1. health and fitness
2. disease

3/11/15
Adverse Drug Events in the
Elderly: An Update for 2015
Dennis J Chapron reports no
real or potential conflicts of
interest relevant to this lecture.
Dennis J Chapron
Medication Safety Pharmacist
Saint Francis Hospital
Hartford, CT
March 17, 2015
Learning Objectives
•  1. Discuss some recent reports and reviews
on drug-induced acute kidney injury and
electrolyte abnormalities.
•  2. Discuss various aspects of drug-induced
gastrointestinal injury including (a) risks
associated with monotherapy vs combination
therapy, (b) the spectrum of injury and (c)
the role of proton pump inhibitors in
influencing sites of bleeding (upper vs
lower).
•  3. Describes the epidemiology of druginduced hepatotoxicity with particular
attention to therapeutic classes
involved, acute vs chronic effects, and
locus of liver injury.
•  4. Discuss some recently reported
drug-drug interactions.
Renal ADRs
AKI
GFR
Incidence of AKI per 100,000 person years
Learning Objectives
Acute Kidney Injury vs Age
Age by Decade
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Acute Kidney Injury and Aging
•  AKI is more common in the elderly
•  The incidence of AKI is increasing
Reasons for Higher Incidence of
AKI in the Elderly
•  Accumulation of co-morbid conditions
that that facilitate renal compromise
(CHF).
•  Co-morbid conditions that necessitate
procedures, surgery and drugs that
may result in kidney injury.
•  Background of age-dependent changes
in kidney function.
Causes of Acute Renal Failure in the
Elderly as Determined by Renal Biopsy
•  Glomerulonephritis (pauci immune crescentric) 31.2%
•  Acute interstitial nephritis - 18.6%
•  Acute tubular necrosis with NS - 7.5%
•  Atheroemboli - 7.1%
•  Acute tubular necrosis alone - 6.7%
•  Light chain cast nephropathy - 5.9%
•  Post infectious glomerulonephritis - 5.5%
•  Misc - 17.5%
Am J Kid Dis 2000;35:433
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Signs and Symptoms of
Acute Interstitial Nephritis
•  Constitutional symptoms of anorexia,
malaise, fever
•  Arthralgia - uncommon
•  Myalgia - uncommon
•  Skin rash
•  Flank pain and tenderness
Up to Date January 2015
Laboratory Signs of Acute Interstitial
Nephritis
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Eosinophilia
Anemia
Increased serum creatinine and urea nitrogen
Hyperkalemia/hypokalemia
Hyperchloremic metabolic acidosis
Proteinuria (usually <1.0-1.5 gm/D
Hematuria
Eosinophiluria
Leukocyturia
Renal tubular epithelial cells/casts
Up to Date January 2015
CAUSES OF
EOSINOPHILURIA
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Urinary tract obstruction
Cystitis
Contrast-induced ARF
IgA nephropathy
Cholesterol emboli
Allergic interstitial nephritis
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Causes of Acute Interstitial
Nephritis (AIN)
•  Medications – 70%
Medication-Induced Acute
Interstitial Nephritis
•  Antibiotics – 49%
•  Proton Pump Inhibitors – 14%
•  Autoimmune diseases – 20%
•  NSAIDs – 11%
•  Infections – 4%
•  Other Medications – 11%
•  Other/Unknown – 5%
•  Multiple Medications – 15%
Antibiotic-Induced Interstitial
Nephritis
•  Penicillins – 40.4%
•  Floroquinolones – 27.7%
•  Cephalosporins – 10.6%
•  Vancomycin – 8.5%
•  Others – 12.5
DRUGS ASSOCIATED WITH
CHRONIC INTERSTITIAL NEPHRITIS
•  Analgesic combinations
•  Cyclosporine
•  Lithium
•  Mesalamine
•  NSAIDS
Recovery from Drug-induced Acute
Interstitial Nephritis
•  Based 6 month postbiopsy findings:
•  49% of patients who received steroid
therapy had complete recovery.
•  39% had partial recovery and 12% no
recovery.
•  Correlates of poor recovery – longer
duration of drug exposure and longer
delay in starting steroids.
Self-Assessment Question
1. Drug-induced interstitial nephritis
has been reported for all of the
following medications except:
A. omeprazole
B. ibuprofen
C. ampicillin
D. lorazepam
E. ciprofloxacin
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Anticoagulation with
Warfarin and AKI
CONH November 2014
Atypical Antipsychotic
Agents and AKI
AKI and
Drug-Drug
Interactions
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Clarithromycin
An Inhibitor of Hepatic
Metabolism and Transport
CYP 3A4
PGP
Renal ADRs
Electrolytes
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Background
The Sodium Phosphate Enema
Fleet Phospho-Soda edema
Saline Enema
February 2012
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Active ingredient in each delivered dose
of 118 mL (133 mL bottle)
Monobasic sodium phosphate – 19 grams
NaH2PO4
Dibasic sodium phosphate – 7 grams
Na2HPO4
ISMP August 2012
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Targeted Drug Report
Sodium Phosphate Enema
84 yo man ordered and received phosphate enema despite elevated serum crea5nine and BUN Targeted Drug Report
Sodium Phosphate Enema
Phosphate Binders
Calcium acetate
Lanthanum carbonate
Sevelamer
Phosphate Enema use in 70 yr CRF pa5ent on sevelamer for phosphate control 2 x 133 mL at 6:21 and 6:56 Phosphate binder 9
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The Major Defense Against
Hyperkalemia
Aldosterone
Bidirectional Block
Urinary
excretion
Self-Assessment Question
2. Which electrolyte complication is
thought to be involved in cases of sudden
death with the combination of
sulfamethoxazole-trimethoprim and ACE
inhibitors?
A. hyponatremia
B. hypercalcemia
C. hypermagnesemia
D. hyperphosphatemia
E. hyperkalemia
Risk increased by 1200%
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Idiosyncratic Drug-Induced
Liver Injury (DILD)
Drug-induced
Liver Injury
“DILI”
•  A frequent cause of fulminant hepatic failure.
•  Accounts for 0.1 – 0.2% of all hospital
admissions.
•  Accounts for 2-3% of all hospital admissions
for adverse drug events.
•  Can mimic any form of hepatobiliary disease.
•  An important cause for withdrawing
medications from the marketplace.
•  No specific test for DILD.
Krahenbuhl & Reichen, in Liver Disease,
Edited by B. Bacon, 2002.
Idiosyncratic Drug-Induced Liver Injury
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Unpredictable
Does not directly depend on dose.
Rare event; 1/1000 to 1/100,000; FDA tolerance ? 1/10,000.
Age is not a strong risk factor, but is medication specific.
Idiosyncratic DILI is very rare among patients given drug doses
less than 10 mg daily, and more likely with daily dose of 1 gram or
more. Daily doses ≥ 100mg and high lipophilicity provides good
predictability.
Drugs with no hepatic metabolic pathways do not cause
fulminant liver failure resulting in death or liver transplantation.
Certain drug appear to enhance the hepatotoxic effect of other
drugs (pyrazinamide or rifampin increasing hepatotoxic effects of
isoniazid).
Alcohol increased the risk of liver injury from isoniazid and
methotrexate.
Patients with underlying chronic liver disease are generally not
more prone to DILI, but are at a higher risk of complications and
adverse outcomes from DILI.
Genetic factors
Some Medications for Which LFT
Monitoring is Recommended.*
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Amiodarone (“monitored on a regular basis”)
Carbamazepine (“periodic evaluation of liver function”)
Diclofenac (“periodic monitoring of transaminases is recommended”)
Disulfiram (“Baseline and follow up liver function tests (10-14 days))”
Fluconazole (none)
Flutamide (“periodic liver function tests should be considered”)
Isoniazid (“carefully monitored and interviewed at monthly intervals”)
Itraconazole (“liver function monitoring should be done”)
Ketoconazole Black Box - Warnings “measured at frequent intervals”
Labetalol (“periodic determination suitable hepatic laboratory tests”)
•  * PDR – WARNIGS, PRECAUTIONS, ADVERSE EFFECTS
Examples of Medications for Which LFT
(AST/ALT/AP) Monitoring is Recommended
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Amiodarone
Bosentan
Carbamazepine
Dapsone
Diclofenac
Disulfiram
Dronedarone
Fluconazole
Flutamide
Isoniazid
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Itraconazole
Ketoconazole
Labetalol
Methotrexate
Nicotinic Acid LA
Pemoline
Pioglitazone
Pyrazinamide
Tolvaptan
Tyrosine Kinase
Inhb
•  Valproic acid
Common Signs and Symptoms Seen in
Drug-Induced Liver Disease
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Fatigue
Pruritus
Jaundice
Eosinophilia
Rash
Hepatomeglia
Dark urine
Nausea
Malaise
Anorexia
Vomiting
Clay-colored stool
Delirium
Somnolence
Weakness
RUQ tenderness
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Liver Function Tests
Two Types of Liver Injury
•  Hepatocellular
•  Cholestatic
Liver Injury from Medications
Although many forms of drug-induced
hepatotoxicity have been described,
most cases manifest as cholestasis
or hepatocellular necrosis or a
combination of both.
Liver Injury from Medications
Hepatocellular
Cholestatic
Liver cell
destruction
Impaired bile
transport
Liver Injury from Medications
Hepatocellular
Cholestatic
Hepatocellular
Cholestatic
Liver cell
destruction
Impaired bile
transport
Liver cell
destruction
Impaired bile
transport
ALT / AST
(aminotransferases)
AP/GGT/5’NT
Mixed
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Liver Function Tests
Injury
Does injury affect function ?
Cytolysis
Cholestasis
AST (SGOT)
LSAP
Gamma GT
5'Nucleotidase
LAP
ALT (SGPT)
Liver Injury from Medications
Hepatocellular
Liver cell
destruction
Increased
bilirubin
Hepatotoxicity
Surveillance Monitoring
Function
Organic Ion Synthesis
Transport
Bilirubin
Bile
Albumin
Prothrombin
Urea
Cholinesterase
Hy’s Law or Hy’s Rule
Drug-induced jaundice
caused by hepatocellular
injury, without a significant
obstructive component,
leads to death or liver transplantation in > 10% of patients.
( ALT ≥3XULN, TBili ≥2xULN)
Surveillance Monitoring
>3X ULN for ALT – discontinue/hold medication
Stop medication with any rise in bilirubin.
Efficacy of Monitoring determined by:
Frequency of testing
Compliance
Education of physician/patient
Rapidity of injury progression
(ximelagatran, troglitazone)
Kaplowitz GE 1999;117:759
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Suspect component: alkaloid aegeline – extract of Asian bael tree
The proportion of liver injury cases attributed to
herbal-dietary supplements has increased significantly.
Liver injury from nonbody- building products is more
severe than from body-building products as evidenced
by unfavorable outcomes – death and transplantation.
Self-Assessment Question
3. Which combination of liver function
tests is used to determine if “Hy’s rule or
law” applies to a case of hepatotoxicity?
A. alkaline phosphatase (AP) and ALT
B. ALT and total bilirubin
C. INR and serum albumin concentration
D. AP and INR
E. AP and total bilirubin
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CYCLOOXYGENASE
INHIBTORS TYPES
GI ADRs
NSAIDS
How Prostaglandins Protect the
Upper GI Tract
–  NONSPECIFIC COX-1/COX-2 INHIBITORS
–  piroxicam, ibuprofen, naproxen,
–  indomethacin, flurbiprofen
–  COX-2 PREFERENTIAL
–  meloxicam, etodolac, nabumatone
–  COX-2 SELECTIVE
–  celecoxib, rofecoxib, valdecoxib
Chronic NSAID Users
15 - 30% Prevalence of Ulcer Disease
•  Enhances mucus production
•  Stimulates bicarbonate output
•  Decreases acid secretion
•  Maintains mucosal blood flow
60% Gastric
40% Duodenal
2% per year develop ulcer
complications (bleeding/perforation)
Upper GI ulceration from NSAIDs
is due to a systemic effect
on prostaglandin biosynthesis
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Relative Risk of Upper GI Bleeding
Relative Risk of Major Upper GI Bleeding
From Various ASA Preparations Referenced
to NonASA users
•  Esophagus: esophagitis, erosions, ulcers
and strictures
•  Stomach and Duodenum: erosions,
ulceration, hemorrhage, perforation and
obstruction.
•  Small Bowel: increased permeability,
inflammation, ulceration, hemorrhage,
perforation and stricture
•  Colon: exacerbation of colitis, ulceration,
hemorrhage, perforation and stricture
3.1
3
2.9
2.8
2.7
2.6
2.5
2.4
2.3
Plain
Enteric-coated
Gastrointestinal Complications of
NSAID Treatment
Buffered
Lancet 1996;348:1413
Studies of NSAID Injury to Distal Small Bowel and Colon
•  Using indium-111 labeled leucocytes (an indirect
measure of inflammation) revealed that about 65% of
NSAID chronic users demonstrated intestinal
inflammation.
•  A major outcome study showed that 40% of serious
GI events in NSAID users involve the lower GI tract.
•  An autopsy study of 713 patients found that small
intestinal ulcerations were much more frequent in
NSAID users than Non-users; 8.4 vs 0.6%).
•  Patients admitted with small and large bowel
perforation and hemorrhages were twice as likely to
be NSAID users.
•  Capsule endoscopy has shown that about 70% of
NSAID users have small bowel erosions or ulcers.
NSAID GI EVENTS – UPPER VS LOWER OVER TIME
NSAID GI EVENTS – UPPER VS LOWER
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PPIs exacerbate NSAID-induced intestinal damage
at least in part because of significant shifts in
enteric microbial populations. Prevention or
reversal of this dysbiosis may be a viable option
for reducing the incidence and severity of NSAID
enteropathy.
“ PPI use appears to increase the risk of small bowel
injury in patients who take continuous low-dose aspirin”.
Risk of Adverse GI Events
When NSAIDs Are Given
x
With Other Medications
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RERI = relative excess risk due to interaction
Monotherapy with nsNSAIDs increased the IRR
for UGIB more than monotherapy with either
coxibs or LDA (4.3 vs. 2.9 or 3.1).
Corticosteroid therapy with nsNSAIDs increased
the IRR to 12.8 and produced an excess risk of 5.5.
Aldosterone antagonists with nsNSAIDs increased the
IRR to 11.0 and produced an excess risk of 4.5.
Serotonin reuptake inhibitors produced significant excess
risk when combined with nsNSAIDs (1.6) or coxibs (1.9 but
not LDA (0.5).
Anticoagulants produced a significant excess risk when combined
with nsNSAIDs (2.4) and LDA (1.9) but not coxibs (0.1).
Antiplatelet agents produced no significant excess risks.
Self-Assessment Question
4. Which combination of medications is
associated with the highest excess risk for
GI bleeding?
A. nonselective NSAID and prednisone
B. low dose aspirin (LDA) and celecoxib
C. SSRI and celecoxib
D. nonselective NSAID and LDA
E. warfarin with LDA
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