Exam 2 Flashcards
What is the definition of preload and afterload? Given these drugs, vasodilators, diuretics, angiotensin inhibitors, inotropic agents, and RAAS inhibitors, what are their effects on preload and afterload?
Pre-load: The volume of blood in the ventricles at the end of diastole. It’s decreased by dilation of veins. If it’s decreased, myocardial perfusion will go up & O2 consumption will go down.
After-load: The force distributed on the ventricular wall when pumping blood to the body. It’s decreased by dilation of arteries. If it’s decreased, O2 consumption will go down.
- Vasodilators: Dilates veins, which lowers preload & congestive symptoms (ex. nitrates, hydralazine)
- Diuretics: decrease blood volume, which helps with HTN & preload (?) (ex. furosemide, bumetanide, torsemide)
- Angiotensin inhibitors: Decrease pressure and volume, which helps with afterload & preload (?)
- Inotropic agents: stimulates cardiac contractility (ex. digoxin, PDE3i, beta agonists)
- Renin/angiotensin system inhibitors: Decreases preload and afterload
How can you tell if a Frank-Starling curve is representing a heathy person or someone with HF? What effects do different HF drugs have on the Frank-Starling curve?
Frank-Starling relationship represents the concept that as the LV end-diastolic volume (aka preload) increases, the stroke volume will increase. Stoke volume is also increases when inotropy (force of contraction) increases.
Compared to a healthy heart, a failing heart will have a lower frank-starling curve.
Afterload and SV are inversely related. As afterload increases, stroke volume decreases. Again, a failing heart will have a lower F-S curve than a healthy heart.
What is the pathophysiology of HF, including the importance of cardiac remodeling and compensatory changes in autonomic nervous system function?
HF is a progressive disease of compensation and decompensation. It has many different causes.
- HFrEF is systolic failure (muscle weakened) and HFpEF is diastolic failure (fibrosis)
There are 3 types of cardiac remodeling:
1. Cardiac dilation - myocyte length > width, can be due to an MI or other insults to the heart, see fibrosis and myocyte death. This is very serious (end stage).
2. Pathological hypertrophy - myocyte length < width, can be due to HTN and aortic valve stenosis, see fibrosis, and can progress to HF.
3. Physiological hypertrophy - optimal muscle growth, can be due to chronic exercise or pregnancy, there’s no fibrosis, and this results in an increase of muscle mass/function.
In the short term, increased cardiac work causes HTN and sympathetic stimulation (more Ca2+). In the long term, this causes increased Ca2+ cycling, which leads to Ca2+-dependent apoptosis, and results in replacement of myocytes with fibroblasts.
Compensatory mechanisms - Help in the short term to increase SV, but eventually cardiac output gets lower and afterload gets higher
1. Sympathetic discharge
2. Renin release
3. Cardiac remodeling
What MOA do these drugs have: cardiac glycosides, PDE3i, β-AR agonists, RAAS inhibitors, diuretics, β-AR blockers, vasopressin antagonists, neprilysin inhibitor (molecular/cellular and physiological level and how it relates to the efficacy of the drug)
cardiac glycosides - ex. digoxin, ouabain; These block the Na+/K+ ATPase, which will increase the intracellular Na+ concentration. Increased Na+ will decrease Ca2+ removal. Therefore, more Ca2+ is reloaded into intracellular stores, more Ca2+ is released in response to stimulation, and muscle contracts with greater force. BUT there’s a risk of remodeling, so this isn’t a long-term solution.
PDE3 inhibitors - ex. milrinone, amrinone; These block the breakdown of cAMP, which activates more PKA, which results in increased intracellular Ca2+ concentration, increasing force of contraction, thus increasing stroke volume.
β-AR agonists - ex. dopamine, dobutamine; These increase stimulation of GPCRs that results in more Ca2+ in the cell.
renin/angiotensin inhibitors - ex. ACEi, ARB, renin inhibitor; Reduce formation of angiotensin II, which would cause aldosterone and ADH to be secreted, which would cause H2O retention & increased sympathetic activity.
diuretics - aldosterone antagonists reduce aldosterone, which reduces salt and water retention, which decreases blood volume.
β-AR blockers - ex. carvedilol, metoprolol, bisoprolol; β1- blockers limit myocyte contraction and slow the pacemaker cells in the heart. These counter increased sympathetic drive, hear workload, and adrenergic tone. Also counter hypertrophic remodeling.
vasopressin antagonists - block vasopressin (ADH) receptors, thus reducing water retention, vasoconstriction, platelet aggregation, and VSM/myocyte proliferation.
neprilysin inhibitor- increases levels of vasoactive peptides, which counters neurohumoral vasoconstriction, Na+ retention, and remodeling.
Which HF drugs are used in acute vs chronic HF, whether or not it would be expected to arrest or reverse cardiac remodeling, what toxicities it has, and whether or not that drug will prolong the patient’s life?
cardiac glycosides - (digoxin) used chronically, but not super long-term, as they can cause remodeling. These do not improve mortality, but they do improve pumping and pressure problems. Has very narrow therapeutic index. Can cause psych (delirium, fatigue), GI (anorexia, N/V), respiratory (increased response to hypoxia), and CV (pro-arrhythmic) toxicities.
PDE3 inhibitors - (milrinone, amrinone) used acutely. These do not improve mortality, but improve pressure & pumping problems. These are pro-arrhythmic and are associated with decreased survival.
β-AR agonists - (dobutamine, dopamine) used acutely. These improve pressure & pumping problems, but cause HTN long term and are prone to desensitization. These have no effect on mortality.
renin/angiotensin inhibitors - (ACE inhibitors like enalapril, ARBs like losartan, renin inhibitors like aliskiren) Used chronically. These stop and reverse remodeling. These alleviate pressure and volume problems. May cause angioedemia.
diuretics - (loop diuretics like furosemide, K+ sparing like spironolactone) These arrest and reverse hypertrophy. They also decrease blood volume.
β-AR blockers - (carvedilol, metoprolol, bisoprolol) Used in early stage HF. These decrease remodeling and reduce mortality in CHF. These inhibit sympathetic overactivity in CHF.
vasopressin antagonists - Used acutely.
neprilysin inhibitor - Counters neruohumoral vasoconstriction, Na+ retention, and remodeling. Used with an ARB (sacubitril/valsartan)
What are the mechanisms of calcium cycling in myocyte contraction?
- Ca2+ ATPase: Uses ATP to pump Ca2+ out of cytosol
- SERCA: (sarco/endoplasmic reticulum Ca2+/ATPase) uses ATP to pump Ca2+ out of cytosol and into the sarcoplasmic reticulum lumen
- NCX: Sodium-calcium exchanger. This doesn’t use ATP and is a MAJOR ROUTE!! Ca2+ is pumped out of cytosol and Na+ is pumped into cell
- Na+/K+ ATPase: Pumps Na+ out and K+ in (need to get the Na+ from NCX out of the cell)
What are the etiologies of HF? Which are associated with HFrEF and HFpEF?
HFrEF - a pumping issue (systolic) that is due to decreased contractility. Caused by dilated ventricles, which could be due to ischemic dilated cardiomyocytes (most common), non-ischemic dilated cardiomyocytes, or other causes (like HTN, obesity, stress, etc.)
- EF < 40%
HFpEF - a filling issue (diastolic) that is due to impairment in ventricular relaxation/filling. Most commonly caused by HTN.
- EF > 50%
(ejection fraction = ratio of stoke volume & end diastolic volume)
What parts of a patient’s PMI and current clinical findings would allow us to identify the patient’s most likely etiology of HF?
- HTN, CAD, DM
Lab assessment -
- EF <40% = HFrEF
-EF >50% = HFpEF
What non-drug and drug factors may result in precipitation and/or cause HF?
Non-drug: lack of compliance (with diet, drugs, or both), uncontrolled HTN, cardiac arrhythmias, etc.
Drug:
- Negative inotropes: antiarrhythmics, b-blockers, nonDHP CCBs
- Direct cardiac toxins: Doxorubicin, 5-FU, Imatinib, ethanol, cocaine, etc.
- Drugs that increase Na+ and H2O retention: Glucocorticoids, NSAIDs, Sodium containing drugs
What compensatory mechanisms occur in HF and how do they each become detrimental?
Increased preload - Good to optimize stroke volume, but causes pulmonary/systemic congestion and edema, and increased oxygen consumption.
Vasoconstriction - Good to maintain BP while there’s reduced cardiac output, but caused increased oxygen consumption, the increased afterload decreases stroke volume, and it further activates the compensatory mechanisms.
Tachycardia & increased contractility - Good to maintain cardiac output, but increases oxygen consumption, causes b-receptor down regulation and decreased responsiveness, causes ventricular arrhythmias, and increases risk of myocardial cell death.
Ventricular hypertrophy & remodeling - Good to maintain cardiac output, reduce myocardial wall stress, and reduces oxygen consumption, but results in diastolic/systolic dysfunction, increases risk of myocardiac cell death/ischemica, increases risk of arrhythmias, and causes fibrosis.
How would a patient with HF present? How can we differentiate between right and left-sided HF, HFrEF, and HFpEF?
Shortness of breath, swelling of feet & legs, chronic lack of energy, difficulty sleeping at night due to breathing problems, swollen or tender absomen with loss of appetite, cough with frothy sputum, increased urination at night, confusion and/or impaired memory
Right:
- Symptoms: abdominal pain, anorexia, nausea, bloating, constipation
- Signs: peripheral edema, JVD, HJR, hepatomegaly, ascites
Left:
- Symptoms: DOE, orthopnea, PND, tachypnea, bendopena, cough, hemoptysis
- Signs: Rales, S3 gallop, pulmonary edema, pleural effusion, Cheyne-Stokes respiration
What are the classifications and stages of HF?
NYHA Classifications:
I. Patients have cardiac disease, but no symptoms
II. Patients with cardiac disease that results in slight limitations of physical activity
III. Patients with cardiac disease that results in definite limitations of physical activity
IV. Patients with cardiac disease that results in symptoms at rest and inability to be physically active
Stages:
A. At high risk for developing HF, but no s/s (ex. HTN, CAD, DM, etc.)
B. Structural heart disease that is strongly associated with HF, but no s/s of HF
C. Current or prior symptoms of HF associated with underlying structural heart disease
D. Advanced structural heart disease and marked symptoms of HF at rest, despite maximal medical therapy & those who require specialized interventions
What are goals/measures we use to treat all HFrEF/rEF patients?
- Treatment depends on the patient’s stage/class
For both asymptomatic rEF & HFrEF:
1. Slow disease progression
2. Reduce s/s and improve QOL and prevent/reduce hospitalizations and the need for emergency care
3. Reduce mortality
General measures:
- Treat underlying causes
- Remove precipitating causes
- Exercise (with caution); Want 20-60mins 3-5x/week
- Reduce sodium to 2-3g/day
- Alcohol reduction to 1 or 2 drinks per day
- Fluid restriction <2L/day if hyponatremic or if diuretics aren’t controlling volume
- Monitor weight
- Smoking cessation
- Immunizations
What are the advantages and disadvantages of using these drugs to treat HFrEF: diuretics, ACEIs/ARBs, ARNIs, b-blockers, MRAs
Diuretics - Reduces intravascular volume, only take when symptomatic, keep pts out of the hospital, but does not reduce mortality
Spironolactone - Blocks aldosterone release, reduces mortality
Positive inotropes - Increase myocardial contractility, but don’t reduce mortality.
ACEi/ARB - Decrease ventricular afterload, block RAAS, reduces mortality
ARNIs - Block RAAS, reduces mortality
Vasodilators - Decrease ventricular afterload, ISDN/hydralazine reduces mortality
Beta blockers - Neurohormonal blockade, reduces mortality
How would we formulate a plan to treat HF patients based on presence or absence of symptoms, HF etiology, individual characteristics, etc.?
If no symptoms, no HF, just at high risk for developing HF: Use ACEi if ASCVD
If no symptoms, but has have structural heart disease that’s strongly associated with HF: Use ACEi and/or beta-blocker if past hx of MI or asymptomatic rEF
If current or prior symptoms associated with HF (rEF) + beyond: Use ARNi, ACEi, or ARB (ACEi/ARB if NYHA class IV), beta blocker, MRA, SGLT2i, and diuretic as needed
- Once doses have been optimized, if pts still have symptoms, can consider hydralazine/ISDN in AA patients, ivabradine if pt still has HR >70 on max b-blocker dose
What are the benefits and potential problems with using ACEIs, ARBs, and ARNIs in heart failure? How do these agents play different roles in whether or not the pt has HFrEF or asymptomatic rEF?
These agents improve symptoms, decrease hospitalizations, improved exercise intolerance, and reduce mortality. We see benefits regardless of etiology or severity of disease, and they MUST be used in all patients who aren’t contraindicated.
- Also additional benefit in patients with IHD, CKD, post-MI, and DM
- Cannot use if the patient is pregnant or planning to get pregnant
- Need to look out for symptomatic hypotension & other adverse effects
What changes would we want to make to a pts HF treatment in order to affect the pt’s morbidity and mortality?
- Want to replace current ACEi/ARB with an ARNI when possible in order to further reduce mortality (can’t use ARNI if pt had angioedema with ACEi, but CAN use ARB if pt had angioedema with ACEi [need to monitor closely])
These agents reduce mortality: ACEi/ARB/ARNI, MRA, SGLT2i, beta-blocker, hydralazine/ISDN
What are the benefits and potential problems with using beta blockers in symptomatic HFrEF and asymptomatic rEF? How would we use these to maximize benefits and reduce adverse effects associated with their use?
Beta blockers (carvedilol, metoprolol succinate, and bisoprolol) have been shown to reverse remodeling. They provide symptom relief, improve QOL, reduce hospitalizations, and reduce mortality.
- Before initiating, pts need to be euvolemic
- Do not abruptly d/c
Double the dose of these every 2 weeks, but monitor very closely for symptoms.
Why do we use diuretics in pts with symptomatic HF? How do we initiate loop diuretics?
Diuretics reduce hospitalizations for HF patients. They reduce the symptoms associated with fluid overload, improve exercise tolerance, and improve quality of life.
For this reason, all patients with s/s of fluid retention should be on a diuretic. Patients who do not have volume overload symptoms should NOT receive diuretics.
- If patient has kidney damage, diuretics probs won’t work as well. Also, they won’t work as well as patients are taking them due to decreasing the patients blood volume.
- We really only use ethacrynic acid if pt has a severe sulfa allergy)
We use thiazide diuretics if patients have mild HF. These lose effectiveness as renal function decreases. Often used in combo with a loop diuretic in pts who become resistant to single-drug therapy.
Initiation:
- Initiate at low-doses, then double and titrate to symptoms
- If pt is fluid overloaded, we want to reduce their weight by 1-2lbs/day
- Dose adjustment may be needed during ACEi/ARNi/ARB or b-blocker initiation
What is the role of aldosterone antagonists and SGLT2 inhibitors in HF?
Aldosterone antagonists - prevents aldosterone effects (sympathetic activation, parasympathetic inhibition, cardiac/vascular remodeling). These can decrease the LOSS of K and Mg, decrease Na retention, decrease sympathetic stimulation, and block the direct fibrotic action on the myocardium.
- Sprionolactione is non-selective, eplerenone is selective
- Use for Stage C patients
SGLT2i - reduces myocardial remodeling, preload, and afterload. These are used to reduce the risk of CV death or hospitalizations for HFrEF pts.
What is digoxin’s role in HF in patients with normal sinus rhythm? How would we use these therapeutically safely and effectively?
Digoxin provides benefits due to its neurohormonal modulation effects. It increases parasympathetic activity. Also binds to Na+/K+/ATPase contraction-coupling, while increases intracellular Ca2+, enhancing force of contraction.
Digoxin is effective in reducing hospitalizations, but not mortality. We would consider dig in patients who are symptomatic, despite being optimized. We would add digoxin before hydralazine/ISDN.
What is the role of ISDN/Hydralazine in patients with HF? How would we use these therapeutically safely and effectively?
- Causes reductions in preload and afterload. Reduces mortality.
- Good for the african american patients who are NYHA class III or IV (very sick) and are also receiving max therapy of other HF drugs.
- Good for patients with symptoms who can’t receive ARNi/ACEi/ARB due to drug intolerance or renal insufficiency
- AEs are a significant problem and major limiting factor in clinical trials.
Recommended oral doses:
BiDil (ISDN/Hydralazine): 20/37.5mg TID -> 40/75mg TID
What are the monitoring parameters and adverse effects of these agents: diuretics, digoxin, ACEIs, ARBs, ARNIs, b-blockers, MRAs, SGLT2s
diuretics - low Mg, K+, Na+, volume depletion, orthostatic hypotension, increase uric acid, increased or decreased Ca2+
- Monitor these after 1-2 weeks of initiation or increase: fluid intake/urinary output, body weight, s/s of congestion, JVD, BP, electrolytes, renal function
digoxin - anorexia, N/V, abdominal pain, visual disturbances, PCVs, AV block, arrhythmias, bradycardia, etc.
- Monitor serum digoxin conc. due to narrow therapeutic index
ACEIs/ARBs/ARNIs - angioedema, acute kidney failure, hyperkalemia, hypotension, cough (ACEi); ARNIs can cause more hypotension, but angioedema is rare.
- Monitor renal function and potassium prior to therapy, 1-2 weeks after each dose increase, then at 3-6 month intervals. Also when other treatments are added that may impact renal function.
b-blockers - Bradycardia, dizziness, hypotension, fatigue, sexual dysfunction, depression
- Monitor BP and HR 1-2 weeks after initiation. If needed, reduce the dose by 50% and try to titrate again. If only hypotension is experienced, reduce other drugs before reducing the beta blocker. Edema, fluid retention, fatigue/weakness.
MRAs - impotence, menstrual irregularities, hyperkalemia, gynecomastia (spironolactone)
- Monitor renal function and K+ within 3 days-1 week
SGLT2s - volume depletion, ketoacidosis in DM, hypoglycemia, infection risk
What are the similarities and differences in the treatment of HFrEF vs. HFpEF?
The most important thing for HFpEF is aggressively treating BP to less than 130/80.
- Diuretics should be used for volume relief
- SGLT2i may reduce hospitalizations and CV mortality
- Management of AF in HFpEF pts can improve symptomatic HF
- Diruetics as needed
- SGLT2i
- ARNi, MRA, ARB
*ACEi/ARBs don’t reduce mortality here, but reduce hospitalizations
*don’t use dig
