Lecture 9: Drugs Used for Heart Failure Flashcards
Left-sided systolic heart failure is due to failure of what?
Failure of the pump function of the heart (EF <45%) due to dysf. or destruction of cardiac myocytes or their molecular components
Left-sided diastolic heart failure occurs due to what?
Ventricular capacitance is diminished and/or when ventricle becomes “stiff” and cannot fully relax during diastole
What are 2 common causes of left-sided diastolic heart failure?
- Ventricular hypertrophy due to chronic HTN
- CT disease such as amyloidosis
What occurs to both afterload and preload in systolic heart failure?
- Increased afterload
- Increased preload
What is the LVEF like in systolic HF and there is usually progressive what?
- LVEF <50% = HFrEF
- Usually progressive chamber dilation w/ eccentric remodeling
Diastolic heart failure is now especially common in whom?
Elderly women
What occurs to the ejection fraction in diastolic heart failure?
Usually normal = HFpEF
What occurs to preload in diastolic heart failure?
Decreased preload
Diastolic heart failure has a poor tolerance of what 2 things and is worsened by an increase in what?
- DHF –> poor tolerance of atrial fibrillation
- DHF –> poor tolerance of tachycardia
- DHF is worsened by ↑ MAP
Worsening of diastolic HF by ischemia raises left atrial pressure which can lead to which life threatening condition?
“Flash” pulmonary edema
With a drop in cardiac output, what are the adpative mechanisms (i.e., what gets increased) contributing to HF?
- ↑ renin + ↑ aldosterone + ↑ natriuretic peptides
- ↑ sympathetic discharge
- ↑ preload and afterload
- ↑ remodeling of heart
ACE-I and ARB’s lead to less angiotensin II which has what 3 positive effects in pt’s with HF?
- Less vasoconstriction (↓ afterload)
- Less aldosterone and less Na+/H2O retention (↓ preload)
- ↓ cell proliferation and remodeling
Define the terms inotropic agent and chronotropic agent.
- Ionotropic agents alter the force/strength of muscle contractions
- Chronotropic agents may change the heart rate and rhythm
ACE-I (-prils) are used clinically for what heart conditions?
- Heart failure w/ reduced EF (HFrEF) = systolic HF
- LV dysfunction following MI
What are 2 major AE’s associated with ACE-I’s?
- Cough
- Angioedema
Which 2 ACE-I are now widely used due their longer half-life permitting 1x/day dosing?
- Benazepril
- Lisonopril
Which drugs can be used for HF if patient is intolerant to ACE-I’s?
ARBs (-sartans)
Which ARB is noteworthy in that it is not a prodrug requiring activation?
Valsartan
Which ARB is noteworthy in that it displays relatively irreversible binding?
Candesartan
What is the MOA of sacubitril and what is it co-crystalized with as a combo drug for HF?
- Prodrug that inhibits neprilysin (neutral endopeptidase [NEP])
- Co-crystalized with the ARB, Valsartan
- Valsartan/sacubitril
What does the neutral endopeptidase blockade by sacubitril lead to?
Increased levels of natriuretic peptides
What are3 common AE’s of valsartan/sacubitril?
- HYPOtension
- HYPERkalemia
- ↑ serum creatinine
What is the effect of ↑ ANP on GFR, renin/aldosterone secretion, Na+/H2O reabsorption, and ADH secretion?
- ↑ GFR
- ↓ renin + ↓ aldosterone secretion
- ↓ Na+/H2O reabsorption
- ↓ ADH secretion and ADH effects in collecting duct
ACE-I’s/ARBs should be administered to all pt’s with LV systolic failure or LV dysfunction w/o HF except in what 5 situations?
- Not tolerated (cough, angioedema; try ARB)
- Pregnant
- HYPOtensive
- Serum creatinine >3 mg/dL
- HYPERkalemia
Which beta-blocker has been shown to work best in HF?
Carvedilol
Which other beta-blocker is a non-selective alpha/beta blocker, used primarily for severe HTN and tx of hypertensive emergencies?
Labetalol
What condition should patient be in for use of carvedilol in HF and what are it’s recommended uses?
- IF clinically stable
- Recent or remote hx of MI or ACS and ↓ EF (rEF; <40%)
- rEF to prevent SYMPTOMATIC HF (even if no hx of MI)
Carvedilol is used to prevent what in the heart as a result of excessive sympathetic stimulation during HF?
Prevent down-regulation of the β1-receptors
List 5 benefits of carvedilol in HF by preventing the down-regulation of β1-receptors?
- Keeps heart responsive to sympathetic drive
- Protects against dysrhythmias
- ↓ renin secretion
- ↓ myocardial O2 consumption
- Limits heart muscle remodeling
Carvedilol should only be administered to which patients?
Clinically stable
Which type of HF’s is carvedilol useful in and should be given along with ACE-I to which pt’s?
- Pts with diastolic HF will benefit from a lower HR
- Should be given to all pt’s w/ symptomatic CHF and LVEF <40% unless contraindications exist
- Given along w/ ACE-I to all pt’s w/ LV systolic dysfunction caused by MI to reduce mortality
What is the MOA of ivabradine and effects on heart?
- Selective and specific inhibition of the HCN channels (f-channels) within SA node
- Disrupts If (“funny” current) to prolong diastole and slow HR
What is the clinical application of ivabradine; specifically in which pt’s?
- Tx of resting HR ≥70 bpm in pt’s w/ stable, symptomatic chronic HF w/ LVEF ≤35% who are in sinus rhythm with:
- Maximally tolerated doses of β-blockers
OR
- Contraindications to β-blocker use
What is the MOA of spironolactone and its effects on ion and volume levels?
- Competitive antagonist of aldosterone receptors
- K+-sparing diuretic due to ↓ ability of aldosterone to promote Na+-K+ exchange in collecting ducts
- ↓ plasma Na+ and volume
Which K+-sparing diuretic is a more selective aldosterone antagonist, approved for use in post-MI heart failure or in combo for tx of HTN?
Eplerenone
What are the pharmacokinetics of spironolactone like and why is a single dose effective for 2-3 days?
Steroid effects are slow on and slow off
What are some possible AE’s associated with Spironolactone?
- HYPERkalemia (duh.)
- Amenorrhea, hirsutism, gynecomastia, and impotence
- Tumorigen in chronic animal toxicity studies (boxed warning)
What are 3 beneficial effects of spironolactone on the heart?
- ↓ myocardial fibrosis
- Reduces early morning rise in HR
- Reduces mortality and morbidity in pt’s with severe HF
Explain the purpose of aldosterone inhibition when treating post-myocardial infarction heart failure?
- Damaged heart vasculature synthesizes aldosterone after MI
- Locally produced aldosterone contributes to cardiac fibrosis
What are some of the effects blocked by spironolactone that occur as a result of aldosterone release following an MI?
- Na+/H2O retention; K+ and Mg2+ loss
- ↓ baroreceptor reflex
- Sympathetic activation
- Cardiac fibrosis + ischemia
Spironolactone is approved for what application in HF?
Tx of symptomatic HF w/ reduced systolic function
Why is spironolactone (and eplerenone) the most underutilized of all classes of meds for HF?
Primarily due to fear of HYPEkalemia
Which loop diuretic has a longer t1/2, better oral absorption and som evidence that it works better in HF?
Torsemide
Furosemide and other loop diuretics are useful in the management of acute pulmonary edema by decreasing what?
Preload
Which class of diuretics is useful in patients with low GFR?
Loop diuretics
When using diuretics to control the congestive heart failure state, which class is used first and then followed by what 2 classes if needed?
- Use loop diuretic first
- Add K+-sparing next if needed
- If still need more diuresis, finally add thiazide
What is the purpose of using diuretics to relieve congestion in HF?
Return ventricular fiber length to more optimal range
Which vasodilator combo is especially useful in tx of chronic HF in African Americans?
Isosorbide dinitrate plus hydralazine
Where are the vasodilatory effects of isosorbide dinitrate and hydralazine seen and what is the effect on preload/afterload?
- Isosorbide dinitrate dilates veins and ↓ preload
- Hydralazine dilates arteries and ↓ afterload
Nitroglycerin has a more prominent effect on what vasculature?
Veins
What is the clinical application of nitroglycerin in HF?
Acute decompensated HF (especially when assoc. w/ MI)
Hydralazine’s MOA is dependent on what, requires activation by, and is mediated by what receptor?
- Endothelium dependent
- Requires activation of COX
- Mediated by PGI2 receptor
What are the clinical applications of hydralazine in HF and use in pregnancy?
- HF w/ reduced EF if intolerance to ACEI or ARB
- HF w/ reduced EF in self-identified African Americans
- Hypertensive emergency in pregnancy
What are some of the major AE’s associated with Hydralazine?
- Angina pectoris
- Flushing
- Peripheral edema
- Tachycardia
- Pruritus
- Drug-induced lupus-like syndrome
What is the MOA of digoxin?
Inhibition of Na+-K+ ATPase pump in myocardial cells
What are the effects of digoxin on myocardial cells via inhibition of the Na+-K+ ATPase?
- Transient ↑ of intracellular Na+ which promotes Ca2+ influx leading to increased contractility (+ inotropic effect)
- Direct suppression of AV node conduction –> ↑ effective refractory period and ↓ conduction velocity
What is the effect of digoxin on inotropy, vagal tone, and ventricular rate?
- Positive inotropic effect
- Enhanced vagal tone
- ↓ ventricular rate to fast atrial arrhythmias
Increased myocardial contractility produced by digoxin has what effect on cardiac output, sympathetic, and vagal tone?
↑ cardiac output –> ↓ sympathetic tone + ↑ vagal tone
What are the clinical applications of digoxin?
- Control of ventricular response rate in adults w/ chronic atrial fibrillation
- Tx for mild-to-moderate HF in adults/kids to increase myocardial contractility
What is the route of administration for digoxin and it’s half-life?
What is required to get beneficial effects immediately?
- Oral w/ t1/2 = 36-48 hrs
- Needs a loading dose
What are the major AE’s associated with Digoxin?
Severe dysrhythmias
Digoxin cardiac toxicity occurs in part because myocytes becomes overloaded with what?
How does this contribute to arrhythmias?
- Overloaded w/ Ca2+ and spontaneous oscillatory uptake and release from SR causes delayed afterdepolarizations and aftercontractions
- Excess free radicals also contribute
What are 3 hemodynamic benefits of Digoxin due to increased cardiac output?
- ↓ sympathetic tone
- ↑ urine production
- ↓ renin release
Digoxin increases the responsiveness of the SA node to what?
ACh
What are the 2 most important effects of Digoxin on the AV node in regard to duration of refracory period and conduction velocity?
- ↑ duration of refractory period
- ↓ conduction velocity
The most important effect of digoxin on purkinje fibers is an increase in what?
Automaticity
What is the major effect of digoxin on the duration of the refractory period in ventricular myocardium?
↓ duration of refractory period
What are typical changes seen on an EKG with therapeutic levels of digoxin?
- Depression of S-T segment
- Longer P-R interval
Toxic effects of digoxin on A-V conduction will be seen how on an EKG?
- A-V dissociation
- Lack of relationship between P and QRS complexes
Toxic effects of digoxin on purkinje automaticity and ventricular refractory period will appear how on EKG?
Ectopic ventricular beats
What are some of the non-cardiac AE’s associated with Digoxin?
- Anorexia, N/V, salivation
- Excessive urination
- Fatigue
- Visual disturbances (blurred vision, halos, and yellowish or greenish tinge to objects)
What are 4 tx’s for digoxin toxicity?
- KCl
- Lidocaine
- Phenytoin
- Antidigitalis Abs
Why are digoxin drug interactions with diuretics a big deal?
Diuretics cause hypokalemia, which leads to ↑ digoxin binding —> digoxin toxicity
Digoxin competes with what ion for binding to Na+-K+-ATPase?
K+
What is the effect of ACE-I and ARBs on levels of digoxin?
ACE-I and ARBs can ↑ plasma K+ levels —> ↓ digoxin effects
Digoxin is used in combo w/ diuretics, β-blockers, and ACE inhibitors in what type of HF?
LV systolic HF
Why is digoxin especially useful in pt’s with atrial fibrillation?
Due to prolongation of effective refractory period at AV node
Which drugs should be used judiciously in pt’s with diastolic HF, but can also lead to what?
Which drug shows mixed evidence of benefit?
- Loop diuretics to tx edema
- BUT can ↓ preload too much –> ↓CO, hypotension, and death
- Mixed evidence with spironolactone
Which 3 drug classes show no evidence of benefit in diastolic HF?
- Nitrates
- PDE5 inhibitors
- Digoxin
What therapy needs to be initiated in pt’s with acute decompensated HF and why?
- Diuretic therapy
- All pt’s with ADHF are volume overloaded, must get rid of excess volume to relieve congestion and return ventricular fiber length to more optimal range
How do the dilatory effects of nitroprusside differ from nitroglycerin?
- Nitroprusside = mixed effects, dilates both arterial and venous sides
- Nitroglycerin = preferentially venous side, decreases preload
Pt’s with ADHF can be hypertensive, normotensive, or hypotensive; how is each treated with vasodilators/diuretics?
- Hypertensive = tx with diuretic + vasodilator (i.e., nitropursside or nitroglycerin)
- Normotensive = tx with diuretic + vasodilator (i.e., nitroglycerin)
- Hypotensive = tx with diuretic
What is the MOA of nitroprusside?
Forms free radical nitric oxide, which in smooth m. activates soluble guanylate cyclase to ↑ cGMP
What are the systemic and cardiac effects of nitroprusside?
- Peripheral vasodilation w/ action on venous and arteriolar smooth m.
- Reduces peripheral resistance
- Will ↑ cardiac output by decreasing afterload
What are 3 clinical applications of Nitroprusside?
- Management of hypertensive crisis
- Acute decompensated HF
- Used for controlled hypotension to reduce bleeding during surgery
One AE of nitroprusside is metabolic acidosis secondary to what?
Cyanide toxicity
When are inotropic agents (i.e., sympathomimetics, PDE inhibitors) indicated for HF pt’s?
If symptomatic HYPOtension w/ end-organ dysfunction despite adequte filling pressure
Before administering inotropic agents to pt with HF what should be discontinued?
Carvedilol
Dobutamine primarily affects what receptors and what is the effect on the heart?
- Stimulates myocardial β1 and β2 AR’s, also so α1 receptors
- ↑ contractility and HR
- Some vasodilation due to β2 receptor stimuation
Which adrenergic receptors are activated by Dopamine in a dose dependent manner and effects on heart?
- Activates β1-AR’s at LOW doses = ↑ HR and contractility
- Stimulates α-AR’s at HIGH doses
Dopamine is used as an adjunct in the tx of what?
Shock that persists after adequate fluid replacement in cases of: MI, open heart surgery, renal failure, and cardiac decompensation
What is the prototypical PDE type III inhibitor used as an inotropic agent in short-term/rescue therapy?
Milrinone
The PDE inhibitor, Milrinone results in increasd levels of what?
What is the effect on the heart and systemic circulation?
Must be given via which route?
- ↑ cAMP —> ↑ contractility in heart + vasodilation
- Decrease preload and afterload
- Must be given via IV
What are the clinical applications for Milrinone?
Inotropic therapy for pt’s unresponsive to other acute HF therapies (i.e., dobutamine)
What are 3 drugs classes to avoid in HF?
- Class I antiarrhythmics
- CCB’s
- NSAIDs
Which drug may improve cardiac responsiveness during ADHF in a patient who was taking carvedilol/is overdosed on carvedilol?
Milrinone
What are some of the concerns with using the PDE inhibitor, Milrinone?
Some studies show it decreases survival time
Which drug classes can be used in diastolic HF if justified by sx’s?
- β-blockers
- ACEI/ARBs
- CCB’s
