Lecture 10: Inotropic Agents and Pharmacology of Heart Failure Flashcards
What drug class is Digoxin?
Cardiac Glycosides
What are the 3 primary mechanisms by which inotropes (increase heart muscle contractions) affect cardiac muscle?
- Increasing intracellular Ca2+ (Cardiac Glycosides = Digoxin)
- Increasing intracellular cAMP (Symphatomimetics = Dobutamine)
- Decreasing breakdown of cAMP (PDE III inhibitors)
Explain calcium-induced calcium release (6)
- Na influx causes depolarization
- After depolarization, calcium flows in
- Calcium binds to RyR receptors and causes conformational change releasing calcium from SR
- Calcium from SR causes contraction
- Na/Ca exchanger removes calcium from the cytosol
- Na/K pump releases calcium to maintain gradient
Review slide 6
Review slide 6
Pharmacodynamics of Digoxin
How does digoxin affect heart failure (3)?
- Decreases sympathetic tone
- Decreases plasma norepinephrine
- Decreases RAAS activity
What are the pharmacodynamics of Digoxin (2)?
- Positive inotropic effect
- Increases vagal tone (increases sodium in the cell = depolarization = increases vagal tone)
- Also inhibits Na/K pump in neurons
Digoxin Clinical Use
How does Digoxin treat heart failure?
- inotropic agent
- helps the heart contract and pump
Digoxin Clinical Use
How does Digoxin treat atrial fibrillation?
- Controls ventricular response rate
- Prevents ventricular tachy or fib
Digoxin Clinical Use
How does Digoxin treat atrial fibrillation in heart failure?
rate control
What are the clinical effects of Digoxin in heart failure (4)?
- Improve symptoms
- Modest reduction in hospitalization
- Lower plasma concentrations in the therapeutic range improve survival
- Higher plasma concentrations in the therapeutic range may increase mortality
Therapeutic range is very low
What are the consequences of cell depolarization by Digoxin (5)?
- Increases vagal activity = increases Na deploarization of vagal neurons
- Decreases S-A Node Rate
- Increases Automaticity
- Increases ectopic beats
Slide 10
Na can _____ so much that it will _____ the antiporter. 3 Na out and 1 Ca in
- increase
- reverse
Review slide 12
Review slide 12
What are the electrical signs of toxicity (3)?
- Loss of plateau
- RMP becomes more positive
- Delayed after depolarization
Review slide 13
Review slide 13
What are the cardiac adverse reactions of Digoxin (5)?
- Asystole = increases vagal tone
- Atrial tachycardia
- AV block
- Premature ventricular contractions (PVCs)
- Syncope
What are the non-cardiac (increases parasympathetic) adverse reactions of Digoxin?
- Diarrhea
- Nausea/Vomiting
What is the therapeutic index for Digoxin?
2
Want 10
What are Digoxin contraindications that affect cardiac muscle (2)?
- Ventricular fibrillation (absolute contraindication)
- Ventricular arrhythmias/tachycardia
Increases cardiac muscle b/c increases excitability of heart
What are Digoxin contraindications that affect the vagus nerve (4)?
- Wolf-Parkinson-White Syndrome
- AV block
- Bradycardia
- Sick sinus syndrome
Increases vagus nerve b/c increases AV node
Digoxin toxicity
What is the treatment for 1st degree heart block and ectopic beats?
reduce dose
Digoxin toxicity
What is the treatment for advanced heart block?
Atropine
block parasympathetic
Digoxin toxicity
What is the treatment for increased automaticity?
KCL
K and digoxin competing for same binding site
Digoxin toxicity
What is the treatment for toxic serum concentration ; acute toxicity?
Fab antibodies
What occurs when heart failure progresses (3)?
- Heart damage = blood is not pumping
- RAAS/Sympathetic increases
- Heart is trying to compensate = causes more damage
Slide 18
What is the severity of Stage A?
- **High risk **for developing HF
- **No structural heart disease **
What medical conditions would a patient have in Stage A (4)?
- Hypertension
- Coronary artery disease
- DM/metabolic syndrome
- Family hx of cardiomyopathy
What is the severity of Stage B?
- **Structural heart disease **
- No sx of heart failure
General measures for patients that are asymptomatic
What medical conditions would a patient have in Stage B (3)?
- Previous MI
- Left ventricle remodeling (LVH and decrease EF) (i.e. reduced ejection fraction, <40% or myocardial injury)
- Asymptomatic valvular disease
What is the severity of Stage C?
** Structural heart disease w/sx of heart failure** (now or previously)
What medical conditions would a patient have in Stage C (3)?
- Known structural heart disease
- Shortness of breath
- Reduced exercise tolerance
What is the severity of Stage D?
- Refractory HF requiring specialized interventions
- Not treatable, only option is heart transplant
What medical condition would a patient have in Stage D?
Marked sx at rest despite maximal medical therapy
E.g. recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions
What are the classifications of recommendation (4) and level of evidence (4)?
Classification of Recommendation
- Class I (Should) = Benefit»_space;>Risk
- Class IIa (Reasonable) = IIa Benefit»_space; Risk
- Class IIb (May be considered) = Benefit ≥ Risk
- Class III (Not helpful or harmful) = Risk ≥ Benefit
Level of Evidence
- A = High quality, multiple RCT
- B = Moderate quality, 1 RCT or non RCT
- C = Limited data/expert opinion
- Z = Lunch
In Stage A Therapy, what is a Class I/Level A drug used for?
Hypertension and lipid disorders that should be controlled to lower the risk of heart failure
Slide 21
What is a Class 1/Level C drug used for in Stage A therapy?
Other conditions that may lead to or contribute to HF, such as **obesity, DM, tobacco use, and known cardiotoxic agents ** that should be controlled or avoided
Why is Stage A therapy: Class III, Level C not recommended?
Routine use of nutritional supplements (Co-Q10, carnitine, taurine, antioxidants, etc.) solely to prevent the development of strucutal heart disease should not be recommended for patients at high risk for developing HF.
All Class I recommendations for Stage A should apply to patients with what condition?
cardiac structural abnormalities who hav enot developed HF
What Stage B Therapy: Class I, Level A drug classes (3) should be used in all patients with a recent or remote hx of MI regardless of EF or prescence of HF?
ACE inhibitors or ARB (alternative to ACE inhibitors) + Beta-blockers
If hx of MI with beta blocker + ACEI/ARB (LOL + Pril/Sartan)
What Stage B Therapy: Class I, Level A drug classes (2) should be used patients with a reduced EF and no sx of HF, even if they have not experienced MI?
ACE inhibitor or ARB (alt to ACE inhibitor)
Reduced EF tx with just ACE inhibitor/ARB (Pril/Sartan)
What Stage B Therapy: Class I, Level C drug classes (1) are indicated in all patients without a hx of MI who have a reduced LVEF with no HF symptoms?
Beta blockers
If LV impaired tx with BB (LOL)
What medical condition under Stage B Therapy: Class I, Level 1 should be controlled in accordance with clinical practice guidelines for HTN to prevent symptomatic HF?
**Blood pressure **
Control BP
What drugs classes combinations (2) are used for the initial treatment of HTN in patients with left ventricular hypertrophy?
- Thiazide/thiazide-like + ACE inhibitor
- ARB + CCB
ACEI cannot be combined with ARB
Beta blockers cause problems for individuals at what age?
60+
Which drugs (2) can increase left ventricular hypertrophy?
Vasodilators:
* Hydralazine
* **Minoxidil **
Which 2 drugs is NOT used to treat HTN?
- Hydralazine
- **Minoxidil **
Which drug in Stage B: Class III, Level C should not be used in patients with low EF, sinus rhythm, and no hx of HF symptoms b/c in this population, the risk of harm is not balanced by any known benefit?
Digoxin
Which drugs class in Stage B Therapy: Class III, Level C may be harmful in patients with low LVEF and no symptoms of HF after MI?
CCB with negative inotropic effects
Stage B Therapy: Class III, Level C: Use of ____ ____ to treat structural heart disease or to prevent the development of symptoms of HF is not recommended.
**nutritional supplements **
Stage C Therapy: Class I, Level B
Which types of drugs (2) should be avoided or withdrawn whenever possible because they are known to adversely affect patients with current or prior symptoms of HF and reduced LVEF?
- NSAID (Fluid)
- Antiarrhythmic drugs
Stage C: Class I, Level A
Which classes of drugs (2) are recommended for patients with HFrEF (heart failure with reduced ejection fraction) and current or prior symptoms, unless contraindicated to reduced morbidity and mortality?
ACE inhibitors or ARBs
Stage C Therapy: Class I, Level B
In patients with chronic symptomatic HFrEF who tolerate an _____ or ____, replacement by an _ is recommended to further reduce morbidity and mortality
- ACE inhibitor or ARB
- ARNI (angiotensin receptor-neprilysin inhibitor)
Stage C Therapy: Class I, Level
Addition of which type of receptors (1) are recommended in patients to reduce morbidity and mortality? Why should K+ be monitored?
- aldosterone receptor anatagonists = Spironolactone
- K+ should be monitored to minimize the risk of hyperkalemia and renal insufficiency
ACE inhibitor (Pril) or ARB (Sartin) + Spironolactone = decreases remodeling
Stage C Therapy: Class I, Level A
Use of 1of the 3 beta blockers proven to reduce mortatlity (i.e. ______, ______, and sustained release _______ ______) is recommended for all stable patients with current or prior symptoms of HF and reduced LVEF unless contraindicated.
- bisoprolol
- carvedilol
- metoprolol succinate
ACEI/ARB + ARB + Spiranolactone + BB
Stage C Therapy: Class I, Level B
Combining these 2 drugs is recommended to reduce morbidity and mortality for patients self-described as African American with NYHA class III-IV HFrEF receiving optimal therapy with ACE inhibitors and beta blockers unless contraindicated.
- Hydralazine
- Isosorbide
Low renin producers = ACEI or ARB + BB + Hydralazine/Isosorbide dinitrate
_____ and ____ are indicated in patients with current or prior symptoms of HF and reduced LVEF who have evidence of fluid retention
- Diruetics
- sal restriction
Stage C Therapy: Class IIa, Level B
Which drug can be** beneficial in patients with HFrEF** unless contraindicatioed to decrease hospitizations for HF?
Digoxin
Stage C Therapy: Class IIa, Level B
The addition of which 2 drugs is resonable for patients with reduced LVEF who are already taking an ACEI and beta blocker for symptomatic HF and who have persistent symptoms?
hydralazine and a nitrate
Normal renin = ACEI or ARB + BB + Hydralazine/isosoribide dinitrate (pallative)
Stage C Therapy: Class IIb, Level B
Addition of which drug class may be considered in persistently symptomatic pateints with HFrEF who are already being treated with an ACE inhibitor and a beta blockers in whom an aldosterone antagonist is not indicated or tolerated?
ARB
Exception to ACE-I ARB rule
A combination of what 2 drugs might be resonable in patients with prior symtpos of HF and reduced LVE who cannot be given ACEI or ARB because of drug intolerance, hypotension, or renal insufficiency?
hydralazine and a nitrate
Intolerance = exception to ACE-I or ARB rule
Stage C Therapy: Class III, Level C = Therapies NOT recommended
Routine combined use of an ____, ____, and ______ is NOT recommended for patients with current or prior symptoms of HF and reduced LVEF
**ACE-I, ARB, and aldosterone antagonist **
Never ACE-I + ARB + AA
Stage C Therapy: Class III, Level C = Therapies NOT recommended
What class of drugs (1) are not recommended as routine treatment for patients with HFrEF?
**Calcium channel-blocking **
Amlodipine is the exception for HTN
Stage C Therapy: Class III, Level C = Therapies NOT recommended
Long-term use of an infusion of a positive _____ drug may be harmful and is not recommended for patients with current or prior symptoms of HF and reduced LVEF
inotropic
Stage C Therapy: Class III, Level C = Therapies NOT recommended
Inappropriate use of aldosterone receptor antagonists is potentially harmful because of ______ or _______ if there is a renal dysfunction and/or elevated plasma potassium
life-threatening hyperkalemia or renal insufficiency
Stage D Therapy: Class I, Level B
Meticulous identification and control of ____ ____ is recommended in patients with refractory end-stage HF.
fluid retention
Controlling fluid overload can increase survival
Stage D Therapy: Class IIa, Level B
Continuous intravenous inotropic support is reasonable as “______” in patients with stage D HF refractory to guideline-directed medical therapy (GDMT) and device therapy who are eligible for an awaiting mechanical circulatory support (MCS) or cardiac transplantation
- bridge therapy
- DOBUTAMINE
