Saving Our Elderly Patients From
Drug Adverse Effects
Abdul Elahi, MD, MPH
Assistant 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 1
Mr. 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.
B.
C.
D.
E.
Metformin
Glipizide
Zocor
Amitriptyline
Cimetidine
Pretest Case 2
Mr. 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
MV PO QD
ASA 81 mg PO QD
Labs and EKG:
145 111 37 112
6.5 25 2 Ca: 9
dig : 3.5
9
10
20.9
KCl 40 meq PO QD
219
You may give all of the following,
except:
A.
B.
C.
D.
Slowly infuse calcium gluconate
Give patient Digibind
Give glucose with insulin
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.
B.
C.
D.
Stop Digoxin
Stop Oral KCl
Stop Erythromycin
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 Switzerland
Died: 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.
2.
Kaufman DW, et al. JAMA 2002;287:337–344.
Lampela P, et al. Eur J Clin Pharmacol 2007;63(5):509-515.
Pattern Of Use Of Prescriptions Among
Elderly Compared To Younger Population
47 %
29 %
< 1%
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.
Herbals & Supplements
• Use by elderly is not uncommon1
– Herbal alone
– Vitamins – minerals supplement alone
– Herbal and vitamins – minerals supplement
5.75 %
36.16 %
4.93 %
• 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 animals
1.
2.
Dergal JM, et al. Drugs Aging 2002;19(11):879-886.
Brazier NC, Levine MA. Am J Ther 2003;10(3):163-169.
Case 1
AB 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 whole
cascade of symptoms?
A.
B.
C.
D.
Zoloft (Sertraline)
Toprol XL (Metoprolol)
Imdur (Isosorbide mononitrate)
Zocor (Simvastatin)
Chain of events
Chest Pain
H/o CAD
Abd Pain
Chronic pain
Rx
Imdur
Rx
Naratriptan
Orthostatic
hypotension,
?
headache
Rx
Lyrica
Rx
Florinef
Joint Pain
Rx
Lasix
Depression
?
Leg
edema
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.
2.
Hastings SN, et al. J Am Geriatr Soc 2007;55(9):1339–1348.
Herr RD, et al. Ann Emerg Med 1992;21(11):1331-1336.
Most Common ADRs In Elderly Patients
Causing ER Visits And Hospitalization
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 rhythm
4.5 %
6 Increased anticholinergic effects
3.3 %
7 Other side effects
5%
Doucet J, et al. J Am Geriatr Soc 1996;44(8):944-948.
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 drugs
Pirmohamed M, et al. BMJ 2004;329:15–19.
Hypothetical Response Of Young And Elderly
Subjects To A Bolus Administration Of A Drug
Serum/plasma
CSF /Brain
Side effect threshold for young adult
Side effect threshold for elderly
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/Sy
llabus_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
Pharmacokinetics
Liver
Gut
Kidney
Portal
circulation
Systemic
circulation
Extra-vascular /
Extracellular space
Other Body
compartments
Pharmacokinetics (Metabolism)
Phase I
Cytochrome P 450
Phase I
Non-Cytochrome P 450
Oxidation
Reduction
Demethylation
Hydrolysis
Phase II
Phase II
Weinshilboum R. N Engl J Med 2003;348:529-537.
Acetylation
Sulfonation
Conjugation
Glucuronidation
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 2
Mr. 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.
B.
C.
D.
E.
Metformin
Glipizide
Zocor
Amitriptyline
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 Clearance
GFR
• Cockcroft-Gault formula for GFR estimate
Cr clearance =
(140 – Age (in years) )x weight (IBW in KG)
72x serum Cr (in mg/dL)
• Abbreviated MDRD Study Equation1,2
-1.14
-0.203
Cr Cl =186 (Cr ) x age
• 24 hour urine collection
Cr Cl=
CrS x VU 24H
CrU 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.
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
OH
H
↑pH
H2O
H
↓pH
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 2
Mr. 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
MV PO QD
ASA 81 mg PO QD
Labs and EKG:
145 111 37 112
6.5 25 2 Ca: 9
dig : 3.5
9
10
20.9
KCl 40 meq PO QD
219
You may give all of the following,
except:
A.
B.
C.
D.
Slowly infuse calcium gluconate
Give patient Digibind
Give glucose with insulin
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.
B.
C.
D.
Stop Digoxin
Stop Oral KCl
Stop Erythromycin
Send pt back to NH on the same
medications
Maxwell DL, et al. BMJ 1989;298(6673):572.
Systemic
circulation
Muscles and
other body
compartments
Myocardial Cell
Extra-vascular /
Extracellular space
Dig
K
Dig
Na
Dig
Na
Na
Ca
Dig
K
Na
Dig
Dig
Risk for Dig toxicity:
– Frailty & ↓ muscle mass
– ↓ renal function /↓ tubular
excretion (Erythromycin
competes with dig)
– Hypokalemia
– Hypercalcemia
Ca
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.
Case 4
Mrs. 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
KCl 20 meq PO QD
Zocor 40 mg PO Qpm
Coreg 12.5 g PO BID
Lasix 40 mg PO QD
MV PO QD,
ASA 81 mg PO QD.
Ibuprofen OTC 2 Tab PO QID
CBC, BMB & cardiac enzyme in ER is within normal range except
with a Cr of 1.5.
Labs & EKG:
What is the most likely cause of this
patient’s current problem?
A.
B.
C.
D.
Noncompliance with her meds
ADR because of Ibuprofen
An acute MI
A Fib
Heerdink ER, et al. Arch Intern Med 1998;158(10):1108-1112.
Efferent
arterioles
Afferent
arterioles
Tubule
Discussion
• Afferent arterioles
constriction
• Efferent arterioles dilatation
• ↓ FF
• Juxtaglomerular apparatus
senses ↓ FF and triggers
Juxtaglomerular
fluid retaining mechanism
apparatus
• May cause azotemia and
renal failure
Peritubular
Capillary
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),
(Demerol), piroxicam (Feldene)
• Others: Chlorpropamide, barbiturates, bisacodyl (Dulcolax), Nitrofurantoin
Fick DM, et al. Arch Intern Med 2003;163(22): 2716-2724.
naproxen, meperidine
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
antidepressants
Fick 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)
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
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.
Delafuente JC. Understanding and preventing drug interactions in elderly patients. Crit Rev Oncol
Hematol 2003;48(2):133-143.
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.
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.
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.
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.
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.
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.
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'd
10. 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'd
19. 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.