	Frequent or regular use of naproxen may reduce the effectiveness of aspirin.	You may need a dose adjustment or more frequent monitoring by your doctor to safely use both medications.
Aspirin and Insulin inhalation rapid acting	Aspirin may increase the effects of insulin inhalation, rapid acting and cause blood sugar levels to get too low.	May need a dose adjustment or more frequent monitoring of blood sugar if using insulin inhalation, rapid acting.
Aspirin and Aliskiren/hydrochlorothiazide	May reduce the effects of aliskiren in lowering blood pressure. more likely to develop impaired kidney function during treatment with these medications.	May need a dose adjustment or more frequent monitoring to safely use both medications.
Aspirin and Valsartan; Aspirin and Tolbutamide	May reduce the effects of valsartan in lowering blood pressure.	May need a dose adjustment or more frequent monitoring to safely use both medications.
Aspirin and Vitamin E	Products containing vitamin E may increase the effects of aspirin and cause to bleed more easily.	May need a dose adjustment or more frequent monitoring to safely use both medications.
Aspirin and Aluminum hydroxide/mineral oil	May decrease the effects of aspirin.	May need a dose adjustment or special test to safely use both medications.
Aspirin and Omega-3 polyunsaturated fatty acids	May increase the risk of bleeding	Seek immediate medical attention if experience any unusual bleeding.
Aspirin and Mesalamine; Aspirin and Sulfasalazine	May cause kidney problems	May need a dose adjustment.
Aspirin and Ciproflaxin	May increase the effects of ciprofloxacin. If have a history of seizures may be at a greater risk.	May need a dose adjustment or special test to safely use both medications.
Aspirin and Magaldrate	May decrease the effects of aspirin	Need a dose adjustment.
Aspirin and Diltiazam	This combination may cause unusual bleeding or bruising, headache, dizziness, or weakness.	May need a dose adjustment or needblood pressure checked more often.

Table 4: Minor interaction of aspirin with other drugs

Drug combination	Interaction	Effective Measures
Aspirin and lansoprazole	May decrease the oral bioavailability of aspirin and other salicylates	Adjustment can be determined by practitioner.
Aspirin and Atenolol	High doses of salicylates may blunt the antihypertensive effects of beta-blockers.	Patients require concomitant therapy should be monitored for altered antihypertensive response whenever a salicylate is introduced or discontinued, or when its dosage is modified.
Aspirin and Metoprolol	Metoprolol may also increase aspirin absorption and/or plasma concentrations of salicylates	Patients who require concomitant therapy should be monitored for altered antihypertensive response whenever a salicylate is introduced or discontinued, or when its dosage is modified.
Aspirin and spirenolactone	Some salicylates may impair the tubular secretion of canrenone, the main active metabolite of spironolactone	The clinician should consider discontinuing the salicylate or increasing spironolactone dosage while paying careful attention to the patient's serum potassium concentration.

Tips for patients to avoid OTC drug interactions

• Patients should thoroughly read the labels of all over-the-counter and prescription medicines.

• Patients should make sure that they know the benefits as well as the potential risks of both prescription and over-the-counter medications they are taking.

• They should look specifically for the section called "Warnings" on the labels of over-the-counter medicines.

• Patients should talk to their doctor or pharmacist before taking any new prescription or over the counter medication.

• Patients should maintain a record containing the list of prescription or over the counter medications and share it with their doctors and their pharmacist.

• Patients should use one pharmacy for all of their family's prescription and over-the-counter medication needs. By filling all prescriptions at one pharmacy, all the important information about (what and when the patients take) could be found in a central location. The pharmacist can help the patients by retrieving all the information about possible drug interactions from any OTC, prescription or herbal medications.

• Learning about interactions with commonly used OTC remedies can also assure smart choices.

• Talk to doctor or pharmacist if you have any medical conditions or take other medications. They can help explain what risks you may have and what precautions to take.

CONCLUSION:

Physicians should be aware of potential drug interactions with OTC medicines when prescribing new medications. Pharmacists can be instrumental in assisting patients with using OTC medications safely and effectively. To achieve maximum efficacy of a medication, drug-drug interactions, drug-disease interactions, and the timing of administration with respect to food should be examined thoroughly before co administration of multiple medications. Physicians and Pharmacists should make patients aware of the potential for toxicity and adverse drug interactions associated with the long-term and inappropriate use of OTC analgesics. They should advise Patients to use OTC analgesics not in higher-than-recommended doses or not in combinations that magnify the risk of adverse interactions. Patients should be notified that OTC analgesics are also found in many common cough, cold, or flu medications. Pharmacists may provide educational materials to patients so that they may learn to recognize the generic names of OTC medications. Pharmacists should warn consumers of the risks of misusing OTC pain relievers. Because many patients self-medicate with OTC analgesics and are unaware of potentially dangerous drug interactions, proper counseling on the appropriate use of these agents can help minimize adverse effects and ensure positive clinical outcomes.

REFERENCES:

1. Tripathi KD. Essentials of Medical Pharmacology. Jaypee brothers, New Delhi India 2003.

2. WHO. The world health report 2000 – health systems: improving performance. Geneva: World Health Organization; 2000.

3. Gilson L, et al. Assessing prescribing practice: a Tanzanian example. International Journal of Health Planning and Management. 8;1993: 37–58.

4. Henschel EO, ed: Malignant hyperthermia: currellt concepts. Appleton-Century-Crofts. New York, 1987.

5. Agency for Health Care Research and Quality (AHRQ). 2011. Health Literacy Interventions and Outcomes: an Update of the Literacy and Health Outcomes Systematic Review of Literature, 2011 (Retrieved October 2012)

6. WHO. The world health report 2000 – health systems: improving performance. Geneva: World Health Organization; 2000.

7. Bennett IM, et al. The contribution of health literacy to disparities in self-rated health status and preventive health behaviors in older adults. Annals of Family Medicine. 7(3); 2009: 204-211.

8. Longmore M, et al. Oxford Handbook of Clinical Medicine oxford University press 2010.

9. Koda-Kombe MA, el al. Applied Therapeutics: the clinical use of drugs. Lippincott Williams and Wilkins North American Edition. 2012.

10. David Lewis, Aspirin: Royal Society of Chemistry 2003. http://www.rsc.org/learnchemistry/content/filerepository/CMP/00/000/045/Aspirin.pdf

11. Harman JG, et al. Goodman and Gillamn’s: The pharmacological basis of therapeutics, McGraw-Hill, New York, 2001.

12. Sweetman SC. Martin Dale, The complete drug reference. The Royal pharmaceutical society of Great Britain, Landon, 2002.

13. Nefesoglu FZ, et al. Interaction of omeprazole with enteric-coated salicylate tablets. Int J Clin Pharmacol Ther. 36; 1998: 549-553.

14. Anand BS, et al. Effect of omeprazole on the bioavailability of aspirin: a randomized controlled study on healthy volunteers. Gastroenterology. 116; 1999: A371.

15. Inarrea P, et al. Omeprazole does not interfere with the antiplatelet effect of low-dose aspirin in man. Scand J Gastroenterol. 35; 2000: 242-246.

16. Yoovathaworn KC, et al. Influence of caffeine on aspirin pharmacokinetics. Eur J Drug Metab Pharmacokinet. 11; 1986: 71-76.

17. Keber I, et al. The influence of combined treatment with propranolol and acetylsalicylic acid on platelet aggregation in coronary heart disease. Br J Clin Pharmacol. 7; 1979: 287-291.

18. Spahn H, et al. Pharmacokinetics of salicylates administered with metoprolol. Arzneimittelforschung. 36; 1986: 1697-1699.

19. Sziegoleit W, et al. Influence of acetylsalicylic acid on acute circulatory effects of the beta-blocking agents pindolol and propranolol in humans. Int J Clin Pharmacol Ther Toxicol. 20; 1982: 423-430.

20. Tweeddale MG and Ogilvie RI. Antagonism of spironolactone-induced natriuresis by aspirin in man. N Engl J Med. 289; 1973: 198-200.

21. Favre L, et al. Interaction of diuretics and non-steroidal anti-inflammatory drugs in man. Clin Sci. 64; 1983: 407-415.

22. Karen Baxter. Stockley's Drug Interactions: A Source Book of Interactions, Their Mechanisms, Clinical Importance and Management. Texas, United States.2010.

23. http://www.researchgate.net/publication/5684542_Adverse_drug _interactions_involving_common_prescription_and_over-the-counter_analgesic_agents

Condition	Dose
Mild to moderate pain	350 mg or 650 mg every 4 hours or 500 mg every 6 hours.
Rheumatoid arthritis	500mg every 4-6 hours; 650 mg every 4 hours; 1000mg every 4-6 hours; 1950 mg twice daily
Heart attacks	81, 162 or 325 mg daily
Antiplatelet	40-80 mg/day
Antipyretic (FEVER)	325-650 mg every 4-6 hours
Rheumatic fever	1g every 4-6 hours
Children	10 mg every4-6 hours