• What are the therapeutic strategies to improve morbidity in CHF?
• What are the drug affects you are going to use to improve morbidity in CHF?

1. Increase cardiac output
2. Relieve congestion 
3. Relieve edema

You are going to obtain these effects by using drugs to:

• Decrease afterload 
• Decrease preload
• Increase contractility 

• What are the therapeutic strategies used to improve mortality in CHF?

• Use drugs that are going to reduce the rate of cardiac remodeling:

-ACE-I or ARBs

-Hydralazine/isosorbide (in ACE-I/ARB intolerant or AA)

-Beta-blockers

-Aldosterone antagonists 

1. Why does a reduction in after-load improve CHF?
2. Why does a reduction in pre-load improve CHF?

1. Reduction in after-load: Decreased after-load increases output in a failing heart and reduces work required by the heart.  More volume comes out w/each stroke. Improves SV. 
2. Reduction in pre-load: Does NOT improve SV. Diuretics are going to cause a decrease in pre-load and improve congestive signs such as pulmonary edema. 

• Effects of diuretics (general)
• Effects of vasodilators (general)
• Effects of inotropic agents (general) 

• Diuretcis: Decrease pre-load and improve congestion but do NOT improve SV
• Vasodilators: Decrease afterload and improve congestion and increase SV
• Inotropic agents: Do NOT necessarily relieve congestion but cause an increase in contractility of the heart 

**This is why you combine different drug therapies**

• Non-inotropic drugs:

ACE-I; ARBs, vasodilators (arterial and veno); diuretics; beta-blockers; aldosterone antagonists; B-naturetic peptide (niseritide) 

• Positive inotropic drugs:

• Decrease production of angiotensin-II
• Increased production of bradykinin (kininase-II)

• The chymase pathway is an alternative pathway for the production of angiontensin-II 

Angiotensinogen + chymnase →  angiotensin-II + AT1 receptor → aldosterone → increased uptake of Na

• Many patients go back to baseline levels of angiotensin-II w/ACE-I treatment via the chymase pathway.  But ACE-I still continues to be effective.  

• What are the effects of angiotensin-II?
• Of these, which ones are especially important in CHF treatment? 

1. Vasoconstriction
2. Release of aldosterone (increased Na + H20 retension) 
3. Release of catecholamines (NE)
4. Causes vascular hypperplasia
5. Promotes myocardial hypertrophy 
6. Stimulates myocyte death

-So by decreasing angiotensin-II you are going to decrease myocardial hypertophy and decrease myocyte death which is going to cause a decrease in myocardial remodeling. 

• Decreased Na/H2O reabsorption (decreased pre-load)
• Vasodilitation (decreased afterload)
• Decreased myocyte death/hypertrophy (decreased remodeling)
• Decreased response to sympathetics 

What are the results of increasing bradykinin via ACE-I?

What is the SE?

Bradykinin functions to:

• Vasodilate (decrease afterload) 
• Prevents vascular and cardiac cell growth (decrease remodeling) 
• Stimulates tPA release 

SE of bradykinin:

• Cause tissue irritation + pain which causes coughing affiliated with ACE-I 

• Decreases MORBIDITY and MORTALITY!

-Relieves dyspnea

-Prolongs exercise tolerance

-Decreases need to emergency care

**These effects are seen in mild/moderate/severe HF**

ALL patients with LV-systolic dysfunction

• Systolic dysfucntion means you have a reduced EF (< 40%) 
• These are going to be used in conjunction with diuretics 

In patients without symptoms it is going to decrease remodeling and will benefit the patient from progression.  

**Advise patients about SE**

• Do NOT use ACE-I in ACUTE HF failure. ONLY use them AFTER you have stabilized the patient.
• Acute HF occurs after an MI or valve rupture.  This is going to cause a primary issue of hypotension which CONTRADICTS the use of vasodilators.  
• Also, you are going to have an overactivation of the RAA system and if you suddenly reduce this, it is going to lead to CV collapse 

• Dry/persistent cough
• Severe hypotension in hypovolemic patients (look at diuretic use)
• Hypotension can lead to azotemia b/c decreased perfusion of the kidneys 
• Acute renal failure in renal artery stenosis 
• Hyperkalemia (especially w/intake of spironolactone and K supplementation and NSAIDs and diabetics) 
• Angioneurotic edema:  NOT immune mediated!

• K-supplementation or aldosterone inhibitor diuretics
• Pregnancy (profound fetal problems in 2nd and 3rd trimester) 
• Renal artery stenosis 
• Hypovolemia/hypotension 

What ACE-I are preferred?

How are you going to dose?

• Captopril, enalapril, lisinopril can all be given:

But captopril is the lesser choice b/c has multiple administrations a day and there are more allergies associated with this agent

• Dosing is goingto begin at low doses and increase as doses are tolerated 

• ACE-I
• Angiotensin (AT1) antagonists (ARBs) 

**There are two receptor subtypes for angiotensin-II**

• AT1:  These are the ones that are responsible for the effects of ARBs that decrease CHF.  These are going to be "sartan" drugs
• AT2:  The role of these are less clear.  These might contribute to increased remodeling of the heart. 

MOA of ARBs?

Why are ARBs not as effective as ACE-I?

• Competitively block AT1 receptors for angiotensin-II.  They are capable of more effective reduction of angiotensin-II at AT1 receptors than ACE-I b/c the body can produce angiontensin-II still through the chymase pathway. 
• They are NOT considered to be a first line of therapy b/c they are not as effective of decreasing remodeling as ACE-I b/c the body causes an increased production of renin and causes increased amounts of angiontensin-II that are going to bind to AT2 receptors which is going to allow for remodeling.  
• These are ONLY effective at HIGH doses of these drugs.  Use in patients that cannot tolerate ACE-I 

What is the benefit of using an ARB vs ACE-I in terms of SE?

What are the SE of ARBs?

• No coughing as seen in ACE-I b/c no increaase in bradykinin 
• Incidence of SE is similar to placebo in uncomplicated HTN 

• What are the classifcations of vasodilators? What is the main way these are going to help CHF?
• What drugs are in each of the classifications?

Arteriodilators: Decrease in afterload 

• Hydralazine

Venodilators: Decrease preload.  These are going to be organic nitrates that are going to cause vasodilation. 

• Isosorbide:  For out-patient treatment
• Nitroglycerin:  For acute HF w/pulmonary edema 

Hydralazine

Type of drug?

MOA?

Effect?

How does it improve CHF?

What might you combine it with?

• Type of drug:  Arteriodilator
• MOA:  Unknown
• Effect:  Arteriodilator (minimal effect on venous system) 
• Improve CHF:  Decreases afterload
• Combined with: You can combine it with a venodilator

**Combining it with a venodilator such as isosorbide dinitrate = more effective**

• Has been shown to decrease mortality when combine with an veno-dilator such as isosorbide dinitrate.  But does not decrease it as mch as ACE-I in CHF 

Hydralzine

Bioavailability?

Indications?

Bioavailability:  Fast vs slow acetylators 

• Acetylated in the bowel + liver
• Acetylation inactivates hydralazine 
• So you need to give large doses to overcome this, and ESPECIALLY in fast acetylators 

Indications:  

• Usually used w/isosorbide dinitrate after failure of ACE-I (m/c because of the cough) and ineffective use of ARBs to alleviate symptoms of HF

Tachycardia and angina:

• Tachycardia is b/c of selective reduction in afterload 
• Angina dueto "coronary steal" 

Drug-induced lupus syndrome:

• Dose related
• Reversible when discontinue the drug 

When are veodilators useful? 

What are examples of vendilators?

• useful in pts w/high filling pressure
• Organic nitrates:

-Isosorbide dinitrate

-Nitroglycerin  

• Decrease preload 
• Increase exercise capacity
• Decrease symptoms of congestion 

• What drug combinations can you use nitrates with? 

• Can combine w/hydralzine = decrease mortality 
• Used by themselves = decrease congestion 

NTG is going to be used as IV in acute HF to decrease ventricular filling pressure.  After O2, NTG is often given as the first DOC in acute heart failure  

• Isosorbide dinitrate
• Nitroglycerin 

• In ALL patients w/symtoms who have fluid retention 

-Loops for acute HF

-Most CHF patients require loop diuretics chronically to maintain euvolemia

• Add metolazone (thiazide-like diuretic)
• Can remove metolazone once kidney function is restored 

• Thiazide-like diuretic 
• But these are more effective than thiazides b/c is is ALSO effective at the proximal Na re-uptake site 

**Do NOT give these alone**

• Do not given alone b/c monotherapy is assocciated w/adverse neurohormonal activation (renin-system) b/c of volume depletion 
• Mortality is also going to be improved w/other drugs being added to diuretics 

• Hypokalemia:  Loops and thiazides 
• Hyperkalemia:  Potassium sparing + cardiac glycosides 

• Contraindicated in acute CHF 
• This is b/c sympathetics are extremely active in acute HF.  If you implement a beta-blocker you are going to reduce the CO by intolerable levels 

1. When are you going to add a beta-blocker to the regiment of CHF? 
2. What is the MOA by which you are going to have the benefit of adding beta-blockers?

• Add AFTER you have CHF under control with ACE-I and diuretics 
• Beta-blockers are useful in slowing the remodeling of the heart via two potential mechanisms:

1. High sympathetic tone in CHF causes beta-receptor down regulation.  Beta-receptors may counteract this by inducing receptor spread
2. May directly prevent remodeling via catecholamines

• Bisoprolol
• Carvedilol 
• Metoprolol extended release (metoprolol succinate)

MOA of carvedilol?

What is carvedilol approved for?

**Carvedilol is a beta + alpha adrenergic receptor antagonist**

**Non-selective beta-blocker**

**Alpha-1 blocker**

Approved for:

1. Class-II and III HF
2. To decrease hospitalizations and decrease in mortality
3. Improves symptoms of HF and slows progression 

• Dramatically decrease mortality in class-II + III patients 
• In 3 months; cardiac output increases in patients w/systolic failure 
• Beta-blockers appear to actually reverse some of the affects of HF 

• Hypotension 
• Fluid retention (give diuretic to help this) 

   

• Bronchospasm in asthmatics 
• HR may initially worsen 

• HF waxes and wanes 
• During an acute decomensated HF episode (patient w/pulmonary edema), it has been previously stated that you should temporarily remove the beta-blocker.  
• However, removing the beta-blocker during an acute HF decompensation, a significant percentage of these patients NEVER return to beta-blockers which is going to cause an increase in morbidity and mortality 

• Technically it is a diuretic
• MOA:  Inhibits aldosterone effects on the collecting ducts

-Decreases Na/K exchange and promotes HYPERKALEMIA but this is only slight if there are no other factors present.  

-Hyperkalemia can be pronounced when w/ACE-I 

What is the use of spironolactone in CHF patients?

MOA by which spironolactone induces this effect?

• Improves mortality and morbidity in patients w/severe (class-IV) CHF 
• Improves class-IV CHF mortality and morbidity by inhibiting the effects of aldosterone 

**Eplerenone has not yet been approved for this**

1. What is nesiritide going to be used for?
2. What is the MOA by which it is going to cause an improvement in this condition?

1. Treatment for acute decompensated HF 
2. Improves heart function by:

-Increase pump-output (b/c of the decreased afterload)

-Reduces preload (by decreasing Na/H2O uptake-diuretic effect)

-Reduces afterload (vasodilation)

-Cause renal efferent constriction to increase filtration 

• Trick question b/c you do NOT use loops ALONE for the treatment of patients w/acute decompensated HF b/c:

-Activates RAA system

-Activates sympathetics 

-Causes vasoconstriction so much that it causes GF to decrease

**MUST use low-dose loop wth an IV-vasodilator**

**Remember it is a beta-natriuretic peptide**

• Decreases aldosterone 
• Decreases endothelin 
• Decreases NE 

**Causes vasodilation w/o activating RAA or sympathetics**

Positive inotropes:  Increases the contractility of myocardium

Examples of cardiac glycoside inotropes:

• Digoxin
• Digitoxin 

• Generally well absorbed but variable dosing b/c gut bacteria (Eubacterium lentum) are in 10% of the population which actually rapidly metabolize digoxin to an inactive metabolite 

Digoxin vs digitoxin

Intestinal absorption

Plasma protein binding 

Elimination half-time

Enterohepatic circulation

Therapeutic concentration

Intestinal absorption: 

     Digoxin:  40-90%** (b/c gut bacteria metabolism) 

     Digitoxin:  90-100%

Plasma protein binding:

     Digoxin:  20-40%

     Digitoxin:  >90%

Elimination half-time:

     Digoxin:  1.7 days

     Digitoxin:  7 days

Enterohepatic circulation:

     Digoxin:  Small

     Digitoxin:  Large

Therapeutic concentration: 

     Digoxin:  0.5-2.0 ng/ml

     Digitoxin:  14-26 ng/ml 

• LOW THERAPEUTIC INDEX
• B/c longer acting drugs have more toxicity, there is a disadvantage of using digitoxin.  So unless special circumstances are present, ONLY CONSIDER DIGOXIN

Digoxin:

• Excreted unchanged by the kidney

Digitoxin:

• Metabolized by the liver and then excreted in bile 
• Enterohepatic circulation causes long elimination half-life

• Since digitoxin is metabolized by the liver and not the kidney like digoxin, may be useful in kidney failure patients 

• Inhibit cell membrane Na/K-ATPase 

-This effect is RELATIVELY selective for cardiac enzyme.  But digoxin side-effects are frequent and toxicity is easily encountered 

• Binds to and stabilizes phosphorylated form of the enzyme Na/K-ATPase 

-Phosphoryalted form of the enzyme is the inactivated form 

• Inhibition of Na/K-ATPase → Enhance Ca inside of the cell → High intracellular Ca causes more Ca to be stored in SR → Now each action potential releases more Ca from SR → Leads to enhanced contractility 

• Digitalis = Cardiac glycoside 
• MOA = Same as digoxin and digitoxin 

Inverse relationship b/t extracellular K+ and phosphorylation of cardiac ATPase

• Elevated K+ → decreased affinity of ATPase for cardiac glycoside
• Low K+ → increased affinity of ATPase for cardiac glycoside 

**So look out for hypokalemia**

***Loop diurectics or thiazides***

Because of increased instensity of actin-myosin interaction:

• Increased myocardial contractile force
• Increased velocity of contraction
• Decreased duration of systole 

There will be a greater effect of digoxin in the failing heart than on a normal heart 

• Digitalis increases contraction force, the problem in systolic-dysfunction is abnormal contraction of the heart so this will have a great effect.  Contraction is NOT the issue in diastolic heart failure, it is compliance, so this will have little effect on a diastolic failure heart. 

• Decrease HR 
• Increase contractility and conduction velocity via purkinje fiber system 

• Glycosides increase cardiac automaticity by increasing the rate of rise in phase-4 depolarization

• ST-segment depression (first to appear)
• T-wave inversion (first to appear)
• Prolonged PR-interval (b/c decreased conduction vel at AV node)
• Shortens QT-interval (b/c accelerated ventricular repolarization) 

B/c these drugs cause a decrease in HR but increase conduction velocity (mixed effects) pretty much any dysrhythmia is possible

1. Bradycardia b/c vagal stimulation
2. Heart block b/c AV node block 
3. Ectopic beats b/c increased spontaneous depolarization
4. Tachycardia b/c increased spontaneous depolarizations from any site in the heart 

• GI
• CNS
• Vascular
• Other 

1)  Anorexia (common)

2)  Diarrhea/abdominal discomfort

• Direct irritant effect

3)  Nausea/vomiting (most common SE)

• B/c of  chemoreceptor trigger zone excitation 

• Headache/fatigue/malaise/drowsiness:  Eearly in digitalis intoxication
• Neuralgic pain:  Lower third of the face. Erly in therapy and is often severe
• Mental symptoms:  Disorientation/confusion/delirium/hallucinations, called "Digitalis delirium."  Nightmare and depression in the elderly.
• Vision:  Blurred vision and white vision w/halos on dark objects; Color vision is affected w/chromotopsia (shift toward everything appearting yellow and green) 

**Going to depend on severity of toxicity**

• Hold glycoside and monitor ECG
• Monitor electrolytes/minimize aggravating circumstances:

Most common cause of toxic effects is because of hypokalemia which allows for increased affect on ATPase binding (usually secondary to loop diuretic treatment).  Also avoid catecholamines and beta-blockers in patients w/ AV-block induced by glycosides.  

• Treat ventricular arrhythmias 
• Treat bradyarrhythmias (w/atropine)
• Avoid cardiovesion b/c might cause arrhythmias 

• Digoxin toxicity even w/elevated extracellular K+:  This is a VERY bad sign b/c normally elevated K+ should reduce effects of cardiac glycosides.  So glycoside toxicity w/elevated potassium can ONLY mean massive dose of glycoside was taken.  This requires use of Fab fragments. 
• Fab Fragments:  Antibodies to digoxin (also recognize digitoxin).  These are very rapid and very effective 

**NO effect on mortality**

• Indicated for CHF w/atrial fibrillation
• Improves clinical status
• Given w/ diuretic, ACE-I, and beta-blockers (watch for SA and AV node function)

Other uses

• Atrial arrhythmias:  fibrillation, flutter b/c blocks AV node and increases contractility of ventricles 
• Paroxysmal tachycardia:  Make sure this is not cauased by digoxin first 

• Cardiac glycosides
• Phosphodiesterase inhibitors
• Adrenoreceptor agonists 

MOA of inamrinone?

What does it cause? 

ROA?

**Phosphodiesterase inhibitor**

• Inamrinone = amrinone 
• Inhibitio of cAMP phosphodiesterase → increases cAMP
• Causes vasodilation
• Used for short-term only
• Parenteral use ONLY

**Causes an increase in cAMP**

• Increases CO in the heart
• Decreases SVR and pulmonary wedge pressure (afterload decreased) 

**Net affect is to improve hemodynamics of the heart**

Indications for inamrinone

ROA and dose 

• Acute heart failure
• ONLY available as IV formulation
• Requires large initial dose for positive inotropic effect 

**Phosphodiesterase inhibitor**

• GI (nausea/vomiting)
• Thrombocytopenia
• Abnormal liver fucntion 
• Long term = increases mortality 

Dobutamine Effects on the heart?

Dobutamine MOA?

• Increases cardiac output (by increasing contractility/inotropic effect and has little affect on the HR) 
• Decreases ventricular filling pressure

MOA

• Beta-1 agonist predominant effect
• Beta-2 agonist (some effect) 

• Short-term support of cardiac output in advanced HF 
• Cannot use long term b/c parenteral route and tolerance 

• Cannot use long term b/c parenteral route + tolerance
• Tachycardia w/increased oxygen consumption (angina) b/c of activation of beta-1 receptors 

• Beta-1 agonist 
• Dopamine-1 receptor agonist 
• At high doses, alpha-1 agonist 

• Used short-term only; usually reserved for SHOCK
• Especially useful in increasing splanchnic and renal blood flow by causing vasodilation via dopamine-1 receptors in the kidney.  This is ESSPECIALLY USEFUL in cases of shock due to hypovolemia (not septic or anaphylactic shock) 

• Tachycardia (worse than dobutamine via beta-1 receptors)
• At higher doses, increases systemic vascular resistance via alpha-1 receptos

**Dobutmaine is generally a better choice**

1. Restrict sodium (restriction of water is very rare)
2. ACE-I 
3. Loop diuretic (if needed)
4. Beta-blocker for Class II-III HF w/LV-systolic dysfunction 
5. Digoxin if atrial fibrillation (be careful if beta-blocker is being used) 
6. Spironolactone for class-IV systolic dysfucntion (improves mortality) 
7. Give vasodilator (ARB or hydralzine/isosorbide) if ACE-I intolerant
8. Phosphodiesterase inhibitor/dobutamine as inotropic agent for acute failure 

• Adrenergics are the mainstay

-Dobutamine is usually DOC unless person has low BP because dopamine will protect against high likelihood of renal ischemia

• PDE inhibitors:  Useful but increased risk of arrhythmia
• Vasodilators:  Shift fluid from central to peripheral 

-Nitroglycerin

-Nitroprusside

• Diuretics as needed