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PHAR 303 > L17. Cardiotoxicity > Flashcards

L17. Cardiotoxicity Flashcards

1
Q

How are we exposed to cardiotoxins?

A

Orally (swallowing) or Inhaling.

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2
Q

What are the pros and cons of taking anti cancer (antineoplastic) drugs? Is it worth it?

A

Pros: cure/help prolong your life from cancer
Cons: Have cardiovascular effects, very high risk.
- Worth taking the drug because it can save your life.

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3
Q

What are the different subgroups of cardiovascular disease?

A
  • Coronary heart disease
  • Cerebrovascular disease
  • Peripheral vascular disease
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4
Q

Describe the electrical system of the heart.

A
  • The SA node is the pacemaker of the heart. It has a rhythmical depolarization that drives the heart beat
  • The ANS is able to alter the rate of the SA node
  • The impulse comes from SA node and spreads to atria which contract
  • The impulse slows down through the AV node. The slowing allows for the atria to contract and pump the blood into the ventricles.
  • Then goes through the His Purkinje system to the ventricles which contract synchronously to pump the blood to the body.
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5
Q

What is the sympathetic nervous system’s built in safety mechanism for the heart?

A
  • If your SA node stops working, the heart has to continue to beat or you will die.
  • So if the SA node fails, the AV will node will take over.
  • If the AV node doesnt work then the His-Purkinje system can take over, it has intrinsic pacemaker activity if necessary.
  • If the heart is working as it should, then the SA node is preferred because its activity is faster.
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6
Q

Explain how/when the heart can be modulated.

A
  • The modulation of the heart is done to accommodate for stress and exercise and it is controlled by the ANS.
  • Sympathetic: NA and adrenaline from adrenal gland speed up HR and increase the force of contraction. Ex: scared, stressed, exercise, etc.
  • Parasympathetic: Acetylcholine slows HR and contraction force
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7
Q

What is the major difference between cardiac muscle and skeletal muscle?

A
  • The cardiac muscle has to work all the time

- You can rest your skeletal muscle but not the cardiac muscle

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8
Q

What are specific characteristics needed for the heart to function properly?

A
  • Electrical connections between the cardiac cells so that electrical impulse flows freely and contraction is synchronous
  • Requires a lot of energy so there are a lot of mitochondria
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9
Q

What is the average HR?Explain the different ECG waves of a typical heart beat.

A
  • Average HR: 60BPM
  • P wave: depolarization of atria
  • QRS: depolarization of ventricles
  • T: repolarization of ventricles
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10
Q

What are the different mechanisms of drug or toxin induced cardiotoxicity?

A
  • Interference with ion channel trafficking
  • Interference with electrophysiology
  • Interference with contractility
  • Interference with mitochondrial function (production of ATP–remember you need continual high generation of ATP)
  • Generation of free radicals (ROS)
  • Apoptosis or Necrosis
  • Causing fibrosis (scarring)
  • Blood clots (thrombosis)
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11
Q

What is a notable category of plant toxins?

A

Cardiac glycosides

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12
Q

What is the mechanism of sodium potassium pumps in cells?

A
  • In a normal functioning cell, Sodium potassium pumps are in the cell membrane. 3 sodiums are bound and pumped out and 2 potassium ions are pumped in to maintain the membrane potential across the cardiac muscle cells (electrical potential difference).
  • This is found in all excitable tissue: Heart cells have a lot of these sodium potassium pumps, the only cells that have more are neurons.
  • Because of this, interference with this system causes problems. everywhere, especially in the heart.
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13
Q

Where does the name glycosides (in cardiac glycosides) come from?

A

It is named this way because there is a sugar portion and a non-sugar portion (aglycone portion) which is attached to an R group which allows for the structure to vary giving different glycoside toxicity.

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14
Q

What are the different types of glycosides? What do we have in Canada?

A
  • Cardenolides: Plant glycosides like digitalis
  • Bufadienolides: found in animals, and especially in toxic frogs
  • In canada we only have cardenolides
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15
Q

What is the mechanism of action of cardenolides (plant cardiac glycosides)? Give an example of one that works in this way.

A
  • They block the sodium potassium pump
  • In the cardiac myocyte there is also a sodium calcium exchange mechanism
  • So when you block the NA/K pump, there is more sodium in the cell, which can be exchanged for calcium so there is an increase in Ca in the cardiac myocyte
  • Ca increases = force of contraction increases
  • Small doses of this toxin has been used to treat heart failure (increases the force of contraction).
  • An example of a cardenolide is foxglove/digitalis.
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16
Q

What happens when you consume a significant mount of cardenolides (plant cardiac glycosides) like foxglove/digitalis?

A
  • Greatly increase calcium and altering the amounts of sodium and potassium which leads to arrhythmia and loss of heart function (fatal).
  • Overall, this lowers pacemaker activity and slows conduction velocity to promote ectopic impulse generation.
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17
Q

What is seen on the ECG of someone who has consumed a toxic dose of the digitalis toxin?

A
  • Evokes after-depolarizations, causes extra systoles, tachycardia (i.e greatly increases HR)
  • decreased QT interval and increase in PR interval
  • Cardiac arrhythmia followed by cardiac arrest ->death
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18
Q

What is atrial fibrillation? Can you survive it?

A
  • Disorganized electrical signals in the atria so the cardiac muscle cells are contracting independently of each other (rather that in sync)=no meaningful contraction of atria.
  • Atrial fibrillation can be survived by either using AV node pace maker activity or something in the ventricle starts up a pacemaker activity. Some impulses slip through and activate the AV node. As long as you get some contraction of the ventricles to pump enough blood into body to avoid peripheral ischemia, you will stay alive.
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19
Q

What is a conduction block? Can you survive it? What’s the risk?

A
  • Impulse not getting to AV node
  • Getting little P waves but no contraction of the ventricle
  • If not severe u can survive as long as you have enough ventricular contractions. The big risk is that the ventricle will fibrillate (asynchronous contractions=fatal) leading to no blood flow to the brain or vital organs ->death.
  • This is the end result of digitalis poisoning: electrical failure of the heart.
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20
Q

What are the early and later symptoms of digitalis?

A
  • Early: Neurological due to its effect on all conductive and electrically active tissue. So some people can feel confused and so on.
  • Later: Life threatening hyperkalemia due to excess K outside of cell. The most likely cause of death would be death from cardiac arrest, ventricular tachycardia, ventricular fibrillation, progressive bradyarrhythmia, etc. End result is cardiac arrest from ventricular failure.
21
Q

What are the pharmacokinetics of digitoxin?

A
  • Well absorbed orally with peak serum concentrations in 1-3 hours.
  • Distribution: Concentrated in tissues such as heart and other rather than staying in the circulation. Because of this, it has a high AVD. It crosses the BBB which explains the neurological symptoms.
  • Takes a long time to get rid of it because it is not well broken down by the P450 system in the liver or elsewhere, therefore it is mainly just excreted by the kidney unchanged via first order kinetics.
22
Q

What are different plant toxins? Who are the most at risk?

A
  • Digitalis/foxglove
  • Oleander
  • Lily of the Valley
  • Milkweed
  • House plants such as Kalanchoe
  • Yew (taxus baccata)
  • ALWAYS CHILDREN. they put everything in their mouths.
23
Q

Explain the toxicity of Oleander.

A
  • Plant everywhere in Mtl
  • If one leaf is eaten (dried or not) = dead
  • Attractive to horses = kills them too
  • One of the most toxic plants in the world
  • Cardiac glycoside in oleander is called oleandrin
  • All/most cardiac glycosides resist heating (not destroyed by cooking)
24
Q

Explain a scenario where a glycoside was not neutralized when cooked.

A

People ate a snail dish at a restaurant and were poisoned. The snails had consumed a glycosidic plant but were immune to its effects. When the snail was cooked to be served the toxicity did not go away so the people were hospitalized.

25
Q

Explain the toxicity of the milkweed plant.

A
  • Monarch butterfly mother only lays eggs on the milkweed plant
  • The caterpillars that are born feeds from milkweed
  • Milkweed is full of cardiac glycosides that kill most insects other than a beetle and monarchs (resistance)
  • Perfect because when the monarch eggs are laid, the caterpillar has a guaranteed source of food because not much else can eat it. Because of its resistance, it accumulates the glycoside, and the butterfly/caterpillar become toxic themselves.
  • Anything that tries to eat them dies.
26
Q

Explain the toxicity of Lily of the Valley.

A
  • Convallarin, convallatoxin is the deadly cardiac glycoside from Lily of the Valley
  • These plants protect themselves from getting eaten
  • Grows in the spring and is a source of perfume
27
Q

What is a dangerous type of house plant?

A
  • Kalanchoes contains cardiac glycosides

- Children and pets are vulnerable

28
Q

Describe the toxicity of Yew.

A
  • An ornamental shrub
  • All parts of the plant are toxic and will kill you except for the red berry
  • Domestic animals vulnerable because grown all around yards in Mtl
  • Contains cardiotoxic taxine alkaloids for which there is no antidote or effective treatment.
  • On an ECG it has a very wide QRS complex
29
Q

What is the mechanism of action of Yew?

A
  • Cardiac conduction is impaired which leads to arrhythmia
  • Blocks Ca channels and death is within 30 min if consumed:
  • Ca channels in heart blocked so the control of heartbeat is interfered with (Ca channel blocker). There is also an indirect change on sodium and potassium channels.
  • The Ca channels being blocked affects the SA node: generation of HR is impaired
  • Also affects the AV node: decreased conduction affecting the electrical conduction
  • This leads to the disturbance of the electrical-mechanical coupling
    and subsequent decreased ventricular muscle contractility.
  • Subsequent ventricular fibrillation and death due to impairment of the cardiac muscle cell (cardiac arrest)
30
Q

What is a type of animal toxin and how is it toxic?

A
  • Snake venoms
  • Can damage heart
  • Cobra venom is a cardiotoxin that inserts itself into heart and forms a pore that interferes with conduction system in heart.
31
Q

What is the major problem anti-cancer drugs? What are its effects?

A
  • The Anthracycline family is the major problem and its toxicity can occur early or later on in life.
  • Early: During treatment or in the first year of treatment there are non specific ST segment and T wave abnormalities
  • Late: at least one year after the completion of treatment. It is cumulative and dose related and can lead to arrhythmia or congestive heart failure.
  • These drugs are given as a last resort and the patients are monitored so that at the first signs of toxicity the dose can be decreased and/or it can be combined with other drugs.
  • Its main affect is on the mitochondria: damages mitochondrial DNA triggering apoptosis and cell death.
32
Q

What is congestive heart failure?

A

Inadequate cardiac output and the various compensation mechanisms (enlargement, etc.) have taken place and are not enough. This leads to peripheral and pulmonary edema.

33
Q

What is Herceptin? What is its mechanism? What is a disadvantage?

A
  • Herceptin is an anticancer drug
  • Targets over expression of a surface molecule in breast cancer patients
  • It can be very effective for these patients, but this target is a surface molecule that is present in many other types of cells so it can lead to congestive heart failure by acting on the heart.
34
Q

What is ischemic heart disease?

A

Inadequate flow of blood to heart.

35
Q

What is ephedra? What is its effect?

A
  • Also called Ma-Huang, it is a plant that has compounds related to epinephrine and amphetamine.
  • Stimulates the ANS
  • Can be sold along other things such as caffeine
  • Mechanism: Increases dopamine and Noradrenaline release (and other neurotransmitters), also blocks reuptake into presynaptic nerve ending, and can stimulate post synaptic receptor. Has a particular effect at the nerve ending supplying the vessels of the heart and the brain.
  • Sold for weight loss, asthma treatment, and enhanced athletic ability (base ball player dropped dead) but leads to myocardial infarct and stroke.
  • Ischemia
36
Q

Why are pollution and more particularly fine particles, dangerous?

A
  • Air pollution is a silent killer that affects lungs, heart, & brain. Can lead to chronic pulmonary disease, cancers, diabetes, kidney disease, etc.
  • Fine particles are more strongly linked to death by cardiovascular disease than from respiratory diseases. At first they thought that you breathed in the fine particles and they went to the lungs where they stayed to cause damage. But actually, the particles don’t stay in the lungs, they can travel to the heart, which is why heart disease is the major killer of air pollution.
  • A quarter of the deaths from strokes and heart disease (ischemic heart disease and hypertensive heart disease) is due to air pollution.
37
Q

What is it in the pollution and the air that is causing cardiovascular problems?

A
  • Pollution and fine particles in air breathed in (MAJOR)
  • Metals
  • Plastics and petroleum-based chemicals
  • Although we have managed to decrease the incidence of CVD by changing our lifestyles, it’s still high due to these other factors.
38
Q

What is the biggest risk for your heart when inhaling air pollution? Why?

A
  • The inhalation of fine particles PM < 2.5 is the biggest risk because they are small enough to get into the circulation.
  • Linear relationship between inhalation of these particles and death by ischemic heart disease as well as death by stroke.
39
Q

What is a way they are using to see the effects of fine particles?

A

Organoids made from human tissue (can contract)

  • Can be exposed to toxins to see the fraction of cells that die, as well as analyze changes in their contractility
  • Used for research
40
Q

What happens when you inhale fine particles?

A
  1. Particles inhaled into lungs
  2. Get into blood stream
  3. 5 Increased risk of platelet activation and clot formation (hypercoagulability)
  4. Damage BV edothelium and trigger atherosclerosis (narrowing blood vessel lumen due to deposition of material leading to impaired blood flow). Also have inflammation.
  5. Formation of thrombus/clot
  6. Can target: Blood flow to heart muscle via coronary artery () , blood flow to brain by cerebral arteries (), and blood flow to periphery.
    - End result: significant risk of myocardial infarct, arrhythmia, and sudden death.
41
Q

Who is at high risk of adverse outcomes due to exposure to pollution?

A
  • For people who are at risk for heart attack (already vulnerable), being exposed to pollution (PM<2.5) can trigger the attack. These people need to monitor the air pollution levels and stay indoors if the levels are too high.
42
Q

What are the risk factors for air pollution?

A
  • Acute exposure to PM<2.5 increases mortality by heart attack
  • Ozone is also an acute risk because it itself increases mortality
  • Together, Ozone potentiates the risk of cardiovascular damage and mortality from PM<2.5
43
Q

What are some new approaches to document the incidence and pathogenesis of air pollution exposure?

A
  • DNA methylation
  • Histone modifications
  • microRNAs that are produced in response to ambient air pollution may serve as valuable biomarkers
  • Want to develop tests to detect stenosis (narrowing of blood vessel) before it gets to severe. Most of the time, you will only start to show symptoms until it is really severe, and by then it might be too late.
44
Q

What are the consequences of inhalation of PM<2.5?

A
  • Thrombus
  • Embolus
  • Hemorrhage
  • Spasm
  • Stroke
45
Q

What is wrong with candles/incense?

A

Burning them releases fine particles. Not safe to breathe.

46
Q

How is Carbon monoxide released?

A

o Released by any malfunctioning gadget

o Wood stove, fireplace, cigarette smoke, car burning gasoline (main source), etc.

47
Q

What level of exposure to CO is dangerous?

A
  • Acute exposure to a high level can kill you quickly

- Chronic exposure to a low level can decrease life span and injure heart

48
Q

What is the sequence of symptoms when exposed to CO?

A
  • Headaches, intellectual impairment, cardiac problems (arrhythmias, myocardial ischemia, etc)
  • All the CNS functions can be impaired: visual (dimmed sight) , central (drowsiness, confusion, dizziness, confusion, headache, unconsciousness), auditory (reduced hearing), respiratory (shortness of breath), musculature (tremor), skin (sweating), heart (increased HR and BP)
49
Q

What is the mechanism of action of CO?

A
  • Hemoglobin transports oxygen to cells, CO blocks Hemoglobin, the carboxyhemoglobin can’t transport oxygen
  • Triggers free radical production, damages the endothelium and myelin
  • CNS effects, then collapse and lose consciousness, die from cardiac arrest.

PHAR 303 (21 decks)

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