Week 4: Drug Induced Cardiac/Kidney/Lung Disease

Question 1

QTc prolongation and Torsades de points(TdP)

what is it:

Answer 1

QTc prolongation: lengthening of the qt interval due to increased positive ions, which increases risk for TdP

TdP: lifethreatening polymorphic ventricular tachycardia triggered by premature ventricular beating during qtc prolongation
*not all QTc leads to TdP

Question 2

normal QTc (must ocrrect for HR)

Answer 2

men: <470 ms
women: <480 ms

Question 3

drug induced QTc dx

Answer 3

QTc >/ 500 ms
OR
QTc of >/ 60 ms from baseline

Question 4

Common medications that cause QT prolongation

also note**

Answer 4

ABCDEF

A:antiarryhtmics (amiodarone,sotalol, dofetilide) (classIII antiaryhtmics)

B: Antibiotics (fluroquinolones[lexoflox,ciproflox,], macrolides[erythromycin,azithromycin])

C: antipsyChotics(Class I worse than Class II)

D: AntiDepressants:( !!Citalopram!!, TCA’s)

E:AntiEmetics (ondansetron)

F: Antifungals (-azole antifungals)

and many many more

notes: DDII or organ function may increase levels of these medications
*additive qt prolongation occurs when one or more than one offending agent

Question 5

risk factors that lead qt prolongation-> TdP

Answer 5

nonmodifiable:
>65 years old
female gender (already have longer qt interval than men)
genetic predisposition
cardiac disease

modifiable:
diuretic treatment( due to electrolyte imbalance during treatment)
electrolyte abnormalities
>1 ST-prolonging agent
organ function

Question 6

approch to drug induced qt prolongation

Answer 6

avoic qtc interval prolongation drugs in pts w. pretreatment intervals >450 msec

reduce dose or d/c prolonging agents if qtc increases >60msec from pretreatment value

d/c prolonging agent if qtc increases >500msec

maintain k>4 and Mg>2

avoid concaminant administratoin of qtc interval prolonging drugs

avoid qtc interval-prolonging drugs in patients with a hx of drug induced tdp

Question 7

Treatment of Tdp

Answer 7

goal: increase HR even faster to avoid introduction of early beat

1.D/C offending agents that can potentially cause prolonged qt (and avoid admin. more qt prolonging agents

2. *!! IV magnesium!! push or infusion (mg is a safe positive ion to admin in an acute setting)
   *if pt does not have a pulse, admin as push
   *if pt still has a pulse , can give infusion
   *pay attention to other electrolytes such as K+, and Ca may need to be repleted

3.Transcutaneous pacing

4. isoproterenol infusion: beta agonist to increase chronitropy and inotropy of heart. DRUG OF CHOICE in Tdp, however $$ and not always available, alternatives are epinephrine or atropine

if at any point the pt is hemodynamically unstable, cardioversion or defribillation is required

Question 8

Drug induced HF causes

Answer 8

sodium and volume retention

direct cardiotoxicity-> cardiomyopathy

negative inotropy

*some drugs or drug classes can cause more than one of these mechanisms

Question 9

drug induced HF

drugs that causeHF due to NA and fluid retention

Answer 9

NSAIDS
steroid
thiazolidinediones (TXDs)

Question 10

drug induced HF

drugs that cause HF due to cardiomyopathy

Answer 10

chemo agents

biologic agents

alcohol

Question 11

drug induced HF

drugs that cause HF due to negative inotropy

Answer 11

Non-dihydropyridine calcium channel blockers

beta blockers

Question 12

considerations for drugs that cause HF due to sodium and fluid retention

Answer 12

nsaid(also increase systemic vascular resistance) and steroids:
in pts w. HF,
avoid if possible!!
if necessary: minimize dose and duration

TZDS: BBW: avoid in pts with NYHA III-IV HF

Question 13

considerations for drugs that cause HF due to cardiomyopathy

Answer 13

chemo agents: anthracyclines, alkylating agents

biologic agents: Trastuzumab

alcohol: direct toxic effect on the myocardium

Question 14

Anthracycline induced cardiomyopathy

most common agents:
moa:
mechanism of damage:
chemoprotective agent to help w. cardiomyopathy

Answer 14

most common agents: doxorubicin, daunorubicin

moa: Topoisomerase 2B (TOP2B) mediator for anthracycline induced cardiopyopathy

mechanism of damage:
*TOP2B: in all cells, including cardiomyoctes
*inhibition of TOP2B (anthracyclines) causes DNA breakdown and cell death
->increase free radicals and cell death
->defective mitochondrial biogenesis

*dexazoxane binds to TOP2B to prevent anthracycline binding(helps prevent cardiotoxicity of anthracyclines

Question 15

risk factors for anthracycline toxicity

Answer 15

treatment related
*cumulative dose of anthracycline (>400mg/m^2)
*dosing schedules
*previous anthracycline therapy
*radiation therapy
*co-administration of potentially cardiotoxic agents

Patient related
*age
preexisting CV disease or risk factors
*obesity
*smoking
*gender

Question 16

maximum dose of anthracyclines (doxorubicin)

Answer 16

Lifetime dose of 550 mg/m^2

Question 17

is anthracycline cardiotoxicity reversible or irreversible

Answer 17

IRREVERSIBLE

Question 18

Trastuzumab induced cardiomyopathy

moa of drug:
moa of cardiomyopathy
is it reversible or irreversible

Answer 18

moa: trastuzumab is a HER2 receptor antagonist that can be used in certain types of breast cancer
moa of cardiomyopathy: inhibition of HER2 receptors->
* increased reactive o2 species (ROS)
*reduced NOS expression
*reduced NO bioavailability
*increased angiotensin
cardiotoxicity is usually REVERSIBLE once drug is d/c

Question 19

risk factors for development of trastuzumab induced cardiomyopathy

Answer 19

1.advanced age

2. presence of cv comorbidities
3. previous treatment with anthracyclines

Question 20

Trastuzumab precautions and BBW

Answer 20

nO CI, bu recommended to avoid in pts with a hX of HF. evvaluate LVEF in all patients prior to and during treatment

BBW: associated w. symptomatic and asymptomatic reductions in left ventricular ejection fraction and development of HF

Question 21

Treatment of Trastuzumab induced cardiomyopathy

Answer 21

dose adjustments based on LVEF
consider dose reduction or discontinuation if HF develops

consider using HF meds during treatment if EF declines
*ACE/ARBS
*beta-blockers

Question 22

HF due to negative inotropy

drug considerations

Answer 22

NON-DHP CCB: avoid in pts w. EF<40%
BB: avoid in acute HF exacerbation

Question 23

General mechanisms of drug induced myocardial ischemia and acute coronary syndrome

Answer 23

1.increased myocardial oxygen demand
2. decrease myocardial oxygen supply
3.drug induced ACS

Question 24

Drug induced myocardial ischemia and acute coronary syndrome

INCREASED MYOCARDIAL DEMAND

Disease and Mechanism
Examples

Answer 24

disease and mechanism: incfreased HR and contractility

examples: cocaine, beta agonists, sympathomimetics, withdrawal of b blockers, potent vasodilators

Question 25

Drug induced myocardial ischemia and acute coronary syndrome DECREASED MYOCARDIAL SUPPLY Disease and Mechanism Examples

Answer 25

sidease and mechanism: increased coronary resistance (vasospasm ex: cocaine, antimigraine agents (triptans)

Question 26

Drug induced myocardial ischemia and acute coronary syndrome DRUG INDUCED ACS Disease and Mechanism Examples

Answer 26

disease and mechanism: A) coronary arthery thrombosis/vasospasm ex: cocaine, oral contraceptives, NSAIDS, estrogens, antimigraine agents B)Increased cardiovascular risk ex: cocaine, NSAIDS estrogens, HIV agents, oral contraceptives, rosiglitazone

Question 27

cocaine induced myocardial infarction moa prevelance

Answer 27

*25% of MI in 18-45 y.o is a ssociated w. frequent cocain euse moa: sympathomimetic crisis, cocaine inhjibits the reuptake of norepineohrine leadint to increased norepineohrine concentrations and enhanced alpha 1 mediated vasoconstriction

Question 28

treatment of cocaine induced MI

Answer 28

chest pain: *aspirin *benzodiazipines(cheat sympathomimetic crisis) persistent HTN *benzos *IV nitroglycerin other acute ACS trtmt *possible aboid acute BB *otherwise proceed as normal Longterm ACS treatment *possibly avoid beta speciic blockers *drug abuse counseling

Question 29

Mechanism of NSAID induced Toxicity

Answer 29

NSAID moa: blocks cox enzyme Cardiovascular effects COX enxymes> vascular vasodilation and decrease platelet aggregation cox inhibition: MI, stroke GI mucosa cox enzymes: increase gastric acid, increase bicarbonate, increase mucosal blood flow cox inhibition: peptic ulcers, bleeding Kidneys cox enzymes: afferent arteriolar vasodilation-> increase GFR increase sodium and water retention cox inhibition: Na/H1O retention, HTN, AKI

Question 30

NSAID BBW

Answer 30

may increase risk of serious CV thrombotic events,MI, STROKE, which can be fatal. may increase w. duration of use. pts w. cv disease or rosk factors for cv disease may be at greater risk

Question 31

risk factors for acute MI with NSAIDS

Answer 31

when: risk of MI early in theraypu rapid onset (w.in 7 days) how much: NSAID use increases risk by about 20-50% which NSAIDs: no diff btw. selectgive and non selective NSAIDs which doses: higher doses, higher risk 1200mg/day ibuprofen 750 mg/day naproxen duration: doesnt appear to increase risk not been well studied

Question 32

Drug Induced Kidney Disease Category: hemodynamic mediated renal injury basic patho: exs: notes:

Answer 32

Category: basic patho: reeuction in glomerular pressure due to alterations in arteriole tone exs:* ACE/ARBS: efferent arteriole dilation via decreased angiotensin II *NSAIDS: afferent arteriole constriction via decreased PGE2 production *SGLT2 inhibitors: deliver Na to macula densa cellsafferent arteriole constriction via tubuloglomerular feedback *calcineurin inhibitors: afferent arteriole constriciton notes: *net effects is a loss of autoregulation-> increase risk of decreased intraglomerular hydrostatic pressure-> decreases GFR *combos of these drug s w. low volume state (dehydration) is highest risk for AKI

Question 33

hemodynamic mediated renal injury Prerenal injury

Answer 33

Prerenal: basic patho: reduced blood flow to kidney ex: diuretics note: decrease effective circulatory volume if over diuresis occurs

Question 34

Drug Induced Kidney Disease Category: intrinsic renalinjury basic patho: exs:

Answer 34

Drug Induced Kidney Disease Category: hemodynamic mediated renal injury basic patho: 1. Glomerular nephritis exs: Gold, Allopurinol 2. Acute tubular necrosis ex: Aminoglycosides, amphotericin B, IV contrast media 3. acute interstitial nephritis ex: PCNs, NSAIDs, PPIs, sulfa drugs 4. vasculitis: PTU, Levamisole ,Allopurinol, Phenytoin

Question 35

Drug Induced Kidney Disease Category: post renalinjury basic patho: exs:

Answer 35

Drug Induced Kidney Disease Category: post renalinjury basic patho: nephrolithiaisis exs: topiramate, furosemide, acyclovir, sulfonamides, allopurinol

Question 36

risk factors for drug induced renal disease

Answer 36

elderly (age>65 y.o) CKD concaminant nephrotoxins renin dependent state (low effective circulating volume; ex HF, cirrhosis) known allergy to drug duration of therapy DM/HTN

Question 37

keys to prveent drug induced kidney disease (DIKD)

Answer 37

direct prevention to underlying mechanism of injusry !!!avoid nephrotoxic meds (and combos of ) in high risk pts!! maintain adequate perfusion (i.e hydration) a. IV isotonic crystaloids in pts at risk of AKI TDM (if possible

Question 38

Prevention of drug induced kidney disease: proactive monitoring

Answer 38

kidney function monitorinf w. an intensity that matches the risk of kidney injury markers: SCr, BUN, eGFR, urinary output frequency: yearly to hourly based on clnical context novel urinary biomarkers '*kidney injury molecule 1 (KIM1-ATN *neutrophil gelatinase associated lipocalin (NGAL)(ischemic injury) *insulin like growth factor binding protein 7(IGFBP7 and tissue inhibitor of metalloproteinase2 (TIMP-2)-markers of cell cycle arrest

Question 39

What is the fluid of choice fo rprevention of AKI

Answer 39

ballance crystalloids (lactated ringers, plasma liteA) isotonic iV crystalloids as fluid of choice for prevention of acute kidney injury foudnd to have improved renal in jury outcomes

Question 40

prevention of drug induced AKI

Answer 40

maintain adequate fluid intake avoic concaminant nephrotoxins in high risk pts, start w. lowest dose of drugs that affect renal hemodynamics *monitor Scr, BUN, K+, weights closely )q2weeks as outpt until stable *titrate slowly *hold diuretics while initiating/titrating these agents *avois NSAID+ACE/ARB combo in CKD, heart disease, or liver disease

Question 41

treatment of prerenal/hemodynamic kindey in jury

Answer 41

D/C offending agent provide sufifcient fluids to maintain effective circulating volume monitor kidney function and electrolyes

Question 42

Intrinsic renal in jury Acute Tubular Necrosis (ATN) causative agents and presentation

Answer 42

#1 cause of in hopsital acute kidney injury causative agents: aminoglycosides, amphotericin B*(conventional>>liposomal), IV contrast media presentation: acutely progressive increase in SCr and BUN with decrease in GFR and urine outpit (oligouria and nonoligouria are both common urinalysis: proteinuria. cellular debirs, mussy brown color, and granular casts metabolic acidosis hyperkalemia FeNa>1% Mg waisting (cisplastin)

Question 43

aminoglycosides and ATN

Answer 43

nephrotoxicity is related to torugh concentrations, importance of TDM and PK individualization goal troughs: gentamicin and tobramycin:

Question 44

mgt of ATN

Answer 44

supportive care d/c drug and other nephrotoxic drugs non-nephrotoxic alternatives mainteain hydration kidney replacement therapy renal dose dopamine (2-5mg/kg/min)? pharmacologic diuresis

Question 45

contrast induced nephropathy risk factors

Answer 45

CKD GFR<60 DM, age, LVEF<40% Low effective circulating volume concaminant nephrotoxic agents large dose volume iodinated contrast high osmolal contrast ionic contrast short time interval btw 2 ocntrast administrations

Question 46

prevention of CIN

Answer 46

1. sodium based hydration- gold standard Saline hydration(normal saloine) maintain output >/150 ml/hr post contrast (need to flush the contrast out of the kidneys) 2. sodium bicarb (not graded): recommended if pt has another indication for bicarb 3.N-acetylcysteine (NAC)-conflicting evidence, possible benefit, contreversial 1200 mg PO BIDx4 doses (if high risk factors, can add

Question 47

examples of contrast media available agents

Answer 47

3 classes (high, low, and iso) examples of high: Diatrazoate (1550) metrizoate (2100) Low: Iohexol (884) *note: low osmolal agents are still higher than plasma osmolality iso: iodixanol:290

Question 48

monitoring parameters for CIN

Answer 48

SCr and BUN q12hrs for 2 days then q24hrs for 5-7 days (as inpt) urine output with strict ins and outs x 4 days medication regimen review (avoid nephrotoxic meds)

Question 49

Acute interstitial nephritis (AIN)

Answer 49

Type 4 cell mediated immune reaction immune activation/hypersensitivity->leukocyte infiltration->inflammation-> AIN

Question 50

drug induced AIN causative agents

Answer 50

BETA LACTAMS NSAIDS SULFA CONTAINING DRUGS PPIs others include vanco diuretics allopurinol anti epileptics

Question 51

treatment of drug AIN

Answer 51

stop offending drug avoid cross reacting drugs supportive care steroids (EARLY INTERVENTION)

Question 52

AIN steroid protocol example

Answer 52

corticosteroid dosing protocols are not standardized early, aggressive steroid therapy may improve long term renal outcomes

Question 53

Vancomycin associated AKI mechanism

Answer 53

mechanism: unclear: AIN plays a role but reports of ATN, oxidative stress, complement fixation, etc.

Question 54

risk factors for vancomycin AKI

Answer 54

elevated trough concentrations 24-hr AUC>600 mcg*h/mL daily dose>4g duration of therapy>7 days severity of illness weight>101.4 kg concaminant nephrotoxic agents (pip/tazo)

Question 55

prevention of vanco associated AKI

Answer 55

stweardship avoid nephrotoxic concaminnat drugs avoid aminoglycosides if possible caution with pip/tazo (cefepime) monitoring: frequent monitoring in high risk patients avoid trough 15-20 mg/L; avoid AUC 400-600

Question 56

refresher: definition of AKI

Answer 56

increase of 0..3 mg/dl in a 48hr period ORRR 50% from baseline in a 7 day period

Question 57

Nephrolithiasis common causative agents

Answer 57

topiramate sulfonamides furosemides

Question 58

nephrolithiasis preventin and treatment

Answer 58

maintain adequate hydration goal output >/2.5L/ day treatment: hydration to induce diuresis *pain management *lithostipsy-shockwave disintegation of ston epassage

Question 59

rhabdomylysis mechanism causative agents prevention management

Answer 59

mechanism:intra tbuular precipitation of myoglobin from muscle breakdown drugs: statins and stain fibrate combos prevention: avoid statin interactions, counsel pts on muscular symptoms management: d/c offenidng agent, aggresive IV fluid admin, +/- urinary alkalization targe t UOP~3ml/kg/hr if urine pH<6.5, alternate sodium chloride and sodium bicarb iv fluids

Question 60

Lithium induced CKD patho: lithium target range(general) risk factors: prevention: treatment:

Answer 60

patho: chornic interstitial nephritis, minimal change disease, focal segmental glomerulanecrosis, NEPHROGENIC DIABETES INSIPIDUS(can be managed by ameloride), distal tubular acidosis , incidence: 1.2% lithium target range: 0.5-1 risk factors: duration of therapy, episodes of acute lithium toxicity.!! CUMULATIVE LITHIUM EXPOSURE. (CHORNIC EXPOSURE) prevention: routine TDM of lithium, avoiding dehydration, monitoring renal function over time, avoid drug interactions (HCTZ) treatment: D/C lithium, hydration, amiloride 5-20 mg daily (treats polyuria and polydipsia), avoid orher nephrotoxic drugs, monitor renal function *amiloride doesnt trat the ckd, just the symptomsof drug induced diabetes insipidus

Question 61

Role of Liver

Answer 61

metabolism *aminoacids, carbs,lipids (bile) synthesis *proteins (albumin, clotting factors, etc.) *cholesterol and tgl *thrombopoeitin Detoxification *food drugs herbals Detoxification

Question 62

problems w. a diseased liver

Answer 62

decreased amino acid metabolism decreaed protein synthesis incrfeased bilirubin altered carb metabolism reduced cholesterol production reduced detoxification

Question 63

Hepatic Labs

Answer 63

Liver function Tests aminotransferases (AST,ALTCGT,ALP) *best markers of acute injury *in cirrohissis(chronic), these normalize, so not a good marker of liver function in chronic disaease synthetic function *albumin (normal albumin levels: 3.4-5.4 g/L *PT/INR *good markers in choronic liver funciton evaluation jaundice

Question 64

aminotransferases lrvrld: maerkers for what kind of injury

Answer 64

AST ALT *both levels 5-40 *found in hepatocytes *hepatocellular injury markers ALK PHOS()ALP) *found in cells of bile ducts (bile canniculi) normal levels (30-140) *cholestatic injury markers

Question 65

bilirubin

Answer 65

derived from degredation of hemoglobin from rbc's normal values: ~1

Question 66

jaundice

Answer 66

physical manifestation of hyperbilirubinemia *accumulation of hyperbilirubinemia

Question 67

causes of liver disease

Answer 67

alcohol hepatitis ABCDE biliary tract disease nonalcoholic fatty liver disease drug induced genetic/metabolic

Question 68

Drug Induced Liver Injury (DILI) etiology

Answer 68

range from asymptomatic elevations in lab liver tests to overt liver failure etiology not completely known most common road block in drug development APAP most common cause

Question 69

adili DEFINITION

Answer 69

newer definition *total bili>2.5 mg/dL and any elevation in ALT, AST, or ALP ALT>5x ULN AST>5X ULN ALP>2x ULN INR>1.5 w. elevated AST, ALT, ALP

Question 70

types of DILI

Answer 70

Hepatocellular *AST AND ALT elevation *R=[ALT/ULN]/[ALP/ULN]>/5 CHOLESTATIC (something preventing bile moving to duodenum) *alp elevation R=[ALT/ALP/ULN]

Question 71

Causes of DILI what is #1 cause of DILI in DILIN

Answer 71

amox-clav known to cause cholestatic jaundice can cause hepatocellular injury associated w. HLA-DRB1*15 allelle symptom onset 2-45 days #1 on the Drug induced liver disease network (DILIN) #2 caude of DILI (after APAP) Treatment: supportive care, will self resolve

Question 72

DILI network

Answer 72

prospective ongoing observational study assessing causation, w. intent to create a national data base of DILI reports, excluding APAP criteria of inclusion: *total bili>2.5 mg/dL and any elevation in ALT, AST, or ALP ALT>5x ULN AST>5X ULN ALP>2x ULN INR>1.5 w. elevated AST, ALT, ALP ABX should be on our radar for causing DILI, esp. augmentin, after APAP

Question 73

DILIN: HErbal and Dietary supplements

Answer 73

16% of DILI cases were du eto herbals and dietary supplements bodybuilding had more cholestatic, nonbuilding had more hepatocellular injury

Question 74

DILN: mortality/transplant and patterns of injury

Answer 74

cholestatic injury less associated w. mortality and transplant

Question 75

rechallenging i nDILI

Answer 75

rechannelenge may only be considered if pt had only cholestatic injury do not rechallenge if pt had hepatocellular injury if mized: used shortest duration of therapy possible in general, avoid rechallengin unless no alternative exists

Question 76

APAP overdose PK

Answer 76

rapid PO absorption wihtin 2 hours APAP crosses BB and placenta meTABOLISM: 25% extracted through pass metabolism

Question 77

APAP toxicity mechanism and toxic acute dose

Answer 77

elimantion processes(glutathione) become saturated toxic acute dose considered >/7.5 g in adults or >/150 mg/kg in children

Question 78

predisposing factors for APAP toxicity

Answer 78

cyp2e1 induction (anticonvulsants, isoniazid, chornic etoh users), recued glutathione stores(malnurished) decreased sulfation and glucuroniation

Question 79

manisfestation of APAP toxicity

Answer 79

N&V, malaise, pallor, diaphoresis doesnt occur until 24-36 hrs post ingestion w. increase in AST max hepatotoxicity occurs btw 72-96 hrs not uncomon to se AST,ALT >10000 can see changes in INR, bilirubin, glucose, lactate, phosphate and pH +/- renal failure those thaqt survive make a ocmplete recovery

Question 80

APAP toxiicty management

Answer 80

activated charcoal in pts who present within 1-2 hours of ingestion N-Acetylcysteine therapy (NAC) is crucial supportive care *IV fluids *management of N/V corrwction of hypoglycemia *vit. K /FFP

Question 81

NAC mOA

Answer 81

serves as glutathione substitute detoxifying NAPQI precursor to glutathione resulting in increased glutathione production follows more nontoxic metabolism thorugh increased sulfation, resulting in less NAPQI production appears to preserve multiorgan function in severe toxiicty thorugh unknown mechanisms

Question 82

NAC efficacy

Answer 82

efficacy nearly complete in trial data when adminstered within 8hrs of APAP overdose decision to treat based on APAP serum levels plotted on the rumack-mathew nomogram available in PO and IV formulations

Question 83

what if the APAP level is outside 4-24 hr window

Answer 83

prior to hour 4: *consider activated charcoal wait and recheck at hour 4 to asess whether or not nac is indicated after hour 24: if AST is elevated regardless of APAP level,begin NAC after 24 hours or unknown late ingestion w. detectable APAP level, beginNAC

Question 84

IV vs PO NAC

Answer 84

equallt efficacious chois eshould be based on side effect profile, whether or not failure is present, and extrahepatic involvement dosings: Po: 72 hr protocol IV: 20 hour protocol AE: Po:bad taste, N/v in50% of pts (pretreat w. antiemetics) IV:anaphylactoid (rash, flushing,nromchospasm) in 17% of pts notes: Po: NAC delivery may be delayed up to an hour po therpay should be changed to IV if liver failure develops *solution shoul dbe diluted to 5% w. a soft drink and covered to cover smell IV: preffered in pts w. liver failure, pregnancy and in ability to tolerate PO *give over 60 min to avoid

Question 85

treatment duration of NAC

Answer 85

anywhere from 20-72 hrs continue if on going liver failure present, elevated pt/inr encephalopathy detecatable apap or ongoing hepatocyte damage