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#FSHP2019

Common Drug-Induced Diseases

Common Drug-Induced Diseases

Doing More Harm than Good

Jeremy Ciavarra, PharmDFSHP Annual MeetingFriday, August 2, 2019

#FSHP2019DisclosureDisclosureI do not have (nor does any immediate family member have):– a vested interest in or affiliation with any corporate

organization offering financial support or grant monies for this continuing education activity

– any affiliation with an organization whose philosophy could potentially bias my presentation

#FSHP2019ObjectivesObjectives• Define drug-induced disease (DID)• Review the pathophysiology of several DIDs• Pulmonary fibrosis• Hyponatremia• QTc-interval prolongation

• Describe signs and symptoms of several DIDs• Outline treatments of these DIDs• Explain prevention strategies to reduce DIDs

#FSHP2019

DID Overview• Drug-induced disease definition:

• “An unintended effect of a drug that may result in mortality or morbidity with symptoms sufficient to prompt a patient to seek medical attention and/or require hospitalization”

• Prevention is preferable to treatment• Many drug-induced diseases are preventable• High cost burden associated with DIDs

Tisdale J. Drug-Induced Diseases. ASHP 2005.

#FSHP2019

Costs of DIDs• Cost-of-illness study from 2001 estimated drug-related

morbidity and mortality annual costs of $177.4 billion• Health care expenditure types:

• Hospital admissions (70%)• Long-term care admissions (18%)• Physician visits (8%)• Emergency department visits (3%)• Additional prescriptions (1%)

Ernst FR, et al. J Am Pharm Assoc 2001;41(2):192-9

Annual Cost in Billions of US Dollars

#FSHP2019

Surveillance of DIDs• Many DIDs are not identified prior to FDA approval

• Clinical trials not designed to identify all drug-related adverse events

• Smaller numbers of people exposed to drug in studies compared to patient population once approved

• Unforeseen side effects not discovered until large numbers of people taking the medication

• Post-marketing surveillance and adverse drug event reporting are important

• Report adverse drug events to FDA via MedWatch

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#FSHP2019Common Drug Classes Causing DIDs

• Drug classes commonly associated with DIDs requiring hospital admission• Hypoglycemics/antidiabetics: hypoglycemia• Antibiotics: allergic reactions• NSAIDS: GI bleeding/anemia• Digoxin: heart block and toxicity• ACE inhibitors: angioedema/acute renal disease

Drug Drug-Induced Disease

Antidiabetic medications Hypoglycemia

Antibiotics Allergic reactions

Non-steroidal anti-inflammatory drugs (NSAIDs) GI bleeding / anemia

ACE inhibitors /Angiotensin Receptor Blockers (ARBs)

Angioedema / acute renal disease

Digoxin Heart block / toxicityACE: angiotensin-converting enzyme; GI: gastrointestinal

#FSHP2019

Pulmonary Fibrosis

lunginstitute.com

#FSHP2019Pulmonary Fibrosis• Scarring of the lung parenchyma

secondary to a chronic inflammatory process

• Accumulation of excess fibrous connective tissue (fibrosis) leads to scars

• Causes thickening of bronchioles and alveoli

• Results in diminished oxygen exchange and reduced oxygen supply in blood

en.wikipedia.orgTisdale J. Drug-Induced Diseases. ASHP 2005.

#FSHP2019

Symptoms of Pulmonary Fibrosis• Chest pain (dull, primarily with inspiration)• Cough (non-productive)• Dyspnea• Tachypnea• Lung crackles• Clubbing of the fingers• Fatigue

Tisdale J. Drug-Induced Diseases. ASHP 2005.healthblog.uofmhealth.org

#FSHP2019Pulmonary Fibrosis ToxicityPulmonary Fibrosis ToxicityMechanisms of toxicity• Oxygen free radicals are

typically counterbalanced by antioxidants

• Drugs and chemicals produce lung toxicity through two basic mechanisms:1. Increased production of oxidants2. Inhibition of the antioxidant system

Drug IncidenceCarmustine 20-30%

Mitomycin 10-35%

Amiodarone 10-15%

Methotrexate 3-7%

Bleomycin 4%

Busulfan 4%

Nitrofurantoin <1%Tisdale J. Drug-Induced Diseases. ASHP 2005.

#FSHP2019Risk Factors for Pulmonary FibrosisRisk Factor Medications Associated with Each Risk Factor

Non-Cytotoxic Drugs Cytotoxic DrugsHigher maintenance/

cumulative dose Amiodarone, methotrexate Bleomycin, busulfan, carmustine

Age Nitrofurantoin (old) Bleomycin (old), carmustine (young)

Oxygen therapy Amiodarone, nitrofurantoin Bleomycin, carmustine, cyclophosphamide, mitomycin

Cardiothoracic surgery Amiodarone ---

Radiation therapy --- Bleomycin, busulfan, carmustine, cyclophosphamide, mitomycin

Vinca alkaloid use --- MitomycinPre-existing pulmonary

disease --- Carmustine

Tisdale J. Drug-Induced Diseases. ASHP 2005.

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#FSHP2019

Pulmonary Fibrosis Treatment Options• Discontinue offending medication• Acute pneumonitis: Prednisone 40-80 mg/day• Chronic fibrosis: Corticosteroid use is questionable

• Consider prednisone if not improving with drug discontinuation• Amiodarone’s long half-life may delay recovery

• Taper corticosteroid therapy slowly over several weeks• Perform pulmonary function testing to monitor for

improvement

Schwaiblmair M, et al. Open Resp Med Journal 2012;6:63-74.

#FSHP2019

Hyponatremia

medicalnewstoday.com

#FSHP2019Hyponatremia Epidemiology

• Medications are a common cause of electrolyte abnormalities• Hyponatremia is the most common electrolyte abnormality

• Usually caused by syndrome of inappropriate antidiuretic hormone secretion (SIADH)

• Cost of treating hyponatremia in US $3.6 billion annually• Associated with 7.6% increased hospital length of stay• Increases 30-day hospital readmission rates

Verbalis J, et al. Am J Med 2013;126:S1-42.

#FSHP2019

SIADH Mechanism

John Wiley & Sons, Inc. 2007.

Criterion DefinitionHyponatremia Serum sodium level < 135 mEq/LHypo-osmotic

plasmaPlasma osmolality < 280 mOsm/kg

Hyper-osmotic urine Urine osmolality > 100 mOsm/kg

Hypernatremicurine

Urine sodium level > 30 mEq/L(without diuretic therapy)

#FSHP2019Symptoms of Hyponatremia

Madeira C, et al. The Hospitalist 2014 August;2014(8)

SYMPTOMS OF SEVERE/ACUTE

HYPONATREMIA

•Nausea and vomiting•Headache•Lethargy•Seizures•Pulmonary edema•Obtundation•Coma

SYMPTOMS OF MILD/CHRONIC HYPONATREMIA

•Fatigue•Nausea•Dizziness•Gait disturbances•Forgetfulness•Muscle cramps

#FSHP2019Medication Causes of HyponatremiaMedication Class HIGH Potential for Hyponatremia Mechanism

DiureticsThiazide diuretics: hydrochlorothiazide, indapamide, chlorthalidoneOther: amiloride

Sodium excretion

Antidepressants SSRIs: sertraline, fluoxetine, paroxetine, citalopramOther: venlafaxine, MAOI inhibitors, TCAs SIADH

Antipsychotics Typical: Haloperidol, fluphenazine, thioridazineAtypical: Aripiprazole, clozapine SIADH

Antiepileptic agents Carbamazepine, oxcarbazepine, valproic acid SIADH

Chemotherapy agentsVinca alkaloids: vincristine, vinblastinePlatinum compounds: carboplatin, cisplatin Other: cyclophosphamide, methotrexate

SIADH

Miscellaneous Amiodarone, nicotine, proton pump inhibitors, opiates, non-steroidal anti-inflammatory drugs (NSAIDs), oxytocin SIADH

Liamis G, et al. Am J Kidney Dis 2008;52:144-53 SSRI: selective serotonin reuptake inhibitor; MAOI: monoamine oxidase inhibitor; TCA: tricyclic antidepressant

JC1

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#FSHP2019Medication Alternatives in Hyponatremia

Medication Class LOWER Potential for Hyponatremia

DiureticsLoop diuretics: furosemide, bumetanide, torsemidePotassium-sparing diuretic: SpironolactoneAlternative blood pressure agent classes

Antidepressants Mirtazapine, bupropion, milnacipranAntipsychotics Olanzapine, risperidone

Antiepileptic agents Levetiracetam, lamotrigine, gabapentin

Chemotherapy agents Cyclophosphamide: hydrate with isotonic saline solution instead of water; use alternative agents when possible

Miscellaneous

Use alternative agents when possible:Amiodarone dronedarone or other antiarrhythmicProton pump inhibitors H2-antagonists Opiates or NSAIDs acetaminophen, topical lidocaine

Sahoo S, et al. J Geriatr Ment Health 2016;3:108-22

#FSHP2019Risk Factors for Hyponatremia• Advancing age (≥65 years)• Concomitant diuretic administration• Female sex• Lower body mass index• Baseline serum sodium < 139 mEq/L• Higher doses of medications• Elevated serum drug concentrations (antiepileptics)• Asian race (vinca alkaloids)

Tisdale J. Drug-Induced Diseases. ASHP 2005.

#FSHP2019Prevention of Hyponatremia• Use the lowest-possible therapeutic doses• Use agents with lower SIADH-causing potential• Avoid coadministration with thiazide diuretics• Avoid polypharmacy and drug-drug interactions• Monitor serum sodium concentrations 1-2 weeks after

initiation of treatment, especially in those with risk factors• Monitor for symptoms: fatigue, anorexia, confusion, falls• Advise against excessive fluid intake

Tisdale J. Drug-Induced Diseases. ASHP 2005.

#FSHP2019Hyponatremia Treatment Options• Discontinue the offending agent• Switch to an alternative agent• Fluid restriction (≤ 1 liter/day)• Isotonic saline + loop diuretic: furosemide 20-40 mg/day• Demeclocycline 150-400mg orally 3 times a day• Urea powder 15-60g orally daily• Tolvaptan 15-30 mg orally daily• Hypertonic saline (acute or symptomatic patients only)

Verbalis J, et al. Am J Med 2013;126:S1-42.

#FSHP2019Hyponatremia Treatment Pathway

• Severe Symptoms:• 3% saline bolus: 100 mL over 10 mins up to 3 doses

• Moderate Symptoms:• 3% saline continuous infusion (0.5-2 mL/kg/hr)

Acute (<48 hours) or Symptomatic

• First line: fluid restriction (≤ 1liter/day)• Second line:

• US Guidelines: demeclocycline, urea, or tolvaptan• European Guidelines: urea, loop diuretic + oral NaCl

Chronic (>48 hours) or Asymptomatic

Serum Sodium Correction Rates

• Normal Risk of ODS:<10-12 mEq/L/24h

• High Risk of ODS:<8 mEq/L/24h

Hoorn EJ, et al. J Am Soc Nephrol 2017;28:1340-49.

ODS: osmotic demyelination syndrome

#FSHP2019

QT Prolongation / Torsades de Pointes

sammlungfotos.online

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#FSHP2019QT Prolongation / Torsades de Pointes• Ventricular arrhythmia that can lead to sudden cardiac

death• Most common cause of drug withdrawal from the market

or restriction of medication use• Dozens of medications can contribute to QT prolongation• Onset of noncardiac drug-induced torsades de pointes:

• <72 hours: 18%• Between 3 – 30 days: 42%• > 30 days: 40%

Tisdale J. Drug-Induced Diseases. ASHP 2005.

#FSHP2019QT Interval• Length of time for heart to

repolarize• ↑ HR ↓ QT interval• QTc corrects for HR• QTc < 440 ms is normal• Prolonged when

• QTc > 450 ms in males• QTc > 470 ms in females

• QTc > 500 ms high risk for ventricular arrhythmias

health.harvard.eduThompson JL, et al. US Pharmacist 2007HR: heart rate; QTc: corrected QT interval

#FSHP2019Symptoms of Torsades de Pointes

• Heart palpitations• Syncope• Dizziness• Shortness of breath• Chest pain• Cold sweats• Nausea

Tisdale J. Drug-Induced Diseases. ASHP 2005.

healthline.com

#FSHP2019QT-Prolonging Medications

Antiarrhythmics

• Amiodarone• Sotalol• Quinidine• Procainamide• Dofetilide• Ibutilide• Flecainide• Disopyramide

Antimicrobials

• Moxifloxacin• Levofloxacin• Ciprofloxacin• Clarithromycin• Erythromycin• Azithromycin• Ketoconazole• Itraconazole

Antidepressants

• Amitriptyline• Imipramine• Nortriptyline• Citalopram• Escitalopram• Mirtazapine• Venlafaxine

Antipsychotics

• Haloperidol• Droperidol• Quetiapine• Thioridazine• Ziprasidone

Others

• Cisapride• Sumatriptan• Zolmitriptan• Ondansetron• Metoclopramide• Methadone• Ranolazine• Cilostazol

Thompson JL, et al. US Pharmacist 2007

• Check CredibleMeds.org for the full up-to-date list of medications

#FSHP2019Psychiatric Medication AlternativesMedication Class HIGH Potential for QT Prolongation LOWER Potential for QT Prolongation

Typical antipsychotics

Thioridazine, haloperidol, droperidol, chlorpromazine, pimozide Loxapine

Atypical antipsychotics Ziprasidone, iloperidone, quetiapine

Olanzapine, risperidone, paliperidone, aripiprazole, asenapine, clozapine, brexpiprazole, lurasidone

SSRIs Citalopram, escitalopram Paroxetine, fluoxetine, sertraline, fluvoxamine

TCAs and TeCAs Amitriptyline, imipramine, maprotiline, nortriptyline, desipramine, clomipramine Doxepin

SNRIs Venlafaxine Duloxetine, desvenlafaxine, levomilnacipran, milnacipran

Other antidepressants Mirtazapine Bupropion, vortioxetine, vilazodone,

trazodone

Dietle A. US Pharmacist 2015 SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic antidepressant; TeCA: tetracyclic antidepressant; SNRI: serotonin norepinephrine reuptake inhibitor

#FSHP2019Risk Factors for Torsades de Pointes• QTc interval >500 ms• Increase in QTc interval by >60 ms from baseline• Female sex• Hypokalemia and/or hypomagnesemia• Advancing age (≥65 years)• Bradycardia• Left ventricular dysfunction• Administration of multiple QT-prolonging medications• Increased doses of medications (especially in renal dysfunction)• Rapid IV infusion of torsades-inducing drugs

Tisdale J. Drug-Induced Diseases. ASHP 2005.

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#FSHP2019Prevention of Torsades de Pointes• Avoid QT-prolonging drugs when baseline QTc > 450 ms• Discontinue QT-prolonging drugs when QTc > 500 ms• Maintain serum potassium > 4 mEq/L• Maintain serum magnesium > 2 mEq/L• Avoid QT-prolonging agents when LVEF < 20%• Renally adjust medication doses• Avoid use of concomitant QT-prolonging drugs• Infuse IV QT-prolonging drugs slowly

Tisdale J. Drug-Induced Diseases. ASHP 2005.

#FSHP2019

Hemodynamically Unstable

• Synchronized cardioversion

Hemodynamically Stable

• Magnesium 1-2g IV over 5-10 minutes (may repeat up to 12g)

• Temporary pacemaker• Isoproterenol 2-10 mcg/min IV

titrated to heart rate• IV lidocaine bolus/infusion• IV phenytoin 10-15 mg/kg

Initial Torsades de Pointes Management• Discontinue the offending agent• Correct abnormal electrolytes

Tisdale J. Drug-Induced Diseases. ASHP 2005.

#FSHP2019ConclusionsConclusions• DIDs are extremely costly but preventable• Pharmacists are on the front lines of

identifying DIDs• Ensure medications are dosed

appropriately for age, renal function, etc.• Be alert for drug side effects and

interactions• Counsel patients about symptoms that

warrant medical attention• Recommend alternative medications

when toxicity or side effects are a concern

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