untitled

Size: px

Start display at page:

Download "untitled"

주원 비
5 years ago
Views:

1 노인에서약동학적특징과다약제사용시주의점 이상화 이화여자대학교의과대학가정의학교실 목차 서론 노화에따른약물체내반응의변화 약물의흡수, 분포, 대사, 제거, 약력학 약물처방 Beer s Criteria 서론 미국에서병원에입원하는환자의 28% 는약물과관련된문제 (70% 는약부작용 ). 우리나라노인의 86.7% 가만성질환에이환. 지역사회거주노인은 3.3 개의만성질환. 입원노인환자는 4.5 개의질환에이환. 미국의경우약처방건수의 30% 이상이노인들에게처방. 대부분의노인은 3~5 개의처방약을복용. 노인에서약부작용의흔한순서 Some changes related to aging that affect pharmacokinetics of drugs 향정신병약 (23%) 항생제 (20%) 항우울제 (13%) 안정제 (13%) 항응고제 (9%) 항경련제 (9%) 심혈관약제 (6%) 혈당강하제 (5%) 비마약성진통제 (4%) 마약성진통제 (2%) 파킨슨약 (2%) 위장관약 (2%) Variables Body water (% of body weight) Lean body mass (% of body weight) Body fat (% of the body weight) Serum albumin (g/dl) Kidney weight (% of young adult) Young Adults (20-30years) (women) 18-20(men) 4.7 (100) Older Adults (60-80years) Hepatic blood flow (% of the body weight) (100)

2 노화에따른약물체내반응의변화 표 1. 약물반응과관련된노화에따른생리적변화와의미 약동학적과정생리적변화임상적의미 노인의약물역동 (pharmacokinetics) 은노화에따른생리적변화들이약물의흡수, 분포, 대사와제거의과정에영향을미치기때문에일반성인과다르게나타난다 ( 표 1). 가령에따르는생리적변화의영향은개인별차이가크고매우다양하므로예측하기가어렵다. 동일연령에서도더취약한경우가발생 노인환자개개인에대해서질병상태, 수분섭취상태, 영양상태, 심박출량이나소변량등에대한충분한고려를통하여얼마나특정약물에대해약물학적인영향을받는가를판단 흡수 분포 대사 제거 수용체감수성 흡수면적감소, 내장혈행감소, 위내산도증가, 위장관운동변화 체내총수분량감소, 제지방체질량감소, 체지방증가, 혈청알부민감소, 단백결합변화 간중량감소, 간혈류량감소, 제 1 상대사 ( 청소율 ) 감소 신장혈류량감소, 사구체여과율감소, 세뇨관분비기능감소 수용체수의변화, 수용체결합변화, 2 차전령물질기능의변화, 세포및핵의반응변화 연령증가에따른흡수차이는없음 지용성약물의반감기및분포증가, 일부단백결합약물의유리형증가 1 차통과대사감소, 약물의생물학적전환감소 신장의약물제거능력감소, 약물제거의개인차증가 약물에대한과대반응및반응저하 약물의분포 약물의분포 체지방의증가, 수분량감소, 제지방체질량감소 : 지용성약물의분포는늘어나고수용성약물의분포는줄어든다. 지용성약물은분포용적이커져약물의혈중농도가낮아지고반감기가길어지며작용시간이연장된다. - Diazepam 의분포량은두배로증가하고반감기는 20 세 20 시간, 70 세는 75~80 시간. - amiodarone, desipramine, diazepam, haloperidol 수용성약물 : digoxin, 분포용적이작아지므로약물투여후초기의혈장농도는증가한다. - 대부분의약물 : procainamide, propranolol, atenolol, sotalol, theophylline, hydrochlorthiazide, antibiotics, sedative-hypnotics 많은약물이혈청단백질과결합 Basic drug : α1-acid glycoprotein 과결합, 변화없음 Acidic drug : albumin 과결합, - 노인에서감소, 만성질환이있는경우크게감소 - heart failure, renal disease, hepatic cirrhosis, RA, malignancy - phenytoin, diazepam, warfarin, digoxin, aspirin, naproxen, thyroid hormone, theophylline - 약물의부작용이나독성이증가 약물의대사 제 1 상대사 : 약물의산화와환원. Cytochrome P450(CYP) 의작용. CYP 3A4 가가제일중요한역할을하는 cytochrome P450 은약 60% 가간에존재. 노인은이제 1 상대사가감소한다 ( 표 2). 제 2 상대사 : 약물이나그대사산물을접합 (conjugation). 연령에따라큰차이가없다

3 이상화 : 노인에서약동학적특징과다약제사용시주의점 표 2. CYP 3A4로대사되거나활동이억제또는촉진하는약물들대사되는약물활성억제약물활성촉진약물 약물의제거 항불안제 Alprazolam Clonazepam Midazolam Triazolam 칼슘길항제 Amlodipine Diltiazem Verapamil 심혈관계 Lovastatin Pravastatin Atorvastatin Losartan Disopyramide Cisapride Warfarin 항진균제 Fluconazole Itraconazole Ketoconazole 항균제 Clarithromycin Erythromycin Metronidazole Norfloxacin 항우울제 SSRI (Fluoxetine) Nefazodone Omeprazole Protease inhibitors Cimetidine grapefruit juice 항경련제 Phenobarbital Carbamazepine Phenytoin 항균제 Rifampin Troglitazone 연령이증가하면서사구체여과율과세뇨관의기능이모두감소. 평균크레아티닌청소율은 25 세에서 85 세까지 50% 줄어든다. 노인에서혈중크레아티닌농도는실제보다과대평가되는경우가많기때문에 Cockroft- Gault 공식을이용하는것이실용적이다. 크레아티닌청소율 = (140- 연령 ) x 체중 (kg) / 72 x ( 혈청크레아티닌 ) ( 여성 : 0.85) 신기능의감소시용량조절이필요한약들 : digoxin, chlorpropamide, indomethacin, metformin, atenolol, methotrexate, procainamide, salicylic acid, many antibiotics Digoxin : 0.125mg/d 초과하면부작용이흔하다. 약력학 (Pharmacodynamics) 노인에서약물치료관련문제의주요원인들 생화학적및생리적인약리기전 노화의영향이제대로밝혀져있지않다. 약물효과의민감도는나이가들어감에따라증가할수도있고감소할수도있다. Diazepam 과같은벤조디아제핀계약물의진정효과는더민감하지만, isoproterenol 이나 propranolol 같은베타아드레날린성수용체에의해매개되는약물의효과에는덜민감하다. 85 세이상의연령 6 가지이상의만성질환 신기능의저하 ( 크레아티닌청소율 < 50mL/min) 낮은체중또는체질량지수 9 개이상의복용약물 하루 12 회이상의약물복용 이전의약물부작용경험 Practical steps to consider in optimizing drug regimens for older adults Review current drug therapy Discontinue unnecessary therapy Consider adverse drug events as a potential cause for any new symptom Consider nonpharmacologic approach Substitute with safer alternative Reduce the dose Beer s Criteria 65 세이상의노인환자에게사용되는약물에대해서주의가필요한약물에대해광범위한문헌검색및노인병진료에관련된의료진및전문가집단의평가에기초 The following medications should be avoided or used very cautiously in persons aged 65 years and over, independent of their health conditions and diagnoses

4 Drug name or class Propoxyphene (Darvon) and combination products (Darvocet-N, Darvon-N, Darvon with ASA) Indomethacin (Indocin and Indocin SR) Pentazocine (Talwin) Muscle relaxants and antispasmodics: Most muscle relaxants and antispasmodic drugs are poorly methocarbamol (Robaxin), tolerated by elderly patients, since these cause anticholinergic carisoprodol(soma), chlorzoxazone(paraflex), adverse effects, sedation, and weakness. Additionally, their metaxalone(skelaxin), effectiveness at doses tolerated by elderly patients is cyclobenzaprine(flexeril), and questionable. oxybutynin(ditropan). Do not consider the exteded-release Ditropan XL. Flurazepam(Dalmane) Amitriptyline(Elavil), chlordiazepoxideamitriptyline(limbitrol), and perphenazineamitriptyline(travil) commnents Offers few analgesic advantages over acetaminophen, yet has the adverse effects of other narcotic drugs. Of all available nonsteroidal anti-inflammatory drugs, this drug produces the most CNS adverse effects. Narcotic analgesic that causes more CNS adverse effects, including confusion and hallucinations, more commonly than other narcotic drugs. Additionally, it is a mixed agonist and antagonist. This benzodiazepine hypnotic has an extremely long half-life in elderly patients (often days), producing prolonged sedation and increasing the incidence of falls and fracture. Medium- or shortacting benzodiazepines are preferable. Because of its strong anticholinergic and sedation properties, amitriptyline is rarely the antidepressant of choice for elderly patients. Severity (high or low) Doxepin(Sinequan) Meprobamate (Miltown and Equanil) Doses of short-acting benzodiazepines: Because of increased sensitivity to benzodiazepines in elderly doses greater than lorazepam (Ativan) 3mg, patients, smaller doses may be effective as well as safer. Total oxazepam (Serax) 60mg, triazolam (Halcion) daily doses should rarely exceed the suggested maximums. 0.25mg, alprazolam (Xanax) 2mg, temazepam (Restoril) 15mg Long-acting benzodiazepines: chlordiazepoxide(alone or in combination:librium, Librax), diazepam (Valium),quazepam(Doral), halazepam(paxipam), and chlorazepate (Tranxene) Digoxin (Lanoxin) (should not exceed mg/d except when treating atrial arrhythmias) Short-acting dipyridamole (Persantine). Do not consider the long-acting dipyridamole(which has better properties than the short-acting in older adults) except with patients with artificial heart valves Because of its strong anticholinergic and sedation properties, doxepin is rarely the antidepressant of choice for elderly patients. This is a highly addictive and sedating anxiolytic. Those using meprobamate for prolonged periods may become addicted and may need to be withdrawn slowly. These drugs have a long half-life in elderly patients (often several days), producing prolonged sedation and increasing the risk of falls and fractures. Short- and intermediate-acting benzodiazepines are preferred If benzodiazepine therapy is required. Decreased renal clearance may lead to increased risk of toxic effect. May cause orthostatic hypotension. Methyldopa (Aldomet) Methyldopa-hydrochlorothiazide (Aldoril) Reserpine at doses > 0.25mg Chlorpropamide (Diabinese) Anticholinergics and antihistamines chlorpheniramine (Chlor-Trimeton), diphenhydramine (Benadryl), hydroxyzine (Vistaril and Atarax), cyprohetadine (Periactin), promethazine(phenergan), tripelennamine, dexchlorpheniramine(polaramine) May cause bradycardia and can exacerbate depression in elderly patients. May induce depression, impotence, sedation, and orthostatic hypotension. It has a prolonged half-life in elderly patients and could cause prolonged hypoglycemia. Additionally, it is the only oral hypoglycemic agent that causes SIADH. GI antispasmodic drugs: dicyclomine GI antispasmodic drugs highly anticholinergic and have (Bentyl), hyoscyamine(levsin and uncertain effectiveness. These drugs should be avoided Levsinex), propantheline(pro-banthine), (especially for long-term use). belladonna alkaloids(donnatal and others), and clidinium-chlordiazepoxide(librax) All nonprescription and many prescription antihistamines can have potent anticholinergic properties. Nonanticholinergic antihistamines are preferred in elderly patients when treating allergic reactions. Ferrous Sulfate >325mg/d All barbiturates (except phenobarbital) except when used to control seizure Meperidine (Demerol) Ticlopidine (Ticlid) Ketorolac(Toradol) Amphetamines and anorexic agents Doses >325mg/d do not dramatically increase the amount absorbed but greatly increase the incidence of constipation. Are highly addictive and cause more adverse effects than most sedative or hypnotic drugs in elderly patients. Not an effective oral analgesic in doses commonly used. May cause confusion and has many disadvantages to other narcotic drugs. Has been shown to be better than aspirin in preventing clotting and may be considerably more toxic. Safer, more effective alternatives exist. Immediate and long-term use should be avoided in older persons, since a significant number have asymptomatic GI pathologic conditions These drugs have potential for causing dependence, hypertension, angina, and myocardial infarction. Diphenhydramine (Benadryl) Ergot Mesyloids (Hydergine) and Cyclandelate May cause confusion and sedation. Should not be used as hypnotics, and when used to treat emergency allergic reactions, it should be used in the smallest possible doses. Have not been shown effective in the doses studied. Long-term use of full-dosage, longer half-life, non-cox selective NSAIDs: naproxen (Naprosyn, Avaprox,and Aleve), oxaprozin(daypro), and piroxicam (Feldene) Have the potential to produce GI bleeding, renal failure, high blood pressure, and heart failure. Daily Fluoxetine (Prozac) Long half-life of drug and risk of producing excessive CNS stimulation, sleep disturbances, and increasing agitation. Safer alternatives exist. Nitrofurantoin (Macrodantin) Potential for renal impairment. Safer alternatives available. Long-term use of stimulant laxatives: bisacodyl (Dulcolax),Cascara sagrade, and Neoloid except in the presence of opiate analgesic use Amiodarone (Cordarone) May exacerbate bowel dysfunction. Associated with QT interval problems and risk of provoking torsades de pointes. Lack of efficacy in older adults. Doxazosin (Cardura) Methyltestosterone (Android, Virilon, and Testrad) Potential for hypotension, dry mouth, and urinary problems. Potential for prostatic hypertrophy and cardiac problems. Orphenadrine (Norflex) Causes more sedation and anticholinergic adverse effects than safer alternatives Thioridazine (Mellaril) Greater potential for CNS and extrapyramidal side effects. Guanethidine (Ismetin) May cause orthostatic hypotension. Safer alternatives exist. Mesoridazine (Serentil) CNS and extrapyramidal adverse effects. Guanadrel (Hylorel) May cause orthostatic hypotension. Cyclandelate (Cyclospasmol) Isoxsurpine (Vasodilan) Lack of efficacy Lack of efficacy Short-acting nifedipine (Procardia and Adalat) Potential for hypotension and constipation

5 이상화 : 노인에서약동학적특징과다약제사용시주의점 Clonidine (Catapres) Mineral oil Cimetidine (Tagamet) Ethacrynic acid (Edecrin) Potential for orthostatic hypotension and CNS adverse effects. Potential for aspiration and adverse effects. Safer alternatives are available. CNS adverse effects including confusion. Potential for hypotension and fluid imbalances. Safer alternatives are available. Beer s Criteria The following medications should be avoided in persons aged 65 years and over, who have the following health conditions and diagnoses Desiccated thyroid Concerns about cardiac effects. Safer alternatives are available. Amphetamines (excluding methylphenidate HCl and anorexics) CNS stimulation adverse effects. Estrogens only (oral) Evidence of the carcinogenic (breast and endometrial cancer) potential of these agents and lack of cardioprotective effect in older women. Disease or Condition Heart Failure Hypertension Gastric or duodenal ulcers Seizure disorders Drug Name or Class Disopyramide (Norpace), and high sodium content drugs (sodium and sodium salts [alginate bicarbonate, biphosphate, citrate, phosphate, salicylate and sulfate]) Phenylpropanolamine HCl (removed from the market in 2001), pseudoephedrine, diet pills, and amphetamines NSAIDs (COX-2 inhibitors excluded) and aspirin >325mg/d Clozapine (Clozaril), chlorpromazine (Thorazine), thioridazine (Mellaril), and thiothixene (Navane) Disorders of blood clotting Aspirin, NSAIDs, dipyridamole (Persantin), (including anticoagulant ticlopidine (Ticlid), and clopidogrel (Plavix) therapy) Comments Negative inotropic effect. Potential to promote fluid retention and exacerbation of heart failure. May produce elevation of blood pressure secondary to Sympathomimetic activity. May exacerbate existing ulcer disease or produce new/additional ulcers. May lower the seizure threshold. May prolong clotting time and elevate INR values or inhibit platelet aggregation, resulting in an increased potential for bleeding. Severity Bladder outflow obstruction Stress incontinence Arrhythmias Insomnia Parkinson's Disease Anticholinergics and antihistamines, gastrointestinal May decrease urinary flow, antispasmodics, muscle relaxants, oxybutynin leading to urinary retention. (Ditropan), flavoxate (Urispas), antidepressants, decongestants, and tolterodine (Detrol) alpha-blockers (Doxazosin, Prazosin, and Terazosin), tricyclic antidepressants (imipramine, doxepin and, and long-acting benzodiazepines Tricyclic antidepressants (imipramine, doxepin and Decongestants, theophylline (Theodur), methylphenidate (Ritalin), MAOIs, and amphetamines Metoclopramide (Reglan), conventional antipsychotics and tacrine (Cognex) May produce polyuria and worsening of incontinence. Concern due to proarrhythmic effects and ability to produce QT interval changes. Concern due to CNS stimulant effects. Concern due to their antidopaminergic/ anticholinergic effects. Cognitive Impairment Depression Barbiturates, anticholinergics, antispasmodics, and muscle relaxants. CNS stimulants: DextroAmphetamine (Adderall), methylphenidate (Ritalin), methamphetamine (Desoxyn), pemolin, Long-term benzodiazepine use. Sympatholytic agents: methyldopa (Aldomet), reserpine, guanethidine (Ismelin) Concern due to CNSaltering effects. May produce or exacerbate depression. Seizure disorder Obesity Bupropion (Wellbutrin) Olanzapine (Zyprexa) May lower the seizure threshold. May stimulate appetite and increase weight gain. Anorexia and malnutrition Syncope or falls SIADH/hyponatremia CNS stimulants: DextroAmpehtamine (Adderall), methylphenidate (Ritalin), methamphetamine (Desoxyn), pemolin, and fluoxetine (Prozac) Short- to intermediate-acting benzodiazepines and tricyclic antidepressants (imipramine, doxepin and SSRIs: fluoxetine (Prozac), citalopram (Celexa), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft) Concern due to appetitesuppressing effects. May produce ataxia, impaired psychomotor function, syncope, and additional falls. May exacerbate or cause SIADH. COPD Chronic constipation Long-acting benzodiazepines: Chlordiazepoxide (alone or in combination: Librium, Librax, Limbitrol), Diazepam (Valium), Quazepam (Doral), Halazepam (Paxipam), and Chlorazepate (Tranxene); Betablockers: propranolol Calcium channel blockers, anticholinergics, and tricyclic antidepressants (imipramine, doxepin and CNS adverse effects. May induce respiratory depression. May exacerbate or cause respiratory depression. May exacerbate constipation

untitled

untitled 年類臨療 ˍˍˍˍˍˍˍ 不 80 1.25 2 1~80 不 1 療女 pyelonephritis 療 Trimethoprim / Sulfamethoxazole Nitrofurantoin Amoxicillin Metronidazole 2 若降都列不度量都不量 3 見 Klebsiella spp. E. coli Proteus spp. Candida