노인에서 약동학적 특징과 다약제 사용시 주의점

노인에서 약동학적 특징과 다약제 사용시 주의점

이 상 화

이화여자대학교 의과대학 가정의학교실

목차

„ 서론

„ 노화에 따른 약물 체내 반응의 변화

약물의 흡수 , 분포, 대사, 제거, 약력학

„ 약물 처방

„ Beer’s Criteria

서론

„ 미국에서 병원에 입원하는 환자의 28%는 약 물과 관련된 문제(70%는 약 부작용).

„ 우리나라 노인의 86.7%가 만성질환에 이환.

지역사회 거주노인은 3.3개의 만성 질환. 입 원 노인환자는 4.5개의 질환에 이환.

„ 미국의 경우 약 처방 건수의 30% 이상이 노 인들에게 처방. 대부분의 노인은 3~5개의 처 방약을 복용.

노인에서 약 부작용의 흔한 순서

„ 향정신병약(23%)

„ 항생제(20%)

„ 항우울제(13%)

„ 안정제(13%)

„ 항응고제(9%)

„ 항경련제(9%)

„ 심혈관 약제(6%)

„ 혈당강하제(5%)

„ 비마약성 진통제(4%)

„ 마약성 진통제(2%)

„ 파킨슨약(2%)

„ 위장관약(2%)

Some changes related to aging that affect pharmacokinetics of drugs

55-60 (100)

Hepatic blood flow (% of the body weight)

80 (100)

Kidney weight (% of young adult)

3.8 4.7

Serum albumin (g/dL)

38-45 36-38 26-33(women)

18-20(men) Body fat (% of the body weight)

12 19

Lean body mass (% of body weight)

53 61

Body water (% of body weight)

Older Adults (60-80years) Young Adults

(20-30years) Variables

노화에 따른 약물 체내반응의 변화

„

노인의 약물 역동(pharmacokinetics)은 노화에 따른 생리적 변화들이 약물의 흡수, 분포, 대사와 제거의 과정에 영향을 미치기 때문에 일반 성인과 다르게 나타난다(표 1).

„

가령에 따르는 생리적 변화의 영향은 개인별 차이가 크고 매우 다양하므로 예측하기가 어렵다.

„

동일 연령에서도 더 취약한 경우가 발생

„

노인 환자 개개인에 대해서 질병 상태 , 수분 섭취 상태, 영 양 상태, 심박출량이나 소변량 등에 대한 충분한 고려를 통 하여 얼마나 특정 약물에 대해 약물학적인 영향을 받는가 를 판단

표

약물에 대한 과대 반응 및 반응 저하 수용체 수의 변화, 수용체 결합 변화,

2차 전령물질 기능의 변화, 세포 및 핵의 반응 변화 수용체 감수성

신장의 약물 제거능력 감소, 약물 제거의 개인차 증가 신장 혈류량 감소, 사구체 여과율 감소,

세뇨관 분비기능 감소 제거

1차 통과 대사 감소, 약물의 생물학적 전환 감소 간 중량 감소, 간 혈류량 감소,

제1상 대사(청소율) 감소 대사

지용성 약물의 반감기 및 분포 증가, 일부 단백결합 약물의 유리형 증가 체내 총 수분량 감소, 제지방 체질량 감소,

체지방 증가, 혈청 알부민 감소, 단백결합 변화 분포

연령 증가에 따른 흡수 차이는 없음 흡수면적 감소, 내장혈행 감소, 위내 산도 증가,

위장관 운동변화 흡수

임상적 의미 생리적 변화

약동학적 과정

약물의 분포

„

체지방의 증가, 수분량 감소, 제지방 체질량 감소 : 지용성 약물의 분포는 늘어나고 수용성 약물의 분포는 줄어든다 .

„

지용성 약물은분포용적이 커져 약물의 혈중농도가 낮아지고 반감기가 길어지며 작용시간이 연장된다.

-

- amiodarone, desipramine, diazepam, haloperidol

„

수용성 약물 : digoxin, 분포용적이 작아지므로 약물 투여 후 초 기의 혈장농도는 증가한다.

- 대부분의 약물 : procainamide, propranolol, atenolol, sotalol,

theophylline, hydrochlorthiazide, antibiotics, sedative-hypnotics

약물의 분포

„ 많은 약물이 혈청 단백질과 결합

„ Basic drug : α1-acid glycoprotein과 결합, 변화없음

„ Acidic drug : albumin과 결합 ,

- 노인에서 감소, 만성질환이 있는 경우 크게 감소 - heart failure, renal disease, hepatic cirrhosis, RA,

malignancy

- phenytoin, diazepam, warfarin, digoxin, aspirin, naproxen, thyroid hormone, theophylline

- 약물의 부작용이나 독성이 증가

약물의 대사

„ 제1상 대사 : 약물의 산화와 환원. Cytochrome P450(CYP)의 작용. CYP 3A4가 가 제일 중요한 역할을 하는 cytochrome P450은 약 60%가 간 에 존재. 노인은 이 제1상 대사가 감소한다 (표 2).

„ 제2상 대사 : 약물이나 그 대사산물을 접합 (conjugation). 연령에 따라 큰 차이가 없다.

표2. CYP 3A4로 대사되거나 활동이 억제 또는 촉진하는 약물들

항경련제 Phenobarbital Carbamazepine Phenytoin

항균제 Rifampin

기타 Troglitazone 항진균제

Fluconazole Itraconazole Ketoconazole 항균제

Clarithromycin Erythromycin Metronidazole Norfloxacin 항우울제

SSRI (Fluoxetine) Nefazodone 기타

Omeprazole Protease inhibitors Cimetidine grapefruit juice 항불안제

Alprazolam Clonazepam Midazolam Triazolam 칼슘길항제

Amlodipine Diltiazem Verapamil 심혈관계 Lovastatin Pravastatin Atorvastatin Losartan Disopyramide 기타

Cisapride Warfarin

활성 촉진 약물 활성 억제 약물

대사되는 약물

약물의 제거

„ 연령이 증가하면서 사구체 여과율과 세뇨관의 기 능이 모두 감소.

„ 평균 크레아티닌 청소율은 25세에서 85세까지 50%

줄어든다. 노인에서 혈중 크레아티닌 농도는 실제 보다 과대평가되는 경우가 많기 때문에 Cockroft- Gault 공식을 이용하는 것이 실용적이다.

„ 크레아티닌 청소율 =

(140-연령) x 체중(kg) / 72 x (혈청 크레아티닌) (여성 : 0.85)

„ 신기능의 감소시 용량 조절이 필요한 약들 : digoxin, chlorpropamide, indomethacin, metformin, atenolol, methotrexate, procainamide, salicylic acid, many antibiotics

„ Digoxin : 0.125mg/d 초과하면 부작용이 흔하다.

약력학(Pharmacodynamics)

„ 생화학적 및 생리적인 약리기전

„ 노화의 영향이 제대로 밝혀져 있지 않다.

„ 약물 효과의 민감도는 나이가 들어감에 따라 증가 할 수도 있고 감소할 수도 있다.

„ Diazepam과 같은 벤조디아제핀계 약물의 진정효 과는 더 민감하지만, isoproterenol이나 propranolol같 은 베타아드레날린성 수용체에 의해 매개되는 약 물의 효과에는 덜 민감하다.

노인에서 약물치료 관련 문제의 주요 원인들

„ 85세 이상의 연령

„ 6가지 이상의 만성 질환

„ 신기능의 저하(크레아티닌 청소율 < 50mL/min)

„ 낮은 체중 또는 체질량 지수

„ 9개 이상의 복용 약물

„ 하루 12회 이상의 약물 복용

„ 이전의 약물 부작용 경험

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

„ 65세 이상의 노인 환자에게 사용되는 약물에 대해

서 주의가 필요한 약물에 대해 광범위한 문헌 검색

및 노인병 진료에 관련된 의료진 및 전문가 집단의 평가에 기초

„ The following medications should be avoided or used very

cautiously in persons aged 65 years and over, independent

of their health conditions and diagnoses

High Because of its strong anticholinergic and sedation properties, amitriptyline is rarely the antidepressant of choice for elderly patients.

Amitriptyline(Elavil), chlordiazepoxide- amitriptyline(Limbitrol), and perphenazine- amitriptyline(Travil)

High This benzodiazepine hypnotic has an extremely long half-lifein elderly patients (often days), producing prolonged sedation and increasing the incidence of falls and fracture. Medium- or short- acting benzodiazepines are preferable.

Flurazepam(Dalmane)

High Most muscle relaxants and antispasmodic drugs are poorly tolerated by elderly patients, since these cause anticholinergic adverse effects, sedation, and weakness. Additionally, their effectiveness at doses tolerated by elderly patients is questionable.

Muscle relaxants and antispasmodics:

methocarbamol (Robaxin), carisoprodol(Soma), chlorzoxazone(Paraflex), metaxalone(Skelaxin),

cyclobenzaprine(Flexeril), and oxybutynin(Ditropan). Do not consider the exteded-release Ditropan XL.

High 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.

Pentazocine (Talwin)

High Of all available nonsteroidal anti-inflammatory drugs, this drug produces the most CNS adverse effects.

Indomethacin (Indocin and Indocin SR)

Low Offers few analgesic advantages over acetaminophen, yet has the adverse effects of other narcotic drugs.

Propoxyphene (Darvon) and combination products (Darvocet-N, Darvon-N, Darvon with ASA)

Severity (high or low) commnents

Drug name or class

High Because of increased sensitivity to benzodiazepines in elderly patients, smaller doses may be effective as well as safer. Total daily doses should rarely exceed the suggested maximums.

Doses of short-acting benzodiazepines:

doses greater than lorazepam (Ativan) 3mg, oxazepam (Serax) 60mg, triazolam (Halcion) 0.25mg, alprazolam (Xanax) 2mg, temazepam (Restoril) 15mg

Low Decreased renal clearance may lead to increased risk of toxic effect.

Digoxin (Lanoxin) (should not exceed 0.125 mg/d except when treating atrial arrhythmias)

Low May cause orthostatic hypotension.

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

High 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.

Long-acting benzodiazepines:

chlordiazepoxide(alone or in combination:Librium, Librax), diazepam (Valium),quazepam(Doral), halazepam(Paxipam), and chlorazepate (Tranxene)

High Because of its strong anticholinergic and sedation properties, doxepin is rarely the antidepressant of choice for elderly patients.

Doxepin(Sinequan)

High This is a highly addictive and sedating anxiolytic. Those using meprobamate for prolonged periods may become addicted and may need to be withdrawn slowly.

Meprobamate (Miltown and Equanil)

High 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.

Diphenhydramine (Benadryl)

High All nonprescription and many prescription antihistamines can have potent anticholinergic properties. Nonanticholinergic antihistamines are preferred in elderly patients when treating allergic reactions.

Anticholinergics and antihistamines chlorpheniramine (Chlor-Trimeton), diphenhydramine (Benadryl), hydroxyzine (Vistaril and Atarax), cyprohetadine (Periactin), promethazine(phenergan), tripelennamine, dexchlorpheniramine(Polaramine)

High May cause bradycardia and can exacerbate depression in elderly patients.

Methyldopa (Aldomet) Methyldopa-hydrochlorothiazide (Aldoril)

Low May induce depression, impotence, sedation, and orthostatic hypotension.

Reserpine at doses > 0.25mg

High GI antispasmodic drugs highly anticholinergic and have uncertain effectiveness. These drugs should be avoided (especially for long-term use).

GI antispasmodic drugs: dicyclomine (Bentyl), hyoscyamine(Levsin and Levsinex), propantheline(Pro-Banthine), belladonna alkaloids(Donnatal and others), and clidinium-chlordiazepoxide(Librax)

Low Have not been shown effective in the doses studied.

Ergot Mesyloids (Hydergine)and Cyclandelate

High 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.

Chlorpropamide (Diabinese)

High Has been shown to be better than aspirin in preventing clotting and may be considerably more toxic. Safer, more effective alternatives exist.

Ticlopidine (Ticlid)

High These drugs have potential for causing dependence, hypertension, angina, and myocardial infarction.

Amphetamines and anorexic agents

High Have the potential to produce GI bleeding, renal failure, high blood pressure, and heart failure.

Long-term use of full-dosage, longer half-life, non-COX selective NSAIDs:

naproxen (Naprosyn, Avaprox,and Aleve), oxaprozin(Daypro), and piroxicam (Feldene)

High Immediate and long-term use should be avoided in older persons, since a significant number have asymptomatic GI pathologic conditions

Ketorolac(Toradol)

High Are highly addictive and cause more adverse effects than most sedative or hypnotic drugs in elderly patients.

All barbiturates (except phenobarbital) except when used to control seizure

High Not an effective oral analgesic in doses commonly used. May cause confusion and has many disadvantagesto other narcotic drugs.

Meperidine (Demerol)

Low Doses >325mg/d do not dramatically increase the amount absorbed but greatly increase the incidence of constipation.

Ferrous Sulfate >325mg/d

Low Lack of efficacy

Cyclandelate (Cyclospasmol)

Low Lack of efficacy

Isoxsurpine (Vasodilan)

High May cause orthostatic hypotension.

Guanadrel (Hylorel)

High May cause orthostatic hypotension. Safer alternatives exist.

Guanethidine (Ismetin)

High Causes more sedation and anticholinergic adverse effects than safer alternatives

Orphenadrine (Norflex)

High Associated with QT interval problems and risk of provoking torsades de pointes. Lack of efficacy in older adults.

Amiodarone (Cordarone)

High May exacerbate bowel dysfunction.

Long-term use of stimulant laxatives:

bisacodyl (Dulcolax),Cascara sagrade, and Neoloid except in the presence of opiate analgesic use

High Long half-life of drug and risk of producing excessive CNS stimulation, sleep disturbances, and increasing agitation. Safer alternatives exist.

Daily Fluoxetine (Prozac)

High CNS and extrapyramidal adverse effects.

Mesoridazine (Serentil)

High Potential for hypotension and constipation.

Short-acting nifedipine (Procardia and Adalat)

High Greater potential for CNS and extrapyramidal side effects.

Thioridazine (Mellaril)

High Potential for prostatic hypertrophy and cardiac problems.

Methyltestosterone (Android, Virilon, and Testrad)

High Potential for renal impairment. Safer alternatives available.

Nitrofurantoin (Macrodantin)

Low Potential for hypotension, dry mouth, and urinary problems.

Doxazosin (Cardura)

Low Potential for orthostatic hypotension and CNS adverse effects.

Clonidine (Catapres)

Low Evidence of the carcinogenic (breast and endometrial cancer) potential of these agents and lack of cardioprotective effect in older women.

Estrogens only (oral)

High CNS stimulation adverse effects.

Amphetamines (excluding methylphenidate HCl and anorexics)

High Concerns about cardiac effects. Safer alternatives are available.

Desiccated thyroid

Low Potential for hypotension and fluid imbalances. Safer alternatives are available.

Ethacrynic acid (Edecrin)

Low CNS adverse effects including confusion.

Cimetidine (Tagamet)

High Potential for aspiration and adverse effects. Safer alternatives are available.

Mineral oil

Beer’s Criteria

„ The following medications should be avoided in persons aged 65 years and over, who have the following health conditions and diagnoses

High May prolong clotting time and elevate INR values or inhibit platelet aggregation, resulting in an increased potential for bleeding.

Aspirin, NSAIDs, dipyridamole (Persantin), ticlopidine (Ticlid), and clopidogrel (Plavix) Disorders of blood clotting

(including anticoagulant therapy)

High May lower the seizure threshold.

Clozapine (Clozaril), chlorpromazine (Thorazine), thioridazine (Mellaril), and thiothixene (Navane) Seizure disorders

High May exacerbate existing ulcer disease or produce new/additional ulcers.

NSAIDs (COX-2 inhibitors excluded) and aspirin >325mg/d

Gastric or duodenal ulcers

High May produce elevation of blood pressure secondary to Sympathomimetic activity.

Phenylpropanolamine HCl (removed from the market in 2001), pseudoephedrine, diet pills, and amphetamines

Hypertension

High Negative inotropic effect.

Potential to promote fluid retentionand exacerbation of heart failure.

Disopyramide (Norpace), and high sodium content drugs (sodium and sodium salts[alginate bicarbonate, biphosphate, citrate, phosphate, salicylate and sulfate]) Heart Failure

Severity Comments

Drug Name or Class Disease or Condition

High Concern due to their antidopaminergic/

anticholinergic effects.

Metoclopramide (Reglan), conventional antipsychotics and tacrine (Cognex) Parkinson's Disease

High Concern due to CNS stimulant effects.

Decongestants, theophylline (Theodur), methylphenidate (Ritalin), MAOIs, and amphetamines

Insomnia

High Concern due to proarrhythmic effects and ability to produce QT interval changes.

Tricyclic antidepressants(imipramine, doxepin and amitriptyline)

Arrhythmias

High May produce polyuria and worsening of incontinence.

alpha-blockers(Doxazosin, Prazosin, and Terazosin), tricyclic antidepressants(imipramine, doxepin and amitriptyline), and long-acting benzodiazepines

Stress incontinence

High May decrease urinary flow, leading to urinary retention.

Anticholinergics and antihistamines, gastrointestinal antispasmodics, muscle relaxants, oxybutynin (Ditropan), flavoxate (Urispas), antidepressants, decongestants, and tolterodine (Detrol) Bladder outflow

obstruction

Low May exacerbate or cause SIADH.

SSRIs: fluoxetine (Prozac), citalopram (Celexa), fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft)

SIADH/hyponatremia

High May produce ataxia, impaired psychomotor function, syncope, and additional falls.

Short- to intermediate-acting benzodiazepines and tricyclic antidepressants (imipramine, doxepin and amitriptyline)

Syncope or falls

High Concern due to appetite- suppressing effects.

CNS stimulants: DextroAmpehtamine (Adderall), methylphenidate (Ritalin), methamphetamine (Desoxyn), pemolin, and fluoxetine (Prozac) Anorexia and malnutrition

High May produce or exacerbate depression.

Long-term benzodiazepine use. Sympatholytic agents: methyldopa (Aldomet), reserpine, guanethidine (Ismelin) Depression

High Concern due to CNS- altering effects.

Barbiturates, anticholinergics, antispasmodics, and muscle relaxants. CNS stimulants:

DextroAmphetamine (Adderall), methylphenidate (Ritalin), methamphetamine (Desoxyn), pemolin, Cognitive Impairment

Low May exacerbate constipation.

Calcium channel blockers, anticholinergics, and tricyclic antidepressants (imipramine, doxepin and amitriptyline)

Chronic constipation

High CNS adverse effects.May induce respiratory depression. May exacerbate or cause respiratory depression.

Long-acting benzodiazepines:Chlordiazepoxide (alone or in combination: Librium, Librax, Limbitrol), Diazepam (Valium), Quazepam (Doral), Halazepam (Paxipam), and Chlorazepate (Tranxene); Beta- blockers: propranolol

COPD

Low May stimulate appetiteand increase weight gain.

Olanzapine (Zyprexa) Obesity

High May lower the seizure threshold.

Bupropion (Wellbutrin) Seizure disorder