Saving Our Elderly Patients From Drug Adverse Effects

Abdul Elahi, MD, MPHAssistant Professor of Medicine

NJISA, UMDNJ-School of Osteopathic Medicine

Stratford, NJ

Saving our Elderly Patients from Drug Adverse Effects

This Care of the Aging Medical Patient in the Emergency Room (CAMPER) presentation is offered by the Department of Emergency Medicine in coordination with the

New Jersey Institute for Successful Aging.This lecture series is supported by an educational

grant from the Donald W. Reynolds Foundation Aging and Quality of Life Program.

Learning Objectives For This Lecture

• To identify risk factors for adverse drug reactions

• To understand pharmacokinetics (absorption, metabolism and clearance) and pharmacodynamics (drug-target interaction and response)

• To know how to use renal function parameter for determining the safe dose of a drug

• To understand drug-drug interaction which affects pharmacokinetics and pharmacodynamics

• To understand drug-disease interaction

Pretest Case 1Mr. AB is a 70 y/o white male who was brought to

the ER with history of confusion, lethargy, and no urine output for 1-2 days. On examination, he was found to have dry mouth, lower abdominal pain, and distended urinary bladder. After insertion of a Foley catheter, patient had a urine output of 1800 cc. Patient had no problem before with his urination . He has no fever, no SOB, no meningeal signs. On laboratory evaluation, CBC, BMP, and UA were within normal range.

He has DM2 for the last 15 years, which has been fairly well controlled with Metformin 850 mg PO BID and Glipizide ER 10 mg PO QD. He is also on Zocor 80 mg PO QHS for high cholesterol, ASA 81 mg PO QD for CAD chemoprophylaxis, and Amitriptyline 100 mg PO QHS for his lower extremity neuropathic pain. Last week, patient developed some stomach discomfort and, on the advice of his wife, he started taking Cimetidine (Tagamet) 400mg PO BID (which they had in their medicine cabinet).

Which of the following is responsible for the current

problem in this patient?A. Metformin B. Glipizide C. Zocor D. Amitriptyline E. Cimetidine

Pretest Case 2Mr. KK is an 80 y/o frail man who has been sent to ER from a nursing home with H/O confusion, N/V and palpitations. His condition was stable in the NH until 3-4 days ago, when he developed a cough, for which he was started on erythromycin 500 mg PO BID for 7 days. He has past medical history of CAD, CHF, HTN and ambulatory dysfunction. He is on:

Meds: Lisinopril 10 mg PO QD Lopressor 50g PO BID Lasix 40 mg PO BID

Digoxin 0.125 mg PO Erythromycin 500 mg PO BID KCl 40 meq PO QDMV PO QD ASA 81 mg PO QD

Labs and EKG:145 111 37 112 dig : 3.5 106.5 25 2 Ca: 9 20.9

9 219

You may give all of the following, except:

A. Slowly infuse calcium gluconate

B. Give patient DigibindC. Give glucose with insulinD. Give 15 g of Kayexalate PO

Sonnenblick M, et al. Br Med J (Clin Res Ed) 1983;286:1089-1091.

After addressing the urgent problem and stabilizing the patient, what

would be the most appropriate step to take?

A. Stop DigoxinB. Stop Oral KClC. Stop ErythromycinD. Send pt back to NH on the

same medications

Maxwell DL, et al. BMJ 1989;298(6673):572.

The Dose Makes the Poison

"All substances are poisons; there is none which is not a poison. The right dose differentiates a poison…."Paracelsus

(1493-1541) Born: in

SwitzerlandDied: in Austria

Paracelsus by Quentin Massys

Image Source: http://commons.wikimedia.org/

Drug & Adverse Drug Reaction

• Drug:– A drug may be defined as any

substance that, when administered into the body of a living organism, alters normal bodily function (1).

• Adverse drug reaction– ‘‘Any noxious, unintended, and

undesired effect of a drug which occurs at doses used in humans for prophylaxis, diagnosis or therapy’’(2).(1)World Health Organization (WHO). WHO Expert Committee on Drug Dependence: Sixteenth report.

Technical Report Series No. 407. Geneva (Switzerland): World Health Organization; 1969.(2)World Health Organization (WHO). International Drug Monitoring: The Role Of The Hospital.

Technical Report Series No. 425. Geneva (Switzerland): World Health Organization; 1966.

Scope of the Problem• Aging population1

• Co-morbidities and chronic diseases• Inappropriate use or over use of

medications (polypharmacy)• Under use of certain medications• Unreported medication • Unreported ADR by patients2

1. Kaufman DW, et al. JAMA 2002;287:337–344. 2. Lampela P, et al. Eur J Clin Pharmacol

2007;63(5):509-515.

47 %

< 1%

29 %

2590 respondents of which 594 were 65 years of age or older

Adapted from: Kaufman DW, et al. JAMA 2002;287:337–344. Data used by permission.

Pattern Of Use Of Prescriptions Among Elderly Compared To

Younger Population

Herbals & Supplements• Use by elderly is not uncommon1

– Herbal alone 5.75 %

– Vitamins – minerals supplement alone 36.16 %

– Herbal and vitamins – minerals supplement4.93 %

• Varies with ethnic back grounds1

– White (54.4%) > Hispanics (37.5%) > Black (31.3%)

– Females > males• Most common are :

– Garlic, Ginkgo biloba, saw palmetto1 and St. John’s Wort

– Glucosamine/Chondroitin– Calcium, MV, Vitamins D, E & C

1. Raji MA, et al. Ann Pharmacother 2005;39(6):1019-1023.

Herbal use and their interaction with drugs

• Ginkgo – Improving blood circulation, oxygenation and memory/

alertness – May ↑ bleeding (If pt is on ASA or Warfarin)1

• Saw palmetto– Enlarged prostate and urinary problems– May interfere with other hormonal therapy

• St. John's Wort2

– For mild to moderate depression or anxiety and sleep disorders

– Interacts with other drugs, such as sedatives, Verapamil, Warfarin, SSRIs

• Garlic– High cholesterol; some interaction with other drugs in

animals1. Dergal JM, et al. Drugs Aging 2002;19(11):879-886.2. Brazier NC, Levine MA. Am J Ther 2003;10(3):163-169.

Case 1AB is a 79 y/o white female weighing

110 lb who visited the ER with h/o fall, which was associated with no loss of consciousness. The fall occurred this morning when she was trying to get out of bed.

She has been feeling dizzy for some time and has a throbbing headache, mostly during the day. She reports multiple visits to her PCP in the last 3-4 months for chest pain, but with no help from medications prescribed. She further says, 'I still have chest pain, but on top of it now I have headache, dizziness and leg swelling also.'

Patient has chronic medical problem of CAD, HTN, depression, hyperlipidemia, and non-specific abdominal and joint pain.

Medications• Patient is currently on the following medications:

– Plavix 75 MG PO QD– Florinef 0.1 MG PO QD– Toprol XL 50 MG PO QD– Zocor 40 MG TABS PO QD– Aspirin 81 MG PO QD– Zoloft 50 MG TAB PO QD– Lasix 40 MG POQD– Potassium Chloride 20 MEQ PO QD– Imdur 120 MG TB24 PO QD– Lyrica 50 MG PO TID– Naratriptan 1 MG PO as need for headache– Tylenol 326 MG 2 Tab PO QID as needed for headache

Based on the history and symptomatology, which of the following drugs has triggered

the wholecascade of symptoms?

A. Zoloft (Sertraline)B. Toprol XL (Metoprolol)C. Imdur (Isosorbide

mononitrate)D. Zocor (Simvastatin)

Chain of events

RxLyrica

RxImdur

H/o CAD

Chronic pain

Chest Pain

Abd Pain

Joint Pain

Orthostatichypotension,

headache

RxLasix

RxNaratriptan

Leg edema

?

RxFlorinef

?

Depression

Which drugs have been used inappropriately?

Home Medications – Plavix 75 MG PO QD– Florinef 0.1 MG PO QD– Toprol XL 50 MG PO QD– Zocor 40 MG TABS PO QD– Aspir-Low 81 MG PO QD– Zoloft 50 MG TAB PO QD– Lasix 40 MG POQD– Potassium Chloride 20 MEQ

PO QD– Lyrica 50 MG PO TID– Imdur 120 MG TB24 PO

QD– Naratriptan 1MG PO as

need for headache– Tylenol 326 MG 2 Tab PO

QID as needed for headache

Medications On Discharge From The Hospital:– Plavix 75 MG PO QD– Toprol XL 50 MG PO

QD– Zocor 40 MG TABS PO

QD– Aspir-Low 81 MG PO

QD– Zoloft 50 MG TAB PO

QHD– Imdur 60 MG TB24 PO

QD– Tylenol 326 MG 2 Tab

PO QID as needed for headache/pain

– Lyrica 50 MG PO TID

Risk and occurrence of ADR • ADR occurs in all setting of health care

provision1,2

• Poor transitional care may contribute to ADRs

• Failure to recognize ADRs– ADR vs. disease-related symptoms– ADR vs. disease progression– ADR vs. new diagnosis

• Failure to recognize suboptimal treatment– Suboptimal treatment vs. disease progression1

– Starting new medication with more side effects• Polypharmacy and old age

1. Hastings SN, et al. J Am Geriatr Soc 2007;55(9):1339–1348.

2. Herr RD, et al. Ann Emerg Med 1992;21(11):1331-1336.

Most Common ADRs In Elderly Patients

Causing ER Visits And Hospitalization

Doucet J, et al. J Am Geriatr Soc 1996;44(8):944-948.

1 Neuropsychological disorder and/or cognitive impairment

44.1 %

2 Global or orthostatic arterial hypotension 21.8 %

3 Acute renal failure secondary to dehydration 15.7 %4 Hypo/hyperkaliemia 5.6 %5 Impairment of heart automatism, conduction,

or rhythm4.5 %

6 Increased anticholinergic effects 3.3 %7 Other side effects 5 %

Drugs Implicated In Causing Hospital Admission

• Diuretics• Warfarin• NSAID and ASA• Chemotherapy• Cardiotonic agents• Anti-epileptic agents• ABX

Modified from: Delafuente JC. Crit Rev Oncol Hematol 2003;48(2):133-143.

Why Are Elderly Patients At ↑ Risk Of Developing Drug

Adverse Effect?• Age related• Presence of other co-morbidities1

– e.g., CHF, PUD, dementia, DM, Sz, and electrolyte abnormalities

• Multiple care provider– Lack of communication– New prescriptions every visit

• Co-administered drugsPirmohamed M, et al. BMJ 2004;329:15–19.

Con

cent

rati

on

Time

Serum/plasma

CSF /Brain

Side effect threshold for young adultSide effect threshold for elderly

Hypothetical Response Of Young And Elderly Subjects To A Bolus Administration Of A Drug

Young adult

Elderly

Adapted from McLeskey CH. Pharmacokinetic and pharmacodynamic differences in the elderly. Available at: http://methodistanesthesia.com/SubspecialtyRotations/CA_1_2_subspecialty_rotations/Supporting_Material/Syllabus_on_Geriatric_Anesthesiology.pdf#page=25. Accessed October 19, 2010.

Basic Pharmacology of Drugs• Pharmacokinetics

– Absorption– First pass effect– Distribution– Metabolism– Elimination / clearance

• Hepatic, renal, intestinal• Pharmacodynamics:

– Therapeutic effects, side effects/ADR

Systemic circulation

Extra-vascular / Extracellular space

Gut

Portal circulation

Other Body compartments

Liver

Kidney

Pharmacokinetics

Cytochrome P 450

Non-Cytochrome P 450

Phase I

Phase II

Pharmacokinetics (Metabolism)

Weinshilboum R. N Engl J Med 2003;348:529-537.

OxidationReductionDemethylationHydrolysis

AcetylationSulfonationConjugationGlucuronidation

Phase I

Phase II

Cytochrome P450 • Substrates:

– Amitriptyline, Fluoxetine, Paroxetine, Sertraline, Metoprolol, Verapamil, Alprazolam, Haloperidol, Risperidone, Erythromycin, Ketoconazole , Warfarin, Phenytoin, Dexamethasone, Omeprazole (and other PPI)

• Inhibitors– Fluoxetine, Paroxetine, Sertraline,

Amitriptyline, Haloperidol, Cimetidine, Erythromycin, Ketoconazole, Quinolones

• Inducers– Phenobarbital, Phenytoin, Ethanol, cigarette

smoke, Dexamethasone, Rifampin, (?Omeprazole)

Pharmacodynamics • Drug target interaction and action/

effects– Drug concentration (x time) at the site of action– Receptors and single transduction– Counter-regulatory process

• Receptor property/pathway of action– β-adrenoceptors down regulation– ↓ dopaminergic receptors in CNS– ↑ inhibitory effect of Warfarin – ↑ sensitivity to anticholinergic effects of drugs– ↑CNS effect of benzodiazepines, opioids &

psychotropics • ↓ in homeostatic mechanism with

aging

Case 2Mr. AB is a 70 y/o white male who was brought to

the ER with history of confusion, lethargy, and no urine put for 1-2 days. On examination, he was found to have dry mouth, lower abdominal pain, and distended urinary bladder. After insertion of a Foley catheter, patient had a urine output of 1800cc. Patient had no problem before with his urination . He has no fever, no SOB, no meningeal signs. On laboratory evaluation, CBC, BMP, and UA were within normal range.

He has DM2 for the last 15 years, which has been fairly controlled with Metformin 850 mg PO BID and Glipizide ER 10 mg PO QD. He is also on Zocor 80 mg PO QHS for high cholesterol, ASA 81 mg PO QD for CAD chemoprophylaxis, and Amitriptyline 100 mg PO QHS for his lower extremity neuropathic pain. Last week, patient developed some stomach discomfort and, on the advice of his wife, he started taking Cimetidine (Tagamet) 400mg PO BID (which they had in their medicine cabinet).

Which of the following is responsible for the current

problem in this patient?

A. Metformin B. Glipizide C. Zocor D. Amitriptyline E. Cimetidine

Renal Clearance• Mechanism:

– Glomerular filtration and tubular excretion

• Depends on: – GFR (kidney function)– Net tubular excretion (excretion minus

reabsorption)– Renal blood flow (age related , disease

related)– Unbound friction of the drug in the

serum (protein /albumin binding )– Molecular size and polarity of the drug

(more hydrophilic)– Urine pH

Renal ClearanceGFR

• Cockcroft-Gault formula for GFR estimate(140 – Age (in years) )x weight (IBW

in KG) 72x serum Cr (in mg/dL)

• Abbreviated MDRD Study Equation1,2

Cr Cl =186 (Cr ) x age• 24 hour urine collection

Cr x VCr x 1440

1. Levey AS, et al. Ann Intern Med 1999;130(6):461-470.

2. Rule AD, et al. Ann Intern Med 2004;141(12):929-937.

Cr clearance =

-1.14

-0.203

U 24HS

U Cr Cl=

Tubular Excretion

• Non-specific and may be saturated• Excretes ions and protein bound

molecules- Acids: Penicillins, Furosemide,

Probenecid, and Glucuronic acid conjugates

- Bases: Procainamide, Dopamine, Neostigmine, and Trimethoprim

- P glycoprotein transport: Clarithromycin, Cyclosporine, Erythromycin, digoxin (inducers: Rifampin and St. John's Wort )

Tubular Re-absorption

• Re-absorption of lipid soluble and protein bound molecules

• Passive (water re-absorption from the tubules increases drug conc. in the tubules).

• Depends on– Concentration/gradient – Intra-tubular pH

↑pH

HOH

H2O

↓pH

H

H

Why Keep In Mind Renal Clearance And Function?

• Absorption– No significant change with age

• Metabolism (phase I and phase II)– Some change with age (phase I)– Not measureable and some times

unpredicted– Varies with individuals

• Renal clearance– Major outlet for drug excretion– Measureable and predictable

Case 2Mr. KK is an 80 y/o frail man who has been sent to ER from a nursing home with H/O confusion, N/V and palpitations. His condition was stable in the NH until 3-4 days ago, when he developed a cough, for which he was started on erythromycin 500 mg PO BID for 7 days. He has past medical history of CAD, CHF, HTN and ambulatory dysfunction. He is on:

Meds: Lisinopril 10 mg PO QD Lopressor 50g PO BID Lasix 40 mg PO BID

Digoxin 0.125 mg PO Erythromycin 500 mg PO BID KCl 40 meq PO QDMV PO QD ASA 81 mg PO QD

Labs and EKG:145 111 37 112 dig : 3.5 106.5 25 2 Ca: 9 20.9

9 219

You may give all of the following, except:

A. Slowly infuse calcium gluconate

B. Give patient DigibindC. Give glucose with insulinD. Give 15 g of Kayexalate PO

Sonnenblick M, et al. Br Med J (Clin Res Ed) 1983;286:1089-1091.

After assessing the patient, evaluating the medications and fixing the urgent

problem, what would be the most appropriate step to take?

A. Stop DigoxinB. Stop Oral KClC. Stop ErythromycinD. Send pt back to NH on the

same medications

Maxwell DL, et al. BMJ 1989;298(6673):572.

NaN

a K

KNa

Na

Dig

Ca Ca

Dig

Dig

Dig

Risk for Dig toxicity:– Frailty & ↓ muscle mass – ↓ renal function /↓

tubular excretion (Erythromycin competes with dig)

– Hypokalemia – Hypercalcemia

1. Smith TW. N Engl J Med 1988;318(6):358-365. 2. Sonnenblick M, et al. Br Med J (Clin Res Ed)

1983;286:1089-1091.

Myocardial Cell

Systemic circulation Extra-

vascular / Extracellular space

Muscles and other body compartments

Dig

Dig

Case 4Mrs. XYZ is a 70 y/o white female who presents to the

ER with c/o progressive SOB. She has history of CHF, CAD, HTN and high cholesterol, for which she receives treatment . Her condition had been stable for the last 2 years until recently when she developed some back pain for which she started taking Ibuprofen (OTC). Her back pain is under control to a great extent currently, but she has now difficulty with breathing. On exam, she was found to be SOB and have B/L rales and some leg swelling. She is on the following medications:Meds: Lisinopril 10 mg PO QD Coreg 12.5 g PO BID Lasix 40

mg PO QD KCl 20 meq PO QD MV PO QD, ASA 81 mg PO QD.

Zocor 40 mg PO Qpm Ibuprofen OTC 2 Tab PO QIDLabs & EKG: CBC, BMB & cardiac enzyme in ER is within

normal range except with a Cr of 1.5.

What is the most likely cause of this patient’s current

problem?A. Noncompliance with her

medsB. ADR because of IbuprofenC. An acute MID. A Fib

Heerdink ER, et al. Arch Intern Med 1998;158(10):1108-1112.

Discussion

Tubule Peritubular Capillary

• Afferent arterioles constriction

• Efferent arterioles dilatation

• ↓ FF• Juxtaglomerular

apparatus senses ↓ FF and triggers fluid retaining mechanism

• May cause azotemia and renal failure

Afferent arterioles

Efferent arterioles

Juxtaglomerular apparatus

Drugs To Avoid In The Elderly(Beers Criteria)

• Muscle relaxant: Carisoprodol (Soma), chlorzoxazone (Paraflex), cyclobenzaprine (Flexeril), metaxalone (Skelaxin)

• Sedatives/ anxiolytics / hypnotics: Alprazolam (Xanax), diazepam (Valium), chlordiazepoxide (Librium)

• Anti-depressants: Amitriptyline (Elavil), chlordiazepoxide-amitriptyline (Limbitrol),

• Antihistamines: Diphenhydramine (Benadryl) , Hydroxyzine (Atarax), Promethazine (Phenergan)

• Anti-hypertensives: Methyldopa (Aldomet), guanadrel (Hylorel) and nifedipine

• Spasmolytic/GI spasm/IBS /urinary bladder: oxybutynin (Ditropan), Dicyclomine (Bentyl) hyoscyamine (Levsin, Levsinex)

• Analgesics/ NSAID/opioids : Indomethacin, ketorolac (Toradol), naproxen, meperidine (Demerol), piroxicam (Feldene)

• Others: Chlorpropamide, barbiturates, bisacodyl (Dulcolax), Nitrofurantoin Fick DM, et al. Arch Intern Med 2003;163(22): 2716-2724.

Common Geriatric Diseases & Drugs To Be Avoided Or Administered With

Caution• CHF: Disopyramide (Norpace), some NSAIDs, Na containing

medications, Thiazolidinediones (1,2)• PUD: NSAIDs (excluding Cx2), ASA (> 325 mg) (1)• COPD: Long acting benzodiazepines (1)• DM: Long acting / Sulfonylureas (chlorpropamide) (1)• HTN: Pseudoephedrine, diet pills, amphetamines (1)• Cognitive impairment: Barbiturates, anticholinergics,

antispasmodics, muscle relaxants, CNS stimulator (dextromethorphan, methamphetamine, methylphenidate (1).

• Incontinence: anticholinergics• PD: Dopamine antagonists (Metoclopramide) (1)• Fall /syncope: Benzodiazepines, tricyclic antidepressants• Chronic constipation: Calcium channel blockers,

anticholinergics, tricyclic antidepressantsFick DM, et al. Arch Intern Med 2003;163(22): 2716-2724.

How To Treat Your Patient Optimally & Avoid ADR

• Know your patient: obtain information– Medical history, Social, support and

function– Exam and relevant labs

• Know the drugs– Drugs you prescribe or drugs patient is

on • No drug is safe drug

– Start low and go slow• Use your Palm/PDA-ePocrates

– Side effects, drug interaction and mechanism of action

• Communication ( Transitional care)

References1. Brazier NC, Levine MA. Drug-herb interaction among commonly used conventional medicines: A compendium for health care professionals. Am J Ther 2003;10(3):163-169.

2. Delafuente JC. Understanding and preventing drug interactions in elderly patients. Crit Rev Oncol Hematol 2003;48(2):133-143.

3. Dergal JM, Gold JL, Laxer DA, et al. Potential interactions between herbal medicines and conventional drug therapies used by older adults attending a memory clinic. Drugs Aging 2002;19(11):879-886.

4. Doucet J, Chassagne P, Trivalle C, et al. Drug-drug interactions related to hospital admissions in older adults: A prospective study of 1000 patients. J Am Geriatr Soc 1996;44(8):944-948.

5. Fick DM, Cooper JW, Wade WE, et al. 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(22): 2716-2724.

6. Hastings SN, Sloane RJ, Goldberg KC, et al. The quality of pharmacotherapy in older veterans discharged from the emergency department or urgent care clinic. J Am Geriatr Soc 2007;55(9):1339–1348.

7. Heerdink ER, Leufkens HG, Herings RM, et al. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med 1998;158(10):1108-1112.

8. Herr RD, Caravati EM, Tyler LS, Iorg E, Linscott MS. Prospective evaluation of adverse drug interactions in the emergency department. Ann Emerg Med 1992;21(11):1331-1336.

9. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States: The Slone Survey. JAMA 2002;287:337–344.

References, Cont'd10.Lampela P, Hartikainen S, Sulkava R, Huupponen R. Adverse drug effects in elderly people - A disparity between clinical examination and adverse effects self-reported by the patient. Eur J Clin Pharmacol 2007;63(5):509-515.

11.Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130(6):461-470.

12.Maxwell DL, Gilmour-White SK, Hall MR. Digoxin toxicity due to interaction of digoxin with erythromycin. BMJ 1989;298(6673):572.

13.Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: Prospective analysis of 18,820 patients. BMJ 2004;329:15–19.

14.Raji MA, Kuo YF, Snih SA, Sharaf BM, Loera JA. Ethnic differences in herb and vitamin/mineral use in the elderly. Ann Pharmacother 2005;39(6):1019-1023.

15.Rule AD, Larson TS, Bergstralh EJ, et al. Using serum creatinine to estimate glomerular filtration rate: Accuracy in good health and in chronic kidney disease. Ann Intern Med 2004;141(12):929-937.

16.Smith TW. Digitalis: Mechanisms of action and clinical use. N Engl J Med 1988;318(6):358-65.

17.Sonnenblick M, Abraham AS, Meshulam Z, Eylath U. Correlation between manifestations of digoxin toxicity and serum digoxin, calcium, potassium, and magnesium concentrations and arterial pH. Br Med J (Clin Res Ed) 1983;286:1089-1091.

18.Weinshilboum R. Inheritance and drug response. N Engl J Med 2003;348:529-537.

References, Cont'd19.World Health Organization (WHO). International Drug Monitoring: The Role

Of The Hospital. Technical Report Series No. 425. Geneva (Switzerland): World Health Organization; 1966.

20.World Health Organization (WHO). WHO Expert Committee on Drug Dependence: Sixteenth report. Technical report series No. 407. Geneva (Switzerland): World Health Organization; 1969.