Lecture 20 - Cardiovascular Toxicology I Flashcards
The CVS is one of the key systems in the body that supplies _____ and _____ with nutrients and respiratory gases.
The system is also important for the transport of ______ products of metabolism to their sites of _______ and generally it maintains internal ________.
Therefore, impact of toxins/toxicants on this system have major implications for the survival of the animal.
The CVS is one of the key systems in the body that supplies cells and tissues with nutrients and respiratory gases.
The system is also important for the transport of waste products of metabolism to their sites of excretion and generally it maintains internal homeostasis.
Therefore, impact of toxins/toxicants on this system have major implications for the survival of the animal.
Several characteristics of the CVS make it highly susceptible to toxicoses.
1. The first is the high level of _______ requirement whereby the continuous ________ and _______ cycles of the heart require constant supply of ____.
2. To synthesize this ATP, the heart requires a steady supply of ________ and _________.
Therefore, anything that affects the delivery of _______ and ______ to the heart will impair CVS function.
3. The CVS also has a high level of exposure to toxicants, and this is because it receives all of the _________ circulation with the ________ xenobiotics and their _________.
4. There are limited __________ mechanisms in the CVS due to less elaborate ________ _________ systems especially for the protection against oxidative stress.
5. In addition, the CVS has limited ability to handle ___________ loss. When cardiomyocytes are injured, they are typically replaced by _______ with ___________ of the remaining cardiomyocytes to compensate for the lost function.
6. Lastly, the _______ distribution and _____ heterogeneity of blood vessels means that toxicoses in _____ body organ will most likely involve the CVS.
- The first is the high level of energy requirement whereby the continuous contraction and relaxation cycles of the heart require constant supply of ATP.
- To synthesize this ATP, the heart requires a steady supply of nutrients and oxygen.
Therefore, anything that affects the delivery of oxygen and nutrients to the heart will impair CVS function. - The CVS also has a high level of exposure to toxicants, and this is because it receives all of the systemic circulation with the parent xenobiotics and their metabolites.
- There are limited protection mechanisms in the CVS due to less elaborate metabolic enzyme systems especially for the protection against oxidative stress.
- In addition, the CVS has limited ability to handle structural loss. When cardiomyocytes are injured, they are typically replaced by fibrosis with hyperplasia of the remaining cardiomyocytes to compensate for the lost function.
- Lastly, the wide distribution and high heterogeneity of blood vessels means that toxicoses in any body organ will most likely involve the CVS.
List why the cardiovascular system is susceptible to toxicants.
High level of energy requirement (heart)
High level of exposure to toxicants
Limited protection mechanisms
Limited ability to handle structural loss
Wide distribution and high heterogeneity
(blood vessels)
What is the direct mechanism of toxicity on the heart?
- Primary effect on ________ or _________ properties of the heart
- Interference with ____ homeostasis (_____ pumps and channels)
- altered ________ blood flow
- altered _________
- __________ stress
- alteration in ________ (Organelle dysfunction: mitos, SR, myofibrils)
- Primary effect on functional or biomechanical properties of the heart
- Interference with ion homeostasis (ion pumps and channels)
- altered coronary blood flow
- altered metabolism
- oxidative stress
- alteration in structure (Organelle dysfunction: mitos, SR, myofibrils)
What is the indirect mechanism of toxicity on the heart?
- Toxicoses in other body systems
- Acid-base disturbances
- Hemodynamic alterations (hypovolemia)
Oncotic pressure (______ ________ pressure) is the osmotic pressure exerted by _________ in blood plasma that usually tends to pull water _____ the circulatory system.
If levels of plasma proteins are reduced, e.g., from being lost in the urine (proteinuria), there is a ________ in oncotic pressure and an _______ in filtration across the capillaries, resulting in fluid _____ ___ in tissues (______).
Oncotic pressure (colloid osmotic pressure) is the osmotic pressure exerted by proteins in blood plasma that usually tends to pull water into the circulatory system.
If levels of plasma proteins are reduced, e.g., from being lost in the urine (proteinuria), there is a reduction in oncotic pressure and an increase in filtration across the capillaries, resulting in fluid build up in tissues (edema).
What are the direct mechanism of toxicity on the vascular system?
Alteration in structure and function, metabolism, and immunological events
What is the indirect mechanism of toxicity on the vascular system?
◦ Altered endothelial _________ e.g. due to changes in ________ and _______ pressure (plasma protein levels)
◦ Impaired _________ e.g. due to altered ______ or ________ factors
◦ Altered endothelial permeability e.g. due to changes in hydrostatic and oncotic pressure (plasma protein levels)
◦ Impaired hemodynamics e.g. due to altered
platelets or coagulation factors
Define cardiac dysfunction
Arrhythmia: disturbances in heart rate (_______), contractility (______), conductivity (_________) and excitability (_______)
◦ ________ heart failure, cardiogenic _____
◦ Weakness, collapse and recumbency
Heart failure:
Left HF → _____ edema;
right HF → ________ edema
Arrhythmia: disturbances in heart rate (Chronotropic), contractility (Ionotropic), conductivity (Dromotropic) and excitability (Bathmotropic)
◦ Congestive heart failure, cardiogenic shock
◦ Weakness, collapse and recumbency
Heart failure: Left HF → lung edema; right HF → peripheral edema
Define vascular dysfunction.
◦ Excessive _______ or ________ of arterioles
◦ Increased capillary __________
◦ Excessive contraction or relaxation of arterioles
◦ Increased capillary permeability
- Inotropic effect – alteration of the __________ of the heart (______/_______).
- An increase in the strength of contraction is a
_______ inotropic effect while a decrease is a
________ inotropic effect. - Chronotropic effect – alteration of the heart _____ (by changing the ______ of electrical impulse
generation in the ______ node, the pacemaker). An increase in heart rate is a _____ chronotropic effect while a decrease is a _____ chronotropic effect. - Dromotropic effect – alteration of heart
_________ (rate of _______ conduction through
the __________ node).
- Inotropic effect – alteration of the contractility of the heart (force/strength of heart contraction).
- An increase in the strength of contraction is a
positive inotropic effect while a decrease is a
negative inotropic effect. - Chronotropic effect – alteration of the heart rate (by changing the rhythm of electrical impulse
generation in the sinoatrial node, the pacemaker). An increase in heart rate is a positive chronotropic effect while a decrease is a negative chronotropic effect. - Dromotropic effect – alteration of heart
conductivity (rate of impulse conduction through
the atrioventricular node).
An increase in conduction velocity is a ______
dromotropic effect while a decrease is a _______
dromotropic effect.
Bathmotropic effect – alteration of heart _________. An increase in heart excitability is a ________ bathmotropic effect while a decrease is a _________ bathmotropic effect.
These terms are mainly used to describe cardiac drugs, but toxicants can induce the same effects, and the cardiac drugs are toxicants when in excess.
In addition, cardiac dysfunction can manifest as __________ heart failure, cardiogenic _____, ________, _________ and __________.
In left-sided heart failure blood builds up in __________ veins ultimately resulting in
_______ ______. It happens because the left __________ is not effectively pumping out the blood it ________ from the lungs.
In right-sided heart failure the right _______ is too weak to effectively pump blood to the heart. As a result, blood builds up in veins leading to edema of _______ very commonly in extremities such as the ____.
An increase in conduction velocity is a positive
dromotropic effect while a decrease is a negative
dromotropic effect.
Bathmotropic effect – alteration of heart excitability. An increase in heart excitability is a positive bathmotropic effect while a decrease is a negative bathmotropic effect.
These terms are mainly used to describe cardiac drugs, but toxicants can induce the same effects, and the cardiac drugs are toxicants when in excess.
In addition, cardiac dysfunction can manifest as congestive heart failure, cardiogenic shock, weakness, collapse and recumbency.
In left-sided heart failure blood builds up in pulmonary veins ultimately resulting in
pulmonary edema. It happens because the left ventricle is not effectively pumping out the blood it receives from the lungs.
In right-sided heart failure the right ventricle is too weak to effectively pump blood to
the heart. As a result, blood builds up in veins leading to edema of tissues very commonly in
extremities such as the legs.
Toxicity manifests as?
Toxicity manifests as:
* Overexpression of pharmacological effects
* Effects unrelated to intended therapeutic effects
List the sources of cardiac glycosides (CGs)
digitalis glycosides
◦ Digoxin and digitoxin
Derived from leaves of purple foxglove
Which species are susceptible to cardiac glycosides?
◦ Pets are most commonly affected with ____ being the most sensitive
- Male cats achieve _______ serum levels of cardiac glycosides than female cats
◦ Pets are most commonly affected with cats being the most sensitive
- Male cats achieve higher serum levels of cardiac glycosides than female cats
What is the ADME of cardiac glycosides?
_______ and nearly complete (______) or variable (______) absorption after oral exposure
Digitoxin is _______ protein bound (70-90%)
- _____ volume of distribution
Digoxin has ____ protein binding (25%)
- ______ volume of distribution
Metabolism occurs in the _____
Elimination is via ______ (digoxin) and ______-____ route (digitoxin). Digitoxin has _______ t½.
Rapid and nearly complete (digitoxin) or variable (digoxin) absorption after oral
exposure
Digitoxin is highly protein bound (70-90%)
- Low volume of distribution
Digoxin has low protein binding (25%)
- High volume of distribution
Metabolism occurs in the liver
Elimination is via urine (digoxin) and biliary- fecal route (digitoxin). Digitoxin has longer t½.
The toxicokinetics of CG depend on the ______.
The greater binding of digitoxin to serum albumin is reflected in its higher ______ concentrations, lower rate of _______ excretion, and ______ half-life compared with digoxin.
Specifically, ______ has a half-life of 7 to 9 days whereas _______ has a shorter half life of 36 to 48 hours.
The toxicokinetics of CG depend on the drug.
The greater binding of digitoxin to serum albumin is reflected in its higher plasma concentrations, lower rate of urinary excretion, and longer half-life compared with digoxin.
Specifically, digitoxin has a half-life of 7 to 9 days whereas digoxin has a shorter half life of 36 to 48 hours.
Cardiac Glycosides Dosage is Based on?
Lean BW
Caution: CGs have a narrow therapeutic index
Plasma drug levels do not change significantly with increase in ?
body fat
What is the MOT of cardiac glycosides?
- CGs inhibit __________ → _______ intracellular K+ and _________ intracellular Na+ concentrations
- The intracellular Na+ is then exchanged for
__________ Ca++→ ^ _________ free Ca++ →
cardiac muscle cell contraction (the desired
effect at therapeutic doses)
decreased intracellular K+ → _________ resting membrane potential in the pacemakers (SA and AV nodes) allowing _____ ____ to predominate.
Vagal tone: _________ impulses mediated by _______ (___) receptors → inhibition of heartbeat
CGs inhibit Na+/K+-ATPase → decrease intracellular K+ and ^ intracellular Na+ concentrations
The intracellular Na+ is then exchanged for
extracellular Ca++→ ^ intracellular free Ca++ →
cardiac muscle cell contraction (the desired
effect at therapeutic doses)
decreased intracellular K+ → decrease resting membrane potential in the pacemakers (SA and AV nodes) allowing vagal tone to predominate.
Vagal tone: Parasympathetic impulses mediated by muscarinic (M2) receptors → inhibition of heartbeat
Vagal tone is?
Parasympathetic impulses mediated by muscarinic (M2) receptors → inhibition of heartbeat
To summarize the mechanism of toxicity of cardiac glycosides, let us firstdiscuss the ionic gradients that exists in a resting cell and how they are maintained.
- The main intracellular cation is __________ which exists at a concentration of 150mM inside the cell compared with only 2.4mM outside the cell.
- The main extracellular cation is _______ which exists at a concentration of 145mM outside the cell compared with 12mM inside the cell. Calcium is maintained at a very low concentration of 0.1uM inside the cell compared with a much higher concentration of 2mM outside cell (recall that calcium is a 2nd messenger hence the need to maintain its low levels in the cell).
- These ionic gradients are maintained by several mechanisms.
1. The first one is the Na+-K+-ATPase an enzyme found on the cell _________ that actively pumps ____ Na+ from inside the cell to the outside in exchange for ____ K+. Because 3 positive charges are removed from the cell and exchanged with 2 positive ions, a membrane potential (_______ inside) of -30 to -80 millivotes is generated.
2. The second mechanism that contributes to the maintenance of these ionic gradients is sodium/calcium (Na+/Ca2+) exchanger which exchanges _________ from inside the cell with ________ from outside the cell. This contributes to the maintenance of low _________ calcium concentration.
3. Lastly, there is the calcium pump or Ca2+-ATPase which found on the cell ________ and on the membrane of the __________ _________. This enzyme either pumps calcium from ______ the cell to the _______ compartment or into the _____ _____ thus contributing to the maintenance of low intracellular calcium concentration.
To summarize the mechanism of toxicity of cardiac glycosides, let us firstdiscuss the ionic gradients that exists in a resting cell and how
they are maintained. The main intracellular cation is potassium which exists at a concentration of
150mM inside the cell compared with only 2.4mM outside the cell. The main extracellular cation is sodium which exists at a concentration of
145mM outside the cell compared with 12mM inside the cell. Calcium is maintained at a very low concentration of 0.1uM inside the cell compared with a much higher concentration of 2mM outside cell (recall that calcium is a 2nd messenger hence the need to maintain its low levels in the cell). These ionic gradients are maintained by several mechanisms. The first one is the Na+-K+-ATPase an enzyme found on the cell membrane that actively pumps 3 Na+ from inside the cell to the outside in exchange for 2
K+. Because 3 positive charges are removed from the cell and exchanged with 2 positive ions, a membrane potential (negative inside) of -30 to -80 millivotes is generated. The second mechanism that contributes to the maintenance of these ionic gradients is sodium/calcium (Na+/Ca2+) exchanger which exchanges calcium
from inside the cell with sodium from outside the cell. This contributes to the maintenance of low intracellular calcium concentration. Lastly, there is the calcium pump or Ca2+-ATPase which found on the cell membrane and on the membrane of the sarcoplasmic reticulum. This enzyme either pumps calcium from inside the cell to the extracellular compartment or into the sarcoplasmic reticulum thus contributing to the maintenance of low intracellular calcium concentration.
Cardiac glycosides inhibit _____/____/______ resulting in an increase in the levels of intracellular _____.
The Na+ initially slows the ____/_____ exchanger and later causes its reversal resulting in the uptake of ____ into the cell. The level of intracellular Ca2+ then increases and that Ca2+ is pumped into the _______ _________by the Ca2+-ATPase so that when there is an action potential there is increased Ca++ release resulting in increased __________ of the heart. In addition, there is a reduction in the levels of intracellular _____ which ______ the resting membrane potential and _______ the heartbeat.
Cardiac glycosides inhibit Na+-K+-ATPase resulting in an increase in the levels of intracellular Na+.
The Na+ initially slows the Na+/Ca2+ exchanger and later causes its reversal resulting in the uptake of Ca2+ into the cell. The level of intracellular Ca2+ then increases and that Ca2+ is pumped into the sarcoplasmic reticulum by the Ca2+-ATPase so that when there is an action
potential there is increased Ca++ release resulting in increased contraction of the heart. In addition, there is a reduction in the levels of intracellular K+ which reduces the resting membrane potential and decreases the heartbeat.
What are the clinical signs pertaining to the heart in a case of cardiac glycoside toxicity?
◦ Decreased sinus rate (bradycardia), heart
block, ventricular tachycardia & fibrillation,
hypotension, weakness, depression, and
recumbency
What are the other clinical signs in a case of cardiac glycoside toxicity?
◦ Nausea, vomiting, diarrhea, dehydration
◦ Hyperkalemia: the most significant and
consistent alteration in serum chemistry
The chemoreceptor trigger zone (CTZ) is an area of the ________ that senses chemicals in ______, and communicates with the _______ center, to initiate ________.
The chemoreceptor trigger zone (CTZ) is an area of the medulla that senses chemicals in blood, and communicates with the vomiting center, to initiate vomiting.
Why do cardiac glycosides lead to nausea, vomiting, and diarrhea?
- CGs stimulate chemoreceptor trigger zone
- CGs irritate gastric mucosa
How do you treat cardiac glycoside toxicity?
- Decontamination: _______ for recent ingestion
+ ________ _______ and a ________ - Administer ______ (antidote)
- Symptomatic treatment:
◦ Treat cardiac ________: _______ for
bradycardia/increased vagal tone, _________ for
ventricular tachycardia
◦ Treat hyperkalemia: ____-_______ or _____ + ______
◦ Give IV fluids to maintain _______/_____ ________
Decontamination: emesis for recent ingestion
+ activated charcoal and a cathartic
Administer Digibind (antidote)
Symptomatic treatment:
◦ Treat cardiac dysrhythmias: atropine for
bradycardia/increased vagal tone, lidocaine for
ventricular tachycardia
◦ Treat hyperkalemia: Na-bicarbonate or glucose + insulin
◦ Give IV fluids to maintain perfusion/blood pressure
Treatment is induced _____ in toxicosis.
- Insulin stimulates ___/____/____ resulting in increased pumping of ____ from the _________ compartment _____ the cell.
Treatment is induced early in toxicosis.
- Insulin stimulates Na+-K+-ATPase resulting in increased pumping of K+ from the extracellular compartment into the cell.
List calcium blocking agents.
Include:
◦ Verapamil, diltiazem, nifedipine, nimodipine
What is the ADME of calcium blocking agents?
Rapidly absorbed from the _______ __________
They have significant ____ pass effect
Rapidly absorbed from the small intestine
They have significant first pass effect
What species are affected by calcium blocking agent toxicity?
cats and dogs
◦ Smaller individuals are at greater risk of
intoxication from ingestion of owner’s medication
- What plant is pictured here?
- Where can this plant be found?
- What does this plant contain?
- Which species are most susceptible?
- This plant is commonly used as?
Herbaceous biennial (4ft).
Common ornamental
Found in many localities in
North America
Contains digitoxin, digoxin,
gitoxin and others
Susceptible species: most
Death results from AV-block
and ventricular fibrillation
Plant is not very palatable, poisoning is infrequent
Herbal remedy for edema and heart disease
- What plant is pictured here?
- Where can this plant be found?
- What does this plant contain?
- Which species are most susceptible?
- What is the lethal dose?
Oleander (
Nerium oleander)
Evergreen shrub (5-25ft)
Ornamental shrub in S &
SW USA
Contains several cardiac
glycosides: oleandrin,
digitoxigenin, gitoxigenin,
etc. and rosagenin
Species: all. Livestock are poisoned by ingesting
clippings or fallen leaves
Lethal dose: 0.005% bw.
- What plant is pictured here?
- Where can this plant be found?
- What does this plant contain?
- Which species are most susceptible?
Lily-of-the-valley
(
Convallaria majalis)
Perennial herb that grows
along valleys
Popular ornamental found
all over North America.
Has escaped cultivation
Contains cardiac
glycosides (convallarin,
convallamarin and
convallatoxin)
Species: livestock, pets
- What plant is pictured here?
- Where can this plant be found?
- What does this plant contain?
- Which species are most susceptible?
Dogbane, Indian hemp
(
Apocynum spp.)
Perennial herb (1-5ft)
Widespread in US and Canada.
Found in open places, coarse
soils, along streams, roadsides,
pastures, rarely tilled fields
Contains cymarin and
apocynamarin both with
digitalis glycoside-like effects
Species affected: horses,
cattle, sheep
Rhododendron
Great Laurel
What are the clinical signs of grayanotoxin toxicity?
- What plant is pictured here?
- Where can this plant be found?
- Yew (Taxus)
- Found around homes
Geographical distribution:
* Northern and southern US
* Pacific region
* Southern Canada
Toxicity values indicate horses are sensitive followed by cows, dogs, sheep.
Goats are rather resistant.
Cestrum diurnum
Ornamentals in CA, FL, TX, HI, Gulf Coast
Solanum malacoxylon
(American egg plant)
