Week 4: Drug Induced Cardiac/Kidney/Lung Disease Flashcards
QTc prolongation and Torsades de points(TdP)
what is it:
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
normal QTc (must ocrrect for HR)
men: <470 ms
women: <480 ms
drug induced QTc dx
QTc >/ 500 ms
OR
QTc of >/ 60 ms from baseline
Common medications that cause QT prolongation
also note**
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
risk factors that lead qt prolongation-> TdP
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
approch to drug induced qt prolongation
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
Treatment of Tdp
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
- *!! 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
- 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
Drug induced HF causes
sodium and volume retention
direct cardiotoxicity-> cardiomyopathy
negative inotropy
*some drugs or drug classes can cause more than one of these mechanisms
drug induced HF
drugs that causeHF due to NA and fluid retention
NSAIDS
steroid
thiazolidinediones (TXDs)
drug induced HF
drugs that cause HF due to cardiomyopathy
chemo agents
biologic agents
alcohol
drug induced HF
drugs that cause HF due to negative inotropy
Non-dihydropyridine calcium channel blockers
beta blockers
considerations for drugs that cause HF due to sodium and fluid retention
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
considerations for drugs that cause HF due to cardiomyopathy
chemo agents: anthracyclines, alkylating agents
biologic agents: Trastuzumab
alcohol: direct toxic effect on the myocardium
Anthracycline induced cardiomyopathy
most common agents:
moa:
mechanism of damage:
chemoprotective agent to help w. cardiomyopathy
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
risk factors for anthracycline toxicity
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
maximum dose of anthracyclines (doxorubicin)
Lifetime dose of 550 mg/m^2
is anthracycline cardiotoxicity reversible or irreversible
IRREVERSIBLE
Trastuzumab induced cardiomyopathy
moa of drug:
moa of cardiomyopathy
is it reversible or irreversible
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
risk factors for development of trastuzumab induced cardiomyopathy
1.advanced age
- presence of cv comorbidities
- previous treatment with anthracyclines
Trastuzumab precautions and BBW
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
Treatment of Trastuzumab induced cardiomyopathy
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
HF due to negative inotropy
drug considerations
NON-DHP CCB: avoid in pts w. EF<40%
BB: avoid in acute HF exacerbation
General mechanisms of drug induced myocardial ischemia and acute coronary syndrome
1.increased myocardial oxygen demand
2. decrease myocardial oxygen supply
3.drug induced ACS
Drug induced myocardial ischemia and acute coronary syndrome
INCREASED MYOCARDIAL DEMAND
Disease and Mechanism
Examples
disease and mechanism: incfreased HR and contractility
examples: cocaine, beta agonists, sympathomimetics, withdrawal of b blockers, potent vasodilators
Drug induced myocardial ischemia and acute coronary syndrome
DECREASED MYOCARDIAL SUPPLY
Disease and Mechanism
Examples
sidease and mechanism: increased coronary resistance (vasospasm
ex: cocaine, antimigraine agents (triptans)
Drug induced myocardial ischemia and acute coronary syndrome
DRUG INDUCED ACS
Disease and Mechanism
Examples
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
cocaine induced myocardial infarction
moa
prevelance
*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
treatment of cocaine induced MI
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
Mechanism of NSAID induced Toxicity
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
NSAID BBW
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
risk factors for acute MI with NSAIDS
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
Drug Induced Kidney Disease
Category: hemodynamic mediated renal injury
basic patho:
exs:
notes:
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
hemodynamic mediated renal injury
Prerenal injury
Prerenal:
basic patho: reduced blood flow to kidney
ex: diuretics
note: decrease effective circulatory volume if over diuresis occurs
Drug Induced Kidney Disease
Category: intrinsic renalinjury
basic patho:
exs:
Drug Induced Kidney Disease
Category: hemodynamic mediated renal injury
basic patho:
1. Glomerular nephritis
exs: Gold, Allopurinol
- Acute tubular necrosis
ex: Aminoglycosides, amphotericin B, IV contrast media - acute interstitial nephritis
ex: PCNs, NSAIDs, PPIs, sulfa drugs - vasculitis: PTU, Levamisole ,Allopurinol, Phenytoin
Drug Induced Kidney Disease
Category: post renalinjury
basic patho:
exs:
Drug Induced Kidney Disease
Category: post renalinjury
basic patho: nephrolithiaisis
exs: topiramate, furosemide, acyclovir, sulfonamides, allopurinol
risk factors for drug induced renal disease
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
keys to prveent drug induced kidney disease (DIKD)
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
Prevention of drug induced kidney disease: proactive monitoring
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
What is the fluid of choice fo rprevention of AKI
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
prevention of drug induced AKI
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
treatment of prerenal/hemodynamic kindey in jury
D/C offending agent
provide sufifcient fluids to maintain effective circulating volume
monitor kidney function and electrolyes
Intrinsic renal in jury
Acute Tubular Necrosis (ATN)
causative agents and presentation
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)
aminoglycosides and ATN
nephrotoxicity is related to torugh concentrations, importance of TDM and PK individualization
goal troughs:
gentamicin and tobramycin: </2mg/L
Amikacin </8mg/L
Extended interval dosing (e.g q24 hrs may reduce risk of nephrotoxicity
goal trough. undetectable
*no difference in risk of nephrotoxicity, maybe some reduce risk
*optimizes pk/pd relationship in comparison to traditional dosing
mgt of ATN
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
contrast induced nephropathy risk factors
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
prevention of CIN
- 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) - 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
examples of contrast media available agents
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
monitoring parameters for CIN
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)
Acute interstitial nephritis (AIN)
Type 4 cell mediated immune reaction
immune activation/hypersensitivity->leukocyte infiltration->inflammation-> AIN
drug induced AIN causative agents
BETA LACTAMS
NSAIDS
SULFA CONTAINING DRUGS
PPIs
others include
vanco
diuretics
allopurinol
anti epileptics
treatment of drug AIN
stop offending drug
avoid cross reacting drugs
supportive care
steroids (EARLY INTERVENTION)
AIN steroid protocol example
corticosteroid dosing protocols are not standardized
early, aggressive steroid therapy may improve long term renal outcomes
Vancomycin associated AKI mechanism
mechanism: unclear: AIN plays a role but reports of ATN, oxidative stress, complement fixation, etc.
risk factors for vancomycin AKI
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)
prevention of vanco associated AKI
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
refresher: definition of AKI
increase of 0..3 mg/dl in a 48hr period
ORRR
50% from baseline in a 7 day period
Nephrolithiasis common causative agents
topiramate
sulfonamides
furosemides
nephrolithiasis preventin and treatment
maintain adequate hydration
goal output >/2.5L/ day
treatment: hydration to induce diuresis
*pain management
*lithostipsy-shockwave disintegation of ston epassage
rhabdomylysis
mechanism
causative agents
prevention
management
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
Lithium induced CKD
patho:
lithium target range(general)
risk factors:
prevention:
treatment:
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
Role of Liver
metabolism
*aminoacids, carbs,lipids (bile)
synthesis
*proteins (albumin, clotting factors, etc.)
*cholesterol and tgl
*thrombopoeitin
Detoxification
*food
drugs
herbals
Detoxification
problems w. a diseased liver
decreased amino acid metabolism
decreaed protein synthesis
incrfeased bilirubin
altered carb metabolism
reduced cholesterol production
reduced detoxification
Hepatic Labs
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
aminotransferases
lrvrld:
maerkers for what kind of injury
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
bilirubin
derived from degredation of hemoglobin from rbc’s
normal values: ~1
jaundice
physical manifestation of hyperbilirubinemia
*accumulation of hyperbilirubinemia
causes of liver disease
alcohol
hepatitis ABCDE
biliary tract disease
nonalcoholic fatty liver disease
drug induced
genetic/metabolic
Drug Induced Liver Injury (DILI)
etiology
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
adili DEFINITION
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
types of DILI
Hepatocellular
*AST AND ALT elevation
*R=[ALT/ULN]/[ALP/ULN]>/5
CHOLESTATIC (something preventing bile moving to duodenum)
*alp elevation
R=[ALT/ALP/ULN]</2
MIXED:
R=[ALT/ULN/ALP/ULN=2-5
Causes of DILI
what is #1 cause of DILI in DILIN
1 on the Drug induced liver disease network (DILIN)
amox-clav
known to cause cholestatic jaundice
can cause hepatocellular injury
associated w. HLA-DRB1*15 allelle
symptom onset 2-45 days
Treatment: supportive care, will self resolve
DILI network
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
DILIN: HErbal and Dietary supplements
16% of DILI cases were du eto herbals and dietary supplements
bodybuilding had more cholestatic, nonbuilding had more hepatocellular injury
DILN: mortality/transplant and patterns of injury
cholestatic injury less associated w. mortality and transplant
rechallenging i nDILI
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
APAP overdose PK
rapid PO absorption wihtin 2 hours
APAP crosses BB and placenta
meTABOLISM: 25% extracted through pass metabolism
APAP toxicity mechanism and toxic acute dose
elimantion processes(glutathione) become saturated
toxic acute dose considered >/7.5 g in adults or >/150 mg/kg in children
predisposing factors for APAP toxicity
cyp2e1 induction (anticonvulsants, isoniazid, chornic etoh users), recued glutathione stores(malnurished) decreased sulfation and glucuroniation
manisfestation of APAP toxicity
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
APAP toxiicty management
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
NAC mOA
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
NAC efficacy
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
what if the APAP level is outside 4-24 hr window
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
IV vs PO NAC
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
treatment duration of NAC
anywhere from 20-72 hrs
continue if on going liver failure present, elevated pt/inr encephalopathy
detecatable apap or ongoing hepatocyte damage
