Aspirin-like drugs and prostaglandins

x44

A nn0tati0n.s

The regres>ioll ec~~utions (l:iRy, 1 .~nd ‘1 1hll< 1~e.. diet---in thih region ~- th,lt the rate c,f new e\ cnt. ot CtiI) will incrdase with 0.12 per 1,000 .tnd 0.1 5 l,cr 1,000 for an increa>e of 1 mg. 1~ 100 ml. of ~.h~,le~terol and 0.01 mmole per liter of trikl) cerides. r~~~l~ectimely. Apl)lying thehe figllreh to the :Ibc>\e lnentioned \.allles of 19 mg. ,,er 100 1111. .mtl 0.50 mmole per liter they would correspond to an incre:che in the rate of ClIl) event5 of 2..< and 7.5, rehpecti5 c-1). or together 9.8 Iper 1,000. This v,dlte ;lrri\-ed at from calculations ubing regreb4on equatioll~, with \t,lti\tic,11 ah well as biological linlitations. is fairly clo-;e to the actual difference of 11 per l,Ol)O betseen the bottom and top hemoglobin quintile. Thul, hemoglobin ab a risk factor for CHI) might be explained not by the high hemoplobilt value it>elf hut t)l the fact that the plasma lipids are increa.sed as well. It should finally also be stressed that >o-~~lletl risk factors for Cl-II) to rl l‘lrge extent c.o\,ariate and are difficult to tre,tt a\ billgle phenomena. ..lh an example, we ,‘dn mention the erythrocyte bedimclltation rate (UK), tvhich w-ah found to be
Aspirin-like

drugs

and

The aspirin-like drugs are a diverse group of compounds, all of whirh possess, in some measure, the anti-pyretic, anti-inflammatory, and analgesic actions which are characteristic of aspirin. Aspirin itself was introduced into clinical medicine in the late 1890’s but decoctions of the bark or leaves of willow trees which contain derivatives of the parent compound (salicylic acid) ha\-e been valued for their medicinal properties for centuries;

I( I<, 1.. t.: I: E‘ N C t< 5 1.

1,

3.

LZ

S. _.

6.

7.

8.

9.

10.

11.

\\'. R., I),lwber, IZ. R., Ka~,in. :\., Revotskic N., alld Stokes, J.: I;actors of risk in the development of coronary heart diseasesix ye,lr follow-ul) esljerience, .111n. Int. Rled. 55:33, 1961. Carlson, I,. ,I., and I.indstedt, S.: The Stockholnl Prospective Study 1. The initial valrles for l)l;lsn~,~ lipids, Xcta Med. Scnnd. Suppl.:493, 1968. Bbttiger, 1.. E.. and Carlson, L. A.: The Stockholm Prospective Study. New events of coronary heart disease in men in relation to findings at initial examination. 9-year follow-up, Stockholm. 1972, Skandia International Symposium (In press) Carlson. I,. A.. and BGttieer. I,. E.: Ischaemic heart disease in relation “to’ fasting values of plasma triglycerides and cholesterol, Lancet i:865, 1972: Dawber. T. K.. and Kannel. \I’. B.: Suscentibility t, coronary disease, Riod. Concepts dardiovasc. Dis. 30:671, 1961. Biittiger, 1~. E., and Carlson, L. A.: Relation between serum cholesterol and triglyceride concentrations and haemoglobin values in nonanaemic healthy persons, Br. hled. J. 3:731, 1972. Elwood, I’. C., Mahler, R., Sweetman, P., Moore, F., and \Velsby, E.: Association between circulating haemoglobin level, serum-cholesterol and blood pressure, Lancet 1589, 1970. Biittiger, I,. E., and Svedberg, C. A.: Normal erythrocyte sedimentation rate and age, Br. Med. J, 2:85, 1967. Lees, K. S., Song, C. S., Levere, R. D., and Kappas, A.: Hyper-betalipoproteinemia in acute intermittent porphyria, N. Engl. J. Med. 282:432, 1970. BGttiger, L. E.: Erythrocyte sedimentation rate and plasma lipids, Acta Med. Stand. 193:53, 1973: BGttiger, L. E., Carlson, I.. A., and Olsson, A. C;. : Elevation of ervthrocvte sedimentation rate in asymptomatic iyperlipidemia, Br. Med. J. (In press, 1973) li.lllnel,

prostaglandins

“The leaves are bitter” reads one account, “and the Hottentots and the Xosns use them in rheumatic Yet despite their long history and widefever.“’ spread use (it is estimated that 4,000 million aspirin tablets are consumed each year in England alone), the question of how the aspirin-like drugs exerted their therapeutic effect remained unanswered. ,;\Ithough they were known to interfere with a wide variety of cellular enzymes, no convincing relation-

V&me Number

86 6

ship could be established between the experimental findings and the observed clinical actions. This situation changed in 1971 when a group of workers at the Royal College of Surgeons of England, led by J, R. Vane, discovered that aspirin-like drugs inhibited the biosynthesis of “prostaglandins.“‘-4 Prostaglandins are a family of long-chain fatty acids which possess an unusually wide spectrum of biological activity. The capacity for generating these extremely potent substances is apparently shared by all tissues of the bod,y, and at the time of this discovery there was some evidence suggesting that prostaglandins participated in the pathogenesis of fever and inflammation. Thus, as Vane pointed out, inhibition of prostaglandin synthesis might explain the mode of action of the aspirin-like drugs. Todav. _ almost two years later, all the available evidence supports this conclusion.5~6 Almost all the aspirin-like drugs have been found to inhibit the enzyme system which synthesizes prostaglandins (“prostaglandin synthetase”). The steroidal anti-inflammatory drugs and the narcotic which have some similar therapeutic analgesics, actions, are ineffective as are many other drugs which do not have any aspirin-like actions and this suggests that inhibition of prostaglandin synthesis is a property peculiar to this class of drugs. In man a single dose of salicylates or indomethacin is sufficient to reduce the synthesis of prostaglandins by an easily detectable amount, and treatment with “therapeutic doses” of these drugs for two or three days results in a very pronounced inhibition. There are several lines of evidence that point to the involvement of prostaglandins in inflammation: prostaglandins are found in inflammatory exudate and, if injected intradermally, reproduce many of the salient features of the inflammatory response. Furthermore, the “delayed” phase of inflammation, which is selectively suppressed by aspirin, is the phase in which prostaglandins appear. The relative therapeutic activity of several well known antiinflammatory drugs fits well with their anti-PG synthetase activity, and the concentrations required for inhibition are within the plasma levels achieved by these drugs during treatment. U:ith regard to the anti-pyretic activity of these drugs (a central action), prostaglandins have been detected in the CSF of cats during fever, and when this was reduced by the administration of aspirin-like drugs there was also a concomitant decrease in the concentration of prostaglandins. Conversely, when injected into the CSF of animals or systematically into man, prostaglandins cause a fever which is not blocked by aspirin-like drugs. The foregoing findings are consistent with the notion that the prostaglandins are causal agents in inflammation and fever, and thus inhibition of synthesis could adequately account for two of the three therapeutic effects of these compounds-but what of their analgesic activity? At first this was more difficult to accommodate within the theory. These drugs possess only a weak analgesic action and are only effective against certain types of low-intensity pain. It was known that prostaglandins were “painful” when injected into man and some animals, but only in much larger concentrations than would be likely to occur in tissues. However, when contin-

Annotations

845

uously infused subdermally in doses too small to cause overt pain, the prostaglandins caused a longlasting hyperalgesia-an increased sensitivity to mechanical stimulation as well as to other endogenous substances such as histamine or bradykinin. It seems from these studies that prostaglandins released, say, from the site of a local lesion could sensitize afferent pain fibers to other mechanical or chemical stimuli. Thus the analgesic action of the aspirin-like drugs could be attributed to the removal of this facilitating effect, and this would explain why aspirin is only a “weak” analgesic. The aspirin-like drugs have a number of unexplained side-effects such as gastric irritation, nephrotoxicity, and disturbances in collagen metabolism, and there are already several lines of evidence which link these effects with their anti-PG synthetase activity. For example, prostaglandins could be released from the gastric mucosa during the churning of the stomach contents after a meal, and since some of the prostaglandins are known to be inhibitors of gastric acid secretion, a negative feedback loop has been postulated which controls the pH of the gastric contents. If this loop were “broken” by the administration of prostaglandin synthesis inhibitors, acid secretion could increase, leading perhaps to irritation or erosion of the gastric mucosa, a side-effect often associated with these drugs. The discovery that the aspirin-like drugs inhibit prostaglandin synthesis has given the clinician an insight into the nature as well as the treatment of pain, fever, and inflammation-but it has also been of value to the physiologist who wishes to assess the function of the prostaglandins in the normal body, and also to the enzymologist who wishes to learn more about the mechanism of synthesis of these fatty acids. One apparent anomaly in the hypothesis has recently been resolved with interesting consequences; paracetamol (acetaminophen, APAP), an aspirinlike drug which has analgesic and antipyretic, but no anti-inflammatory actions, was inactive against the prostaglandin synthetase prepared from peripheral tissues such as skin or spleen, against which the standard drugs were active. Did it work by a different mechanism? The only alternative appeared to be that paracetamol exerted its actions only within the CNS. When a prostaglandin synthesizing system was prepared from brain tissue it was found that the drug was indeed very active against prostaglandin synthesis.’ This finding suggests that the enzymes responsible for prostaglnndin biosynthesis in the various tissues of the body may be differentially sensitive to inhibition by the nspirinlike drugs. It may even be possible to produce drugs of this type which have selective actions on certain organs or which are free from unwanted side-effects. In conclusion, it is pertinent to ask what relevance these findings have to cardiology. This is difficult to answer at the moment: prostaglandins have a positive inotropic effect on the myocardium of the isolated heart, and increase the cardiac output and coronary flow in man and animals. More than one study suggests that they may be involved in autoregulation of coronary blood flow.* At the time of writing, however, no disease condition has been

846

specifically production

Annotations

associated with by the heart.

Royal

abberant

prostaglnndiri

4.

R. J. Flower Department of Pharmacology College of Surgeons of England Lincoln’s Inn Fields London WCZA 3PN, England

REFERENCES 1. VVatt, J. M., and Breyer-Brandwijk, M. G.: The medicinal and poisonous plants of Southern Africa, Edinburgh, 1932, E. & S. Livingstone, Ltd. 2. Vane, J. R.: Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs, Nature New Biol. 231:232, 1971. 3. Smith, J. B., and \i:illis, A. I,.: Aspirin selectively inhibits prostaglandin production in human platelets, Nature New Biol. 231:235, 1971.

Surgical

versus

medical

coronary

heart

disease

management

Comparisons of the operative risks of medical and surgical management of ischemic heart disease are summarized in Table I. No surgeon will ever “top” the “surgical risks” of the cardiologists. Therefore, the evaluation of the surgical treatment is reduced to the answers to two questions, namely: 1. Vt;hat employed?

is the

survival

Table I. Comparisons heart disease

rate

when

surgery

of operative risks

I-‘erreira, S. H., lloncada, S., and \.arre, J. R.: Indomethacin and aspirin abolish prostaglandin release from the spleen, Nature New Biol. 231:237. 1971. 5. Vane, J. K.: Prostaglandins and the aspirin-like drugs, Hosp. Practice 7:61, 1972. 6. Vane, J. Ii.: Prostaglandins in the inhammatory response, ifz: “Inflammation, mechanisms and control.” Ed. by I. H. Lepow and P. A. \Vard. Academic Press Inc., New York and London, 1972. 7. Flower, K. J., and V,.ane, J. R.: Inhibition of prostaglandin synthesis in brain explains the anti-pyretic activity of paracetamol (I-acetamidophenol), Nature 240:110, 1972. 8. Karim, S. M. M., and Somers, K.: Cnrdiovascular and renal actions of prostaplandins, in Knrim, S. M. M., ed.: Prostaglandins, progress and research, Oxford and Lancaster, 1972, Medical and Technical Publishing Co., Ltd.

2. Do suffering,

of

the benefits of surgery and costs? If so, where

justify the risks, is the evidence?

George E. Burch, M.D. Department (If Medicine Tulane Unrversit>l School of Medicine 1430 Tulane Ave. New Orleans, La. 70112

is

of medical and surgical management of ischemic

Treatment

I Operative mortality Operative complications, early and late (myocardial hemorrhage, infection, thromboembolism, etc.) Total cost of operation Closure of shunt Cures Operative pain and suffering Operative psychic stress to patient and family Survival time

infarction,

Medical

Surgical 4 to 25 + 25’,b

Zero Zero

‘,i,

$8,000 to $35,000 25Oj, in 2 years Zero lOOo/, loo?;, Unknown

$

Zero Zero Zero Zero Zero Known