Drugs to Treat CHF Flashcards
CHF occurs when
the heart is unable to pump enough oxygenated blood to meet the demands of the body
The heart is failing when
cardiac output is insufficient to meet the needs of the body
CO is mainly affected by which two factors:
stroke volume and heart rate, each of which are affected by different factors
Cardiovascular consequences of decreased CO
tachycardia; cardiomeglia; arrhythmias; fatigue/exercise intolerance
Respiratory consequences of decreased cardiac output (CO)
shortness of breath; pulmonary edema; cyanosis; orthopnea
Preload is the
left ventricular end diastolic pressure or volume, meaning the amount of stretch on the heart at the end of diastole before contraction
Afterload is the
force that the ventricle has to push against to eject blood during systole
Frank-Starling Relationship
input-output relationship of the heart
Why can the heart respond with greater stroke volume when it is stretched more?
Stretching the heart (sarcomeres in the myocytes) results in the myocyte responding with greater force of contraction
How does the heart contract more forcefully with more stretch?
actin and myosin become aligned better when the sarcomeres are stretched, with a maximum force being generated when sarcomeres are 2 to 2.2 microns in length
What happens when the sarcomeres are stretched ore tha 2 to 2.2 microns?
the actin and myosin are not aligned properly and force cannot be further increased
Contractility is
the force with which the heart contracts
What happens to stoke volume in conditions that increase inotropy (contractility)
stroke volume increases for a given LVEDV or preload
What do optimized hearts look like on the Frank-Starling relationship curve?
optimized hearts have a steeper curve, where small changes in preload (LV end diastolic volume) results in large increases in stroke volume
What do failing hearts look like on the Frank-Starling relationship curve?
Failing hearts do not respond well to increased preload, and a CHF patient will often exhibit a flatter curve resembling the red one
How are afterload and SV related?
inversely
Failing hearts start to show signs of being sensitive to what?
of being “sensitive” to afterload, with severe cases of heart failure being very sensitive to increases in afterload
What increases stroke volume for a given value of afterload?
preload and inotropy
Compensation in CHF
compensation is when heart function is stable, though there is an underlying disease, and the patient is able to participate in many or more normal activities (though symptoms of CHF are present)
Decompensation in CHF
Decompensation is a period of time when the heart/CV system cannot compensate adequately for the reduced effectiveness of the CHF heart, and the person often experiences symptoms sufficient enough to put them in the hospital
Systolic heart failure
primarily a deficit in contraction; the heart muscle itself is weak and often dilated, making it unable to contract with sufficient strength to meet the needs of the body
Diastolic heart failure
primarily a deficit in relaxation; it may be strong enough to contract, but it can’t expand enough to allow blood to enter during diastole, resulting in reduced cardiac output
Describe progression of CHF
increased vascular resistance -> heart works harder and requires more oxygen ->hypoxia -> decreased functioning of the heart ->increased pre-load, pulmonary edema -> hypertrophic response (eventually exacerbates the problem)
Compensatory mechanisms in early heart failure
- sympathetic discharge
- RAAS activity
- cardiac remodeling
Compensatory mechanisms in early heart failure results in
increased SV but at a cost
What is afterload, SV and preload like in early heart failure
afterload is potentially high (hypertention); SV is reduced; preload stands to increase
What happens to the Starling curve in early HF
the patient starts to drop off the normal healthy Starling curve and begins to have a lowered curve
Increased sympathetic discharge can lead to
arrhythmias and remodeling via activation of beta Ars
Angiotensin II causes
vasoconstriction, stimulates remodeling, and induces aldosterone (which causes salt and water retention, increasing preload)
What does a CHF heart look like compared to a normal heart
CHF heart will have thicker ventricular walls and increased deposition of connective tissue
Increased connective tissue in a CHF heart is due to
myocyte cell death and replacement of these dead myocytes with fibroblasts
Calcium signals in cardiac myocytes contributes to
changes in gene expression as part of the hypertrophic remodeling response
What contributes to the increased expression of genes that mediate the hypertrophic remodeling response
when the heart cell goes through more rounds of calcium entry/exit (calcium cycling)
Patients with congestive heart failure can have their CHF exacerbated by what disease?
hyperthyroidism
What does it mean to say that patients are “afterload sensitive”
increases in afterload (basically blood pressure) bring about sharp reductions in stroke volume
What happens in late stage congestive heart failure
compensatory mechanisms can no longer adequately compensate for the problems; preload continues to increase; afterload increases; SV decreases; preload values in the “congestive range” where pulmonary function is compromised
Two main categories of drugs to treat CHF
- Manipulate hemodynamics
2. Inhibit compensation
Manipulate hemodynamics by
alleviating the extreme pressure problems of CHF and improve ability of the heart to function as a pump
Inhibit compensation by
using agents that seek to reverse the cardiac remodeling that occurs during CHF
ACE inhibitors address
both compensation as well as hemodynamics
What do vasodilators do?
dilate veins, lower preload and congestive symptoms
Vasodilators
organic nitrates, hydralazine
Diuretics
furosemide, bumetamide, and torsemide
decreases blood volume
Angiotensin inhibitors
ACE inhibitors, ATII rec. antagonists, renin inhibitors
decrease pressure and volume
Inotropic agents
digoxin, PDE3 inhibitors, beta-AR agonists
stimulate cardiac contractility
Inotropic agents for CHF
- Cardiac glycosides
- Phosphodiesterase inhibitors
- beta-adrenergic agonists
Glycosides (digoxin) only used for
chronic therapy
PDE inhibitors and beta agonists are only used for
acutely decompensated patients, typically in hospital/ER settings
PDE inhibitors have a risk of inducing
arrhythmias long-term
What can beta agonists cause long term
desensitization
Role of calcium in cardiac myocyte contraction
Ca2+ enters through L-type channels and triggers further release of Ca2+ from internal stores via ryanodine receptors; Ca2+ must be removed from the myocyte before the next depolarization
How is Ca2+ removed from the myocyte
- Ca2+ ATPase pumps Ca2+ out of the cell
- SERCA pumps Ca2+ into the SR
- NCX (Na+/Ca2+ exchange protein) extrudes Ca2+ in exchange for Na+
Key to NCX function
maintaining the sodium gradient outside/inside the cell (high Na+ outside and low Na+ inside)
partial blockade of the ATPase results in
increased release of Ca2+ into the cytoplasm during contraction and an increase in the strength of contraction
Overall, what does mild to moderate blockage of the sodium potassium ATPase do?
increases cardiac contractility by enhancing Ca2+ release during contraction
Specific effects of Na+/K+ ATPase blockade
increases [Na+]in which will decrease Ca2+ extrusion; more calcium is reloaded into intracellular stores; more Ca2+ is released in response to stimulation; muscle contracts with greater force
What does digoxin do?
increase cardiac contractility increase AV node refractoriness decrease heart rate decrease vascular sympathetic tone in CHF secondary to resensitization of baroreceptors vasodilation in CHF patients
Digoxin blocks
the sodium potassium ATPase
blocking the sodium potassium ATPase alters
the sodium gradient across the membrane, resulting in lower than normal sodium outside the cell and higher than normal sodium inside the cell
If you don’t know the mechanism of action of digoxin go look at it
it’s on page 26 and it’s honestly really stupid; I don’t feel like writing it out
Describe the structure of glycosides
all glycosides have a steroid nucleus; sugar moieties and lactone moieties define different classes of glycosides
Problems with glycosides
glycosides have a narrow therapeutic window; loading doses must be monitored closely (serum levels, EKG)
Common toxicities of glycosides
psychiatric: delirium, fatigue, malaise, confusion
G.I.: anorexia, N&V, abdominal pain
respiratory: increased response to hypoxia
CV: pro-arrhythmic (atrial tachy, AV block)
Pharmacodynamics interactions of glycosides
- beta-blockers and Ca2+ channel blockers: depress the heart, oppose digoxin action
- Kaliuretic diuretics (increase K+ elimination): decrease K+, promoting digoxin action, raising risk for arrhythmias
beta-AR agonists
dobutamine, dopamine
prone to densensitization; cause hypertension
Phosphodiesterase 3 inhibitors
milrinone, amrinone
proarrhythmic; decreased survival
Inotropic agents for acute failure
beta-AR agonists
phosphodiesterase 3 inhibitors
CHF drugs: inhibiting compensation
- Renin/angiotensin system inhibition
- aldosterone antagonists
- beta-AR blockers
Renin/angiotensin system inhibition
alleviates pressure and volume problems
some stop/reverse remodeling
first line treatment for CHF
ACEi; ATII receptor antagonist, aliskiren
Aldosterone antagonists
decrease blood volume (diuretic-like)
reverse/arrest hypertrophy
spironolactone = aldosterone
beta-AR blockers
inhibit sympathetic overactivity in CHF
decrease remodeling, reduce mortality
carvedilol, metoprolol, bisoprolol
Spironolactone is used to block
the effects of aldosterone and inhibits angiotensin II’s ability to increase preload
Pathophysiological effect of increased Na+ and water retention
edema, elevated cardiac filling pressures
Pathophysiological effect of K+ and Mg2+ loss
arrhythmogenesis and risk of sudden cardiac death
Pathophysiological effect of reduced myocardial NE uptake
potentiation of NE effects: myocardial remodeling and arrhythmogenesis
Pathophysiological effect of reduced baroreceptor sensitivity
reduced parasympathetic activity and risk of sudden cardiac death
Pathophysiological effect of myocardial fibrosis, fibroblast proliferation
remodeling and ventricular dysfunction
Pathophysiological effect of alterations in Na+ channel expression
increased excitability and contractility of cardiac myocytes
Beta blockers inhibit
the increased sympathetic drive in CHF, reducing the work of the heart, increasing time for filling in diastole, and prevention of remodeling
Common beta blockers in CHF
metoprolol
bisoprolol
carvedilol
afterload and preload with beta blockers
they decrease afterload though they might actually cause an increase in preload due to increased filling time during diastole
Angiotensin II stimulates ADH (vasopressin) secretion, resulting in
- water retention
- vasoconstriction
- enhanced platelet aggregation
- VSM and myocyte proliferation
Vasopressin receptor antagonists in CHF
Tolvaptan and Conivaptan
Adverse reactions of tolvaptan and conivaptan
hypotension, osmotic demyelination, CYP3A substrate
Tolvaptan and conivaptan used in
treatment of hyponatremia in HF and SIADH in acute care settings
What does neprilysin inhibition do?
increases levels of vasoactive peptides
counters neurohumoral vasoconstriction, Na+ retention, and remodeling
is investigation for CHF
What does neprilysin do?
neutral endopeptidase that degrades endogenous vasoactivate peptides (natriuretic peptides, bradykinin, adrenomedullin)
When do ventricles secrete natriuretic peptides (vasodilators)
in response to increased blood volume and stretch
Do inotropes improve preload problems?
No (only helps with the low output symptoms, not congestive symptoms)
ACE inhibitors reduce
both preload (via blood volume reduction) and afterload (via blood pressure reduction)
What would ACE inhibitors be expected to do with the Starling curve
might be expected to move a curve both upward out of the low-output range as well as leftward out of the congestive range
What do diuretics do to the Starling curve
they improve pulmonary edema by reducing blood volume but don’t have much impact on stroke volume
