spirin and Gastrointestinal Bleeding John C. Krantz, Jr., PhD Gibson Island, Maryland
There is no other over-the-counter (OTC) drug having the widespread use of aspirin. Evoking the well-established analgesic, antipyretic, and anti-inflammatory activities with an amazingly low degree of toxicity, its use has increased in this country to the astounding figure of more than 20 tons daily. The observation that comparatively small daily doses of aspirin may serve as a means of preventing certain types of cardiovascular disasters may lead to even more widespread use of the drug. The most frequent untoward side effect of aspirin is gastric discomfort with or without microbleeding. The amount of bleeding is usually quite small but owing to the long interest of the author in buffered aspirin, it is prudent to determine whether or not this action of aspirin is serious. It has been shown in many clinical studies that buffering aspirin in the tablet will reduce the incidence of gastric discomfort and microbleeding by the drug. If the aspirin is highly buffered and ingested with much water, such as the solution of an effervescent product, the incidence of the gastric discomfort is reduced. If gastric bleeding exists, microbleeding blood loss above the normal 1 ml/day is not detected.
Etiological Considerations The cause of the gastric irritation and/or microbleeding has been the obRequests for reprints should be sent to Dr. John C. Krantz, Gibson Island, MD 21056.
ject of many studies. Davenport' showed that unbuffered aspirin alters mucosal permeability, particularly around particles of aspirin, and causes an increase in the net movement of Na+ into the lumen of the stomach. A net loss of H+ from the stomach results. A fall in the transmucosal electrical potential is known to occur in humans with plain aspirin and not with highly buffered aspirin. Gastric erosion has been observed after plain aspirin ingestion, but this does not occur in the presence of sufficient buffer. The H+ increases the mucosal damage. Davenport showed that when aspirin was buffered with sodium citrate, the mucosal barrier was not damaged and bleeding did not occur. It is the opinion of the author that mucosal barrier changes are initiated by contact with particulate aspirin, such as a whole tablet or portion
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 70, NO. 10, 1978
thereof. Cellular damage occurs and certainly this will be intensified by back diffusion of H+. Aspirin is the acetic acid ester of salicylic acid, CQH4"3C0CH3. Salicylic acid is orthohydroxy benzoic acid. It is a white crystalline powder soluble in water 1-400 imparting a pH of 2.4. The free acid, the form present in the stomach when plain aspirin is taken, can cause desquamation of tissues and has been used locally as an escharotic. Once the lipotropic acid form enters, sequential events within the gastric mucosal cell are not clear. If the molecule is hydrolyzed (as is known to be the case in the general circulation), perhaps the phenolic hydroxyl group imparts the property of tissue corrosion to salicylic acid and not the carboxyl group. Further evidence supporting this view is that benzoic acid (C6H5.COOH) is only mildly irritating. It is not the acidity of phenol 761
owing to the dissociation of the hydroxyl group into hydrogen ions since the pH of an aqueous solution of phenol is about six. It appears, therefore, that it could be the inherent tissue erosive characteristics of the phenolic hydroxyl group that are responsible for the gastric irritation and microbleeding evoked by plain aspirin. Phenol and many compounds containing the phenolic hydroxyl group in contact with protoplasm cause a coagulation of the protein. The coagulum formed with the protoplasm and phenol is unlike that which is formed by mercuric chloride and protoplasm. Phenol permeates its own coagulum and goes deeply into the tissue potentially rupturing the walls of blood vessels and producing bleeding. Julius Wohlgemut,2 who was one of the first two clinicians to use aspirin in the treatment of rheumatic disease, reported that the drug was given in solution. As it was insoluble in water, he suggested alcohol to facilitate the solubility. It is now known that forming the sodium salt and, thus, solubilizing and ionizing produces a lipophobic entity which will not enter, and, therefore, cannot harm the gastric mucosa.
Incidence Bleeding
of
Gastrointestinal
Aspirin has been "associated" with gastrointestinal hemorrhage but the incidence is so low as to make clear-cut proof unavailable. When one considers the widespread use of aspirin by the American public with medical direction, and as a home medication, the incidence of major gastrointestinal bleeding is strikingly small. Levy3 estimates that upon heavy use of aspirin the incidence of such bleeding is about 0.015 percent. When one considers thataspirin is anti-inflammatory, conferring upon it properties unique among the commonly used over-the-counter analgesics, its spectrum of benefit is greatly increased. Ingelfinger4 said it is "questionable practice if a fear of gastric effects causes the drug to be withheld from a patient who desperately requires the relief provided by this excellent analgesic."
Conclusion It is clear that if the aspirin is highly buffered, solubilized, and well diluted, gastrointestinal distress is eliminated as a possibility in evoking gastrointestinal
bleeding. It is certain that selfmedication imposes its dangers, as does every human endeavor. The Internal Analgesic Panel of the Food and Drug Administration,5 through the Federal Register, recommended that analgesics like aspirin can be used to relieve neuromuscular pain for a period of ten days. If the pain is not relieved in this period, medical advice should then be sought. As long as the medication is safe and taken with reasonable judgement the danger is not great. When the possible danger is compared to the relief of neuromuscular pain without gastrointestinal discomfort enjoyed by millions of people, the danger is dwarfed into insignificance.
Literature Cited 1. Davenport HW: Salicylate damage to the gastric mucosa. N Engl J Med 276:1307-1312, 1967 2. Wolgemut J: Uber aspirin (acetylsalicylsaure). Ther Mh (Halbmh) 13:276-278, 1899 3. Levy M: Aspirin use in patients with major upper gastrointestinal bleeding and peptic ulcer disease. N EngI J Med 290:1158-1162, 1974 4. Ingelfinger FJ: The side effects of aspirin. N EngI J Med 290:1196-1197, 1974 5. Internal analgesics. Federal Register 131:42 (July 8) 1977
Howard University Receives $6 Million Bequest Howard University announced receipt of a $6 million bequest from the late Cliland B. Powell, MD, a graduate of its College of Medicine. The bequest is the largest amount of money ever donated to the University. It is to be used in the University's Student Scholarship and Loan Program. Dr. Powell's widow, Mrs. Lena Powell of Briarcliff Manor, NY, announced that recipients of loans and scholarships must study medicine, pharmacy, dentistry, or engineering. Dr. James E. Cheek, Howard's President, said that the bequest was a step forward in the school's $100 million capital fund drive. He further 762
stated, "This is a major moment in the life of the University, not only because the sum is so generous, but because the bequest came from a man revered by so many." Dr. Powell was former owner, editor, and publisher of the Amsterdam News and the first Afro-American physician to become a certified radiologist. He also founded and operated the Victory Mutual Life Insurance Company, the Community Personal Finance Corporation, Midway Technical School, and Unity Funeral Parlors. Dr. Powell died in September 1977, at the age of 83.
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 70, NO.
10,
1978
There is no other over-the-counter (OTC) drug having the widespread use of aspirin. Evoking the well-established analgesic, antipyretic, and anti-inflammatory activities with an amazingly low degree of toxicity, its use has increased in this country to the astounding figure of more than 20 tons daily. The observation that comparatively small daily doses of aspirin may serve as a means of preventing certain types of cardiovascular disasters may lead to even more widespread use of the drug. The most frequent untoward side effect of aspirin is gastric discomfort with or without microbleeding. The amount of bleeding is usually quite small but owing to the long interest of the author in buffered aspirin, it is prudent to determine whether or not this action of aspirin is serious. It has been shown in many clinical studies that buffering aspirin in the tablet will reduce the incidence of gastric discomfort and microbleeding by the drug. If the aspirin is highly buffered and ingested with much water, such as the solution of an effervescent product, the incidence of the gastric discomfort is reduced. If gastric bleeding exists, microbleeding blood loss above the normal 1 ml/day is not detected.
Etiological Considerations The cause of the gastric irritation and/or microbleeding has been the obRequests for reprints should be sent to Dr. John C. Krantz, Gibson Island, MD 21056.
ject of many studies. Davenport' showed that unbuffered aspirin alters mucosal permeability, particularly around particles of aspirin, and causes an increase in the net movement of Na+ into the lumen of the stomach. A net loss of H+ from the stomach results. A fall in the transmucosal electrical potential is known to occur in humans with plain aspirin and not with highly buffered aspirin. Gastric erosion has been observed after plain aspirin ingestion, but this does not occur in the presence of sufficient buffer. The H+ increases the mucosal damage. Davenport showed that when aspirin was buffered with sodium citrate, the mucosal barrier was not damaged and bleeding did not occur. It is the opinion of the author that mucosal barrier changes are initiated by contact with particulate aspirin, such as a whole tablet or portion
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 70, NO. 10, 1978
thereof. Cellular damage occurs and certainly this will be intensified by back diffusion of H+. Aspirin is the acetic acid ester of salicylic acid, CQH4"3C0CH3. Salicylic acid is orthohydroxy benzoic acid. It is a white crystalline powder soluble in water 1-400 imparting a pH of 2.4. The free acid, the form present in the stomach when plain aspirin is taken, can cause desquamation of tissues and has been used locally as an escharotic. Once the lipotropic acid form enters, sequential events within the gastric mucosal cell are not clear. If the molecule is hydrolyzed (as is known to be the case in the general circulation), perhaps the phenolic hydroxyl group imparts the property of tissue corrosion to salicylic acid and not the carboxyl group. Further evidence supporting this view is that benzoic acid (C6H5.COOH) is only mildly irritating. It is not the acidity of phenol 761
owing to the dissociation of the hydroxyl group into hydrogen ions since the pH of an aqueous solution of phenol is about six. It appears, therefore, that it could be the inherent tissue erosive characteristics of the phenolic hydroxyl group that are responsible for the gastric irritation and microbleeding evoked by plain aspirin. Phenol and many compounds containing the phenolic hydroxyl group in contact with protoplasm cause a coagulation of the protein. The coagulum formed with the protoplasm and phenol is unlike that which is formed by mercuric chloride and protoplasm. Phenol permeates its own coagulum and goes deeply into the tissue potentially rupturing the walls of blood vessels and producing bleeding. Julius Wohlgemut,2 who was one of the first two clinicians to use aspirin in the treatment of rheumatic disease, reported that the drug was given in solution. As it was insoluble in water, he suggested alcohol to facilitate the solubility. It is now known that forming the sodium salt and, thus, solubilizing and ionizing produces a lipophobic entity which will not enter, and, therefore, cannot harm the gastric mucosa.
Incidence Bleeding
of
Gastrointestinal
Aspirin has been "associated" with gastrointestinal hemorrhage but the incidence is so low as to make clear-cut proof unavailable. When one considers the widespread use of aspirin by the American public with medical direction, and as a home medication, the incidence of major gastrointestinal bleeding is strikingly small. Levy3 estimates that upon heavy use of aspirin the incidence of such bleeding is about 0.015 percent. When one considers thataspirin is anti-inflammatory, conferring upon it properties unique among the commonly used over-the-counter analgesics, its spectrum of benefit is greatly increased. Ingelfinger4 said it is "questionable practice if a fear of gastric effects causes the drug to be withheld from a patient who desperately requires the relief provided by this excellent analgesic."
Conclusion It is clear that if the aspirin is highly buffered, solubilized, and well diluted, gastrointestinal distress is eliminated as a possibility in evoking gastrointestinal
bleeding. It is certain that selfmedication imposes its dangers, as does every human endeavor. The Internal Analgesic Panel of the Food and Drug Administration,5 through the Federal Register, recommended that analgesics like aspirin can be used to relieve neuromuscular pain for a period of ten days. If the pain is not relieved in this period, medical advice should then be sought. As long as the medication is safe and taken with reasonable judgement the danger is not great. When the possible danger is compared to the relief of neuromuscular pain without gastrointestinal discomfort enjoyed by millions of people, the danger is dwarfed into insignificance.
Literature Cited 1. Davenport HW: Salicylate damage to the gastric mucosa. N Engl J Med 276:1307-1312, 1967 2. Wolgemut J: Uber aspirin (acetylsalicylsaure). Ther Mh (Halbmh) 13:276-278, 1899 3. Levy M: Aspirin use in patients with major upper gastrointestinal bleeding and peptic ulcer disease. N EngI J Med 290:1158-1162, 1974 4. Ingelfinger FJ: The side effects of aspirin. N EngI J Med 290:1196-1197, 1974 5. Internal analgesics. Federal Register 131:42 (July 8) 1977
Howard University Receives $6 Million Bequest Howard University announced receipt of a $6 million bequest from the late Cliland B. Powell, MD, a graduate of its College of Medicine. The bequest is the largest amount of money ever donated to the University. It is to be used in the University's Student Scholarship and Loan Program. Dr. Powell's widow, Mrs. Lena Powell of Briarcliff Manor, NY, announced that recipients of loans and scholarships must study medicine, pharmacy, dentistry, or engineering. Dr. James E. Cheek, Howard's President, said that the bequest was a step forward in the school's $100 million capital fund drive. He further 762
stated, "This is a major moment in the life of the University, not only because the sum is so generous, but because the bequest came from a man revered by so many." Dr. Powell was former owner, editor, and publisher of the Amsterdam News and the first Afro-American physician to become a certified radiologist. He also founded and operated the Victory Mutual Life Insurance Company, the Community Personal Finance Corporation, Midway Technical School, and Unity Funeral Parlors. Dr. Powell died in September 1977, at the age of 83.
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION, VOL. 70, NO.
10,
1978
