슬라이드 1

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1 약물중독 Drug intoxication

2 Case 1 가. 처음에는자신의의지로시작했으나마약을복용한것처럼한번느끼면미련을버리지못하고중독된다. 나. 마약중독과작용기전이유사하다. 다. 이것이없으면불안하고초조한금단현상이매우심하게나타난다. 라. 같은쾌락을맛보기위해서는점점더많은양이필요하다. 마. 중독이심해지면신체에과도한무리를주어상해를입히는등건강을해칠수있다바. 다른중독과는달리어느정도까지는몸이점점더건강해진다.

4 Case 2

6 심각한알콜문제 오늘날우리나라 4 천 5 백만명의인구중음주인구는 2 천만명에달한다 년말한국보건사회연구원이밝힌자료에의하면심한알콜중독에빠져있는사람들이무려 3 백만명정도되고당장입원치료를받아야할사람만도 15 만명이넘는다고한다.

8 알콜의대사 보통때는 Ethanol Alcohol dehydrogenase Acetaldehyde Aldehyde dehydrogenase Acetic acid 로대사됨 술을많이마시면 Ethanol Procarcinogen Alcohol dehydrogenase P450 2E1 Acetaldehyde Carcinogen Aldehyde dehydrogenase Acetic acid 로대사됨

10 태아알콜증후군 (Fetal alcohol syndrome) 임산부가만성적으로술을마시거나과음을하게되면정신지체나육체적으로이상이있는아이를낳을가능성이높아진다. 음주로인해태아가정신지체, 소뇌증, 저체중, 그리고짧은안검열등의특징적인증세가나타나는데이를태아알콜증후군이라고한다. 알코올은분자가작아서태반을쉽게통과하기때문에태아의알코올수치도모체와같아진다. 특히임신초기의음주는태아에게더심각한영향을주는것으로알려져있다. 얼굴모습은코밑인중이없고, 윗입술이아래입술에비하여현저하게가늘며, 미간이짧으면서눈이작은특징이있다.

12 약물치료 Fomepizole (4-methylpyrazole) A competitive inhibitor Ethanol Ethanol 이 Alcohol dehydrogenase 에친화력이높은성질을이용

13 Case 3 A 6-year-old boy is brought to the ER because of severe vomiting. The patient was helping his father in the garage when he saw an antifreeze bottle and, out of curiosity, drank it. On arrival at the local pediatric emergency room, the boy started having tonicclonic sezures.

14 Fomepizole Ethanol Ethanol 이 Alcohol dehydrogenase 에친화력이높은성질을이용

15 알콜의대사 Ethanol Acetaldehyde Alcohol dehydrogenase Methanol Formaldehyde Ethyleneglycol Glycolaldehyde

16 농약파전사건 (2006 년 )

17 Case 4

19 타이레놀에의한간독성 보통때는 Tylenol Phase II Sulfate 가붙어서배설됨 P450 2E1 독성물질미량생성 술을많이마시면 Tylenol Phase II 별문제없음 Sulfate 가붙어서배설됨 P450 2E1 독성물질대량생성 간독성유발

21 Acetaminophen (paracetamol, TYLENOL, N- acetyl-p-aminophenol) At therapeutic doses: TYL N-acetyl-p- CYP1A2 CYP2E1 benzoquinonimine GSH conjugation elimination At high doses: GSH depletion the metabolite binds to cellular macromolecules cell death more toxic following ethanol exposure antidotes: N-acetylcysteine, methionine

22 Drug Interaction ( 약물상호작용 ) 입원환자는보통 5가지이상의약물이병용투여되는경우가많다. 약물상호작용으로인한부작용발생가능성은 ( ) 와관련이많다. 예 ) Warfarin Tylenol 약물상호작용은섭취하는식품과도관련있다. 약물상호작용이있는약물의병용투여를무조건피할필요는없다. 잘조절하여사용하면약물치료에더좋은효과를가져올수도있다.

23 Case 5 KCN

24 년타이레놀청산가리주입사건 1982 년 9 월에 Mary Kellerman 이라는 12 살짜리아이가감기진통약을복용하면서타이레놀청산가리주입사건이시작되었다. 아이는복용한지몇시간후에죽었고, 이약을복용했던다른 7 명또한죽음에이르렀다. ( 이정확한약의명칭은 Extra-Strength Tylenol 이며, 미국에서이사건은미해결사건리스트중에서도 top-10 에꼽힌다.) 누군가가고의적으로캡슐형태였던약에청산가리를주입해상점선반에놔두었던이사건은그후 270 종이넘는유사모방범죄로번져나갔다., 이러한사실은미국전역에공황상태를가져오면서제조사인 Johnson&Johnson 은약 1 억달러의 recall 을하게이르렀다.

25 2. Johnson&Johonson 사의대응 Johnson&Johnson 사에서는 80 년대초독극물사건이발생하자최고경영자제임스버크가중심이되어위기대책본부를구성 먼저타이레놀을사용하지말라는 TV 광고 450 만통의편지를미국내모든의사들에게발송또한문제가된제품을전부회수조치하고, 새제품으로교환해주었다. 기존타이레놀의캡슐생산을금지하고, 독극물에노출되기힘든형태의새로운타이레놀을개발하였고포장의형태또한개선하였다. 1 억달러의비용을들여생산설비또한바꾸었다.

26 3. 타이레놀독극물주입사건에대한사회적귀결 타이레놀사건은모두를공황사태에빠뜨릴정도의이었으나, 한편으로는상품안전규격의혁명을가져옴 타이레놀사건에경각심을갖게된제약회사들과식품산업계에서는포장법의향상시켜, 현재의타이레놀포장처럼밀봉방법을도입했고, 제품이생산되는동안의보안통제방법또한발전되었다. 그로인해서수많은모방범죄또한급격히축소될수있었다. < 그림 1. 현재의타이레놀 >

27 Case 6

30 Paraquat: Ingestion or skin contamination bloodstream taken up by type II pneumocytes in lung biotransformation single-electron cyclic reduction-oxidation subsequent formation of superoxide anion radical lipid peroxidation pulmonary toxicity

33 Case 7

TERATOGENESIS Thalidomide Developed as sedative and anti-nausea drug Causes birth defects in humans (phocomelia), banned from clinical use in the 1960s New therapeutic activity in

34 TERATOGENESIS Thalidomide Developed as sedative and anti-nausea drug Causes birth defects in humans (phocomelia), banned from clinical use in the 1960s New therapeutic activity in leprosy 2 nd Thalidomide Anti-inflammatory: suppression of cytokine (TNF-α) expression Anti-oncogenic: inhibition of angiogenesis In combination with DEX Thalidomide treat multiple myeloma

35 Thalidomide Thalidomide was sold in a number of countries across the world from 1957 until 1961, when it was withdrawn from the market after being found to be a cause of birth defects in what has been called "one of the biggest medical tragedies of modern times". [5] It is not known exactly how many worldwide victims of the drug there have been, although estimates range from 10,000 to 20,000. [6] FOR REFERENCE ONLY

an application from the Richardson-Merrell company to market thalidomide,

36 In the United States, pharmacologist and M.D. Frances Oldham Kelsey refused Food and Drug Administration (FDA) approval for an application from the Richardson-Merrell company to market thalidomide, saying further studies were needed, which reduced the impact of thalidomide in United States patients. FOR REFERENCE ONLY

37 Thalidomide Brazil Brazil has the second-highest prevalence rate of leprosy in the world, [citation needed] and thalidomide has been used by Brazilian physicians as the drug of choice for the treatment of severe ENL since A study published in 1996 reported 33 people born in Brazil after 1965 with thalidomide embryopathy. [39] Since 1994, the production, dispensing, and prescription of thalidomide have been strictly controlled, but cases of thalidomide embryopathy continue. [40][41] FOR REFERENCE ONLY

38 The mechanism of thalidomide's teratogenic action Thalidomide intercalates (inserts itself) into DNA in guanine-cytosine-rich regions. Such intercalation impacts upon the promoter regions of the genes controlling the development of limbs, ears, and eyes, such as IGF-I and FGF-2. These normally activate the production of the cell surface attachment integrin αvβ3, with the resulting αvβ3 integrin dimer stimulating angiogenesis in developing limb buds. Therefore, by inhibiting the chain of events, thalidomide causes the truncation of limb development. Developing limbs are particularly susceptible because of their relatively immature, highly angiogenic vessel network.

39 Enantiomer Teratogen Sedative Anti-nausea 분리하기어려움체내에서다른광학이성체로변함

40 Extrapolation? Human

41 Case 8

Anaphylaxis - Cause: dust, penicillin, cephalosporin, aspirin, ibuprofen - throat couphing, wheezing, swelling, blue lips, an itchy rash, and low blood pressure. - up to 1% may die as a result.

43 Anaphylaxis - Cause: dust, penicillin, cephalosporin, aspirin, ibuprofen - throat couphing, wheezing, swelling, blue lips, an itchy rash, and low blood pressure. - up to 1% may die as a result. approximately 1,500 deaths per year in the United States. -is caused by degranulation of mast cells or basophils mediated by immunoglobulin E (IgE) - epinephrine, oxygen, anti-histamine, steroids

44 약물유해반응

45 Quiz 1. Where is IgE? mast cell membrane 2. Which cell produce IgE? Plasma cell 3. Most chemical drugs are too small to be immunogen. How immune cell sensitize them? Hapten should bind to protein carrier 4. Can we trust negative patch-test? No, still we need to watch out

46 Penicillin Penicillin binds to IgE but does not cross-link IgEs. It requires serum protein to cross-link IgEs.

47 응급상황에대처 철수와영희가지나가던길에지하도에서의식을잃고쓰러져있는사람을보았다. 옆에는농약병처럼보이는병이뒹굴고있었다. 얼른환자의상태를보니맥박은뛰고있었고호흡도가늘지만유지되고있었다. 철수와영희가취한행동중적절하지않은것은? 에신속히연락하였다. 2. 환자를옆으로누운자세로해주었다. 3. 환자에게신문지를덮어주었다. 4. 농약을제거하기위하여손가락을넣어구토를유발하였다.

48 Drug Intoxication

49 Treatment for acute drug intoxication Primary cause of death in acute drug intoxication respiratory insufficiency: CNS paralysis, airway block by tongue, foods cadiovascular failure: hypotention, hypovolemic shock, arrhythmia 1. Emergency treatment for life - 호흡상태확인 : 산소공급또는인공호흡 - 기도확보 : 환자를옆으로눕히고, 필요한경우기관지삽관으로기도를확보한다. - 심장박동상태확인 - 정맥주사통로확보 - 혈압측정 : 수액요법또는약물요법으로혈압을정상화 - 환자의의식상태확인 : 포도당주사 2. Information of toxicant

50 3. Physical Examination 응급처치하는과정에서호흡, 혈압, 맥박및체온등을측정눈, 구강, 피부, 복부등을검사신경학적검사및의식의정도를측정중독된약물의특징적인임상증상눈 miosis: opioid, organophosphates (parathion) anti-cholinesterase mydriasis: atropine, cocaine, amphetamine, LSD nystagmus: phenytoin, alcohol, barbiturate 구강검사구강내화상 : 부식성물질그을음 : 연기흡입에의한중독냄새 : 알코올, 유기용매마늘냄새는유기인제농약, 비소제제신경기능검사일반적인임상병리검사혈액, 소변또는구토물로부터약물분석

51 4. Prevention of further absorption 일단환자의생명에위협이없을정도로응급처치가된이후에는먼저더이상흡수가되지않도록처치를해준다. 소화기에서흡수를지연하는방법으로는희석법, 구토법, 위세척, 활성탄투여, 설사약투여등이있다. 정제나캡슐제제에의해중독된경우의식이없는환자환자가경련할경우, 부식성물질에중독된경우흡착되지않는물질 (CN, alcohol, iron, mercury, lithium, malathion) 이나강산, 강알칼리에중독된경우

52 4. Antidotes Antidotes Atropine Atropine Botulism antitoxin Deferoxamine Dimercaprol (BAL) Epinephrine Ethanol, Fomepizole Fuller s earth N-acetylcysteine Naloxone Na nitrite, thiosulfate Physostigmine Vitamin K Toxicants Organophosphates Nerve gas Botulism Iron Arsenic, mercury Anaphylaxis Methanol, ethylene glycol Paraquat Acetaminophen Morphine, heroin Cyanide Atropine Warfarin

53 5. Excretion of toxicant 응급처치와흡수억제를위한처치가끝나고중독약물에대한해독제를처치한후에중독약물의배설을촉진시키는처치에대하여고려해야한다. 가. 강제이뇨이뇨제를투여하여강제이뇨시키고, 소변을산성화또는알칼리화시켜소변을통한배설을촉진한다. 이뇨제 : mannitol 과 furosemide, 효과가크지는않다. 소변을알칼리화 : NaHCO 3 단독또는 acetazolamide 와병용투여하여 ph 를 8.0 까지만든다. 산성약물 : 비소화합물, barbiturate, isoniazid, litium, naphthalene, salicylate 등 HA H + + A - 소변을산성화 : Ascorbic acid, ammonium chloride 투여하여 ph 를 5.0 까지만들수있다. 알칼리성약물 : amphetamine, phencyclidine, phosphorus, quinidine, strychnine 등 B + H + -> BH +

54 나. Dialysis and perfusion Peritoneal dialysis: 복막이반투막으로작용, 쉬운방법이나비효율적이다. 약물제거능력이혈액투석의 1/5 1/10 정도 Hemodialysis: 셀로판막을반투막으로사용, 이를통한약물이동을이용하여제거하는방법, 수분과전해질평형장애가있는경우이를교정할수있다. 분자량이작은물질, 단백결합이작은물질, 분포용적이작은물질 (salicylate) 이쉽게제거된다. Hemoperfusion: 혈액을흡착제가있는관류원주 (perfusion column) 를통과시켜중독약물이흡착제와결합되도록하여제거하는방법흡착제로활성탄, 이온교환수지중독약물제거에있어혈액투석보다효율적이다. 지용성이크거나단백결합약물등투석으로잘제거되지않는약물도효과적이다. 고분자약물로서물에대한용해도가적은약물, 분포용적이작고반감기가긴약물제거에도효과적이다.

55 Peritoneal dialysis Hemodialysis

56 오늘은여기까지

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract