Acta Dermatoven APA Vol 12, 2003, No 4 143KEY WORDSBackground. An unwarranted increase in the prescription and intake of drugs can be observed in the developed countries. The data on the incidence of adverse drug events is not reliable, but estimated tobe close to 10%. Most drug eruptions affect the skin and are not life-threatening, but some veryserious adverse drug events also occur. The cost of the drugs themselves, as well as the treatments,are becoming a burden on both insurance company and state budgets. Underlying causes of the excessive use of drugs. Information about drug usage may be partially biased. One effect of intensive and costly research has been to increase the supply of drugs. Articlesin the popular press, advertising and also the sponsorship of congresses and symposia by drug manufacturers may also be seen as contributing to the awareness of and excessive use of drugs. Those involved in the misuse of drugs are frequently those most highly affected by the stress ofmodern life, psychopathic personalities, and drug addicts. Mechanisms by which adverse drug events are provoked. Allergic, non-allergic and pharmaco- genetic mechanisms as well as drug overuse, toxic effects and the incompatibility of different drugstaken together are the most frequent trigger factors. Means by which the number of adverse drug events may be reduced. Adverse drug events may be reduced given the dissemination of correct information, through controlled clinical studies, througha strict editorial policy by the editors of medical journals, through an epidemiological approach to thephenomenon of adverse drug events, through pharmacogenetic studies, through appropriate reactionto biased data, and through general education in the sense of making the patient more aware and more careful of their psychic and physical condition.Excessive use of drugs and adverse events Epidemiologic and pathogenetic aspects A. Kansky drug eruptions, adverse drug events, biased information, provoking mechanisms, allergic, non-allergic, pharmaco- genetics, epidemiology, fostering factors, prevention, recreation facilitiesABSTRACT Introduction Excessive use of drugs presents itself as a major con- temporary problem in the developed countries. Manypeople see their doctor or are even admitted to hospi-tal because of adverse drug reactions (ADR). Some authors prefer the term adverse drug events (ADE) tak- ing the latter expression to include both adverse drugreactions and various other toxic phenomena. Skinmanifestations triggered by drugs are frequent, and are generally referred to in dermatological literature as drugR e v i e w Excessive use of drugs and adverse events Acta Dermatoven APA Vol 12, 2003, No 4 145eruptions . The offending drugs have either been pre- scribed by medical professionals, are available over-the- counter, or have been obtained through individual ini-tiative. The incidence of ADEs is estimated at 10-20% (1,2), but the information is incomplete, even in the devel-oped countries. This dearth of adequate documenta- tion is due to the lack of time of doctors, the lack of suitable questionnaires, and also due to diagnoses thathave not been confirmed by laboratory tests as well asfor fear of possible litigation. Years ago, interested per-sons started to collect data on ADEs on their own initia-tive; in the present situation, however, the problem is dealt with in many countries by professional groups and official institutions.Table1. Different methods have been employed for the collection of data, and they share different advantagesand disadvantages. The most efficient is the so-calledintensive system, which has enabled the detection of up to 100% of ADE cases. Unfortunately only small groups of patients can be studied in this way (3,4). Another big problem created by the extensive use of drugs is the high cost to the budgets of both statesand health insurance companies. According to a reportbased on a hypothetical cohort of ambulatory patients, the overall cost of drug related morbidity and mortal- ity in the USA was estimated at $177 billion for the year 2000 (3). Underlying causes of theexcessive use of drugs Advances in biochemistry, immunology, molecular biology and other basic sciences offer unprecedentedopportunities to both scientists and their employers todevelop new drugs. The high cost of introducing newmeans of preparing drugs, when considered as a com-mercial proposition within a highly competative mar- ket, have forced both companies and all the subjects involved to market such products as soon as possible.To illustrate this tendency I would like to cite the cur-rent trends in the systemic treatment of psoriasis. Immunosuppressive treatments including meto- threxate, hydroxyurea, cyclosporin, mycophenolic acid,6-thioguanine and even pimecrolimus are familiar todermatologists, and the same can be said for metabolicpreparations like psoralens, acitretin and 13-cis retinoicacid (5,6,7). A series of new biological and immunologi- cal substances which suppress inflammation have been introduced (8). Alefacept inhibits the release of inflam- matory cytokines from CD4 and CD8 effector cells (9),efalizumab interferes with the lymphocyte function associated antigen 1 (LFA-1) and thus inhibits bindingwith the ligand intercellular adhesion molecule-1 (ICAM- 1) (10). Etanercept (11), a human dimeric fusion pro- tein, blocks the receptors for the tumor necrosis factorα (TNF α). Infliximab (12) is a chimeric antibody com- posed of a murine variable and a human constant partof IgG 1/ α that binds to TNF molecules. There are re- ports on 16 cases of ADEs after infusions of infliximab (13). A number of further substances like adalimuab, baxaroten, onercept, simulect or zorcell (IR 502) areeither in development or already entering the market.At the moment it is not possible to foresee the eventuallong range ADEs that will involve the lymphatic sys-tem. A further and compelling reason for the overuse of drugs must be attributed to the attitude of a consumer society and the suggestibility that prevails among the general population. Unstable persons, hypochondriacs,neurotics and maniacs and also a substantial number ofotherwise normal people believe that drugs can solve their problems. The high level of stress in everyday life in the developed countries is responsible for a numberof psychosomatic disorders like hypertension, gastriculcers and psoriasis among others. A part of the responsibility for this must lie with phar- maceutical companies that employ sophisticated pro- paganda and advertising, as well as with those mem- bers of the medical profession who succumb to such publicity. It must be admitted that pharmaceutical com- panies are the major sponsors of medical books andperiodicals, and of congresses and symposia as well asfor supporting participants and speakers at such gath-Table 1. Listed are professional groups or bodies collecting epidemiologic data on drug eruptions. Adverse Reaction Collaborating Centre WHO Upsala Yellow Card Reporting System United Kingdom Pharmacovigilance France Adverse Drug Reaction Reporting System Food and drug Administration USAAdverse Drug Reaction Reporting System Amer Acad Dermatol Gruppo Italiano Studii Epidemiologici in Dermatologia Italy Reporting Systems by Pharmaceutical Companies Various National SchemesR e v i e w Excessive use of drugs and adverse events 146 Acta Dermatoven APA Vol 12, 2003, No 4erings. Undoubtedly they make valuable contributions to the level of medical and biological education and tothe exchange of ideas, but through this generosity theyacquire for themselves ample opportunity to promote their own interest and what must be seen as one-sided information. And finally, any such partial or even biased informa- tion on health problems and drugs is disseminatedthrough newspapers, magazines and various periodi-cals. As a general rule, people prefer to read articles on medical topics that have been prepared by non-profe- ssionals: it makes for interesting and easier reading, butit is often over-simplified and not exact. Mechanisms of adverse drugevents It is widely known that the majority of ADEs are of allergic origin . Specially in acute allergic ADEs the IgE attached to mastocytes play a crucial role. There arereliable tests for the assessment of total as well as ofcertain specific IgE. On the other hand, the IgG maybind to the antigen and thus inhibit the allergic r eaction. The cellular response (delayed type response) seems to play a major role in cutaneous ADRs ( drug eruptions ). T lymphocytes, receptors, mediators, interleukines, signal-ling and transcription molecules are the main factors. Onthe molecular level these events are highly com plicated. Toxic (nonallergic) ADEs are provoked by the di- rect toxic action of a drug or its metabolite primarily on enzymes, but also on the other above-mentioned fac-tors. They are mainly provoked by a dose of the drugthat is excessive, or a genetically deficient enzyme. Photoallegic and phototoxic ADE represent another category of side effects (15).Genetically induced ADEs are usually severe and even life-threatening, and research in molecular biol-ogy deserves credit for the two new fields that havebeen introduced. Pharmacogenetics , which deals with DNA mutations and their influence on the expression of enzymes, transporting molecules, receptors and fur-ther factors, and pharmacogenomics, which is con- cerned with investigation to which extent such phar-macogenetic changes influence the pharmacodynam-ics and pharmacokinetics of drugs. The following examples may be helpful for a better understanding of the problem. In persons affected by deficient enzymes of por- phyrin synthesis, drugs or substances like barbiturates,estrogens, alcohol or lead induce porphyria. The dis- ease type itself depends on the enzyme involved. For example, deficient ferrochelatase causes erythropoi- etic protoporphyria (15,16,17). Diaminodiphenylsulfon(dapson) triggers methemoglobinemia in patients de-ficient in glucose-6-phosphate dehydrogenase activity(18). Table 2. Familial hypercholesterolemia is causedby hyperproduction of choleesterol and the inability to synthesize LDL receptors. Statins inhibit the enzyme β- hydroxy- β-methyl coenzyme A reductase and indirectly increase the number of hepatic LDL receptors. Unfor-tunately, in such cases, severe ADEs like myopathy orrabdomyolysis may develop (19). Antipsychotics usedin psychoses and psychoneuroses may provoke ADEs in certain patients (20). Acute allergic ADRs may ap- pear even during treatment with cytostatics like epiru-bicin (21) or carboplatin (22). Transporter protein likeMDR1 is a glycoprotein involved in drug resistance oftumor cells and confers intrinsic resistance to tissues byexporting toxic exogenous substances. Genotyping of MDR1 may become important in the future indivi- dualized pharmacotherapy (23). ADEs occur relatively frequently after the intake ofTable 2. Drug reactions in persons with genetic deficiencies, triggered by drugs. Disease Deficient enzymes or proteins Incriminated drug lupus erythematosus slow acetilation procainamid (arrhythmia) hydralazin (hypertension) hemolysis glucose 6 phosphate aspirin, antimalarials, sulfonamides, dapson, dehydrogenase vicia fava, nitrofurantoin methemoglobinemia pathologic Hb (HbM) nitrates, nitrites, aniline, sulfonamide, antimalarials, dapson porphyriae, various types ↑ ALA synthetase, ↓ ferro-chelatase, barbiturates, alcohol, chloroquine, estrogens ↓ PBG deami-nase, ↓ UPG decarboxylase apnoe, suxamethonium sensitivity deficient pseudocholin-esterase suxamethonium ALA delta aminolevulinic acid PBG porphobilinogenUPG uroporphyrinogenExcessive use of drugs and adverse events R e v i e w Acta Dermatoven APA Vol 12, 2003, No 4 147analgesics or nonsteroid anti-inflammatory drugs. They range from benign exanthematous drug eruptions tolife-threatening toxic ADEs. Paracetamol (acetami- nophen ) in a dose of 0.5-1.0 gram up to 4 times daily, has analgesic, antipyretic and weak anti-inflammatoryeffects. It may be given alone or in combination with another analgesic, often with aspirin or codein (24). Acute allergic ADRs (25), and also sever hepatocellu-lar necrosis and granulomatous lesions have been re-ported, and caused by higher dosages or prolongedintake (26). Diagnostic possibilities Great efforts have been made to devise tests suit- able for the detection of the drug held responsible for causing the ADR, but unfortunately the majority of theseare not precise enough. Positive total and specific IgEtests strongly support the diagnosis of allergic ADR,while a number of toxic ADEs caused by genetic defi-ciency can be confirmed by biochemical tests. Intrader- mal and scratch tests with drugs are potentially danger- ous and many doctors try to avoid them, in which casespatch testing may be sometimes useful (27). Immuno-genetic tests are mostly highly complicated and still inthe stage of development. In view of such diagnostic difficulties the epidemio- logic approach is favored by many clinicians. Data on ADEs are collected and ordered according to the clini-cal manifestation or according to the drug that is heldresponsible. Useful data, that is suitable for clinical workmay be found in manuals such as the short and practicalwork by Bruinsma (28) or the more extensive study by Litt (29).Diagnostic algorithms have been proposed in the attempt to verify the offending drug. The basis of such an approach is to have made a sufficiently large collec-tion of epidemiologic data on ADEs including patients’histories, drugs found responsible, and types and gradesof the ADEs observed. A special questionnaire has to beprepared, and data on those patients suspected to be affected with an ADE entered. On the basis of the score yeilded by the questionnaire it would be possible tomake a decision concerning the suspected drug. Table3. An example of the application of the Naranjo ADR probability scale score (30) is shown in the study done by Hafner (4). Among 13004 patients of an emergency department involved in the study, 321 were screenedfor a possible ADR, and in 217 of them the score of >4was obtained, in effect supporting the diagnosis. Thestudy revealed that the most frequent offending drugwas insulin , followed by the anticoagulant warfarin , diuretic furosemid , various chemotherapeutics and by other drugs. The global index of safety (GIS) is a further algo- rithm which allows for the comparison of the relativesafety of two or more drugs. Symptoms observed inpatients are graded, entered in a special questionnaire, scored and the GIS was calculated therefrom. Sacristan et al investigated antipsychotics and found that olanza- pin caused less ADRs than riperidon or haloperidol (31). Means by which the number of adversedrug events may be reduced In developed countries a number of safety regula- tions have been implemented to keep the number ofADEs at a relatively low level: preclinical and clinicalTable 3. Naranjo Adverse Drug Reaction Probability Score. Clin Pharmacol Ther 1981: 30: 239-45 Questions Yes n o unsure Previous conclusive reports on this reaction +1 0 0 Did ADR appear after the drug was administered +2 -1 0 Did ADR improve when the drug was discontinued or a specific antagonist was given +1 0 0 ADR appearance after drug readministration +2 -1 0 Are there alternative causes other than the incriminated drug -1 +2 0 Did ADR appear after placebo -1 +1 0Drug detected in blood (fluids) in toxic concentration +1 0 0 ADR more severe with large dose, less severe with small dose +1 0 0 Similar ADR to same or similar drug in past exposure +1 0 0 ADR confirmed by objective evidence +1 0 0 Total score ADR probability scale score: 0 – doubtful, 1 – 4 possible, 5 –8 probable, >9 definiteR e v i e w Excessive use of drugs and adverse events 148 Acta Dermatoven APA Vol 12, 2003, No 4studies, the registration of drugs, the insertion of guide- lines into drug packaging, the institutional monitoring of ADEs and others. In view of the fact that that ADEsmay become evident only years after a drug has beenused, postmarketing surveillance of ADEs is suggested. Clinical studies including patients have to be approvedby an ethical commission. Editors of medical journals are supposed to accept for publication only clinical stud- ies in which patients were selected randomly, studiesthat include a reasonable number of patients and con-trol persons and that have been statistically evaluated.All authors are required to declare their financial inter-ests. In cases where ADEs are suspected the necessary tests on patients have to be done. ADEs may also be reduced by means of the intro- duction of personalized medicine, which anticipates the screening of patients for immunologic and meta-bolic incompatibilities, prior to the drug intake. This kindof policy foresees the introduction of new sophisticated tests, especially in the field of immunogenetics, like DNA microarrays or DNA chips (30,31). To educate and warn the general population not to use drugs indiscriminately, is important. Editors of news-papers and magazines should be asked to publish only reliable information on drugs. Any biased or incorrect information must be able to be identified and coun-tered immediately by a competent authority. Peoplehave to be encouraged to try to solve minor health prob-lems by adopting adequate habits or by exercising. Thebodies planning new settlements should foresee sport and recreation facilities. And a certain degree of respon- sibility must lie with the authorities and politicians. Conclusion The problem of overuse of drugs and ADEs is a sub- stantial and complex issue, and it is difficult to find anadequate solution. The primary responsibility to com-bat ADEs must lie with health authorities and drug com-panies. New fields of research such as the epidemiol- ogy of ADEs, pharmacogenetics and pharmacovigilance are expected to play an essential role in controllingADEs. The role of the medical profession itself can onlybe limited, the essential emphasis being to educatepatients and the general population. 1. Parish WE, Breatnah SM. Clinical Immunology and Allergology. V Rook A et al. Textbook of Dermatology, 6 th ed, Champion RH et al eds, Blackwell, Oxford,1998: 277-336. 2. Braun Falco O, Plewig G, Wolf HH, Burgdorf WHC. Dermatology 2nd ed Berlin, Springer 2000: 403-33. 3. Ernst FR, Grizzle AJ. Drug related morbidity and mortality: updating the cost of illness model. J Am Pharm Assoc (Wash) 2001; 41(2): 192-9. 4. Krebs S, Dorman H, Hahn EG et al. Unerwünschte Arzneimittelwirkungen. Dtsch Med Wschr 2000; 125: 984-7. 5. Hafner JW, Belknap SM, Squillante MD et al. Adverse drug events in emergency department patients. Annals Emergency Medicine 2002; 38 (3): 258-67. 6. Menter AM, Krueger GC, Feldman SR, Weinstein GD. Psoriasis treatment at the new millenium. J Am Acad Dermatol 2993; 49, Suppl S39-44. 7. Yamauchi PS, Rizk D, Kormeili T et al. Current systemic therapies for psoriasis. Where are we now. Ibidem S66-77. 8. Gupta AK, Chow M. Pimecrolimus: a review. J Eur Acad Dermatol Venereol 2003; 17(5): 493-403. 9. Mehlis SL, Gordon KB. Immunology of psoriasis and biologic immunotherapy. Ibidem S44-50. 10. Krueger GG, Callis KP . Development and use of alefacept in treatment of psoriasis. Ibidem S87-97. 11. Leonardi CI. Efalizumab: An overview. Ibidem S98-104. 12. Goffe B, Cather C. Etanercept: An overview. Ibidem S105-111. 13. Gottlieb AB. Infliximab for psoriasis. Ibidem S112-17. 14. Cheifetz A, Smedley M, Martin S et al. The incidence and management of infusion reactions to infliximab: a large center experiences. Am J Gastroenterol 2003; 98(6), 1315 –24. 15. Kansky A. Fotodermatoze. V Kansky A. in sod. Ko`ne in spolne bolezni. Zdru`enje slovenskih dermatologov, Ljubljana, 2002. 16. Kansky A, Gregorc J, Pavli~ M. Oral contraceptives and their influence on porphyrin concentration in erythrocytes and urine. Dermatologica 1978; 157: 181-5.R E F E R E N C E SExcessive use of drugs and adverse events R e v i e w 150 Acta Dermatoven APA Vol 12, 2003, No 417. Gross U, Hoffmann GF, Doss MO. Erythropoietic and hepatic porphyrias. J Inherit Metab Dis 2000; 23: 641-61. 18. Ritter MJ, Lewis LD, Mant TGK. Pharmacogenetics. In: A Textbook of Clinical Pharmacology, Arnold, London, 1999: 108-18. 19. Schmitz G, Drobnik W. Pharmacogenomics and pharmacogenetics of cholesterol-lowering therapy. Clin Chem Lab Med 2003; 41(4): 581-9. 20. Collier DA. Pharmacogenetics in psychosis. Drug News Perspect 2003; 16(3): 159-65. 21. Oltmans R, van der Vegt SG. Serious allergic reaction to administration of epirubicin. Neth J Med 2003; 61(6): 226-7. 22. Ottaiano A, Tambaro R, Greggi S et al. Safety to cisplatin after severe hypersensitivity reaction to carboplatin in patients with recurrent ovarian carcinoma. Anticancer Res 2003; 23(4): 3465-8. 23. Sakaeda T, Nakamura T, Okumura K. Pharmacogenetics of MDR1 and its impact on pharmacoki- netics and pharmacodynamics of drugs. Pharmacogenomics 2003; 4(4): 397-410. 24. Martindale, Reynolds JEF editor. Pharmaceutical Press; 36th ed, London 2002. Analgesics/ Paracetamol: 72-5. 25. Van Diem L, Grilliat JP . Anaphylactic shock induced by paracetamol. Eur J Clin Pharmacol 1990; 38: 389-90. 26. Lindgren A, Aldenborg F , Norkrans G et al. Paracetamol-induced cholestatic and granulomatous liver injuries. J Intern Med 1997; 241(5): 1997. 27. Mesec A, Rut U, Perkovi~ T et al. Carbamazepine hypersensitivity syndrome presenting as vasculitis of the CNS. J Neurol Neurosurg Psychiatry 1999; 66: 249-50. 28. Brunsma W. The Guide to Drug Eruptions. 6th ed, Free University Amsterdam, 1995. 29. Litt J. Drug eruption Reference Manual. 8th ed, Parthenon Publishing Group, 2002. 30. Naranjo CA, Busto U, Sellers EM. Difficulties in assessing adverse drug reactions in clinical trials. Prog Neuropsychopharmacol Biol Psychiatry 1982; 6: 651-7. 31. Sacristan JA, Gomez JC, Badia C, Kind P . Global index of safety: A new instrument to assess drug safety. J Clin Epidemiol 2001; 54(11): 1120-5. 32. Meisel C, Roots I, Cascorbi I et al. How to manage individualized drug therapy: application of pharmacogenetic knowledge of drug metabolism and transport. Clin Chem Lab Med 2000; 38(9):869-76. 33. Oscarson M. Pharmacogenetics of drug metabolizing enzymes: importance of personalized medi- cine. Clin Chem Lab Med 2993; 41(4): 573-80. Aleksej Kansky MD, PhD, Professor of dermatology, Dept of Dermatology, Zalo{ka 2, 1525 Ljubljana, SloveniaAUTHOR'S ADDRESSExcessive use of drugs and adverse events R e v i e w