NEWSLETTER FROM THE DIVISION OF PHARMACEUTICAL SERVICES Volume 8 Number 1 January 2001 Special subject Cytochrome P450 과약물상호작용 (Ⅰ) 최근다제병용요법의증가와다양한약물의출현으로약물상호작용의가능성이커졌으며, 그중약물대사와관련하여 cytochrome P450(CYP-450) 의유도또는저해에대한정보가급증하고있다. 따라서 CYP-450 의기질 (substrates), 저해제 (inhibitors) 및유도제 (inducers) 에대한지식을갖추는것이그에의한심각한약물상호작용을예측하는데도움이될것이다. CYP-450 은헴 (heme) 을함유한효소무리를일컬으며모든식물과동물에서발견된다. 주로간세포의내부원형질의망상구조 (endoplasmic reticulum) 의막에있으나소장에도많이분포하며기타신장, 폐, 뇌에도소량존재한다. 기능은 steroid hormones, fatty acids, prostaglandins 과같은내인성물질및외인성물질 ( 특히약물 ) 의산화적대사 (oxidative metabolism) 에관여함으로써이들물질이소변이나담즙으로쉽게배설될수있도록친수성물질로전환시키는것이다. CYP 의명명은 1987 년 Nebert 등에의해처음제안된방법이지금까지널리사용되고있는데, CYP 의아미노산배열순서의유사성을기초로하여 3 단으로분류된다. CYP 라는접두어에아라비아숫자, 영문자대문자, 다시아라비아숫자를덧붙여서각각 family, subfamily, isoenzyme 을나타낸다. 예로 CYP3A4 는 family 3, subfamily A, isoenzyme 4 를가리킨다. 이때 families 는아미노산배열이 40% 이상비슷한경우이고, subfamilies 는 55% 이상의동일한아미노산배열을갖는무리이다. 인간의 CYP-450 isoenzyme 은 30 가지이상이발견되었으나 CYP3A4, CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2E1 등이약물대사에주로많이관여하는것으로알려져있다. CYP-450 저해 (inhibition) 는한약물 ( 저해제 ) 이효소의활동을감소시킴으로써결과적으로그효소의기질인다른약물의혈중농도를증가시키는데, 이는두가지기전으로설명된다. 가장흔한기전은경쟁적저해 (competitive inhibition) 로서두개이상의기질 ( 약물 ) 이하나의효소반응부위에서경쟁할때발생한다. 이과정은효소에대한기질의친화도, 기질의농도, 저해제의반감기및항정상태 (steady-state) 에이르는시간에의존한다. 예를들면 cimetidine(cyp1a2) 은한번투여후 24 시간이내에다른약물의대사를저해하지만 amiodarone(cyp2c9) 은반감기가길기때문에몇달이지나도효과가나타나지않는다. 또한최대로약물대사를저해시키는데걸리는시간은대사저해를받는약물이항정상태에도달하는데필요한시간에도영향을받는다. 예로 cimetidine 과 theophylline 의상호작용에서 theophylline 농도가최대로증가하는데약 2 일이걸리는데, 이는 theophylline 이항정상태에도달하는데시간이필요하기때문이다. 경쟁적저해과정은기질 ( 대사를저해받는약물 ) 의양을증가시킴으로써극복할수있다. 두번째기전은드물기는하나, 기질과정상적으로결합해있는효소를불활성화시키는 (mechanism- based inhibition) 방법이다. 이경우는기질의양을추가해도이불활성화를극복할수없으며저해효과가없어지려면저해제의투여를중단한후효소가재합성되어야하므로저해기간이더길어질수있다. CYP-450 유도 (induction) 는간혈류가증가하거나혹은 CYP-450 의생성이많아질때발생하며 CYPs 이약물을대사할수있는용량이증가됨으로써기질 ( 약물 ) 의혈중농도는떨어진다. 이작용은수시간에서수일후에발생하는데, 부가적인효소가합성되기까지시간이필요하기때문이며마찬가지로유도효과가소멸되는데도시간이걸린다. 이러한시간경과에영향을미치는것이유도제의반감기다. 반감기가짧은 rifampin(cyp3a4, CYP2C) 은 24 시간이내에 induction 이일어나는반면 3-5 일정도로반감기가긴 phenobarbital (CYP3A4, CYP1A2, CYP2C) 은 1 주일정도소요된다. 시간경과에영향을미치는또다른요소는효소가분해되고다시새효소가생성되는데걸리는시간이다. 즉 rifampin 배설속도는효소 turnover 속도보다더빠르기때문에율속단계 (rate-limiting step) 가 CYP-450 효소의재생성시간 (1-6 일 ) 인반면 phenobarbital 은이약물의축적과배설속도가율속단계이다. Induction 작용은나이와간질환에도영향을받는데 60 세이상인경우유도하는능력이감소하며간염, 간경변등의간질환이있는경우효소유도에덜민감하다. 임상적으로심각한약물상호작용을일으킬수있는경우를살펴보면 (1) theophylline 이나항전간제처럼혈중치료영역이좁은약물이유도또는저해되는경우, (2) prodrug 에서치료적활성이있는물질로전환되는것을저해혹은유도할때, (3) 약물상호작용에의해약효가있는대사체나이성질체로전환되는경우등이다. 약물상호작용을일으키는정도는개인마다다양하게나타나는데, CYP 에존재하는약물의양과 CYP 에대한약물의친화도뿐만아니라나이, 영양상태, 질환상태, 다양한 CYP 에의한대사경로등에따라차이를나타낸다. 성별에따라서도활성도가달라여자의 CYP3A 의효과가남자보다더높다. 유전적다형성 (genetic polymorphism - ie, rapid vs poor metabolizers) 도 CYP 의활성을좌우하는중요한요소이다. 약물상호작용에주로관여하는 CYP 의기질, 저해제, 유도제들은 Table 에나열되어있으며, 각 CYP 의특징과그와관련된대표적인약물들은다음과같다. Table 1. Inhibitors, inducers, and substrates of cytochrome P450 enzyme CYP- Enzyme Inhibitor Inducer Substrate 1A2 Anastrozole Charbroiled food Acetaminophen Olanzapine Testosterone
Cimetidine Cigarette smoke Caffeine Ondansetron Theophylline(major) Ciprofloxacin Omeprazole Clozapine(major) Phenacetin TCAs(demethylation) Enoxacin Phenobarbital Diazepam Propafenone Amitriptyline Erythromycin Primidone Haloperidol Propranolol Clomipramine Grapefruit juice(?) Rifampin Isotretinoin Riluzole Imipramine Mexiletine Mexiletine(minor) Ropivacaine Nortriptyline Propranolol Mirtazapine Tacrine Verapamil Tacrine Naproxen Tamoxifen R-Warfarin 2A6 Ketoconazole Tamoxifen Methoxsalen Pilocarpine 2B6 Phenobarbital Cyclophosphamide Phenytoin Ifosfamide Primidone Tamoxifen 2C8-10 Amiodarone(2C9) Carbamazepine(2C9) Barbiturates Phenytoin(2C9) Anastrozole(2C8/2C9) Ethanol(2C9) Carvedilol(2C9) Piroxicam(2C9) Chloramphenicol(2C9) Phenobarbital(2C8) Dapsone(2C9) Retinoic acid(2c8) Cimetidine(2C9) Phenytoin(2C9) Diazepam(2C8) Torasemide(2C9) Diclofenac(2C9) Primidone(2C8) Diclofenac(2C8/2C9) TCAs Fluconazole(2C9) Rifampin(2C9) Fluoxetine(2C9) Amitriptyline(2C9) Fluoxetine(2C9) Flurbiprofen(2C9) Imipramine(2C9) Flurbiprofen(2C9) Glimepiride(2C9) Paclitaxel(2C8;major) Ketoprofen(2C9) Ibuprofen(2C9) S-Warfarin(2C9) Metronidazole(2C9) Indomethacin(2C9) Omeprazole(2C8) Isotretinoin(2C8) Sertraline(suspected) Losartan(2C9) Sulfonamides(2C9) Mefenamic acid(2c9) Sulfamethoxazole (2C9) Mirtazapine(2C9) Sulfinpyrazone(2C9) Naproxen(2C9) Trimethoprim(2C9) Omeprazole(2C8) 2C18-19 Cimetidine(2C18) Rifampin(2C19) Diazepam(2C19) Omeprazole(2C19) TCAs Zolpidem Fluoxetine(2C19) Divalproex- Piroxicam(2C18) Imipramine(2C19) Omeprazole(2C19) sodium(2c19) Propranolol(2C19) Valproic Acid(2C19) Topiramate(2C19) Naproxen(2C18) Retinoic acid(2c18) S-Warfarin(2C18) 2D6 Amiodarone not affected by Carvedilol Perphenazine Cimetidine common inducers Chlorpromazine Propafenone Codeine Clozapine Propranolol(minor) Doxorubicin Codeine Risperidone Fluoxetine Dextromethorphan Ropivacaine Haloperidol Donepezil Selegiline Mirtazapine(weak) Fluoxetine Sertraline Paroxetine Haloperidol Tamoxifen Perphenazine Hydrocodone Thioridazine Propafenone Labetalol Timolol Propranolol Metoprolol Tramadol Quinidine Mexiletine(major) Trazodone
Ranitidine Mirtazapine TCAs(hydroxylation) Sertraline(suspected) Morphine Amitriptyline Thioridazine Olanzapine(minor) Imipramine Venlafaxine Ondansetron Nortriptyline Vinblastine Paroxetine Venlafaxine Vinorelbine Pentazocine Zolpidem 2E1 Ethanol Acetaminophen Isoflurane Tamoxifen 3A3 Cimetidine Erythromycin Isoniazid Dapsone Isoniazid Theophylline Ranitidine Midazolam Ethanol(minor) Ondansetron 3A4 Anastrozole Carbamazepine Acetaminophen Doxorubicin Pimozide Cimetidine Glucocorticoids Alfentanil Erythromycin Progesterone Clarithromycin Dexamethasone Alprazolam Ethinyl Estradiol Propafenone Clotrimazole Macrolides Amiodarone Ethosuximide Quinidine Danazol Phenobarbital Amlodipine Etoposide Salmeterol Diltiazem Phenytoin Astemizole Felodipine Sertraline Erythromycin Primidone Atorvastatin Fentanyl Simvastatin Fluconazole Rifampin Bromocriptin Granisetron Tacrolimus Fluoxetine Carbamazepine Hydrocortisone Tamoxifen Graprfruit juice Cerivastatin Ifosfamide Teniposide Itraconazle Chlorpromazine Itraconazole(?) Testosterone Ketoconazole Cisapride Ketoconazole Theophylline(minor) Metronidazole Clarithromycin Lidocaine Tretinoin Mirtazapine(weak) Clonazepam Losartan Triazolam Nefazodone Codeine Lovastatin TCAs(demethylation) Paroxetine Cyclophosphamide Midazolam Amitriptyline Propranolol Cyclosporine Mirtazapine Imipramine Quinidine Dasone Nicardipine Venlafaxine Ranitidine Dexamethasone Nifedipine Verapamil Sertraline Dextromethorphan Nimodipine Vinblastine Diazepam Omeprazole R-Warfarin Diltiazem Ondansetrone Zolpidem(major) Donepezil Paclitaxel(minor) 3A5-7 Ketoconazole Phenobarbital Ethinyl Estradiol Quinidine Vincristine Metronidazole Phenytoin Lovastatin(3A5) Testosterone Primidone Midazolam(3A5) Triazolam Rifampin Nifedipine(3A5) Vinblastine < 장승연약사 > 다음호에계속 FDA 승인약물 성분명상품명함량 / 제형적응증제약회사 FDA Bivalirudin Angiomax vial use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA) Medicines Co 200
Femepizole Antizol 1.5 g/vial for suspected or confirmed methanol poisoning, either used alone or in combination with hemodialysis. Orphan Medical, Inc 20 최신약물정보 Peginterferon Alfa-2a in Patients with Chronic Hepatitis C Covalent attachment of a 40-kd branched-chain polyethylene glycol moiety to interferon alfa-2a results in a compound (peginterferon alfa-2a) that has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified interferon alfa-2a. We compared the clinical effects of a regimen of peginterferon alfa-2a with those of a regimen of interferon alfa-2a in the initial treatment of patients with chronic hepatitis C. We randomly assigned 531 patients with chronic hepatitis C to receive either 180 μg of peginterferon alfa-2a subcutaneously once per week for 48 weeks (n=267) or 6 million units of interferon alfa-2a subcutaneously three times per week for 12 weeks, followed by 3 million units three times per week for 36 weeks (n=264). All the patients were assessed at week 72 for a sustained virologic response, defined as an undetectable level of hepatitis C virus RNA (<100 copies per milliliter). In the peginterferon group, 223 of the 267 patients completed treatment and 206 completed follow-up. In the interferon group, 161 of the 264 patients completed treatment and 154 completed follow-up. In an intention-to-treat analysis in which patients who missed the examination at the end of treatment or follow-up were considered not to have had a response at that point, peginterferon alfa-2a was associated with a higher rate of virologic response than was interferon alfa-2a at week 48 (69% vs. 28%, P=0.001) and at week 72 (39% vs. 19%, P=0.001). Sustained normalization of serum alanine aminotransferase concentrations at week 72 was also more common in the peginterferon group than in the interferon group (45% vs. 25%, P=0.001). The two groups were similar with respect to the frequency and severity of adverse events, which were typical of those associated with interferon alfa. In patients with chronic hepatitis C, a regimen of peginterferon alfa-2a given once weekly is more effective than a regimen of interferon alfa-2a given three times weekly. New England Journal of Medicine 2000;343:1666-72 Health outcomes associated with calcium antagonists compared with other first-line antihypertensive therapies: a metaanalysis of randomised controlled trials Several observational studies and individual randomised trials in hypertension have suggested that, compared with other drugs, calcium antagonists may be associated with a higher risk of coronary events, despite similar blood- pressure control. The aim of this metaanalysis was to compare the effects of calcium antagonists and other antihypertensive drugs on major cardiovascular events. We undertook a meta-analysis of trials in hypertension that assessed cardiovascular events and included at least 100 patients, who were randomly assigned intermediate-acting or long-acting calcium antagonists or other antihypertensive drugs and who were followed up for at least 2 years. The nine eligible trials included 27,743 participants. Calcium antagonists and other drugs achieved similar control of both systolic and diastolic blood pressure. Compared with patients assigned diuretics, ß-blockers, angiotensin-converting-enzyme inhibitors, or clonidine (n=15 044), those assigned calcium antagonists (n=12,699) had a significantly higher risk of acute myocardial infarction (odds ratio 1.26 [95% CI 1.11-1.43], P=0.0003), congestive heart failure (1.25 [1.07-1.46], P=0.005), and major cardiovascular events (1.10 [1.02-1.18], P=0.018). The treatment differences were within the play of chance for the outcomes of stroke (0.90 [0.80-1.02], P=0.10) and all-cause mortality (1.03 [0.94-1.13], P=0.54). In randomised controlled trials, the large available database suggests that calcium antagonists are inferior to other types of antihypertensive drugs as first-line agents in reducing the risks of several major complications of hypertension. On the basis of these data, the longer-acting calcium antagonists cannot be recommended as first-line therapy for hypertension. Lancet 2000;356:1949-54 A Comparison of Etanercept and Methotrexate in Patients with Early Rheumatoid Arthritis We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing. As compared with patients who received methotrexate, patients who received the 25 mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20%, 50%, and 70% improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P=0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25 mg dose of etanercept, 72% had no increase in the erosion score, as compared with 60% of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P=0.006) than the group that was treated with methotrexate. As compared with oral methotrexate, subcutaneous etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis. New England Journal of Medicine 2000;343:1586-93
Efficacy and Tolerability of Levetiracetam 3000 mg/d in Patients with Refractory Partial Seizures: A Multicenter, Double- Blind, Responder-Selected Study Evaluating Monotherapy To evaluate the efficacy and tolerability of levetiracetam (LEV) monotherapy in selected patients with refractory partial seizures, we conducted this multicenter, double-blind, placebo-controlled, parallel-group, responder-selected study. Patients were randomized (2:1 ratio) to receive oral LEV 1500 mg twice daily or placebo during a 12-week add-on phase. Treatment responders (patients with a reduction in partial seizure frequency of 50% or more compared with baseline) entered a monotherapy phase that included a maximum 12-week down-titration period and 12 weeks of monotherapy at 1500 mg twice daily. In both phases, responder rate, seizure frequency, and adverse events were analyzed. A total of 286 patients (placebo, n=105; LEV, n=181) entered the add-on phase, and 86 patients (placebo, n=17; LEV, n=69) were eligible for the monotherapy phase. Thirty-six of 181 patients (19.9%) who received LEV completed the entire study compared with only 10 of 105 patients (9.5%) in the placebo group (P=0.029). The odds of completing the study on LEV were 2.36 times (95% CI 1.08-5.57) higher than on placebo. The responder rate during the add-on phase was significantly higher in the LEV group compared with the placebo group (42.1% vs. 16.7%, respectively; P<0.001). In the LEV monotherapy group, the median percent reduction in partial seizure frequency compared with baseline was 73.8% (P=0.037), with a responder rate of 59.2%. Nine patients (18.4%) remained seizure-free on LEV monotherapy. Conversion to LEV monotherapy (1500 mg twice daily) is effective and well tolerated in patients with refractory partial seizures who responded to 3000 mg/d LEV as add-on therapy. Epilepsia 2000:41:1276-83 Inhaled Zanamivir for the Prevention of Influenza in Families We performed a double-blind, placebo-controlled study of inhaled zanamivir for the treatment and prevention of influenza in families. We enrolled families (with two to five members and at least one child who was five years of age or older) before the 1998-1999 influenza season. If an influenza-like illness developed in one member, the family was randomly assigned to receive either inhaled zanamivir or placebo. The family member with the index illness was treated with either 10 mg of inhaled zanamivir (n=163) or placebo (n=158) twice a day for 5 days, and the other family members received either 10 mg of zanamivir (n=414) or placebo (n=423) once a day as prophylaxis for 10 days. The primary end point was the proportion of families in which at least one household contact had symptomatic, laboratoryconfirmed influenza. The proportion of families with at least one initially healthy household contact in whom influenza developed was smaller in the zanamivir group than in the placebo group (4% vs. 19 %, P<0.001); the difference represented a 79% reduction in the proportion of families with at least one affected contact. Zanamivir provided protection against both influenza A and influenza B. A neuraminidase-inhibition assay and sequencing of the neuraminidase and hemagglutinin genes revealed no zanamivir-resistant variants. Among the subjects with index cases of laboratory- confirmed influenza, the median duration of symptoms was 2.5 days shorter in the zanamivir group than in the placebo group (5.0 vs. 7.5 days, P=0.01). Zanamivir was well tolerated. When combined with the treatment of index cases, prophylactic treatment of family members with once-daily inhaled zanamivir is well tolerated and prevents the development of influenza. In this study there was no evidence of the emergence of resistant influenza variants. New England Journal of Medicine 2000;343:1282-9 의약품안전성정보 Insulin : Recurrent generalised urticaria at injection sites Insulin 의존형당뇨를앓고있는 6 세소년이진단 1 년후 insulin 을주사한모든부위에가려움을동반한발적을호소하였다. Human Mixtard 30(Novo Nordisk) 을팔, 허벅지, 둔부에주사하고 10 분후가려움을동반한발적이시작되었으며 12 시간후사라졌다. Insulin 을 Humulin M3 (Lilly) 로바꾼후에도 3 차례소양반응이있었다. 평균 insulin 용량은 0.61 units/kg/day 였다. 평균 hemoglobin Alc 은 8.0%, blood count 는정상이었다. Insulin specific IgE 결과는음성이었으며 insulin specific IgG 는높은수준이었다. 소년은그동안 animal insulin 을투여받은적이없으며아토피과거력도없었다. Humulin M3 와 Mixtard 30 의각구성성분의이상반응검사는수행되지않았다. Protophane (Insulatard;Novo Nordisk), Velosulin (Novo Nordisk) 와 enalapril 을투여받은 68 세환자가이전에주사한부위에급성가려움및홍반을호소한다는또다른보고도있었다. Mixtard 30 과 Humulin M3 의구성성분은 human insulin, m-cresol, zinc oxide, sodium hydroxide, hydrochloric acid, sodium phosphate, phenol, protamine 이다. 이반응은 zinc allergy 와는크게연관이없으며 protamine 에의한가능성도배제할수는없으나 insulin 주사부위의 mast cell 에고정된 insulin specific IgE 의매개작용때문으로생각되어진다. British Medical Journal 2000;321:1449 Levofloxacin : Anaphylactoid reaction 49 세의여성이지난며칠간짙은가래를동반한기침을호소하며응급실에내원했다. 비충혈, 빈호흡, 가슴통증, 천명등의증상도동반되었는데흡입기로는개선되지않았다. 환자는과거 8 년동안천식을앓아왔으며평소 albuterol, flunisolide 와성분이정확치않은흡입기두개를사용하였다. 응급실에서 albuterol 및 ipratropium 을흡입하고 methylprednisolone 을정맥투여하였으나흡 / 호기천명은지속되었으며천식악화로인한이차성감염으로입원하게되었다. 4 시간마다 albuterol (5 mg) 과 ipratropium (0.5 mg) 을흡입하였으며 methylprednisolone (6 시간마다 30 mg IV), heparin (12 시간마다 5,000 U SC), levofloxacin (500 mg IV) 처치
를받았다. Levofloxacin 투여 5 시간 30 분후빈호흡이급속히악화되어 albuterol 과 ipratropium 의투여간격을 3 시간으로앞당겼으며저녁늦게다시호흡곤란을호소하여 albuterol 5 mg 을추가하고 methylprednisolone 투여량을 60 mg 으로증가시켰다. 다음날아침두통증상이있어 ibuprofen 600 mg 을투여하고 90 분후빈호흡과함께경련증상이발생하였다. 삽관한후 diazepam, epinephrine, magnesium sulfate 를투여하고중환자실로옮겼다. 중환자실에서투여한약물은이전과동일하였으며 normal/half saline, diazepam, sucralfate 가추가되었다. 다음날환자상태는매우호전되어삽관제거하였으며회복속도는천식악화로인한급성호흡곤란증상에서흔히기대하는것이상으로빨랐다. 다음날아침 levofloxacin 을투여받은즉시빈호흡이다시시작되고흡 / 호기천명이있었으며, 불안, 심박동수및혈압상승이있었다. Albuterol 과 ipratropium 을투여했으나효과가없고산소포화도가급속히저하되어재삽관하였으며환자의얼굴과손, 등에홍반과두드러기가발생하였다. Epinephrine (0.3 mg SC 2 회 ), diphenhydramine (50 mg), methylprednisolone (125 mg) 을투여하고 levofloxacin 은 anaphylactic reaction 이의심되어투여중단하였다. 약물치료및삽관을수일동안유지한후삽관제거및 prednisolone taper 에성공하여퇴원하였다. 저자는 levofloxacin 에의한 anaphylactoid reaction 이드물기는하나일어날수있는부작용임을알아야하며 fluoroquinolone 계열의구조적유사성때문에한가지약물에과민반응을보일경우다른 fluoroquinolone 의투여는피해야한다고결론지었다. Pharmacotherapy 2000;20(12):1520-3 Mefloquine : Acute hepatitis 3 주전에동남부아시아를여행하고돌아온 68 세의남자환자가수주일동안권태, 피로, 구역의증세로내원하였다. 여행출발전에 hepatitis A 와 salmonella 에대해수동면역하였으며출발 1 주일전에는 malaria 예방으로 mefloquine (250 mg/week) 을복용하였다. 여행에서돌아오는길에식욕부진과피로등의증세가있었으나발열이나설사는없었다. Mefloquine 은피로와구역증세가심해지자입원 1 주일전에복용중단하였다. 환자는심부전및간울혈을동반한재발성심방조동의병력이있으며, transaminase, cholestatic enzyme 이약하게상승되었으나처치후호전된과거력이있다. 또한 complete atrioventricular block 으로인하여영구심박조율기를지니고있다. Digoxin (0.25 mg/ 일 ), furosemide (40 mg/ 일 ), spironolactone (100 mg/ 일 ), warfarin (5 mg/ 일 ) 을복용하고있으며몇년전부터고뇨산혈증으로 allopurinol (100 mg/ 일 ) 을함께복용하고있다. 입원 3 일전에심방조동진단으로 propafenone (150 mg 1 일 3 회 ) 을처방받았으며비처방약이나기타영양요법은시행받지않았다. 환자는야위고약간황달기가있었으나체온은정상이었으며호흡기계나임파계에병적증상은발견되지않았다. 경정맥압이약간상승되어있었으며간이압통없이약간커져있었다. 검사결과 alanine aminotransferase 1277 U/L, aspartate aminotransferase 1344 U/L, lactate dehydrogenase 7770 U/L 로상승되어있었으며 alkaline phosphatase, γ-glutamyl transpeptidase 는정상이었다. albumin 3.2 g/dl 로약간저하되어있고 total billirubin 1.87 mg/dl, creatinine 1.8 mg/dl, urea 58.8 mg/dl 로상승되었다. Hepatitis A, B, C, E, cytomegalovirus, antinuclear, antimitochondrial, smooth muscle antibody 에대한혈청검사결과는음성이었으며기생충감염의증거도없었다. 환자는급성간염, 탈수, 심방조동으로진단되었으며수액처치를받은후신기능이호전되었다. Mefloquine 투여중지후간기능은서서히회복되었으며 allopurinol 도간독성의가능성이있어투여중지되었다. Mefloquine 은신경정신계, 위장관계, 피부계등의부작용이알려져있으나간기능에도영향을미친다는보고가있으므로간질환이있는환자에게는신중히투여되어야한다. Pharmacotherapy 2000;20(12):1517-9 Hydralazine sulfate : Fatal hepatorenal failure 좌측상악동편평세포암을앓고있는 55 세남자환자가수술, 방사선요법과항암요법대신, 식욕촉진과 cancer cachexia 호전을위해 hydralazine sulfate 를복용한후발진, 소양, 권태, 황달의증세를 2 주동안경험하였다. 환자는인터넷을통해 hydralazine sulfate 를대체약물로판단하고, 진단후 4 개월동안 1 일 180 mg 씩 self-medication 하였다. 환자는간염, 담석, 췌장염등의과거력이없으며간질환에대한가족력도없었다. 갑각류, 버섯류를섭취하였으며최근에는알코올, acetaminophen, androgen, 한약등을복용하였다. 환자는 2 주전발진증세로인해 hydralazine sulfate 의복용을중단한상태로혈중농도는확인하지못했다. 손바닥, 가슴및사지에홍반과발진이있었으며공막성황달증세가심했다. 간비대나다른간이상의징후는없었으며기타검사도정상이었다. Leptospira antibody test, hepatitis A/B/C 혈청검사에는모두반응이없었다. 입원 3 일째되는날환자는간성혼수상태로악화되었으며 lactulose 에반응하지않았다. 신부전으로인하여혈액투석이필요하였으며 vitamin K 및몇가지혈장액투여에도불구하고혈액응고장애는지속되었다. 7 일째되는날식도십이지장경검사직후토혈증세가시작되어식도염과출혈성위염으로발전되었으나식도 / 위정맥류는없었다. 환자는적극적인처치에도불구하고호전되지않았으며가족들이치료를포기하여사망했다. 신장과간생검결과신장부위에 autolysis, 간의소엽중앙부와중간대의넓은부위에괴사가있었음을알수있었다. 간의 iron, copper strain 은음성이었으며이전에간질환이있었다거나종양이전이된증거는없었다. 이사례는미국 FDA Medwatch 에 hydralazine sulfate 의발현가능한부작용으로보고되었다. Hydralazine sulfate 는간에서당신생, 이화작용등을비가역적으로억제함으로써몸에서단백질이나아미노산등의소모를줄여 cancer cachexia 를개선시키는데사용할수있다고는하나, 논란의여지가많으며치명적인간 / 신부전을유발할수있으므로신중히투여되어야한다. Annals of internal Medicine 2000;133(11):877-80 Dietary supplements containing ephedra alkaloids : Adverse cardiovascular and central nervous system events Ephedra alkaloids 를함유한식품 ( 예 : 마황 ) 류는체중감소와활력증강의목적으로많이섭취되고있는데, 최근이성분을함유한제품들의부작용이보고되면서미국 FDA 에서는복용량과기간에제한을두어야한다고제안하고있다. Ephedra alkaloids 가함유된식품을복용한후부작용을경험한사례 140 건이 FDA 에보고되었는데이중 43 건 (31%) 이 ephedra alkaloids 로인한확실혹은가능한부작용이었으며 24 건 (17%) 은관련이없고 44 건 (31%) 은가능성이있는것으로생각되며 29 건 (21%) 은정보가불충분하여인과관계규명이어려웠다. 심혈관계증상이전체의 47% 로서이중고혈압이가장많고동계, 빈맥순이었으며중추신경계부작용은 18% 로서가장빈번한부작용이졸중 (10 건 ), 경련 (7 건 ) 이었다. 10 건은사망에이르렀으며 13 건은영구불능이되었다.
Ephedrine 과관련 alkaloids 는심혈관계부작용이있으며출혈성, 허혈성뇌졸중을일으킬수있다. Ephedra alkaloids 를함유한많은식품들이 caffeine 도함께함유하고있는데, caffeine 은 ephedrine 의심혈관계및중추신경계에대한효과를증진시키고혈관수축, 혈압상승작용이있으며 catecholamine 을유리하여중추신경계와심혈관계를자극시킨다. Ephedrine alkaloids 류에포함된또다른성분인 phenylpropanolamine 은 caffeine 과함께복용할경우혈압에대하여상가작용을유발할수있다. Ephedra alkaloids 를함유한식품은여러가지부작용을유발할수있기때문에적절한투여용량과지침이제시되어져야할것으로생각된다. New England Journal of Medicine 2000;343:1833-8 복약상담코너 - - - 건선 (Psoriasis) - - - 건선은선홍색의구진 (papule) 및은백색의인설 (scale) 을특징으로하는질환으로악화와호전을반복하는만성피부질환이다. 남녀간의발생빈도의차이는없으며호발시기는 20-60 세사이이며평균호발연령은 27 세정도이다. 건선자체가생명을위협하는치명적인질환은아니지만외관상이나정신적인면에서생활에많은불편을초래하는만성재발성질환이므로우수한효과를내면서도부작용이적은치료법이요구된다. 건선의정확한원인은알려져있지않지만몇가지가설이있다. 첫째로피부표피세포의이상증식으로, 건선표피세포의세포주기는 37.5 시간인데비해정상세포주기는 300 시간으로건선의표피세포의주기가정상세포의세포주기보다약 7 배정도빨리증식한다는것이다. 두번째로건선표피세포에서는비정상적으로 arachidonic acid 의양이증가되어있으며 lipoxygenase 에의해 2-L-hydroxy 5,8,10,14-eicosatetraenoic acid(hete) 와 leucotriene B4(LTB4) 를증가시킨다. LTB4 는강력한 chemotatic factor 로작용하여호중구를유입하며염증매개물질의분비를촉진시킨다. 그외유전적요인이나외부영향, 면역등과관련된것으로알려져있다. 외부영향으로는날씨, 스트레스, 감염, 외상, 약물에의해영향을받는것으로, 건조한기후나자외선의노출이적고피부가건조한겨울에건선이더악화되며, 정신과에서쓰는 Lithium carbonate 나고혈압약으로사용되는 β-adrenergic blockers 에의해서도악화될수있다. 건선의증상은초기에는작은구진이생기고이것이점차커지거나융합하여동전모양, 또는판상형태를취하며, 이런병변들은경계가분명하며은백색의인설로덮여있다. 인설을제거하면점상의출혈이나타나는데이는표피는얇고그아래의혈관이확장되어있기때문이다 (Auspitz sign). 발진은주로대칭성으로오며무릎이나팔꿈치, 둔부, 두부, 귀에나타날수있으며, 손톱이나관절에까지영향을미친다. 피부병변이무릎이나관절의병변보다일반적으로앞서서일어나지만동시에일어나기도한다. 건선의임상적인증상이여러가지다른피부질환과혼동될수있으므로정확한진단을해야하며, 치료는환자의연령과건선의발생범위, 활성도, 형태및발생부위에따라치료법이달라지며, 일반적으로국소치료 (topical therapy), 전신치료 (systemic therapy) 와광선치료 (phototherapy) 가있다. - 원내사용중인건선치료제 - 국소치료제 Topical corticosteroids 분류성분약품코드제형함량 피부연화제 각질용해제 Grade I (Very High Potency) Grade II(High Potency) Grade III (Medium Potency) Grade IV (Low Potency) Olive oil OLI-Z solution Vaseline VASE-O ointment 10 g/tube Salicylic acid Clobetasol-17-propionate SA5-O ointment 5% 15 g/tube SA10-O ointment 10% 15g/tube C17P-O ointment 0.05% 10 g/tube C17P-L solution 4.7% 25 ml/bottle Diflucortoline valerate DIF-O ointment 0.3% 10 g/tube Desoxymethasone DESO-C ointment 0.25% 10 g/tube DESO-L lotion 0.25% 10 ml/bottle Methylprednisolone aceponate MPD-C cream 0.1% 10 g/tube Desoxymethasone DESG-C gel 0.05% 15 g/tube Diflucortolone valerate 0.1%/Isoconazole nitrate 1% ID-O ointment 10 g/tube Hydrocortisone-17-butyrate H17B-L solution 0.1% Hydrocortisone-17-valerate H17V-O ointment 0.2% 15 g/tube Prednicarbate PDC-O ointment 0.25% 10 g/tube Dexamethasone DEXA-L lotion 0.0025% 100 ml/bottle Hydrocortisone HC5-C cream 0.5% 10 g/tube
전신치료제 광선요법제 Vitamin D3 유도체 면역억제제 Hydrocortisone 1%/Salicylic acid 3%/Vaseline HC-C cream 1% 10 g/tube HC-O ointment 1% 10 g/tube HL-L lotion 1% 118 ml/bottle SH-O ointment 15 g/tube Prednisolone PD10-L lotion 0.25% 100 ml/bottle Prednisolone valerate acetate PDV-O ointment 0.3% 10 g/tube Calcipotriol Cyclosporin DAIV-L lotion 5% 30 ml/bottle DAIV-O ointment 5% 30 g/tube CSPN capsule 25 mg CSPN10 capsule 100 mg Methotrexate MTX tablet 2.5 mg Tacrolimus TACRO capsule 1 mg Methoxalen MXS capsule 10 mg MXS1-C cream 0.1% 10 g/tube MXS2-C cream 0.2% 10 g/tube Ⅰ. 국소치료제 (Topical treatment) 1. 피부연화제 (emollients) 와각질용해제 (keratolytics) 피부연화제는각질층으로부터수분의증발을최소화하여인설을감소시키며피부의유연성을증가시킨다. 올리브유와같은식물유나바세린이있으며하루에 3 4 회정도로환부에발라주는데이런약물들은광선치료시광선의투과를증가시키는역할도한다. 부작용으로써모낭염이나알러지성접촉성피부염이생길수있다. 각질용해제는인설을제거하는직접적인작용과다른약물의피부침투를증가시키는간접작용이있으며주로 2 10% 정도의 salicylic acid 를국소적용한다. 5% 이하에서는각질용해효과가있으며그이상에서는표피박리의특성을가진다. 하루에 2 3 회정도발라주며국소자극감이나타날수있다. 적용부위가넓을때는오심, 구토, 이명, 과호흡등의 salicylic acid 중독증상으로인한전신부작용을초래할수있으므로주의한다. 2. Coal tars Coal tar 는수백년간건선의치료에이용된약물로작용기전이명확하게알려져있지는않으나표피세포분열과인설의생성및피지분비를감소시키며항염증효과가있다. 특히심각한가려움증을동반하는건선에효과적이며경증혹은중등증의건선에단독으로사용시효과적이다. 아스팔트질의 coal 을고온으로증류하여얻어진 tar 제제는불쾌한냄새가나고끈적이며, 피부와옷을착색시키기는단점이있다. 보통취침전에적용하나목욕시사용하거나샴푸로사용할수있으며, 부작용으로피부자극감이나모낭염, 드물게일광에노출시광독성반응으로작열감과통증이올수있다. 3. Topical corticosteroids 건선치료에서발적, 가려움, 인설을감소시키는데중요한역할을하는약물로건선의치료에가장많이쓰이고질환초기에사용하는약물이다. Phospholipase A 를저해함으로 arachidonic acid 의합성을억제하여 prostaglandins, leukotriens 등염증매개체의방출을억제함으로서항증식작용, 항소염작용과면역억제효과를나타낸다. Steroid 의사용목적은건선소실기간을증대시키는데있다. 크림, 연고, 로션등의제형이있으며, 현재나타난병변의모양이나제형의기제특성을고려하여선택한다. 연고는 lipophilicity 가있어진피층안으로 corticosteroids 의투과를증가시키며피부를수화 (hydration) 시키므로병변부위가건조하거나각질이심하고인설이많을때사용한다. 크림과로션은수성기제를사용하며, 끈적이지않고쉽게흡수되므로마찰이잦은부위나털이많은부위나두피건선에적용한다. 사용중이던 steroid 를갑자기중단하면건선이쉽게재발될수있으므로서서히용량을줄여가야한다. 치료후 3 14 일이후피부위축을비롯한색소침착감소, 알러지성접촉피부염, 여드름, 모세혈관확장등의부작용이나타날수있으며, 전신적으로흡수되면부신기능을억제할수있다. 또한, 강력한 steroid 를장기간사용하는경우피부저항력이소실되면서세균이나곰팡이로인한피부병이유발되거나악화될수있으므로주의한다. 4. Anthralin 건선치료에매우효과적이고전신적부작용이없는안전한치료법중의하나로작용기전은명확히알려진바없지만세포증식을억제하고염증을감소시키며세포분화를촉진한다. 치료초기에는 0.05% 0.1% 의농도로시작하고주로취침전에사용한후다음날아침씻어내고보습제를바른다. 정상피부에적용시감염되거나자극이나타날수있고피부를착색시킬수있기때문에반드시건선부위에만사용해야한다. 이러한부작용을최소화하면서적절한효능을유지하기위해 0.1% 의농도를 5 20 분간적용하거나 1% 의농도를 5 분간사용하고씻어내는단기접촉요법을적용하기도한다. 5. Calcipotriol 1,25-dihydroxyvitamin D3 유도체로경증혹은중등증의판상건선에적용하는약물로표피각질세포의수용체에결합하여세포분화를촉진시키고세포증식을억제시킨다. 인설을감소시키더라도홍반은사라지지않으므로 steroids 와병용한다. 부작용으로고칼슘혈증이나고칼슘뇨증이일어날수있고조직의석회화를초래할수있으므로 1 주에 calcipotriol 로 5 g(0.005% 제제로 100 g) 을초과하지않도록주의한다. 0.005% 농도로하루에 2 번적용하는데약물사용후 2 주이내에병변의개선이나타나며, 70% 의환자에게서 8 주이후에는뚜렷한개선을보인다. 작열감, 자극감, 홍반, 피부건조, 표피박리등의부작용및안면피부염이나타날수있으므로얼굴에는사용하지않도록한다. 임신및수유시는금기이며어린이에게는안전성이확립되어있지않다.
6. Tazarotene Retinoid 유도체로다른 retinoid 와약물학적활성은유사하지만 retinoic acid receptors(rar) 인 RAR-β, RAR-γ 에선택적으로작용함으로써다른 retinoid 유도체에비해부작용이감소되었다. RAR-γ 는피부에우세하게존재하는 RAR 로생성과분화에핵심적인역할을하는것으로추정되며, 비정상적인세포분화를정상화시키고항소염효과를나타낸다. 0.05% 또는 0.1% 농도로 1 일 1 회, 12 주간사용하며판상건선및안면건선에효과적이다. 부작용으로소양증, 작열감, 홍반이나타날수있으며용량또는사용횟수와관계가있다. 피부에습진이있거나바르는부위가몸전체의 20% 이상일때에는전신적인부작용을초래할수있으므로주의한다. 적용초기에는 'retinoid erythema' 라고하여홍반이나타나거나더심해질수있는데이는건선이악화되는것이아니라치유가시작되는과정이므로환자가걱정하지않도록설명해줘야한다. Ⅱ. 전신치료제 (Systemic treatment) 1. Acitretin Etretinate 의활성대사체로최기형성을낮추기위해반감기를줄인경구용 retinoic acid 유도체로농포성, 홍반성의심각한건선에주로적용한다. 농포성건선의초기량은 1 일 0.75 1 mg/kg 로투여하며 2 10 일이내반응이나타난다. 유지량은 0.125 0.25 mg/kg 이다. 홍반성건선에서는 1 일 0.25 0.4 mg/kg 의용량으로시작하며 2 4 주후에나증상이호전되기시작한다. 유지량은농포성홍반시와동일하다. 피부연화제나국소용 corticosteroids 를병용하면치유에도움을줄수있다. 부작용으로피부건조감, 탈모, 근육통, 눈의자극감등이생길수있으며, 간독성이나타날수있기때문에규칙적으로간기능을모니터링해야한다. 간또는신장애가있는환자는금기이며, 최기형성을유발하므로임신부에게는금기이다. 또한, 약물복용한달전부터투약종료후 2 년동안피임을해야하므로약물복용후 3 년이내에임신계획을가지고있는여성에게는금기이다. 2. Cyclosporin 초기단계의 T- 세포활성을억제시킴으로써면역억제를나타내고비만세포나호염기세포, 다형구세포의염증매개체의유리를차단함으로서항염증효과를나타낸다. 초기량은 1 일 3 mg/kg 로시작하며한달후에도개선이없으면용량을증량하되, 1 일 5 mg/kg 는넘지않도록한다. 보통 7 10 주후면 90% 정도의환자에서증상완화가나타나며증상이완화되면점차용량을감량하여최소량을유지하도록한다. 부작용으로오심, 구토, 혈압상승, 지각이상, 다모증, 신독성이나타날수있다. 3. Methotrexate 엽산길항제로표피의유사분열과 DNA 합성을억제함으로서치료효과를나타낸다. Methotrexate 는초기치료제는아니고국소치료나 retinoic acid, 광선요법등에반응하지않는심각한농포성건선및홍반성건선, 체표면적 20% 이상의판상건선에적용한다. 복용량은 1 주에 7.5 15 mg(1 주최대 30 mg) 을복용하되, 1 주에 3 회, 12 시간간격으로 1 회 2.5 5 mg 씩복용한다. 예를들면, 매월월요일오전 8 시와오후 8 시, 그리고화요일오전 8 시에각각 2.5 5 mg 씩복용하는방법이다. 빈혈, 백혈구감소증, 혈소판감소증, 폐섬유화, 원형탈모증, 담마진, 광독성반응등의부작용이나타날수있으며, 간이나신장기능이나쁘거나빈혈이심한경우및임부및수유부에게는금기이다. 4. Tacrolimus Interluekin 생성을저해시킴으로써면역억제효과를나타내며, cyclosporin 과비교시면역억제효과는 10 100 배정도더강하다. 다른치료에반응하지않는판상건선에효과적이며초기 1 일 0.05 mg/kg 로시작하여반응을관찰하며 3 주간격으로 0.05 mg/kg 씩증가시켜 0.15 mg/kg 까지증량한다. 주된부작용으로설사, 복통, 오심, 지각이상, 고혈압, 심계항진, 신독성, 간효소의변화등이나타날수있다. Ⅲ. 광선요법제 (Phototherapy) 광선요법은중등증이나중증의건선치료에이용되며자외선 A, B 가피부질환을치료하는데효과적이다. 가장일반적인광선요법은광감각물질인 psoralen 과자외선 A 를이용하여광치료를하는 PUVA(Psoralen + Ultraviolet A phototherapy) 이다. PUVA 는 psoralen 이자외선 A 에의해피부내에서활성화되어 pyrimidine 염기에공유결합함으로서 DNA 합성을저해하여표피세포의과증식을억제한다는이론과 PUVA 에의해표피세포에서 free-radical 이생성되어이 free-radical 이세포에손상을주어세포의과증식을억제한다는이론에근거하여적용하게되었다. 일반적으로 8-methoxypsoralen(Methoxsalen) 이사용되며 0.6 0.8 mg/kg 의용량을자외선 A 조사 2 시간전에복용한다. Psoralen 의부작용으로변비, 설사, 오심, 소양증이나타날수있으며, 주로국소치료에반응이없는사람에게사용한다. Ⅳ. 복약상담 1. 건선은만성질환이므로 corticosteroid 의장기사용시부작용초래의가능성이커지므로너무강한스테로이드를먼저사용하지않도록한다. 또한강한스테로이드를갑자기중단하면병변이악화될수있으므로점차감량하도록한다. 2. 건선은겨울철에악화되기쉽기때문에겨울철에는피부가건조하지않도록국소적용오일이나보습제를충분히사용하도록한다. 3. 건선은정신적인스트레스나육체적과로에의해악화될수있다. 4. 건선환자는너무장기간목욕하는것을피하도록한다. 목욕후잠깐동안은물기가남아서좋은것같으나물기가증발하면서피부는더욱더건조해지고가려움증도동반하므로목욕시간을되도록짧게하고비누를사용하지않도록한다. 특히때밀이수건으로문지르는것은피해야한다. 5. Lithium carbonate, β-adrenergic blockers, Chloroquine, Interferon, Indometacin 또는 NSAIDs 복용시건선이유발될수있다.
6. Retinoic acid 유도체복용시최기형성이유발될수있으므로임산부의복용을금기하며, 복용후 3 년내임신계획을갖고있는여성에게도금기이다. 참고문헌 1. Kenneth G. Linden, MD, phd, Gerald D, Weinstein, MD, Current Perspectives with an Emphasis on Treatment. Am J Med.1999;107:595-605 2. Bryan P. Peters, Fred G. Weissman, and Mark A.Gill, Pathophysiology and treatment of psoriasis. Am J Health-Syst Pharm. 2000;57:645-62 3. Mark Lebwohl, MD, Advances in psoriasis therapy. Dermatologic clinics. 2000;18:13-19 4. G. Scott Drew, DO. Psoriasis. Prim Care. 2000;27:385-406 5. Pharmacotherapy 4th Ed. 1496-1502 6. 피부과학, 대한피부과학회편저 : 여문각 7. 건선, 고려의학 1996 < 홍수연약사 >