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Cardio: 1:00 - 2:00
Monday, April 27, 2009
Dr. Ku
CO = Cardiac Output
SV = Stroke Volume
HR = Heart Rate
I.
Drugs Used in Treatment of Chronic Low Output Heart Failure
Scribe: Marjorie Hannon
Proof: Caitlin Cox
Page 1 of 8
Introduction [S1]:
a. CO = SV x HR. These represent 3 major properties of the heart.
b. Cardiac output is related to the flow of blood in the vessels. Heart rate is electrical and was covered Friday.
c. Today’s lecture is stroke volume; we will talk about muscle mechanics or how the cardiac muscles contract to
push the blood out. If you have a problem with this you will start to develop heart failure.
d. Most people have low output heart failure, but there are also high output heart failures for example a woman in
pregnancy can get this. Because the heart has to supply the mother and the fetus, we may see high output
heart failure. Also, hypothyroidism may cause high output heart failure. Today we will talk about low output
heart failure.
II. Low Output Heart Failure [S2]
a. Low output heart failure is a pathologic state in which a derangement of myocardial structure/contractile function
(cardiac muscle mechanics) leads to an inability of the heart to maintain a cardiac output sufficient to meet the
demands of the metabolizing tissues. It is a catch all phrase, so let us now qualify the statement:
i. Or when the heart can do so only with an elevated filling pressure.
1. Increased venous return gets more blood back to the heart increasing cardiac output.
2. This is a compensatory mechanism and is classified as early compensated heart failure because
they have a derangement of cardiac contractility; the underlying problem is up there. Just because
they compensate it, it does not mean the patient does not still have heart failure. You would not see
any signs and symptoms this early on and that is the problem with diagnosing heart failure.
3. Very early on you do not see any signs and symptoms, the patient feels fine because the body
compensates. Clinically we define them as early compensated heart failure.
ii. As the disease progresses, despite a satisfactory venous filling pressure or venous return, you still
decrease cardiac output. This is called late decompensated heart failure.
1. This is the kind where we see the signs and symptoms of heart failure. Once we see the symptoms
it is late, so prevention is the key. However, early diagnosis is difficult because the patient typically
doesn’t come see the doctor until they are having problems.
III. Causes of Heart Failure [S3]
a. Acute causes of heart failure are circulatory collapse, massive hemorrhage, and shocks (cardiogenic, septic
etc.). The pressure drops, the cardiac output drops.
i. This is not what we will talk about today because management for these cases is different. We will discuss
chronic low output failure.
b. Major Causes of Chronic Low Output Congestive Heart Failure
i. Old age- invariably, we will all develop some sort of heart failure. Eventually our hearts will wear out, think
about how many beats it beats per minute, day, or year, then 60 years. It is simply the physiology- the
heart cannot continue pumping forever.
ii. Hypertension (the major cause of low output heart failure in this country) - this is part of the reason we see
so many drugs that treat hypertension for heart failure: because the major underlying cause in this country
is hypertension.
iii. There are other pathological causes that include: viral myocarditis, rheumatic fever, alcohol (these people
tend to have very early onset of heart failure), acute myocardial infarction (if a percent of the cardiac
muscle dies in the heart attack, you will eventually get heart failure), idiopathic dilated cardiomyopathy, and
nutritional deficiencies (mostly in 3rd world countries).
iv. We will talk today about how to manage these causes of chronic low output heart failure.
IV. Cardiac Output = Stroke Volume X Heart Rate [S4]
a. Stroke volume (muscle mechanics) has two components: systolic and diastolic functions. One is contraction
(emptying the blood) and one is filling (relaxation).
i. Most of the time, heart failure is talking about systolic dysfunction.
ii. We talk about ejection fractions- normal is 60-65% ejection fractions. When you go down to 40% EF you
will develop stage 1, stage 2 heart failure. When you go down to 20-30%, that is inability of the heart to
contract and push the blood out.
b. Emptying: EF (ejection fraction) effective. Systolic function
i. The parameters of contractility that we talk about are: afterload, preload, or structure/remodeling issues.
Agents that increase the contraction emptying or ejection fraction are inotropic agents. A positive inotropic
agent will increase contractility; a negative inotropic agent will decrease contractility.
c. Filling: ED (end diastolic) volume. Diastolic function.
Cardio: 1:00 - 2:00
Scribe: Marjorie Hannon
Monday, April 27, 2009
Proof: Caitlin Cox
Dr. Ku
Drugs Used in Treatment of Chronic Low Output Heart Failure
Page 2 of 8
i. The left ventricle distensibility, relaxation, left atrium, mitral valve, pericardium.
ii. When the walls are thin, it is very easy for them to relax and let the blood fill the heart. When they develop
hypertrophy and the muscle gets thicker, you lose compliance; it is very rigid and doesn’t relax as well. If it
doesn’t relax to let the left ventricle fill, when you contract the stroke volume will decrease. This is a
relaxation problem. Left atrium or mitrovalve prolapse: leaky. Instead of pushing blood into the aortic
valve, it backs up to the left atrium. Those are valvular problems related to diastolic dysfunction.
Pericarditis or inflammation of the pericardial sac makes it hard to relax.
iii. Don’t have good drugs for this.
1. Lusitropic drugs can modify relaxation (increase relaxation so that it can fill).
iv. We will not talk much today about diastolic problems because we do not have good drugs for this.
V. Myocardial Injury/Damage flow chart [S5]
a. Underlying problem is some kind of myocardial muscle injury or damage. This could include myocardial
infarction (10% of cardiac muscle dies), or remodeling (hypertrophy).
b. The first trigger is decreased contractility due to the myocardial injury or damage. The heart will compensate.
i. If you decrease contractility, you decrease cardiac output, and your end diastolic volume goes up because
the heart is no longer pushing all the blood out of the left ventricle. This triggers compensatory
mechanisms right away.
c. This is a sequence of events with four different steps.
VI. Compensatory Mechanisms in LOCHF [S6]
a. Frank-Starling’s Law of the Heart-- first mechanism to activate
i. Length-Tension Relationship (relating to preload and venous return).
ii. This is what we call beat to beat. As soon as the first beat decreases in contractility and you have an
increased end diastolic volume, the very next beat will pump it out very fast.
iii. Basically you are stretching the muscle fibers (due to the increased end diastolic volume), so when you
contract the next time, it will increase.
1. If the first time you have problems and do not push all of the blood out, the end diastolic volume will
increase and the muscle fibers will be stretched. The next time they contract, they will contract
more. Starling’s law kicks in.
2. This is beat to beat regulation and happens very fast.
b. Baroreceptor reflex activation—this is the second step and happens within seconds.
i. When you decrease cardiac output, it decreases stretch on the aortic arch. The baroreceptors detect this
drop in pressure and signal to the heart to contract faster and stronger (sympathetic).
ii. Sympathetic Activation (norepinephrine release)
1. Increase contractility, increase HR, and increase Vascular Resistance (afterload). This will increase
blood pressure and increase cardiac output.
c. Renal Mechanisms—this is within minutes
i. Activation of Renin-Angiotensin-Aldosterone (RAS) system:
ii. Decrease blood flow to the kidneys, decrease the GFR, and activate renin. This will help synthesize more
angiotensin 2 which will stimulate aldosterone. This will cause you to retain sodium and water, increase
blood volume, and increase venous return.
d. Myocardial Hypertrophy (intrinsic mechanism)— the fourth step, takes days and weeks
i. When the heart realizes it is not pumping enough blood out, it wants to become stronger.
ii. The problem is that hypertrophy is self limiting: so initially this mechanism is good, but not for long term.
1. When the muscle gets too thick and too strong, then you are getting less compliance: it will not relax
as well and it does not pump blood as well.
e. The idea of all of these compensatory mechanisms is to increase and maintain cardiac output. Sympathetic will
increase afterload, venous constriction will increase the preload, also want to increase venous return and blood
volume. They are all trying to maintain blood pressure.
VII. Myocardial Injury/Damage [S7]
a. Early on it is compensated heart failure. Because it is a compensated mechanism, you maintain cardiac outputthere are no signs and symptoms.
b. When the compensatory responses fail, you can no longer keep up and you get decompensation. Then you
start to see signs and symptoms.
VIII. Clinical Signs and Symptoms of CHF [S8]
a. Pulmonary Edema (dyspnea, cough, rales in the lung)
i. Left heart failure will result in pulmonary edema.
ii. If you listen to the lungs, you hear rales or basically it sounds like water in the lungs. They cannot breathe,
they cough.
b. Systemic Edema (swelling of the extremities)
Cardio: 1:00 - 2:00
Scribe: Marjorie Hannon
Monday, April 27, 2009
Proof: Caitlin Cox
Dr. Ku
Drugs Used in Treatment of Chronic Low Output Heart Failure
Page 3 of 8
i. Especially when you have a right heart failure.
ii. This is common in older people. We say that older people are restless at night. This is because when they
are lying down and they have a lot of fluid in their chest they cannot breathe and start to cough; they stand
up. Now all of the fluid clears from the lungs and goes to the lower extremities such as the legs; they feel
pain and sit down with their feet up. Now the fluid goes back to the lungs… up and down all night.
c. Palpitation (sympathetic activation of the heart), Tachycardia (very fast heart rate), and 3rd Heart Sound
(because there is a lot of fluid in the left ventricle)
d. Cardiomegaly (as well as Hepatomegaly)
i. Long term you will see a thick heart or thick liver. There is a lot of fluid backed up in the venous side.
e. Treatment Goals:
i. Reduce symptoms, prolong survival, improve the quality of life, and prevent disease progression.
ii. They used to only want to improve cardiac output by improving contractility. Now we do so much more in
the treatment than just relieve the symptoms. We want to increase survival (life expectancy) and decrease
hospitalization.
IX. Clinical Management of LOHF [S9]
a. Non-pharmacological :
Decrease physical activities
Decrease emotional stress
Decrease Na and water intake
i. This is done very early on. Basically, we tell them don’t put any more stress on the heart.
ii. If these will no longer alleviate the signs and symptoms, we will move to pharmacological drugs.
b. Pharmacological :
1. Decrease Preload
Diuretics (Spironolactone, Triamterene, Amiloride & Lasix)
Venodilators (Nitrates, such as sodium nitroprusside)
2. Decrease Afterload
Vasodilators (Hydralazine, Phentolamine, Prazosin, Ca Channel Blockers)
RAS Antagonists (ACE Inhibitors, AT receptor Antagonists)
Endothelin Antagonists (under investigation)
3. Beta Blockers (mostly the 3rd and 4th generations)
4. Positive Inotropic Agents
i. These are the four classes of drugs that we will discuss so that we can understand the whole picture.
c. Surgical :
i. Left Ventricular assisted devices, heart transplantation, ventricular remodeling, resynchronization, and etc.
ii. Used when the drugs can no longer keep up and the patient continues to deteriorate.
iii. Lots of time heart failure is because the right and left hearts are not contracting at the same time. When
the right side can’t keep up, then the left heart starts to fail because not enough blood is getting to the left
ventricle.
1. Resynchronization is when they pace it to contract at the same time.
X. Treatment Algorithm for HF with a Reduced EF [S10]
a. Eugene Braunwald, from Harvard, is a famous cardiologist. He formed a treatment algorithm which shows how
to approach treatment of heart failure with a reduced ejection fraction.
b. First you need the diagnosis to confirm that there is heart failure. Once you have confirmed heart failure, then
you have to assess the fluid retention, whether they are congested or not. If they are congested or have fluid
retention, then you should give a diuretic right away to get rid of the fluid so that the patient can breathe. This
will reduce the swelling in the extremities.
c. If they don’t have fluid retention or they have been controlled, give an ACE inhibitor. That is the first drug that
will be prescribed. ACE inhibitors are the number one antihypertensive drug.
d. Beta blockers are given next.
e. For those patients that cannot tolerate ACE inhibitors, we give ARB (angiotensin receptor blocker).
f. Those are divided by the New York Heart Association into 4 classes (I-IV) or stages of heart failure. Usually the
patient will not see the doctor until II or III. For class I-IV you are to give ACE inhibitors, Beta blockers, or ARB.
If they still have symptoms or you still cannot manage it, then you give them aldosterone, vasodilator,
hydralazine, isosorbide, or eventually you give digoxin; positive inotropic agents.
g. That is the algorithm: Give a diuretic to get rid of the fluid, and then give ACE inhibitor beta blocker and ARB.
h. This is what we called resynchronization therapy here with defibrillators. People come up with different
approaches to treat this disease, but he will focus on the pharmacological approach.
XI. Myocardial Injury/Damage flow chart [S11]
a. First step is to try and control the fluids- give diuretics or aldosterone inhibitors. Then you give ACE inhibitors to
or angiotensin receptor blockers. Then you move onto Beta blockers if those two don’t work. Then give
vasodilators and finally give inotropic agents.
Cardio: 1:00 - 2:00
Scribe: Marjorie Hannon
Monday, April 27, 2009
Proof: Caitlin Cox
Dr. Ku
Drugs Used in Treatment of Chronic Low Output Heart Failure
Page 4 of 8
XII. Diuretics & Nesiritide [S12]
a. Diuretics : Thiazides, Loop diuretics, Triamterene
i. Promotes dieresis, promotes vasodilatation, and relieves pulmonary and systemic edema.
ii. All they do is get rid of fluid, they do not treat the cause of the problem (contractility issues).
iii. They are usually used as a combination therapy, not alone.
b. Nesiritide (B type natriuretic peptide)
i. Promotes vasodilatation, promotes dieresis, no neurohumoral activation.
ii. Clinical role in the management of CHF remains undefined.
XIII. Aldosterone [S13]
a. Has very early onset (minutes).
b. It decreases the GFR, activate renin, angiotensin, and angiotensin will stimulate aldosterone.
c. Known actions of Aldosterone:
i. Retention of Na+ and H20
1. Initially this is good: it increases blood volume. Increase of blood volume increases venous return
which increases cardiac output.
2. Too much aldosterone will cause too much salt and water retention which will cause edema.
ii. Excretion of K+ and Mg2+
1. Causes arrhythmias
iii. Collagen deposition
1. Causes remodeling of the heart
iv. Basically, Aldosterone long term is not good. With that understanding, why don’t we try and block it?
b. Aldosterone inhibitors:
i. Spironolactone-- (competitive antagonist of the aldosterone receptors in myocardium, arterial walls and
kidney).
1. Adverse effects: stimulate the steroid receptors: in men it would block testosterone and in women it
would have a progesterone-like effect. These sex steroid side effects are not good.
ii. Eplerenone-- (modified spironolactone)
1. More selective for the mineralocorticoid than the steroid receptors. Shorter half life. Much easier to
manage
XIV.
Major Differences Among Different ACE inhibitors (ACEI) [S14]
a. Currently about 13 ACE inhibitors on the market.
b. Catopril (Capoten) – The 1st ACEI that was approved back in the 70s. So we’ll call it the gold medal
i. It contains -SH moiety. (fentiapril, pivalopril, zofenopril, etc).
ii. A lot of patients cannot tolerate the sulfhydryl derivative—they lose taste, hypersensitive to sulfhydryl
compounds. That is why a lot of the drugs now are carboxyl derivatives.
c. Enalapril (Vasotec) – Was the 2nd ACEI, so we will call this the silver medal
i. Prodrug and needs to be hydrolyzed to Enalaprilat, also contains proline surrogate (-COOH).
d. Lisinopril (Prinivil, Zestril) - 3rd ACEI, so it is the bronze.
i. direct acting, lysine analog (-COOH)
e. You should remember these first 3 (gold, silver, and bronze).
f. They have different derivatives/moieties based on ADME (absorption, distribution, metabolism, and excretion).
i. Sulfhydryl, carboxyl, phosphorus
ii. Both sulfhydryl and carboxyl moieties are metabolized through the liver. If the patient has a liver problem,
they cannot excrete these drugs and have a prolonged duration of action which is not good.
iii. The phosphorus derivative (Fosinopril) can be excreted through the kidney.
g. Catopril and Lisinopril are direct acting. Enalapril is a prodrug.
h. Other prodrugs: Benazepril (Lotensin), Trandolapril, Quinapril, Ramipril, Fosinopril (-PO2) etc.
i. Prodrugs need to be metabolized in order to be active. The onset of action is slower for prodrugs. Once they
activate, then they have a long half life and stick around in the body.
j. Potency is another issue. From a patient standpoint, it is not that relevant (they just know to take a pill and don’t
care the mg) but from a research standpoint, we try and concentrate on making the drug more potent so that
you don’t have to use as much drug.
XV.
ACE Inhibitors Hemodynamic Effects [S15]
a. Why do we use ACE inhibitors to treat heart failure related to hypertension?
b. Arteriovenous Vasodilation:
i. Decrease pulmonary capillary wedge pressure; less congestion of the lungs.
ii. decrease systemic vascular resistance, decreasing afterload, decrease blood pressure
iii. increase cardiac output
iv. increase exercise tolerance
Cardio: 1:00 - 2:00
Scribe: Marjorie Hannon
Monday, April 27, 2009
Proof: Caitlin Cox
Dr. Ku
Drugs Used in Treatment of Chronic Low Output Heart Failure
Page 5 of 8
c. No change in HR/Contractility:
i. Does not cause reflex tachycardia like pure vasodilators would do. Pure vasodilators put more stress on
the heart. An ACE inhibitor will not do this, especially if you are using a prodrug because its action is very
slow. Vasodilators act very quickly causing pressure to drop; this causes reflex tachycardia. If it is a
gradual change, the body compensates and adjusts without reflex tachycardia.
d. Decrease MVO2 (myocardial oxygen demand):
i. This makes it less likely to have a heart attack.
e. Increase renal, coronary, and cerebral blood flow
f. Diuresis and natriuresis (get rid of fluid)
XVI.
ACE Inhibitors Advantages [S16] other advantages, long term
a. Inhibit LV remodeling or decrease progression of the heart remodeling.
b. Modify the progression of chronic CHF: increase survival and decrease hospitalizations.
c. No neurohumeral activation, no reflex tachycardia.
d. Do not develop tolerance with chronic use.
XVII. ACE Inhibitors Undesirable Side Effects [S17] can be grouped into two types of side effects:
a. Inherent in their mechanism of action:
i. Will cause hypotension, hyperkalemia, angioneurotic edema, dry cough (frequently), renal insufficiency
(causing renal damage).
b. Related to their chemical structure:
i. Cutaneous eruptions, GI disturbances, neutropenia, thrombocytopenia, dysgeusia (loss of taste mostly
because of sulfhydryl drugs), proteinuria.
XVIII. Diagram [S18]
a. Ang converting enzyme is right here, converting angiotensin I to II. You can see its chain of events.
i. When you have ACE Inhibitors, it blocks this and decreases angiotensin II preventing all of these problems.
b. There is another enzyme system called the kinase system (bradykinin).
i. ACE inhibitors also block this kinase blocking the breakdown of bradykinin. Now you will have too much
bradykinin causing NO synthesis, increased prostaglandins, causing vasodilation.
ii. This allows fluid extravization (it gets outside) which causes cough.
iii. With that idea in mind, we thought to just block the angiotensin receptor instead of using ACE inhibitors in
order to bypass all of these problems.
c. ACE inhibitors were a great idea because they blocked Ang converting enzyme which blocked the formation of
angiotensin II. However, the ACEI also blocked the kinase II. That is where the idea arose to just develop a
competitive and selective angiotensin I receptor blocker.
XIX.
AR1 Receptor Blockers (ARBs) [S19]
a. The first ones were Losartan and Valsartan. Now there are around 7 or 8 ARBs including Irbersartan and
Candesartan.
b. Notice that in pharmacology, a lot of times the names for drugs in the same thing, just the front of the name is
changed. The ARBs end in –tan. This is to help us remember the drugs. You should at least remember the
prototype (the first one listed) not necessarily the name in parenthesis.
c. Mechanism of action:
i. More complete inhibition of Angiotensin II effects because they directly block the AR1 receptor.
ii. Similar beneficial effects as ACEIs for heart failure.
iii. Similar mechanisms-related side effects, but less common and less chemical/structure related side effects.
XX.
Myocardial Injury/Damage [S20]
a. Now we move onto Beta blockers.
b. 10 years ago he would have said to stay away from these because heart failure already has decreased
contractility and cardiac output. The last thing he would think you would want is to give a beta blocker and
depress the heart. However, as we learned more and more, we found out that there was more to it than that.
XXI.
Carvedilol [S21]
a. Carvedilol is a combined alpha and beta blocker.
i. Remember from autonomic physiology, that sympathetic has alpha and beta receptors. (a1, a2, b1, b2). A
good drug would be a selective alpha 1 blocker would decrease peripheral vascular resistance and
decrease blood pressure (because alpha 1 causes vasoconstriction). Blocking beta 2 would trigger asthma
(bronchospasm) so this is not to be used in patients with emphysema. You want a cardio-selective beta 1
blocker.
ii. That is the rationale behind this (to develop a drug selective for a1 and b1).
b. Carvedilol significantly decreased the mortality rate, hospitalization, and medication, while increased the ejection
fraction.
Cardio: 1:00 - 2:00
Scribe: Marjorie Hannon
Monday, April 27, 2009
Proof: Caitlin Cox
Dr. Ku
Drugs Used in Treatment of Chronic Low Output Heart Failure
Page 6 of 8
i. People then began to think that the reason was not due to the beta blockade but due to the alpha blockade
(decreased afterload).
XXII. Effect of β-Blockade on Mortality in CHF [S22]
a. Metoprolol- cardio selective beta 1 blockers.
i. Very effective. However, this is not true for all of the other “-lol” beta blockers (propenolol, etc); they are no
good. Need to be selective beta blockers.
b. That is what the trick question will be: Can you use all beta blockers for heart failure? NO. There are only 3
beta blockers that you can use:
i. Carvedilol (combined alpha and beta)
ii. Metoprolol (cardio selective beta blockers)
iii. Bisoprolol (third generation, newest beta blocker)
c. Referring to the charts: Decrease mortality, increase survival
XXIII. Possible Beneficial Effects of β-Adrenergic Blockers in Treatment of CHF [S23]
a. The question is why do they work? Well, no one really knows why.
b. Possibly an increase density of B1 receptors, inhibit cardiotoxicity of catecholamines, decrease neurohumoral
activation, and decrease heart rate. They are also antihypertensive and antianginal, antiarrhythmic, antioxidant,
and antiproliferative.
c. Again, there are only 3 beta blockers (Carvedilol, Metoprolol, and Bisoprolol). Don’t worry about Bisoprolol, so
only two beta blockers are recommended for heart failure: Carvedilol and Metoprolol (not any other kind of –lol.
Be careful with this).
d. SQ: did you say that propenolol is not indicated? A: Propenolol is not indicated for heart failure, it is used for
other things (arrhythmias, angina, and other things, but NOT heart failure).
XXIV. Mechanisms of Vasodilator Action [S24]
a. Preload: venovasodilation, reduced intracardiac volume
i. This decreases venous return and there is less stress on the heart.
ii. The heart is already really thick and cannot pump the blood out so the goal is to decrease the volume it has
to pump out.
b. Afterload: reduce systemic vascular resistance or impedance so that it is easier for the heart to pump blood out.
i. Vasodilators: hydralazine, nitroprusside, minoxidil, diazoxide
ii. Calcium channel blockers: prazosin
iii. There are also alpha blockers, ACE inhibitors, and ARBs.
iv. Basically, we have all different drugs that are all antihypertensive drugs.
c. Vasodilators can also decrease myocardial ischemia – increase coronary blood flow or decrease oxygen
demand. These are mechanisms of vasodilators that are beneficial for heart failure patients that make it less
likely for them to have a heart attack.
XXV. Myocardial Injury/Damage [S25]
a. Now let’s talk about inotropic agents. He advocates using these because of the underlying problems of
decreased contractility (and because that is what his PhD was in). However, now we give ACEIs, diuretics, beta
blockers, and vasodilators first and the inotropic agents are used as a last resort.
b. From the pathophysiology, from the mechanism standpoint, we know that the underlying physiology is here and
we need to increase contractility.
XXVI. Cardiotonic Agents used in the Management of LOHF [S26]
a. These are the cardiotonic drugs used in the management of low output heart failure.
b. Cardiac Glycosides
c. Sympathomimectic amines
i. Autonomic physiology and pharmacology of catecholamines (norepinephrine).
d. Phosphodiesterase inhibitors
e. Calcium-sensitizing Drugs
f. Basically you have these 4 major groups of drugs (cardiotonic agents) that improve contractility.
XXVII. Sympathomimetic Amines and phosphodiesterase inhibitors [S27]
a. Sympathomimectic amines:
i. Autonomic physiology: Nor epinephrine, Epinepherine, Isoproterenol, Meteraminol.
1. These are positive inotropics: increase contractility and cardiac output.
2. We don’t use these because of the disadvantages:
a. They are very short acting and you would have to take it all the time. They can cause
tachycardia; increased cardiac demand for oxygen; NE would increase peripheral vascular
resistance; cause arrhythmia.
3. In ICU sometimes when the patient fails you give epinephrine and you defibrillate them. Amines can
be used for short term treatment but not for long term treatment of heart failure.
Cardio: 1:00 - 2:00
Scribe: Marjorie Hannon
Monday, April 27, 2009
Proof: Caitlin Cox
Dr. Ku
Drugs Used in Treatment of Chronic Low Output Heart Failure
Page 7 of 8
ii. Dopbutamine (synthetic isoproterenol) and dopamine are seen in the emergency room. When people
come in with shock, they will give them this to (inaudible word 42:57) the blood pressure and cardiac
output.
b. Phosphodiesterase inhibitors:
i. Amrinone, Milronone, and Vesnarinone
XXVIII. Diagram [S28]
a. This is to refresh your memory. Remember beta receptors? Coupled to the G-protein, activate adenyl cyclase,
convert ATP to cAMP. This is what we call second messenger.
b. That can trigger a number of these events: lipase, the metabolic conversion of glycogen to glucose, many
metabolic events depend on cAMP.
c. For cardiac, we increase calcium, increase the cardiac muscle, and increase the inotropic effect.
XXIX. β-Adrenergic Effects on Contraction [S29]
a. We depend on beta receptors and we depend on cAMP to maintain our cardiac output. The bottom line is that
we cannot live without cAMP.
b. With beta receptors and cAMP, we can do two things:
i. Increase contractility (inotropic action)
ii. Accelerate relaxation (lusitropic action)
c. The three cellular mechanism involved in the signaling:
i. They activate cAMP, they increase calcium (they increase force of contractions), and they also remove the
calcium right away.
XXX. Diagram [S30]
a. When you give a catecholamine, you increase the time to peak. Contraction is very fast and very high- a
positive inotropic action. As soon as they contract, then right away the protein kinase system removes the
calcium so that it will relax right away (lusitropic). This is important because when you relax there is more time
to fill so that the next time it contracts there is more blood to push out. That is why we depend on cAMP to
maintain our cardiac functions.
b. The problem with cAMP is that it is very rapidly metabolized by phosphodiesterase. Therefore, we came up with
drugs that block this—Methylxanthines, Theophylline, Caffeine—they are nonselective blockers of
phosphodiesterase. So when you have a cup of coffee, you are increasing cAMP by inhibiting its breakdown.
XXXI. Cardiotonic Agents used in the Management of LOCHF [S31]
a. Those are what we call cardio selective phosphodiesterase inhibitors that produce a positive inotropic effect:
Amrinone, Milrinone, Vesnarinone.
i. Caffeine is not selective so it is not very good. Need a cardioselective phosphodiesterase inhibitor.
b. Calcium-sensitizing drugs are still in development. None have been approved yet, all in clinical trials.
XXXII. Pharmacologic Actions of Cardiac Glycosides [S32]
a. In the old days this was the drug of choice for treating heart failure because you increase contractility
independent of the cAMP pathway (has nothing to do with the beta receptor)
b. Decreases the heart rate because when you have heart failure you get tachycardia/palpitations. Cardiac
glycosides will slow them down. Once calmed down, it will contract more efficiently.
c. Increase vasomotor tone (that is not good) but overall peripheral vascular resistance decreases because of the
sympathetic withdrawal. When you increase contractility, you decrease sympathetic stimulations.
d. Has a diuresis/naturesis effect.
e. Remember these three things: increase contractility, decrease heart rate, and improve water excretion. That is
the primary mechanism of action.
XXXIII. Mechanism of Action of Cardiac Glycosides [S33]
a. All they do is inhibit the sodium potassium pump. We need this pump to maintain a chemical gradient, and
without a sodium pump, the cell will die. A cardiac glycoside is a partial poison of the sodium pump.
b. By inhibiting the sodium pump, it causes transient increase in intracellular sodium, increase in calcium inside the
cell, activation of the actomysin contractile proteins. That is the mechanism for its positive inotropic actions.
c. The side effects:
i. Potassium is not being pumped in due to inhibition of the pump. This causes the cell membrane to become
irritable and it is very easy to get arrhythmias.
ii. Also, there is too much calcium and there is no mechanism to remove it. Too much calcium = arrhythmia.
d. From a therapeutic stand point it is very good because of increased contractility. However there are side effects
such as decreased intracellular potassium and a calcium overload.
e. When we talk about therapeutic index (LD50/ED50), cardiac glycoside is about 2. Every time you double the
serum level of cardiac glycoside, you get toxicity. It is very toxic and would never get approved by the FDA
these days. Fortunately, it has been used for over 200 years and that is why it is still around. Many
cardiologists stay away from it because it can be too toxic and there are better drugs.
Cardio: 1:00 - 2:00
Scribe: Marjorie Hannon
Monday, April 27, 2009
Proof: Caitlin Cox
Dr. Ku
Drugs Used in Treatment of Chronic Low Output Heart Failure
Page 8 of 8
XXXIV. Major Electrophysiologic Effects of Cardiac Glycosides [S34]
a. The electrophysiological effects are related to the sodium pump because of the sodium potassium imbalance.
b. AV node will decrease conduction velocity, increased ERP causing heart block. Too much calcium, can see
arrhythmias.
c. Associated EKG changes :
i. Increases P-R interval
ii. Decreases Q-T interval
iii. Decreases or inverts T-waves
iv. Decreases ST-segment (gives false sign of AMI)
XXXV. Electrophysiological Effects of Cardiac Glycosides may be used to treat certain types of atrial
arrhythmias [S35]
a. Because of this sodium potassium pump inhibition, and blocking AV transmission, cardiac glycosides are
considered one of the secondary anti arrhythmic drugs (because you can block AV transmission). But, as he
said, it is too toxic and they now have better drugs for this.
b. Aim of the treatment is to control the ventricular rate, but now we have better drugs.
i. Calcium channel blockers replace cardiac glycosides for this purpose.
XXXVI. Cardiac Glycoside Toxicity [S36]: Various severities.
a. Cardiotoxicity:
i. Even at therapeutic concentration you will see heart block. There are various degrees of heart blocks that
Dr. McNichols talked to us about.
ii. Also have sinus arrhythmia, PVCs, tachycardia, and ventricular fibrillation.
iii. Basically, cardiac glycosides are very toxic.
b. There are GI, neurological, and visual (yellow-green) disturbances.
i. People speculate that Van Gough took these because many of his pictures are yellow green.
XXXVII. Drug Interactions and Cautions with the combined use of Cardiac Glycosides [S37]
a. There are a lot of drug interactions. The bottom line is that they are related to potassium and calcium. You
have too much calcium it is not good.
b. Quinidine elevates serum digoxin levels.
c. Verapamil has additive effects on AV block.
d. Basically too much calcium or decreased cellular potassium causes all of this toxicity.
XXXVIII.
Treatment of Cardiac Glycosides Toxicity
a. When you have a drug toxicity, the first thing you do is stop the drug. Then you correct hypokalemia, treat the
heart block and arrhythmias, give antibodies to rid all of the digoxin from the blood, or you defibrillate them.
XXXIX. Clinical Management of LOCHF
a. This is the clinical management. Know the big picture:
i. non-pharmacological
ii. pharmacological: there is a sequence of events
1. decrease preload, decrease afterload, beta blockers, and positive inotropic agents
iii. We will later learn about the surgical approach.
[end 52 min]