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Lecture 15

PHAR 303 Lecture Notes - Lecture 15: Cardiac Glycoside, Cardiac Arrhythmia, Cardiac Muscle Cell

Pharmacology and Therapeutics
Course Code
PHAR 303
Bernard Robaire

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March 10, 2016
Phar 303
Lecture 15: Cardiotoxicity
The cardiovascular disease triad
The blood flow to the brain, heart, and periphery is vital
Cardiotoxins can interfere with any of this
The heart
The innervation comes from the ANS which comes from the depolarization of the SA node (pacemaker) and the impulses
travel to the AV node and through the two ventricles so they can contract
The electrical system is essential: SA/AV node, bundle of His/purkinje fibers
The atria and the ventricles are insulated from each other so the impulse has to go through this conduction system
Should something go wrong, the heart has intrinsic pacemakers that can take over if the SA and AV nodes don't work properly
The rate of the heart will increase and decrease depending on what you're doing; it is controlled by the autonomic nervous
o There is sympathetic or parasympathetic input to the sinus node
SA node: pacemaker
Intrinsic rate increases or decreases depending on the ANS
The AV node and His-Purkinje system can take over as a pacemaker if the SA node fails but its activity causes slower
Cardiac muscle
The heart has to beat all the time
The heart has a high energy requirement; as a consequence, the cardiac muscle has a lot of mitochondria
Mitochondria are the only organelles with their own DNA
o They are recreated all the time
o They are incredibly important
Plant toxins - Cardiac glycosides
Foxglove plant
It contains cardiac glycoside toxins
The cell
The cardiac muscles have a very great demand on the Na/K pump and therefore a great requirement for ATP
The brain has the highest concentration of Na/K pumps, but skeletal and cardiac muscles also have high levels
Contains digitoxin which is a cardiac glycoside
Cardiac glycoside
A cardiac glycoside is composed of an aglycone portion and a sugar portion
o There are variations of sugar and aglycone molecules
o Changing the portion of either the aglycone or sugar molecules makes different types of cardiac glycosides
Cardiac glycosides block the Na/K pump
In the cardiac myocyte, there is also a Na/Ca exchange mechanism
When you block the Na/K pump, the level of Na inside the cell is going up
Via the Na/Ca exchange mechanism, Na is dumped out and the level of Ca in the cell rises
o This increases the force of contraction of the muscle
o Some plant compounds are used medicinally to induce this
Cardiac myocyte
High energy requirement: electrical, mechanical
Low energy reserve

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March 10, 2016
Phar 303
Must work continually
Cardiac arrhythmia
The normal conduction is from the SA node through the His-Purkinje system
o There is a normal depolarization of the atria followed by the ventricles
Atrial fibrillation: no coordinated contraction of the atria
o There is no more P-wave on the ECG
But the ventricular tissue can also have their own pacemaker activity
o So you get intermittent contraction of the atria and the ventricles will fill passively
o It is not efficient but will keep you alive
o If the ventricles are not able to contract properly, there will be death
Conduction block
The impulse doesn't get through the AV node so there is no depolarization of the ventricle
Electrical failure: arrhythmia
Severe digitalis intoxication can cause a massive shift of potassium from inside to outside the cell, leading to life-threatening
Manifestations of life-threatening toxicity include:
o Ventricular tachycardia (increase in heart rate)
o Ventricular fibrillation (fatal)
o Progressive bradyarrhythmias (decrease in heart rate)
o Heart block
o Death from cardiac arrest
Pharmacokinetics: Digoxin
o Oral - peak serum concentrations at 1-3 hours
o Large AVD (concentrated in tissues)
o 6-8 hours tissue distribution phase
o Crosses BBB and placenta
o Only a small fraction (16%) is metabolized
o Not via P450 system
o First order kinetics
o Has a half-life of several days
o 50-70% excreted unchanged in the urine
Hedges are made out of it
They grow all year round in the U.S.
Contains so much cardiac glycoside (oleandrin) that eating one leaf can cause death
When the leaves dry, they lose their toxic taste or smell so horses tend to eat them
Snails can feed on oleander and accumulate toxins; they may in turn poison whoever eats them
Lily of the valley
They also contain cardiac glycosides (convallarin)
They bloom in shaded regions
Monarch butterfly and milkweed
Milkweed contains cardiac glycosides as well
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