Medicinal Chemistry of Aspirin and elated Drugs prepared by J. CHEM. EDUC. Staff
NonprescriptionAnalgesics Asvirin mav be one of the most versatile drugs ever devised. I t acts as an analgesic (pain-killer), an antipyretic (to reduce fever). an antiinflammatorv agent (to reduce swelling, redness, and other symptoms), andanuricosuric (to relieve symptoms of arthritis and gout). Recently it was found to be effective against stroke, the third leading killer disease (after heart disease and cancer) in the United States. Although it has some dangers, it also has a low order of toxicity. An average dose consists of two 5-gr tablets (650 mg). Consumption of aspirin in the US. ranges between 26 and 74 million lblyear. In 1973, the American public spent more than $642 million on aspirin and other internal analeesics. Other analgesics found in popular nonprescription preparations include acetaminovhen. ohenacetin, and saliculamide.
little value as an antiinflammatory agent, and it acts a little more slowly than aspirin in relieving pain. Phenacetin is slightly less effective than aspirin as a pain reliever. Its effectiveness as an antipyretic is in dispute; it is not an antiinflammatory agent. Salicylamide, given in large doses, acts like aspirin. It also has a slight sedative effect. Caffeine is added to some preparations largely hecause of its diuretic (increasing urine output) properties.
Discovery of Aspirin Many of the pharmacologic properties of salicylic acid and substances related to it were known before the Christian era. Preparations from various harks were used for treatment of pain, fluid retention, and gout. However, because of St. Augustine's dictum that all diseases of Christians were due to Table 1.
Product
aspirin a c e t ~ l ~ a l i c y l acid ie
1
OH acetaminophe?. 4hydrorvacetaml1de
Alka-SeltreP Anacinm A.P.C." Bayer Aspirin" Bayer Aspirin" (Timed Release) Bufferinm
Composition of Some Over-the-counter Analgesic Products (amounts in milligramsltablet) Substance Acetamino-Phenace- SalicylAspirin phen tin amide
325 400 226 325 650
...
325
...
Na2C03, 1.9X 10' . . . . . . Caffeine. 32.4 . . . Caffeine. 32.4 162
... ... ...
...... . . . . . .
...
. . . . . . aluminum glycinate, 48.6 magnesium carbonate.
I
OCH. phenacelin, , 4-cthoxvaeetaml~de
Other
. . . . . .
97.2 129 Caffeine. 64.8 . . Caffeine. 32.4
Excedrinm Mid@
194 454
97.2
...
. .
. . . .
Tylenola Tylenol@ (Extra Strenathl
...
325 500
. . . . . .
Cinnamedrine. 14.9
Table 1gives the ingredients in some nonprescription analgesic products. Acetaminophen is as effective as aspirin in analgesic and more effective in antipyretic performance. However, it has
...
...
...
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1 331
punishment by demons, physicians during the early years of Christianity were reluctant to interfere with God's will. Hence most available information on the medical effects of salicylic acid was repressed. The drug and its properties were rediscovered by Edward Stone in England, late in the 18th century. Stone had heard an old wives' tale to the effect that because willow trees grow well in moist or wet soil where human aches chiefly abound, these trees must contain remedies for moisture-caused aches and pains. Following up on this tale, htt administered p(9tions mad(. of 20 r: of rwwdered willow hark dissolved in a dram of water everyffou; hours to 50 victims of such aches and pains. T h e results were excellent, and salicylic acid again became a drug of repute. In 1859, Adolph Kolhe working with a group of organic chemists a t the Bayer Company in Germany synthesized salicylic acid, sodium salicylate, and phenylsalicylate, all of which were used in medicinal preparations. Aspirin itself was first used by Felix Hoffmann, a junior chemist a t Baver whose father had severe rheumatoid arthritis. ~ o f f m a n nfoundthat the new synthetics were very helpful to his father. hut that they were much too irritating to tht: gastric area for continuo~tsingestim. In htr search ior a better mrrliratim, he set wit to modiiv salicylic arid in a way that would make it more soluble in stomach acids. The more soluble form might pass through the stomach more rapidly, causing less irritation. By replacing a phenolic hydrogen atom with an acetyl group, Hoffmann synthesized acetylsalicylic acid. After satisfying himself by laboratory tests and by administering it to his father that this substance was far superior to the other salicylate drugs, he assembled his notes and carried them to Heinrich Dreiser, director of pharmacologic research a t the Bayer Company. Dreiser, an imposing figure in European science, took one look a t the data and knew he had a winner. He piloted acetylsalicytic acid through its first full clinical e v a l u a t k He discarded its systematic name because it was too hard to pronounce and~impossihleto patent. As a replacement, he coined the term aspirin- from acetyl, spirin from a common name that in the past had been associated with the active components of willow hark. This was in 1899, and we have had Bayer Aspirin" ever since.
of pain. The elevated concentrations of prostaglandins appear to activate pain receptors (nerve endings) in the tissues making the tissues more sensitive to any pain stimulus. Simply rubbing tender skin areas, for example, can result in prostaelandin svnthesis and pain. Table 2 gives the formulas and b x h e m i c a l roles of some ~ r o s t a ~ l a n d i n s . Recent studies suggest that aspirin can inhibit the synthesis of prostaglandins by inactivating the enzymes involved in this synthesis. If this is true, the presence of aspirin could prevent prostaglandin coucentrations from reaching the levels needed to oversensitize pain receptors. This, in effect, would relieve pain by making the affected area less sensitive to pain stimuli.
Inflammation and the Role of Chemical Agents Inflammation is a bodily response to injury or abnormal stimulation caused by a physical, chemical, or biologic agent. Usually it is accompanied by redness, swelling, heat, and pain. wheninjury occurs, the hody releases powerful vasodilators such as histamine and hradykinin in the vicinity of the injury. These substances are chemical aaents that cause capillarv hlood vessels to dilate (expand),atowing fluid and chexnicak from blood to move into the damaaed area. Prostaglandin synthesis also increases in the area of injury. The hormones produced sensitize pain receptors to the swelling and the presence of foreign chemicals. Thus the area becomes painful. Certain prostaglandins also act as vasodilators. Although aspirin is very effective in treating inflammatory conditions, the mechanism by which it acts is not known with certainty. It has been suggested that aspirin actually blocks the action of vasodilators by physically occupying critical chemical sites and denvinr , .. them to the vasodilators. Also propused is the idea that by inhibiting prostaglandin synthciii, aspirin diminishes the efl'rrti\~rnessof the \,asodtlators, and in this way reduct>sthe k g w dfluid aud blood chemicals into the afferted art:n. T h ~ sof , course, dimini>hesinflnmmation. ~
~
Table 2. Formulas and Biochemlcal Roles of Some Prostaglandins
Pain and Analgesic Activity Pain is a s~ecificsensory experience transmitted by means of nerve str;ctures that Hppiar to he separate from those which transmit other sensations, such as touch, pressure, heat, and cold. Evidence indicates that the stimulus for pain is tissue damage. Physical stimuli that compress or stretch sensiti\.e tissue or the presence of chemicals that act directly on nerw: endings or on chemical receptors unn elicit the pain rrsponse. The source of pain usually can be identified as: (11 pain frum skin or subcutaneous tissue (rissut: just helorv the n skeletal muscle: or (3) visceral pain (pain skin): .,121 .~ a i from from internal organs and systems). Although pain from-any of these sources may be relieved without recourse to medication, drugs are often the fastest and most sensible way of obtaining relief. Two types of analgesic drugs are recognized: those that act on the outer parts of the hody (peripherally), such as a local anesthetic, and those that act on the central nervous sy$tem and hrain irentrnlly), such as a general anesthetic. Nonnarcotic analgesics, such as aspirin and aretaminwhen, act primarily in the periphery; narcotic analgesics, such as morphine, ~~
~
A major portion of peripheral pain appears to result from the Dresence in tissues of higher than normal concentrations of hormones known as pros~glandins.Although prostaglandins are normal constituents of most tissues, any stimulation of or damage to cells or tissues results in the rapid synthesis of more ~rostaalandinmolecules, the appearance of higher concentr&ons i f these substances in thetissue, and the onset 332 1 Journal of Chemical Education
OH
;
AH
uil
bH
hH
bH
& ,,,, blHm & H
E
OH
AH
>
K;F ,,,,
OH
AH
OH
bH
Biochemical Roles
AS the formulas show, many kinds of prostaglandins are known. They possess a wide range of pharmacological propenies. Same of the effects they appear to facilitate indude: increasing permeability of capillary blood vessels, producing edema and inflammation -activation of pain receptors
-1owerino of blood oressure -reg" at on 01 body heat: nir alian of level - ohm toon of gastr c secret on -release of pituitary hormones -coagulation of blood platelets -contraction of soft muscle -induction of labor or abortion -facilitation of fertiliration
0 Fever and Its Reduction T h e temperature regulating center of the hody is located in the hypothalamus regi~mof the hrain. Thermoregolation isaccompliihed by rapi(l communication between the hyputhalamus and all parts of the hody. 'l'emperature-srnsiti\,e ncunmi in the skin and in uthrr b ~ d yparts constantly relay temperature information to the hypothalamus. Responding to this infurmution, the hypothalamus can initiate activity to conserve heat and to increase hrnl production, or to increase heat loss. T h e skin is the body's primary heat loss medium. Heat, carried by the hlood from internal structures to the body surface is lost to the surroundings by radiation, conduction, and evaooration. Heat oroduction can be increased bv increases in cellular metabolism, and by increased muscle ac. tivity and shivering. Heat loss can be minimized hy ernstricting the size of the capillary hlood vrssels and hv decreasing the rate of blood flow through them. Fevrr, the elevation of hody temprrature nlwve normal, is an ind~cationthat the body's defense have been overwhelmed hy bactrrlal or viral infection, or hy amditinni such as those caused 11sdrugs, dehydration, hrain tumor, or heat struke. In hncterial-caused fevers. toxins nruduced IIV the bacteria enter the blood and travel e;entualiy to the h{pothala&us where thev can cause an elevation in the body's temperature setpoint. As temperature rises, chills, shivering, and feeling of cold often are experienced. These are all manifestations of the mechanisms by which the body handles heat conservation and oroduction-vasoconstriction and skeletal muscle activity k i t h shivering. When prostaglandin EI is injected into the anterior hypothalamus or into cerebral ventricles, it produces fever almost immediately. In fact, this substance is the most powerful fever-wodocine" aeent known. The ereater the auantitv in" jected, the higher the temperature becomes. This suggests a mechanism for the antipwetic urouerties of asuirin. We know that a s p i r k moves into the hypbthalamus to produce its antipyretic effect. We also know that the presence of bacterial toxins in the hypothalamus can cause fever. Presumably the presence of toxins also initiates prostaglandin synthesis. The prostaglandins increase the body temperature even more. Therefore, if aspirin can inhibit the production of prostaglandins in the hyp&halamus, a t least one fever producing element will have been diminished, and the fever itself will he less intense.
Aspirin in Stroke Prevention Strokes usually result when blood VIOLS break loose from the walls of arteries carrying t)hx>dto the brain. These clots can
move on to block hlood flow in smaller hlood hrain, causing oxygen insufficiences. In a recent clinical study a group of patients who had histories of stroke and who tool four aspirin tablets a day suffered many fewer new stroke than a control group. Research studies indicate that aspirin inhibits clot forma tion in arteries by blocking synthesis of the prostaglandin that are involved in hlood coagulation processes. In health: persons who take occasional aspirin, this effect is temporap and usually harmless. In stroke-prone individuals, the fou tabletsfday regime could keep the clotting mechanism unde control. However, individuals with any history of peptic ulcen vitamin K deficiency, or hemophilia should avoid taking as pirin because it actually diminishes the blood's ability to forn clots.
Toxicity and Side Effects Although aspirin has a low toxicity, an overdose of 25-3! tablets (162 mg) can be lethal to a child 1-5 years old. Pro longed ingestion of relatively large doses can result in acido sis-the hlood becoming too acidic. Doses in the range of 9-2! (324 mg) tablets may cause ringing in the ears, dizziness, anc hilaterial hearing loss. These conditions usually disappea within a week after stopping use of the drug. Gastrointestinal disturbances with internal bleeding cal be a problem with aspirin. Approximately 5% of the individ uals who take two tablets complain of heartburn and dys pepsia. Of those who take two tablets three times daily, 705 show a daily hlood loss of 2-6 ml, and 10% show a loss of a! much as 10 ml. In healthy persons this loss is not clinicall! significant, hut for older persons and those with certain healt1 problems it could be important. Acetaminophen does no cause gastric bleeding or distress. Allergic reactions occur in 0.2-0.9% of those who take as pirin. These may he characterized by skin rash andlor respi ratory difficulty, edema, and shock. Aspirin hypersensitivit! occurs most frequently in individuals having a history of al lerg~cdisease, especially asthma. Approximately 3-5% o asthmatics exhibit this hypersensitivity. Acknowledgment The staff acknowledges with appreciation the assistana of Dr. Julius Kerkay in preparing this article. References "Handbook of Nonprescription Drugs." 5th Ed.. American Phsrmaceufieal Assaiafion 1977. Comaahis, Harold J.. "Consumer Health." Mmhy, St. Louis. 1978. Mslmon, K. L,and Morrelli, H. F., (Ediroml, "Clinical Phsmaeoloby."Maemillsn, Na, Y n k , 1972. Ferrein. S. H.. and vane. .l. R.."New A ~ p e e t a o f t h e M d e oAction f orNon.t.roid Antiin flemmstary Drugs," in "Annual Review of Pharmacology."11.57 (1974).
Volume 56, Number 5, May 1979 1 333
