Review Article 노인에서의약물에의한어지럼증 이원재 보훈공단중앙보훈병원재활의학과 Drug-induced Dizziness in the Elderly Patients Won Jae Lee, M.D., Ph.D. Department of Physical Medicine and Rehabilitation, Veterans Health Service Medical Center Seoul 134-791, Korea Abstract Older persons have a significantly higher disease burden compared with younger adults, and they consume almost half of total drug expenditures. Because of the changes in pharmacokinetics and pharmacodynamics with aging, and the risk for adverse drug reactions can be increased. Beers criteria was introduced to identify the potentially inappropriate medications (PIMs) in elderly patients since 1991, and the american geriatrics society (AGS) has been revised the criteria. Anticholinergics, antithrombotics, analgesics, skeletal muscle relaxants, cardiovascular and central nervous system drugs correspond with PIMs associated with dizziness in 2012 AGS beers criteria. Physicians should pay particular attention to identifying the medication history in the elderly patients with dizziness, and keep the principle for appropriate prescription. Key Words Dizziness, Potentially inappropriate medications, Beers criteria, Appropriate prescription 접수일 : 2014년 12월 29일게재승인일 : 2015년 1월 30일교신저자 : 이원재주소 : 서울시강동구진황도로 61길 53 보훈공단중앙보훈병원재활의학과 Tel : 82 2 2225 1497 Fax : 82 2 2225 1579 e-mail : braddom@nate.com 서론 어지럼증은다양한상태나질환에의해발생하는여러가지주관적인느낌을표현하는단어로, 증상적특징에따라현훈성 (Vertigo), 실신성 (Pre-syncope), 균형장애 (Dysequilibrium), 심인성 (Psychogenic), 안성 (Ocular), 복합성 (Multisensory), 가성어지럼 (Pseudo-diziness) 의 7가지아형 (subtype) 으로나뉜다. 1 이중복합성어지럼증은주로노인에서나타나며, 약물에의해유발되는것인지를감별해야한다. 노인에서의약물오남용은현재큰사회문제가되고있다. 미국의국민건강영양검진조사에따르면, 65세이상 74세이하노인의 50% 이상이 2개이상의약을복용하고 12% 는 5개이상의약을복용하고있다고보고되었다. 또한 75세이상노인의경우 60% 이상이 2개이상의약을복용하고 16% 가 5개이상의약을복용하는것으로조사되었다. 우리나라의경우국내한종합병원에입원한 4,519명의노인환자와외래를방문한 20,575명의노인환자를대상으로한연구에의하면입원환자는평균 18개의약물을, 외래환자는평균 6개의약물을처방받는것으로조사되었다. 2 이에본종설에서는약물에의한부작용이더심각해지는노인에서의약동학적변화에대해알아보고, 대표적인부작용 8
중하나인노인에서의만성어지럼증을유발하는약물들에대해살펴본후, 노인환자에서의약물처방원칙에대하여알아보고자한다. 본론 1) 노인에서의약동학적변화 젊은성인에비해노인에서는약물에대한생리적반응이훨씬예측하기어렵기때문에약의처방이나병합투여에신중을기해야한다. 노인의약물처방에서약물의선택이나용량, 용법등은노화에따른약물의흡수, 분포, 대사및배설등약역학적 (pharmacodynamic) 및약동학적 (pharmacokinetic) 측면이반드시고려되어야한다. 노화가진행되면약역학적측면에서위장관의전반적노화현상으로위액의산도는높아지며, 내장의혈류량감소와위장관기능의저하로장점막의흡수력이낮아진다. 또한체내총수분량이감소되고체중이감소되면서노화로인한근육감소증 (age-related sarcopenia) 이유발되고, 상대적으로지방질이증가한다. 이로인해수용성약물의경우분포용적 (volume of distribution) 이작아지므로약물투여후초기의혈장농도가증가하는현상이관찰되며, 지용성약물은분포용적이커져약물의혈중농도가낮아지고소실반감기가길어지며작용시간이연장된다. 또한노화로인한혈장내알부민감소, 간기능과신기능의저하는약물의분포, 대사, 배설에영향을미치며, 신기능저하에따른크레아티닌청소율 (Creatinine clearance) 의저하가가장큰요인으로알려져있다. 이러한변화들로인해약물별로노화에따른약동학적변화들이나타나는데, 베타작용제와베타차단제, 이뇨제중 furosemide는약물작용시간이짧아지며, 항정신병약제, 벤조다이아제핀계제제, 비타민 K 길항제, Morphine, Propofol, Verapamil 등은약물의작용시간이길어지는것으로알려져있다. 결과적으로노화에따라약물에대한감수성이증가하고조직수용체기능의저하도함께나타나므로약을처방함에있어신중함이요구된다. 3 2) 노인에서의만성어지럼증을유발하는약물들 1991년미국 UCLA 의과대학보건대학원 Beers 교수의주도로노인의학, 장기요양보험, 노인약학, 노인정신약학, 약물역학등각분야의전문가 13인이모여너싱홈 (Nursing home) 거주자를대상으로부적절한약물처방을평가할수있는기준을발표하면서, 이를 Beers Criteria라고명명하였다. 4 이기준에는 65세이상노인에있어서약물부작용 (adverse drug events, ADEs) 을유발할수있는부적절약물 (potentially inappropriate medications, PIMs) 들의목록을작성하여이에대한처방을피하도록권고하고있으며, 미국노인의학회 (American Geriatrics Society, AGS) 의주도로 1997년과 2003년, 그리고가장최근에는 2012년에개정되어 2012 AGS Beers Criteria가발표되었다. 5-7 약물목록을무작위로나열했던이전버전에비해 2012 Beers Criteria에서는노인환자에서처방을피해야할부적절약물들을계통별로정리하였으며, 약물상호작용을고려하여특정질환에서피해야할약물목록도함께제시하고있다. 실제로국내외에서이를이용한노인에서의약물처방적정성에대한연구가활발히진행중이다. 8-10 2012 Beers Criteria에따른노인에서의어지럼관련약물들을살펴보면, 우선항콜린작용제 (anticholinergics) 중에서는 hydroxizine, pseudoephedrine 등의 1세대항히스타민제 (antihistamines) 들이혼돈 (confusion) 상태를유발하므로처방에주의해야한다. 항혈전제 (antithrombotic) 중 dipyridamole과대부분의혈압강하제들은기립성저혈압의위험성이크므로처방에신중을요한다 (Table 1). 중추신경계관련약물중 amitriptyline 을포함한삼환계항우울제 (Tertiary TCAs) 들은항콜린, 진정 (sedation), 기립성저혈압을유발하기쉬우므로노인환자에서처방에주의를요한다. 벤조다이다제핀 (Benzodiazepine) 계열약물들은진정, 섬망 (delirium) 의부작용이있으므로작용시간이긴 diazepam, clonazepam보다는작용시간이짧은 alprazolam, lorazepam의사용이추천된다. 비벤조다이아제핀계수면제로알려진 zolpidem도섬망의부작용이있으므로노인환자의상태를고려한신중한처방이필요하다 (Table 2). 통증관련약물들을살펴보면, NSAIDs 중에서는 Indomethacin 사용시중추신경계부작용을고려해야함을경고하고있으며, Opioids 중에서는발작 (seizure) 의역치를낮춘다고알려진 Tramadol과혼돈등의중추신경계부작용위험성이큰 Pentazocine 처방에는신중해야한다고권고하 9
Table 1. Potentially Inappropriate Medications Associated with Dizziness in 2012 American Geriatrics Society Beers Criteria (Anticholinergics, Antithrombotics and Cardiovascular Drugs) Therapeutic category or drug Rationale R Quality of evidence Strength of R Anticholinergics (exclude TCA) First-generation antihistamines (as single agent or as part of combination products) Highly anticholinergic; clearance reduced with advanced age, and tolerance develops when used as hypnotic; greater risk of confusion, dry mouth, constipation, and other anticholinergic effects and toxicity. Avoid Hydroxyzine and promethazine: high Brompheniramine Carbinoxamine Chlorpheniramine Cyproheptadine Dexbrompheniramine Hydroxyzine Use of diphenhydramine in special situations such as acute treatment of severe allergic reaction may be appropriate All others: moderate Antithrombotics Dipyridamole, oral short acting (does not apply to extended-release combination with aspirin) Ticlopidine May cause orthostatic hypotension;intravenous form acceptable for use in cardiac stress testing Safer effective alternatives available Avoid Moderate Avoid Moderate Cardiovascular Alpha-1 blockers Doxazosin Prazosin Terazosin Alpha agonists, central High risk of orthostatic hypo-tension; not recommended as routine treatment for hyper-tension; alternative agents have superior risk/benefit profile High risk of adverse CNS effects; may cause bradycardia and ortho-static hypotension; usually not recommended for hypertension Avoid use as an antihypertensive Avoid clo-nidine as a 1 st line antihypertensive Moderate Low Clonidine Guanabenz Reserpine (> 0.1 mg/d) Disopyramide Avoid others as listed Disopyramide is a potent negative inotrope and therefore may induce heart failure in older adults; strongly anticholinergic; other antiarrhythmic drugs preferred Avoid Low R: recommendation, TCA: tri-cyclic antidepressant. 10
Table 2. Potentially Inappropriate Medications Associated with Dizziness in 2012 American Geriatrics Society Beers Criteria (Central Nervous System Drugs) Therapeutic category or drug Rationale R Quality of evidence Strength of R Tertiary TCAs, alone or in combination: Amitriptyline Imipramine Thioridazine Benzodiazepines Short and intermediate acting: Alprazolam Lorazepam Oxazepam Triazolam Long acting: Chlordiazepoxide Clonazepam Diazepam Flurazepam Meprobamate Nonbenzodiazepine hypnotics Eszopiclone Zolpidem Zaleplon Highly anticholinergic,sedating, and cause orthostatic hypo-tension; safety profile of low-dose doxepin ( 6 mg/d) is comparable with that of placebo Highly anticholinergic and risk of QTinterval prolongation Older adults have increased sensi-tivity to benzodiazepines and slower metabolism of long-acting agents. In general, all benzodiazepines increase risk of cognitive impairment,deli-rium, falls, fractures, and motor vehicle accidents in older adults May be appropriate for seizure disorders, rapid eye movement sleep disorders,benzodiazepine withdrawal, ethanol withdrawal, severe generalized anxiety disorder, periprocedural anesthesia, end-of-life care High rate of physical dependence; very sedating Benzodiazepine-receptor agonists that have adverse events similar to those of benzodiazepines in older adults (e.g., delirium, falls, fractures); minimal improvement in sleep latency and duration Avoid High Avoid Moderate Avoid benzodiazepines for treatment of insomnia, agitation, or delirium Avoid Avoid chronic use (>90 days) High Moderate Moderate R: recommendation, TCA: tri-cyclic antidepressant. 고있다. 노인에서항콜린, 진정작용의발현빈도가높다고알 려진대부분의근이완제은가급적처방을피하도록권고하고 있다 (Table 3). 마지막으로 2012 AGS Beers Criteria 에서는자체적인제 한점으로각종처방적정성연구에서파악되지않는노인환 자들이다수있을수있는점, 노화에특이적이지않는일반 11
Table 3. Potentially Inappropriate Medications Associated with Dizziness in 2012 American Geriatrics Society Beers Criteria (Analgesics and Skeletal Muscle Relaxants) Therapeutic category or drug Rationale R Quality of evidence Strength of R Pain Meperidine Indomethacin Pentazocine Skeletal muscle relaxants Chlorzoxazone Cyclobenzaprine Methocarbamol Orphenadrine R: recommendation. Not an effective oral analgesic in dosages commonly used; may cause neurotoxicity; safer alternatives available Increases risk of GI bleeding and peptic ulcer disease in high-risk groups. Of all the NSAIDs, indomethacin has most adverse effects Opioid analgesic that causes CNS adverse effects, including confusion and hallucinations, more commonly than other narcotic drugs; is also a mixed agonist and antagonist; safer alternatives available Most muscle relaxants are poorly tolerated by older adults because of anticholinergic adverse effects, sedation, risk of fracture; effectiveness at dosages tolerated by older adults is questionable Avoid High Avoid Moderate Avoid Low Avoid Moderate 적인부적절약물들까지광범위하게정리되지는않은점, 그리고부적절한약물분류에속하지만증세호전을위해불가피하게사용될수밖에없는완화치료나호스피스환경에서의처방이반영되지않은점등을들고있다. 이러한사항들을고려하여노인환자들의약물처방에있어각신체조건과질환, 치료목적에따른개별적인접근이필요함을강조하고있다. 3) 노인환자에서의약물처방원칙일반적으로노인에게는처방없이복용하는일반의약품 (over-the-counter, OTC) 이반드시있을거라는전제하에문진을해야하며앞으로의치료계획, 약복용의이유와방법들을쉽고분명한말투로설명해주어야한다. 또한동반된내과질환과인지저하, 우울증, 불안증등의정신과질환에대한고려도약물부작용을줄이고약물순응도를높이기위해필요하다. 2 이러한노인의약물처방에서부작용의빈도를줄이고, 최적의치료효과를얻기위해서는다음과같은몇가지중요한지 침이추천된다. 11 첫째, 현재복용중인약물에대한조사가철저하게이루어져야한다. 가능하다면복용중인모든약물을가져오라고하여검토해야하며, 알레르기및약물부작용에대한병력, 음주, 흡연, 카페인등기분전환용약물에대해서도조사를해야한다. 둘째, 약물을처방해야하는가장최적의시점을찾는다. 진단이불분명하거나증상이경미하거나비특이적일때, 혹은약물치료의유용성을확신할수없을경우에는약물을처방하지않는다. 따라서매번방문할때마다약물목록을검토하고개편하여, 더이상적응증이되지않는약물은복용을중지시켜야한다. 한시적으로사용되는약물과처방이필요없는일반의약품 (OTC) 에대해서도감시해야한다. 셋째, 자신이처방한약물에대한완벽한지식을갖고있어야한다. 처방한약물에대한약리학적및약동학적특성과부작용, 독성등에대해충분히숙지해야한다. 넷째, 저용량으로시작하고서서히적정 (titration) 해야한다. 항상필요한최소용량을투여해야한다. 12
다섯째, 환자의상태와질환에적합한약물치료를해야한다. 치료목적을달성하기위해충분한용량을충분한기간동안사용해야한다. 여섯째, 약물치료의순응도 (compliance) 를높여야한다. 치료목표를설명하고여기에도달하기위해환자및보호자들과충분한의사소통을해야한다. 약복용법, 비용, 부작용등을문서화한안내문배포도고려해야한다. 일곱째, 새로운약물투여에대해서는신중하게접근해야한다. 대부분의약물들은노인들을대상으로철저하게평가되기가어렵기때문에, Beers criteria 같은부적절약물목록을적극적으로참고하고최근개정여부를확인한다. 결론 노인에서는분포용적의변화와신장의사구체여과율의저하로약물의부작용이발생하기쉽다. 이러한 65세이상노인에서처방하기에부적절한약물들의목록을미국노인의학회가주도하여정리한 beers criteria가있고, 이를통해어지럼증을흔히일으키는약물의종류를확인할수있다. 만일특별한이유없이어지럼증을호소하는노인이있다면, 약물복용력을면밀히검토하는작업이선행되어야하며, 약물처방원칙에입각하여약물의유지여부및용량조절을신중히결정해야한다. REFERENCES 1. Lee TK, Sung KB. Diagnostic approaches to the patient with dizziness. J Korean Med Assoc 2008;51:960-974 2. Hong CH, Oh BH. Inappropriate prescribing in the elderly patients. J Korean Med Assoc 2009;52:91-99 3. Jansen PA, Brouwers JR. Clinical pharmacology in old persons. Scientifica (Cairo) 2012;2012:1-17 4. Beers MH, Ouslander JG, Rollingher I, Reuben DB, Brooks J, Beck JC. Explicit criteria for determining inappropriate medication use in nursing home residents. Arch Intern Med 1991;151:1825-1832 5. Beers MH. Explicit criteria for determining potentially inappropriate medication use by the elderly. An update. Arch Intern Med 1997;157:1531-1536 6. Fick DM, Cooper JW, Wade WE, Waller JL, Maclean JR, Beers MH. Updating the beers criteria for potentially inappropriate medication use in older adults: results of a US consensus panel of experts. Arch Intern Med 2003; 163:2716-2724 7. The American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2012;60:616-631 8. Jang IY, Lee YS, Jeon MK, Cho H, Oh JS, Lee Y, et al. Potentially inappropriate medications in elderly outpatients by the 2012 version of beers criteria: a single tertiary medical center experience in South Korea. J Korean Geriatr Soc 2013;17:126-133 9. Lee JH, Roh JH, Suh YW, Lee JH, Lee ES, Lee BK, et al. Comparison between beers criteria and screening tool of older person's prescriptions as a screening tool for the detection of potentially inappropriate medicines and adverse drug events in the elderly patients. J Korean Geriatr Soc 2013;17:28-36 10. Oliveira MG, Amorim WW, de Jesus SR, Heine JM, Coqueiro HL, Passos LC. A comparison of the beers and STOPP criteria for identifying the use of potentially inappropriate medications among elderly patients in primary care. J Eval Clin Pract 2015;21:320-325 11. Bergman-Evans B. Evidence-based guideline. Improving medication management for older adult clients. J Gerontol Nurs 2006;32:6-14 13