Congestive Heart Failure and Diuretics Action Potential (AP) of Cardiac Myocyte

Dr. Ravelo

Congestive Heart Failure

- It is about problem of cardiac contractility
- But not all congestive heart failure is due to failure
of contraction, sometimes it also about the blood

Physiology of Myocardial Contraction

- For action to happen, there are different phases

- Phase 4
o Na leakage
o K channel closure
- Phase 0
o Na entry
- Phase 1
o Na channel closure
o K channel slight opening
- Phase 2
o Ca channel entry
- Phase 3
o K efflux

- Therefore there are 3 ions that play an important

part in cardiac contraction
- When AP reach the myocyte, there is a Na channel,
which is purely for Na entry
- Na-K ATPase pump is also present, they pass Na out
of the cell and pass the K inward
- K channel is also present, it is the gate where K
moves out of the cell
- Na-Ca exchanger (NCX) is a 2 way channel,
depending on the gradient of Na and Ca inside and
- Before contraction Ca is the main electrolyte that is
outside of the cell, the movement of the electrolyte
necessary
can be both ways
- The myocardium is dependent on extracellular and
o When Na is high inside the cell the NCX
intracellular Ca for contraction
pumps Na out of the cell and allows for Ca
- The figure above is a schematic diagram of a
entry
myocyte
o When there is increase Ca inside the cell,
o Cell membrane is where different channels
the NCX tend to pass Na out and allows Na
are located
entry
o Sarcoplasmic reticulum is where the
o Thus, it is called an anti-porter and it is 2
intracellular Ca is stored
way
- The release of the stored Ca from the endoplasmic
- Ca channel can be seen one way, it only allow Ca
reticulum requires the trigger Ca
entry
- When an AP reach the cell the Na channels opens
and allow for Na to enter, making the cell positively
charged
- When the Na channel opens, the NCX opens as well

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 - NCX then pumps Na out in exchange for Ca - In the same manner that the stroke volume is
- Then there will be opening of Ca channel, which directed by preload, contractility and afterload
opens longer, and it allows more Ca entry into the - If there is increase in either preload, contractility and
cell decrease in afterload then the SV will increase as
- The role of Na-K ATPase is that when there is too well
much Na is inside the cell, then it can also pump out
Na in exchange for K
- So the Na goes out of the cell via 2 channels; either
in NCX or Na-K ATPase pump
- Majority of the Na goes out into the cell via the Na-K
ATPase pump
- Ca will now enter the cell (via NCX and Ca channel)
- This Ca is what we call the Trigger Ca which will
stimulate the sarcoplasmic reticulum to open up
and release stored Ca
- The stored Ca is the one necessary for actin-
troponin-tropomyosin complex where the Ca brings
- In HF, CO is generally reduced
about the contractile interaction of actin and myosin
- For example the patient suffers from MI or
- Relaxation:
arrhythmia, then there is compromised cardiac
- After the contraction there will be a release of CHON
function
that will stimulate the Sarcoplasmic Endoplasmic
- The net effect is that there will be not enough blood
Reticulum Ca ATPase pump (SERCA) which will pump
to be pumped into the circulation
the Ca back into the sarcoplasmic reticulum
- So the heart is weak since it cant pump the blood
- The rest of the Ca remaining in the cytoplasm will be
effectively as compared to the normal heart
pumped out of the cell through the NCX
- The amount of blood that it pumps into the
circulation may not be enough
- The force of contraction is related to the intracellular
- There will be a decrease in the arterial pressure by
Ca
virtue of decreased output
- Source of Ca:
- Because there is decreased blood coming out of the
o Extrcellular Ca via the Ca channel and NCX
heart the baroreceptors from the different vessels
o Sarcoplasmic reticulum
will sense it
- The baroreceptor reflex will then increase the
- Heart Failure inability of the heart to pump oxygen
sympathetic outflow
into the body
- There will then be a release of neurotransmitter that
- It is a progressive clinical syndrome that is
will activate the alpha and beta receptors
characterized by
o Dyspnea
o Fatigue
o Fluid retention
- There is not enough Cardiac Output
- CO is the blood that goes into the systemic
circulation
- In HF, this CO is not enough for the requirement of
the body
- CO = SV x HR
- Stroke volume
o Preload
o Contractility
o Afterload
- CO is the product of SV and HR

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 - By activating the alpha receptors in the blood vessel response to congestive heart failure
there would be vasoconstriction
- Thus, there will be an increase in the afterload
- There will also be increase in the myocardial oxygen
demand in the heart and that can worsen the HF
- In the same manner, the activation of beta receptor
in the JG cell will increase the release of renin
- This will cause the activation of the RAAS system
that will eventually will increase the preload
- This will then result to the increase in myocardial
demand
- Thus, leading to worsening of HF
- These are all the compensatory mechanism of our
body in response to a decrease CO from the heart
- As much as these are the compensatory mechanism
these are vicious cycle because the end effect is
worsening of the HF
- Thus, we really have to target the problem
- For example, the patient suffers from MI - Figure above shows the activation of the JG cells
o There will be necrosis in the cardiac tissue - When there is a decrease of the blood volume to the
o Gradually it may heal and becomes fibrotic kidneys there would be release of Renin and that
o It then gives you the problem of reduced would be the beginning of RAAS
ability of the heart to contract - Renin release will convert Angiotensinogen to
- And so in those cases we need to give something to Angiotensin I (AI)
increase the ability of the heart to pump blood - A I would be converted to angiotensin II (A II)
- A II is a potent vasoconstrictor so it would further
- Other problems: Arrhythmia cause an increase in blood pressure
- In can increase or cause a rapid heart rate - And that increase blood pressure is an added
- If HR decreases then there will be a reduced filling workload to the failing heart
time - A II will also stimulate the release of aldosterone
- Thus not enough blood will come into the heart and which will in turn result to water and salt
there is not enough blood that will be pumped into reabsorption
the systemic circulation - There is water and salt retention in the body that
would increase the blood volume
- Sometimes it is also because the patient have - And that would increase the preload, and this
chronic hypertension (HPN) or valvular defect that increase would again worsen the problem of the
the heart has to pump hard just to get blood from heart
the systemic circulation
- If there is a valvular defect the heart will have a hard Cardiac Remodelling
time contracting thus it is a problem again in
contractility

- Those are just few of the cases that will lead to

congestive HF
- Congestive HF is a syndrome, thus you have to find
the root cause why the patient have congestive HF

- The drugs that will be discussed are the - As the heart failure continues, it becomes chronic
Pharmacologic treatment that we can use to temper there is what we call as the cardiac remodeling
the compensatory mechanism of the body in - Because of the increase in wall stress the heart

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 hypertrophy
- There are 2 types of hypertrophy
o Concentric Hypertrophy
o Eccentric Hypertrophy
- Concentric Hypertrophy
o Thickening of the walls of the ventricles
o That would then decrease the blood inside
the ventricle
o There would be lesser blood in the heart
- Eccentric Hypertrophy
o There is too much blood going in
o The heart would find it difficult to pump
blood to the systemic circulation
- We dont want this to happen to our patients
because they would worsen the heart failure
- Preload venous return
- Afterload Reduction or After load unloaders this
address the problem of arterial circulation
- Intotrophic Agents drugs that can increase the
MISSION, JMM (2E) / LIMPIN, JCE (2C)
force of cardiac contraction
Drugs
A. Cardiac Glycosides
- 1. Digitalis Parenterally given, less hydrophilic
- 2.Digoxin prototype of Cardiac glycosides
Mechanism of Action Molecular event
- Both of them inhibit the Na-K ATPase pump
- If there would be no Na-K ATPas pump
- When AP reach the heart, Na moves in
- The Na cannot be removed by the Na-K ATPase
pump
- Na will then be moved out by the NCX, such that
there would be more Ca inside the cell
- When there is enough cytoplasmic Ca, it then
stimulate the sarcoplasmic reticulum to the Ca
- That will then cause more contraction
- This is how the cardiac glycosides exert their
inotrophic activity
Effects of Digoxin
- Increase Ca, increase force of contraction
- It also exert electric effect on the heart
- They decrease the action potential duration
o shortening to atrial and ventricular
refractoriness
o In the Atrium and Ventricle there would be
a reduce in action potential duration
- But it is different with the automatic cells:
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 o AV nodal block
o Premature ventricular contraction
Because of the possible block of AV
node
The bundle of his and the Purkinje
fiber can contract on their own
Causing ventricular contraction
- Hypokalemia
o If there is hypokalemia, digitalis/digoxin
bind to the cardiac muscles longer as
compared to having a normal Potassium
level in the heart
- This drug exert a parasympathomimetic effect on
the AV node
- From SA node, the signal will then go to the AV
nodebundle of HisPurkinje Fibers
- If there is parasympathomimetic effect there would
be a delay
- The conduction of the electrical impulse from the SA
node to the AV node
- That in essence would decrease the heart rate

Summary
- So the drug (Digoxin) exert a positive inotrophic
- Affected GIT because of Digoxin can cause:
activity by Na-K ATPase inhibition
o Anorexia, nausea, vomiting, and diarrhea
- And decrease the heart rate by parasympathetic
that can lead to potassium deficiency
effect on the AV node nd
o That can lead to 2 toxicity which is
arrhythmia
Decrease in Heart Rate Effect of Digoxin
- In CNS it can cause
- This is also the reason why Digoxin can be used as an
o Disorientation, hallucination, and visual
anti-arrhythmic agent
disturbances
- It is used to treat supra-ventricular tachyarrhythmia

- Note that Digoxin is both an anti-arrhythmic and

arrhytmogenic drug
- All drugs that can be used to treat arrhythmia are
themselves arrhytmogenic when they are given at
high doses

- Digoxin is an oral preparation of Cardiac Glycosides

- It has an heterohepatic recirculation that contributes
to its prolong half life
- 2/3 of the drugs are excreted in the kidney
- Arrhythmia brought about by toxicity of Digoxin o it can be given to patients with Renal
o Atrial tachycardia or Atrial fibrillation Failure (RF) provided that their dosage will

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 be computed
- Characteristically Digoxin has a narrow therapeutic
index
- The therapeutic dose is not far from the toxic dose

- Digoxin antibodies may be given to enhance the

removal of digoxin in our body
- These antibodies will bind with digoxin and then it
will be excreted out in our body
* Note:
- Ca channel Blockers are contraindicated with CHF
- They are antagonist of Digoxin

B. Beta Adrenoreceptor Agonists

- Remember the different drug interaction with

Digoxin
- It is important to note that Digoxin has a narrow
therapeutic effect and it is also active
- When it is given with other drug then one should be
careful

- To increase the contractility of the heart the patient

should be given with Beta adrenoreceptor agonist
- Beta 1 receptors can be found in the heart
o There are also alpha 1 receptor in the heart
o Stimulation of both these receptors would
increase the force of contraction
o They could increase the heart rate
- Pure beta 1 agonist Dobutamine
- Catecholamine that could exert beta 1 effect
Dopamine
o Not a pure beta 1
o At low dose it would stimulate d1 receptors
which are found in the coronaries and
kidneys

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 o At high dose (2-10mcg) it can activate beta
1 receptor
o At higher dose (>10mcg) it can stimulate
the alpha 1
- These 2 drugs (Dopamine and Dobutamine) can also
be used in Acute Heart Failure (HF)
- If youre going to use them for HF these are the
things that you should remember:
o Both should be administered via IV
o Because they can be metabolized by COMT
(Catechol-O-methyl transferase)
o Not used orally; for parenteral use only

- Dopamine can cause tolerance and desensitization

- There is a decrease efficacy of the drug as the drug is
given at prolong period of time
- 1. This is because of Receptor Endocytosis
o There would be gradual reduction of
number of beta receptor in the heart
nd
- 2. There would also be a 2 Messenger Feedback
nd
o 2 messenger would be affected

- Thus they are not the drugs for Chronic Heart Failure
- They also lack oral efficacy

C. Bipyridines
- It is said that its inotrophic effect is greater that its
- Phosphodiesterase Inhibitors
chronotrophic effect
- This is the reason why Dobutamine is used in the
treatment of Heart Failure
- Since we are not increasing the heart rate, but rather
we are increasing the force of contraction
- Thus, the heart cannot get tired easily

- Relaxation is also accelerated

- There would be an increase in conducting activity
through the AV node with decrease in refractory
period
- Which is not seen in Digoxin
o Since its conduction velocity through the AV
node is delayed or slowed
- The same goes with Dopamine
- If the enzyme is inhibited, cAMP will be increased
inside the cell
- If cAMP is increased in the cardiac muscle then it will
increase phosphorylation of the phosphokinases
necessary for the release of the Ca from the
sarcoplasmic reticulum
- Thats the reason why bipyridines are inotrophs
- These drugs are also vasodilators
- In the smooth muscle the phosphodiesterase
inhibitors increases the cGMP
- The cGMP in the smooth muscle of the blood vessel

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 will cause relaxation
- Bipyridines have dual effect, therefore they are very
suitable for the management of CHF
- Figure above shows how the phosphodiesterase
inhibit cAMP
o It converts cAMP to AMP
o Blocking this enzyme will promote cAMP
proliferation inside the cell
- If cAMP is present then it will activate
Phosphokinase A (PKA) to release the Ca inside the
sarcoplasmic reticulum
- Thereby promoting or activating contraction
- Thus, bipyridines (phosphodiesterase inhibitors)
exhibit inotrophic effect
MISSION, JMM (2E) / LIMPIN, JCE (2C)
- On the other hand, figure above shows the effect of
cGMP in the smooth muscle
- If the phosphodiesterases will be inhibited then it
will decrease production of cGMP
- Decreasing cGMP will promote the relaxation of the
smooth muscle specifically the blood vessels
D. Diuretics
- One of the manifestation of CHF is volume overload
by activation of RAAS and leading to Na and water
retention
- This is the reason why we are giving diuretics
o To reduce venous pressure and ventricular
preload
- Pulmonary congestion
o Left Side of Heart:
o When there is left ventricular failure and
there is an increase in systemic blood
pressure
o The heart is not pumping enough blood into
the systemic circulation so the blood
overflows
o There would be increase pressure in the
ventricle
o It will then go to the atrium and it will go
back into the lungs
o Right side of Heart:
o If there is volume overload, preload is also
increased
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 o The blood will go into the right atrium then E. ACE Inhibitors
to the right ventricle and eventually to the - Angiotensin Converting Enzyme Inhibitor
lungs
o Result:
o There is too much blood going into the
lungs Pulmonary Congestion
- Systemic Manifestation
o Edema on the feet
o Hepatomegaly
o Ascites
- Thus Diuretics are given to decrease Volume
Overload
- Different Diuretics that can be given
o Loop Diuretics
o Aldosterone Antagonist
o ADH Antagonist

- There would be vasodilation

- There is a reduce aldosterone secretion because of a
decrease in Angiotensin II
- Aldosterone is also responsible for Cardiac - It cuts the RAAS pathway
remodeling - Reduce Remodeling of Heart and BV
- The remodeling of the heart and blood vessels would o Due to decrease Aldosterone
decrease by giving aldosterone antagonist
o Result of Remodeling:
o Vessels thicken
o Heart hypertrophy
o With Sirinolactone these effects would
decrease
- K sparer
o Spirinolactone enhance Na and H2O
secretion but retains K
- Note that Aldosterone acts on DCT and Collecting
Tubules

- Most of the ACE inhibitors are Pro-drugs

- So they have longer half life with the exception of
Captopril

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 - Nitrates will release Nitric Oxide through the
Glutathione S-transferase (GST) enzyme

Long Acting Nitrates

- MOA:
- Nitrates will be acted upon by enzymes GST that will
release Nitric Oxide (NO)
- NO released by the epithelium will cause smooth
muscle relaxation
- Effect Dilation of the vessels
- It is both used for CHF and Angina
- One adverse effect is hyperkalemia
- In CHF because of its venodilatory effect and
- Others are due to its pharmacologic effect
because of its arteriolar dilatory effect
o Because of vasodilation there could be
o It reduce preload and afterload
edema
o Therefore improving the manifestation of
- ACEI inhibits the degradation of Bradykinin
pulmonary congestion
o It is the ACE that degrades the Bradykinin in
our body
o Bradykinins are responsible to some allergic
reactions like: Angioedema
o ACEI Bradykinin is not degraded
vasodilation angioedema dry cough / Nitroprusside
allergic cough - It is a relative of Nitrates however, it may release NO
via GST or Non-enzymatic
- It will also cause vasodilation
F. Vasodilators
- It more used for treatment of Angina
- Vasodilators decrease the preload, afterload or both
- Vasodilators dilate all types of vessels
Hydralazine
o They dilate vein / capacitance vessels
- Pure arteriolar dilator no MOA (not fully
o They also dilate arteries / resistance vessels
understand)
- There are drugs that are purely preload unloader or
- It is a pure afterload unloader
purely afterload unloader

Long Acting Nitrates

- Kinetics:
- It is metabolized by acetylation
- They are issues for patients who have polymorphism
- There are rapid acetylators and slow acetylators
- If you are rapid acetylators you will metabolized
acetylene faster
- They are both venodilators and arteriolar dilators - Adverse Effect:
- Veins are more sensitive to the effect of nitrates - Lupus-like Syndrome
o The veins will be the one that will respond - If you are slow acetylators then chances of having
to the nitrates adverse effect is high

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 Combination of Nitrates and Hydralazine Other Beta Blockers
- Prolong life of patient with CHF as compared to
those receiving Digitalis and Diuretics alone

G. Beta Blockers
- They may act both on beta 1 and beta 2 receptors
- There are beta blockers that are partial antagonistic
and there are also beta blockers with alpha blocking
properties (review 4 types of beta blockers)
- Propanolol it prevents reflux tachycardia induce by
- They outweigh their negative inotrophic effect
vasodilators (because of the baroreceptors)
- They are used because of their NEGATIVE
CHRONOTROPHIC effect
- Beta blockers will block beta 1 in the heart
decreasing force of contraction and the heart rate
- They are also blocking the beta 1 receptors in the JG
cells thereby reducing renin
o Resulting to decrease activity of RAAS

- Esmolol selective beta 1

o Fast acting activity

Different Types of Drugs

Bisoprolol
- Acebutalol and Pindolol - Partial antagonist
- Partial antagonist
- Note that partial antagonist are also partial agonist
Two Categories (Pharmacokinetic properties):
- They may be better used for patients with
1. Eliminated by hepatic metabolism and relatively
congestive heart failure
short half-lives (Propranolol, Metoprolol)
- Because after all we are only after their Negative
2. Eliminated unchanged by the kidneys with longer
Chronotrophic Effect
half-lives (Atenolol)
- We dont want to remove the beta 1 in the heart
Toxicities
because we want the POSITIVE INOTROPHIC effect in
- bronchoconstriction
CHF
- bradycardia, hypotension
Carvedilol
- fatigue, sedation, depression, insomnia (highly
- Beta-blocker with alpha blocking properties
lipophilic drugs)
- Because you decrease the heart rate and at the
- impaired exercise tolerance, exacerbation of
same time the blood vessels are opened or dilated
peripheral vascular disease, impotence
- increased triglycerides, hyperglycemia
Metropolol, Atenolol and Esmolol (AME)
- They are all cardioselective beta blockers

Note:
- These drugs can worsen CHF if not done cautiously
at low doses

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SUMMARY
Drugs Proven By Clinical Trials to Prolong Life of CHF Patient
- ACE Inihibitors vasodilatory/ reducing afterload /
decreasing aldosterone secretion
- Beta Blockers - because of their negative
chronotrophic effect
- Spironolactone antagonizing aldosterone / diuretic
activity / K sparing activity
DIURETICS
- Act by reduction of blood volume and direct vascular
effects
- Deplete body sodium stores
- Often provide adequate treatment for mild to
moderate hypertension
- In more severe hypertension, in combination with
sympathoplegic and vasodilators
Different Types
- Thiazide diuretics
- Loop diuretics
- Potassium-sparing diuretics
Thiazides
- Prototype: hydrochlorothiazide
- One of the first-line agents for hypertension
- Inhibit NaCl transport predominantly in the distal
convoluted tubule
- Reduces blood volume and cardiac output initially
- Eventually, normal cardiac output, PVR
o With prolong use it can cause Vasodilation
Toxic Effects
- Hypokalemic metabolic alkalosis
- Hyperuricemia
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o Not good for patients with gout
o If thiazides are used for prolong period of
time then the patient may have gouty
arthritis
- Impaired carbohydrate tolerance
o Not good for patients with diabetes
- Hyperlipidemia (5-15% increase in serum cholesterol
and LDL)
o Diuretics and beta-blocker combination is
not good
o Because both of them causes lipidemia for
prolong period of time
- Hyponatremia
- Hypercalcemia
o It should not be given to patients taking
Digoxin because it can enhance Digoxin
Tocixity
- Allergic reactions (cross-reactivity in sulfonamide-
sensitive patients, photosensitivity, hemolytic
anemia, thrombocytopenia)
Loop Diuretics
- Prototype: furosemide
- Most potent diuretics available
- Inhibit NaCl reabsorption in the thick ascending loop
of henle (Na+/K+/2Cl- transporter)
- Do not reduce PVR (Peripheral vascular resistance)
to the same extent as thiazides
- Commonly used in patients with fluid overload
Furosimide Toxicity
- Hypokalemic metabolic alkalosis
- Ototoxicity- dose related, usually reversible
- Hyperuricemia
- Hypomagnesemia not good for patients taking
Digoxin
- Skin rash, eosinophilia, interstitial nephritis
- Cross-reactivity in patients sensitive to sulfonamide
Potassium Sparing Diuretics
+ +
- Inhibit Na reabsorption (and K and H excretion)
in the distal and collecting tubules
- Limited natriuretic activity
- Usually given to reduce K loss
- Amiloride, triamterene inhibits Na+ influx through
ion channels (Na/K transporters) in the luminal
membrane
- Spironolactone, eplerenone - competitive
ALDOSTERONE antagonists
Note: Please Read Katzung and Golan
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