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Diuretics: much water under the bridge diuretics: Chemistry, pharmacology and medicine
T I P S - May 1984
208 could _,epresent the link between the ei~sanoid and immunological systems ~'2. Anaphylactoid reactions lhave been infrequently reported with alclofenac, aminopyrine, dipyrcne, ibuwofen, ketoprofen, mefenamic acid, sul~indac, tolmetin and zomepirac ~. With zomepirac the incidence of fatal cases was sufficiently high as ~o necessitate withdrawal of the drug recently. Not all hypersensitivity reactions from NSAI drugs may haw.' such untoward effects. A flu-like syndrome which develops in rheumatoid arthritic patients taking levamisole has some characteristics of a hypersensitivity reaction t. This has been shown by Veys and co-workers to be the consequences of drug-induced lympholysist. This appears to be a reflection of changes in the proportion of T-suppresso:/cytotoxic cells and is certainly associated with an improvement in the disea~ ~. Other side.effects Of the rarer side-effects, the occurrenc¢' of aplastic anaentia, agranuh,o,.'losis and related bha,d dyscrasias have been increasing most markedly, even in comparison with all d~e other advers,: drug reactions reported over the past decade or so. Reports of drug-induced aplastic anaemia have been declining with reduction in prescribing of the pyr~tzolones but are increasing due to increasing numbers of the new NSAI drugs ~-'. These potentially fatal conditions have been most frequently associated with benoxaprofen, fenciofenac, feprazone and especially with phenylbutazone and oxyphenylbutazone ~2. An abnormality in T-cell functions is fawmred at present as the cause of druginduced aplastic anaemia ~.2. The actions of NSAI drugs on bone marrow could be related to their propensity to accumulate in this tissue (as shown by autoradiography studies in rats) -~, .so there may be inherent risks of bone marrow abnormalities or depresI
sion with those drugs exhibiting long plasma half-lives and showing the capacity to accumulate in body o)mpartments as a consequence of inappropriate pre~ription of high do~-s "s. Amibodies against platelets develop during thrombocytt~paenia induced by acetylsalieylic acid, phenylbutazone and propylphenazone ,~:~ this implies that an immunolo#cal mechanism is involved in the pathogenesis of this condition t. Stevens,-Johnson syndrome, a particularly pernicious side-effect, manifest by inflammatory eruptions of the mucous membranes of the mouth, pharynx, anogenital region, and conjuctiva and which can be fatal, has been reported not infrequently with some of the new NSAI drugs (e.g. benoxaprofen, diflunisal, fenclofenac, fenbufen, feprazone, sulindac) 2. CNS effects are infrequent with most NSA' drugs, but the characteristic indometal: '1 headache is a notable exception 2. The new indene derivative of indometacin, sulindac, appea~ to have bee,-, successful in overcoming this side..effect2. Acetylsalicylic acid has been implicated as a cause of teratogenesis in man (especially i,n the first trimester of pregnancy) and ia high derses it can induce abnormalities in some laboratory species:. Other NSAI drugs may induce these effects. Both the CNS effects and the teratogenic actions of some NSAI drugs may in part be due to perturbations of the synthesis of vasoactive prostaglandins-'. Foetal toxic effects of salicylate may also be due to inhibition of mucopolysaccharide and RNA synthesis during critical stages of foetal growth 2. Conclusions It has only been possible here to briefly cover some salient aspects of the incidence and possible mechanisms involved in the development of the wide variety of ~dde-effects that occur with the NSAl/mmlgesic drugs. Recent reports in the lay press highlights their real
importance but it is necessary to carefully evaluate the role of drugs and clinical basis for the development of these disorders. Most especially there is also need for extensive laboratory investigations into the mechanisms of the development of these drug-induced sideeffects. Some side-effects could be simply prevented by more careful attention to drug dosage, patient compliance and avoiding prescription of drug mixtures. Intrinsic toxic properties of some drugs may be prevented but we are still at an early stage in understanding the mode of action of some NSA! analgesic drugs. Side-effects of NSAl/analgesic drugs are an unfortunate complication in the commercial life of drug companies. However, they need to be taken very seriously if the full potential of this useful class of compounds is to be realized. Reading list I Rainsford. K. D. and Velo. G. P. (edsl (1983)
Side-EffecL~ ~f Anti-hdlammatot3.:,4nalgesic Drags Raven Press, New York 2 Rainsford. K. D. Anti-in]lammmo~" Agent~ (Williamson. W. R. N.. ed.). MarcelI-Dckker. New York. (in press) 3 Pre~ott. L. F. 11979) Br. J. Clin. Phamzaeol. 7.
453--462 4 Nanra. R. S. (19811)Br. J. C/in. Phannacol. 111. 359S--368S 5 Rainsford, K. D.. Schweitzer, A. and Brune. K. 11981)Arch. hit. Pharmacodvn. Ther. 2511. 1811--194 6 Rainsford. K. D.. Schweitzer, A. and Brune. K. (1983) BhJchem. Pharmacol. 32. 13111-13118 7 Axelson. R. A. (1975) Br. J. Exp. PathoL 56, 92-97 8 Ne~,, R. 11971) Biochem. J. 122, 311-315 9 Mohandas. J., Duggan. G. G.. Hovath. J. S. and Tiller, D J. (1981) Toxieol. Appl. Pharmacol. 61,252-260 Kim Ramsford is currently a Senior Research Associate hi the Pharmacology Department at the Unit,ersity of Cambridge. He has" prevhntsly worked at Universities in Switzerland, Att~'tralia and m 1981--82 briefly in Zimbabwe. His research interests are on the mechanisms of the actions of anti-b~flammator3.' and antiparasitic drags.
1
Books Diuretics: much water under the bridge Diuretics: Chemistry. Pharmacology and Medicine edited by Edward J. Cragoe Jr, John Wiley and Sons, 1983. £71.20 (xx + 694 pages) I S B N 0 471 08366 6
it is now exactly 20 years since de
Stevens produced his classical monograph on diuretics, and even a cursory comparison of the present and previous volume is evidence enough of the trem,~:ndous advances that have been made in the last two decades.' de Stevens' book has a chapter on the thiazides in the 186 pages but no mention of frusemide (at one time the most important of drugs currently available), and relatively few references. Cragoe's work explodes
into 694 pages, quoting throughout the book no less than 2 153 references, a massive work by any standard, and perhaps a surprise to those pharmacologists who instinctively feel that diuretics are not in the main line of research. The current authors obviously have no such inhibitions, indeed they make some bold claims such as, 'These two comp o u n d s . . , have had a dramatic effect on human longevity and the quality of
T I P S - May 1984
2119
A l l t h e y s t o l e w a s tt, e h o o k
life that is as profound in a subtle way as any drug discovered in this century'. The two drugs are chlorothiazide and hydrochlorothiazide! The text is presented in 12 chapters. the most interesting and readable parts (at least t o t h e pharmacologist) appearing at the beginning and the end. Following the introduction, where the editor outlines the historical development of renal physiology and pharmacology and discusses new areas for exploration. comes a chapter on the basic principles of renal physiology and pharmacology.
. . .
In 30 pages it provides an up-to-date and useful outline fl~r those wishing to become initiated in the field. The body of the book consists of nine chapters described as a "complete account of the compounds that pos~ss diuretic activity" and these are classified according to chemical structure. Indeed there are dozens of tables listing the activity of hundreds of structural analogues of known, new and abandoned diuretics: for example there are no less than 257 analogues of frusemide listed. However. should the reader wish to learn the basic
pharmacology of bumetanide (a relatively new drug. not vet well covered in the basic pharmacology texts, but imFawtant clinically) one reads that. "The pharmacology of bumetanide (Burincxl has bee1: reviewed IRefs) and is. Ior all practical purl~.~s, analogous to furosemidC. No doubt the medicinal chemistrv is reviewed elsewhere too. it neverthelcss features strongly, and .~ should at leas! the basic pharmacology of all the clinically useful drugs in a work of this size and importance. The tweltlh chapter is a gem. however. Itere Dr Smith discus.~s endogenous agents affecting kidney function and the ~ell-rel;:renced sections on antidiuretic hormone, the renin-angiotensin-aldosteronc ,~vstem. kinins, prostaglandins and natriurctic hormone are a delight to read The book is said to be designed to be of interest to the medicinal chemist, the renal pharmacologist and ph.~siologist and the physician, and it is to I~~texpected that the ranking of interest will be the same. Unfortunatel,,. ;it £72.2~ not too many will be able to afford a personal copy: there are 21t ,,ears" more ssork but the volume is 25 times as expensixc a~, de Stevens" effort which costs 5t~ shilhngs. .I.M. T]IC t l t H h o r l~ (]lolrrpll2tt I,'rtlthtatt" [:ntrerwtv.
.~tltdlt'~
ttl
Bradt,,rd.
1"( ~
,~t tiff" .~tJt,~,'[ ,~t I ~ , , l -
Pll,lrtrl~lt'~ i/t lk'~. ,i[ Br~tdtl,¢,J [ K
Pharmacological safari Reviews of Physiology. Biochemistry and Pharmacology: Vol. 96
edited by R. H. Adrian, H. Zur Hausen, E. Hehnreich. H. HoLzer, R. Jung, O, Krayer, R.J. Lb~den, P. A. Mh'scher, J. P@er, H. Rasmussen, U. Trendelenburg, K. Ullrwh, W. Vogt and A. Webber, Springer-Verlag, 1983. DM 94/ US$37.60 (iv + 194 pages) ISBN 3 540 11849 7 This book continues the ,~eries of Springer-Verlag reviews that have been so well received in the past. As usual it is beautifully produced with clear print and well thought out tables and figures. There are three subjects. The first by Murer and Burckhardt phmges with great confidence and enormous, erudition into the tiger country of "Membrane Transport of Anions across Epithelia of the Small Intestine and Proximal Tubule'. The authors to my mind emerge unscathed and with enhanced reputations from this difficult safari. Reading the review reminded me once again of
the rapid pace of m o d e m discovery (,lot badly one needs a review of this kind to many of the references relate to the clarify an almost impossible situation. years prior to the seventies), how ~.x~m- Condensation and clarification are the plex the literature has become and how names of the game. For the non-expert
208 could _,epresent the link between the ei~sanoid and immunological systems ~'2. Anaphylactoid reactions lhave been infrequently reported with alclofenac, aminopyrine, dipyrcne, ibuwofen, ketoprofen, mefenamic acid, sul~indac, tolmetin and zomepirac ~. With zomepirac the incidence of fatal cases was sufficiently high as ~o necessitate withdrawal of the drug recently. Not all hypersensitivity reactions from NSAI drugs may haw.' such untoward effects. A flu-like syndrome which develops in rheumatoid arthritic patients taking levamisole has some characteristics of a hypersensitivity reaction t. This has been shown by Veys and co-workers to be the consequences of drug-induced lympholysist. This appears to be a reflection of changes in the proportion of T-suppresso:/cytotoxic cells and is certainly associated with an improvement in the disea~ ~. Other side.effects Of the rarer side-effects, the occurrenc¢' of aplastic anaentia, agranuh,o,.'losis and related bha,d dyscrasias have been increasing most markedly, even in comparison with all d~e other advers,: drug reactions reported over the past decade or so. Reports of drug-induced aplastic anaemia have been declining with reduction in prescribing of the pyr~tzolones but are increasing due to increasing numbers of the new NSAI drugs ~-'. These potentially fatal conditions have been most frequently associated with benoxaprofen, fenciofenac, feprazone and especially with phenylbutazone and oxyphenylbutazone ~2. An abnormality in T-cell functions is fawmred at present as the cause of druginduced aplastic anaemia ~.2. The actions of NSAI drugs on bone marrow could be related to their propensity to accumulate in this tissue (as shown by autoradiography studies in rats) -~, .so there may be inherent risks of bone marrow abnormalities or depresI
sion with those drugs exhibiting long plasma half-lives and showing the capacity to accumulate in body o)mpartments as a consequence of inappropriate pre~ription of high do~-s "s. Amibodies against platelets develop during thrombocytt~paenia induced by acetylsalieylic acid, phenylbutazone and propylphenazone ,~:~ this implies that an immunolo#cal mechanism is involved in the pathogenesis of this condition t. Stevens,-Johnson syndrome, a particularly pernicious side-effect, manifest by inflammatory eruptions of the mucous membranes of the mouth, pharynx, anogenital region, and conjuctiva and which can be fatal, has been reported not infrequently with some of the new NSAI drugs (e.g. benoxaprofen, diflunisal, fenclofenac, fenbufen, feprazone, sulindac) 2. CNS effects are infrequent with most NSA' drugs, but the characteristic indometal: '1 headache is a notable exception 2. The new indene derivative of indometacin, sulindac, appea~ to have bee,-, successful in overcoming this side..effect2. Acetylsalicylic acid has been implicated as a cause of teratogenesis in man (especially i,n the first trimester of pregnancy) and ia high derses it can induce abnormalities in some laboratory species:. Other NSAI drugs may induce these effects. Both the CNS effects and the teratogenic actions of some NSAI drugs may in part be due to perturbations of the synthesis of vasoactive prostaglandins-'. Foetal toxic effects of salicylate may also be due to inhibition of mucopolysaccharide and RNA synthesis during critical stages of foetal growth 2. Conclusions It has only been possible here to briefly cover some salient aspects of the incidence and possible mechanisms involved in the development of the wide variety of ~dde-effects that occur with the NSAl/mmlgesic drugs. Recent reports in the lay press highlights their real
importance but it is necessary to carefully evaluate the role of drugs and clinical basis for the development of these disorders. Most especially there is also need for extensive laboratory investigations into the mechanisms of the development of these drug-induced sideeffects. Some side-effects could be simply prevented by more careful attention to drug dosage, patient compliance and avoiding prescription of drug mixtures. Intrinsic toxic properties of some drugs may be prevented but we are still at an early stage in understanding the mode of action of some NSA! analgesic drugs. Side-effects of NSAl/analgesic drugs are an unfortunate complication in the commercial life of drug companies. However, they need to be taken very seriously if the full potential of this useful class of compounds is to be realized. Reading list I Rainsford. K. D. and Velo. G. P. (edsl (1983)
Side-EffecL~ ~f Anti-hdlammatot3.:,4nalgesic Drags Raven Press, New York 2 Rainsford. K. D. Anti-in]lammmo~" Agent~ (Williamson. W. R. N.. ed.). MarcelI-Dckker. New York. (in press) 3 Pre~ott. L. F. 11979) Br. J. Clin. Phamzaeol. 7.
453--462 4 Nanra. R. S. (19811)Br. J. C/in. Phannacol. 111. 359S--368S 5 Rainsford, K. D.. Schweitzer, A. and Brune. K. 11981)Arch. hit. Pharmacodvn. Ther. 2511. 1811--194 6 Rainsford. K. D.. Schweitzer, A. and Brune. K. (1983) BhJchem. Pharmacol. 32. 13111-13118 7 Axelson. R. A. (1975) Br. J. Exp. PathoL 56, 92-97 8 Ne~,, R. 11971) Biochem. J. 122, 311-315 9 Mohandas. J., Duggan. G. G.. Hovath. J. S. and Tiller, D J. (1981) Toxieol. Appl. Pharmacol. 61,252-260 Kim Ramsford is currently a Senior Research Associate hi the Pharmacology Department at the Unit,ersity of Cambridge. He has" prevhntsly worked at Universities in Switzerland, Att~'tralia and m 1981--82 briefly in Zimbabwe. His research interests are on the mechanisms of the actions of anti-b~flammator3.' and antiparasitic drags.
1
Books Diuretics: much water under the bridge Diuretics: Chemistry. Pharmacology and Medicine edited by Edward J. Cragoe Jr, John Wiley and Sons, 1983. £71.20 (xx + 694 pages) I S B N 0 471 08366 6
it is now exactly 20 years since de
Stevens produced his classical monograph on diuretics, and even a cursory comparison of the present and previous volume is evidence enough of the trem,~:ndous advances that have been made in the last two decades.' de Stevens' book has a chapter on the thiazides in the 186 pages but no mention of frusemide (at one time the most important of drugs currently available), and relatively few references. Cragoe's work explodes
into 694 pages, quoting throughout the book no less than 2 153 references, a massive work by any standard, and perhaps a surprise to those pharmacologists who instinctively feel that diuretics are not in the main line of research. The current authors obviously have no such inhibitions, indeed they make some bold claims such as, 'These two comp o u n d s . . , have had a dramatic effect on human longevity and the quality of
T I P S - May 1984
2119
A l l t h e y s t o l e w a s tt, e h o o k
life that is as profound in a subtle way as any drug discovered in this century'. The two drugs are chlorothiazide and hydrochlorothiazide! The text is presented in 12 chapters. the most interesting and readable parts (at least t o t h e pharmacologist) appearing at the beginning and the end. Following the introduction, where the editor outlines the historical development of renal physiology and pharmacology and discusses new areas for exploration. comes a chapter on the basic principles of renal physiology and pharmacology.
. . .
In 30 pages it provides an up-to-date and useful outline fl~r those wishing to become initiated in the field. The body of the book consists of nine chapters described as a "complete account of the compounds that pos~ss diuretic activity" and these are classified according to chemical structure. Indeed there are dozens of tables listing the activity of hundreds of structural analogues of known, new and abandoned diuretics: for example there are no less than 257 analogues of frusemide listed. However. should the reader wish to learn the basic
pharmacology of bumetanide (a relatively new drug. not vet well covered in the basic pharmacology texts, but imFawtant clinically) one reads that. "The pharmacology of bumetanide (Burincxl has bee1: reviewed IRefs) and is. Ior all practical purl~.~s, analogous to furosemidC. No doubt the medicinal chemistrv is reviewed elsewhere too. it neverthelcss features strongly, and .~ should at leas! the basic pharmacology of all the clinically useful drugs in a work of this size and importance. The tweltlh chapter is a gem. however. Itere Dr Smith discus.~s endogenous agents affecting kidney function and the ~ell-rel;:renced sections on antidiuretic hormone, the renin-angiotensin-aldosteronc ,~vstem. kinins, prostaglandins and natriurctic hormone are a delight to read The book is said to be designed to be of interest to the medicinal chemist, the renal pharmacologist and ph.~siologist and the physician, and it is to I~~texpected that the ranking of interest will be the same. Unfortunatel,,. ;it £72.2~ not too many will be able to afford a personal copy: there are 21t ,,ears" more ssork but the volume is 25 times as expensixc a~, de Stevens" effort which costs 5t~ shilhngs. .I.M. T]IC t l t H h o r l~ (]lolrrpll2tt I,'rtlthtatt" [:ntrerwtv.
.~tltdlt'~
ttl
Bradt,,rd.
1"( ~
,~t tiff" .~tJt,~,'[ ,~t I ~ , , l -
Pll,lrtrl~lt'~ i/t lk'~. ,i[ Br~tdtl,¢,J [ K
Pharmacological safari Reviews of Physiology. Biochemistry and Pharmacology: Vol. 96
edited by R. H. Adrian, H. Zur Hausen, E. Hehnreich. H. HoLzer, R. Jung, O, Krayer, R.J. Lb~den, P. A. Mh'scher, J. P@er, H. Rasmussen, U. Trendelenburg, K. Ullrwh, W. Vogt and A. Webber, Springer-Verlag, 1983. DM 94/ US$37.60 (iv + 194 pages) ISBN 3 540 11849 7 This book continues the ,~eries of Springer-Verlag reviews that have been so well received in the past. As usual it is beautifully produced with clear print and well thought out tables and figures. There are three subjects. The first by Murer and Burckhardt phmges with great confidence and enormous, erudition into the tiger country of "Membrane Transport of Anions across Epithelia of the Small Intestine and Proximal Tubule'. The authors to my mind emerge unscathed and with enhanced reputations from this difficult safari. Reading the review reminded me once again of
the rapid pace of m o d e m discovery (,lot badly one needs a review of this kind to many of the references relate to the clarify an almost impossible situation. years prior to the seventies), how ~.x~m- Condensation and clarification are the plex the literature has become and how names of the game. For the non-expert