the toxicity caused by the drugs on the cardiac system

1. CardiaC
ToxiCiTy
PRESENTED BY-
SHIPRA OMAR
M.Ph-2ND
SEM
CLINICAL PHARMACY
1

2. Cardiac
Toxicity
2

3. • Cardiotoxicity is the occurrence of heart
electrophysiology dysfunction or/and muscle damage.
The heart becomes weaker and is not as efficient in
pumping and therefore circulating blood.
• Cardiotoxicity may be caused
• by chemotherapy treatment, complications
from anorexia nervosa, adverse effects of heavy
metals intake, or an incorrectly administered drug
such as bupivacaine. 3

4. Cont….
• Cardiotoxicity, if severe lead to cardiomyopathy
• Cardiomyopathy is a serious disease in which
the heart muscle becomes inflamed and doesn't
work as well as it should. There may be multiple
causes including viral infections.
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5. Hypertrophic Cardiomyopathy
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6. Compound-Induced
Toxicity(acc.to mechnism of
toxicant)
• Toxicants that alter aerobic metabolism
• Toxicants that alter myocardial conduction
• Toxicants that alter cell membrane
function
• Toxicants that directly damage
myocardium
• Toxicants that induce vascular changes
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8. Toxicants That Interfere With
Aerobic Metabolism
• High energy demands of the heart make it susceptible to
toxicants that interfere with:
– oxygen availability (e.g., nitrite, carbon monoxide)
– carbohydrate metabolism (e.g., fluoroacetate), or
– oxidative phosphorylation (e.g., dinitrophenols)
• rotenone
• antimycin A
• cyanide and carbon monoxide
• Toxicity may result in myocardial necrosis 8

9. Toxicant Interference With
Oxidative Phosphorylation
Rotenone
X
Antimycin A
X
Cyanide
and carbon
monoxide
X
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10. Toxicants That Alter
Myocardial Conduction
• Alter impulse formation and cause
arrhythmias
– Toxicants that cause acidosis and
hyperkalemia (e.g., ethylene glycol)
• enhance slow current activity
• increase automaticity and promote arrhythmia
– Cardiotoxic divalent ions (e.g., barium,
strontium)
• replace calcium in slow-current channels
• alter efflux of potassium from myocardial cells →
hypokalemia and arrhythmias
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11. Toxicants That Alter Myocardial Conduction
• Alter impulse formation and cause
arrhythmias
– Toxicants that cause prolongation of the QT
interval (e.g., seldane)
– Blockage of multiple ionic channels that may
lead to syncope and ventricular fibrillation
(torsade de pointes)
P
Q S
R
T
U
QT Interval
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12. Toxicants That Cause
Prolongation of the QT Interval
Over 100 marketed pharmaceutical agents
cause interference in ventricular repolarization
QT prolongation is mentioned in the FDA-
approved labeling as a known action of the drug
e.g.
Terfenadine (Seldane®
) – antihistamine/removed in 1997
Chlorpromazine (Thorazine®
) – anti-psychotic
Arsenic trioxide (Trisenox®
) – anti-cancer/leukemia
Erythromycin (Erythrocin®
) – antibiotic
Fluoxetine (Prozac®
, Sarafem®
) – anti-depressant
Haloperidol (Haldol®
) – anti-psychotic/schizophrenia
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13. Toxicants That Alter Cell Membrane
Function
• Alter cell membrane control of ion
movement and affect cardiac contraction
– Cardiac glycosides and catecholamines
– Chemical ionophores (e.g., monensin)
• facilitates the passage of sodium, potassium, or
calcium
• monensin: alters Ca2+
and Na+
transport → increased
intracellular calcium → changes myocardial
contractility
• excessive calcium accumulation impairs
mitochondrial oxidative phosphorylation →
myocardial necrosis
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14. • Alter cell membrane control of ion movement
and affect cardiac contraction
– Toxicants that bind to phospholipids (e.g.,
gossypol)
• effect potassium transport → hyperkalemia →
arrhythmias
– Toxicants that selectively block sodium channels
• tetrodotoxin, saxitoxin
• decreased intracellular Na+
→ depression of normal
pacemaker function and conduction → arrhythmias
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15. Toxicants That Directly
Damage Myocardium
• Damage the pumping effectiveness by
reducing the number of active myocytes
– Toxicants that cause oxidative damage and lipid
peroxidation (e.g., doxorubicin, ethanol)
• redox cycling of doxorubicin → semiquinone
and superoxide radicals
• ethanol metabolism → lipid peroxidation of
myocytes
• results in cell swelling, altered Ca2+
homeostasis,
and irreversible myocyte injury
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16. Toxicants That Directly
Damage Myocardium
• Damage the pumping effectiveness by
reducing the number of active myocytes
– Toxicants that cause sarcolemmal injury and
calcium alterations (e.g., catecholamines)
• endogenous: epinephrine and norepinephrine
• exogenous: isoproterenol (> toxicity than above)
• sarcolemmal damage through lipid peroxidation
• increased calcium uptake → impaired mitochondrial
function and activation of neutral proteases and
phospholipases → myocyte dysfunction and toxicity
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17. Cardiotoxicity of cytotoxic drugs
Cardiotoxicity is a well-known side effect of several
cytotoxic drugs, especially of the anthracyclines and
can lead to long term morbidity.
o The mechanism of anthracycline induced
cardiotoxicity seems to involve the formation of free
radicals leading to oxidative stress.
o This may cause apoptosis of cardiac cells or
immunologic reactions.
o Cardiac protection can be achieved by limitation of
the cumulative dose.
o addition of the antioxidant and iron chelator
dexrazoxane to anthracycline therapy has shown to
be effective in lowering the incidence of anthracycline
induced cardiotoxicity. 17

18. • Other cytotoxic drugs such as 5-fluorouracil,
cyclophosphamide and the taxoids are
associated with cardiotoxicity as well, although
little is known about the possible mechanisms.
• Recently, it appeared that some novel
cytotoxic drugs such as trastuzumab and
cyclopentenyl cytosine also show cardiotoxic
side effects.
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19. • Mechanism of cardiotoxicity :
• Three mechanisms are involved in the cytotoxic action of
anthracyclines:
• high affinity binding to DNA, via nucleic intercalation, which
causes inhibition of DNA and RNA synthesis and cleavage
of DNA strands by alterations of topoisomerase II
• binding to the cell membrane which alters its normal fluidity
and transport of ions
• semiquinonic and oxygen free radical production, via
reduction enzymatic reaction.
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20. CARDIOTOXICITYCARDIOTOXICITY
 Incidence ranging from 5% to 65% of treated
cases, in relation to the total dose of drugs
administered and over the duration of follow-up
considered
 Drugs most frequently associated with
cardiotoxicity are anthracyclines (doxorubicin,
epirubicin), taxanes, alkylating agents and
trastuzumab
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21. CARDIOTOXICITYCARDIOTOXICITY
Acute or subacute
Alteration of ventricular repolarization phase,
duration of QT, arrhythmias, ischemia, acute heart
failure, myocarditis-pericarditis-like syndrome
Chronic (early / late)
Asymptomatic left ventricular dysfunction, systolic
and/or diastolic dysfunction, severe form of dilated
cardiomyopathy, cardiac death
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22. CARDIOTOXICITYCARDIOTOXICITY
 Formation of oxygen free radicals and calcium
overload in myocytes
 Deficiency of antioxidant systems, as catalase
and superoxide dismutase
 Possible immunological reaction induced by the
drug
Pathophysiological MechanismsPathophysiological Mechanisms
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23. What are the symptoms of
cardiac toxicity?
• Cardiac toxicity is a serious condition.
Notify your doctor immediately if you have
any of the following symptoms:
• Fatigue
• Shortness of breath on exertion, worsening to
shortness of breath at rest
• Discomfort lying on your back
• Swelling of the ankles
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24. How is cardiac toxicity
diagnosed?
• Cardiac toxicity is diagnosed with a number of
examinations and tests:
• Physical exam: Your doctor may listen to your heart
with a stethoscope. If it does not sound normal, there
may be damage to your heart.
• Chest X-ray: Your doctor can see if your heart looks
too big or if fluid is building up in your lungs.
• Echocardiogram: Your doctor may use ultrasound to
see your heart in action. The doctor will be able to
see if the heart is pumping enough blood. This is the
test used to measure your left ventricular ejection
fraction (LVEF).
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25. • Electrocardiogram (ECG): This test lets the doctor see
your heart rhythm in detail.
• Multi-Gated Acquisition (MUGA) scan: For this test, a
radioactive substance is injected into your vein. The
doctor can then see how well your heart is pumping.
The doctor can also see how well the vessels bringing
blood to the heart are working.
• Blood test: Less often, your doctor may look for
factors called troponins in your blood. These factors
are released by heart cells as they die. Troponins may
be in your blood even before a decline in LVEF is
seen. The use of troponins in the blood to predict
heart problems is still being studied.
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26. How can cardiac toxicity be
prevented?(pharmacological
&non pharmacological )
• Heart problems may be prevented by altering the amount of
drug administered (dose), method of administration and type of
anthracycline. Also, some medications that can prevent
damage from doxorubicin have been developed.
• Cardiac toxicity can often be prevented by giving less of the
cancer drug. Or the schedule of the drug can be changed so
that you get lower doses more often (rather than larger doses
less often). There are also forms of drugs that may be
less toxic. For example, liposomal anthracyclines might have
less cardiac toxicity than regular anthracyclines. 26

27. • The problem is balance. You don’t want to have any
more treatment than is needed to cure the disease.
But you don’t want to lower the chance of cure just to
lower the chance of side effects several years later.
You should talk to your doctor about the balance of
risks and benefits of cardiotoxic drugs for your
individual case.
• There is a drug called dexrazoxane (Zinecard) that
may prevent or lessen the damage to the heart by
anthracyclines. It is given at the same time as the
cancer drug to protect your heart from damage.
However, this drug may affect your chance of being
cured, and there may be other risks when you take it.
It is usually only given to patients who have the
highest risk for cardiac toxicity. 27

28. • Other drugs are now being tested for
prevention of damage to the heart in high-risk
patients. These include enalapril, an
angiotensin-converting enzyme (ACE) inhibitor,
and carvedilol, a beta-blocker.
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29. • ACE inhibitors: These drugs also make it easier for your
heart to pump blood to the body by opening your arteries and
lowering your blood pressure. This improves blood flow to
your kidneys, which do not function properly with low blood
flow. Some examples of ACE inhibitors include benazepril
(Lotensin), enalapril (Vasotec) and fosinopril (Monopril).
• Beta-blockers: These medications slow down your heart rate
and may be used if you have a myocardial infarction (heart
attack.) Examples are: metoprolol (Lopressor), propranolol
(Inderal) and atenolol (Tenormin).
• a digitalis drug (to make your heart stronger and
to regulate heart rhythm)
In severe cases, a heart transplant may be needed.
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