Cardiac Toxicity

PRESENTED BY- SHIPRA OMAR M.Ph-2ND SEM CLINICAL

PHARMACY1

Cardiac

Toxicity

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• 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

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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Hypertrophic Cardiomyopathy

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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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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

Toxicant Interference With Oxidative Phosphorylation

RotenoneX

Antimycin AX

Cyanide and carbon monoxide

X

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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 10

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)

PQ S

R

TU

QT Interval

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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

1997Chlorpromazine (Thorazine®) – anti-psychoticArsenic trioxide (Trisenox®) – anti-cancer/leukemiaErythromycin (Erythrocin®) – antibioticFluoxetine (Prozac®, Sarafem®) – anti-depressant Haloperidol (Haldol®) – anti-psychotic/schizophrenia

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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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• 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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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 injury15

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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Cardiotoxicity of cytotoxic drugsCardiotoxicity 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

• 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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• 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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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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CARDIOTOXICITYCARDIOTOXICITYAcute or subacuteAlteration 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 21

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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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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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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• 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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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

• 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

• 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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• 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.29

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