Pharmacotherapy for Heart Failure Flashcards
Describe the factors that control cardiac output
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Describe the Frank-Starling relationship in different myocardial contractile status
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Describe the pathophysiologic mechanisms for heart failure and major sites for drug action.
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List the drug groups used in the management of heart failure. Describe their relevant mechanisms of action.
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Describe the hemodynamic responses to pharmacologic interventions in heart failure.
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List the factors controlling intrinsic myocardial contractility and describe how they are exploited therapeutically
β receptor stimulation by beta-adrenergic agonists such as epinephrine or isoproterenol initiates a complex series of cellular interactions that ultimately result in increased intracellular Ca2+ concentrations.
Initial stimulation of the β receptor produces stimulation of G proteins, also known as guanine nucleotide regulatory proteins, to activate adenylate cyclase. Adenylate cyclase increases cyclic adenosine monophosphate (cAMP) production which mediates increased metabolism (left) and protein kinase phosphorylation of the Ca2+ channel protein (P). This leads to opening of the calcium channel and increased influx of calcium through the sarcolemma (SL) of the myocyte. These Ca2+ ions then cause release of more calcium from the sarcoplasmic reticulum (SR) which increases cytosolic calcium. The combination of calcium’s interaction with troponin C and enhanced myosin adenosinetriphosphatase (ATPase) activity produces an increase in the rate and peak force of contraction (enhanced inotropy).
- Inhibition of phosphodiesterases leads to increased cAMP and intracellular Ca2+ levels and, consequently, enhanced contractility. An increased lusitropic (relaxant) effect of β-receptor stimulation is produced by cAMP activation of the protein phospholamban (PL). ADP—adenosine phosphate; ATP—adenosine triphosphate; GTP—guanosine triphosphate; Pi—inorganic phosphate; TnI—troponin-I.
Describe the mechanisms of action of digoxin
Digoxin blocks the Na+ -K+ ATPase in the myocardium, leading to intracellular accumulation of Na+. Increased cytosolic Na+ reduces Na+ -Ca2+ exchanger activity, leading to increased influx of Ca2+ from the extracellular space. Contraction is increased as a result of enhanced cytoplasmic Ca2+.
pharmacokinetic properties, digoxin
T1/236-48 hours in patients with normal or near-normal renal function, permitting once-daily dosing.
Near steady-state blood levels are achieved 7 days after initiation of maintenance therapy.
Excreted by the kidney – affected by rx that change RBF
Inactivated by Eubacterium Lentum (10% pop) rx tolerance.
Plasma concentration affected by many drugs:
CV rx: Antiarrhythmics class Ia & IV, spironolactone, vasodilators …
Cimetidine
role of digoxin in the treatment of heart failure
Used very frequently in HF, especially CHF with AF
- Improves symptoms significantly
- Improve patient’s quality of life
- Reduce hospitalizations
• Does not improve all-cause mortality no longer a first-line therapy for HF
adverse effects digoxin
Low margin of safety (TI
Describe the mechanism of action of phosphodiesterase 3 inhibitors
The cyclic AMP–PDE inhibitors decrease cellular cyclic AMP degradation,
resulting in elevated levels of cyclic AMP in cardiac and smooth muscle myocytes
Describe the cardiovascular effects of phosphodiesterase 3 inhibitors
Directly stimulate myocardial contractility
- Accelerate myocardial relaxation
- Balanced arterial & venous dilation
↓ TPR, PVR, ↓ LV, RV filling pressures increased cardiac output
Describe the therapeutic uses of phosphodiesterase 3 inhibitors in heart failure.
Inamrinone and Milrinone have short half-lives. They are approved for the short-term circulation support in advanced congestive heart failure.
Stage A (High risk for developing HF)
Hypertention
CAD
family history of cardiomyopathy (MI b4 55)
Diabeties
Stage B (Asymptomatic HF, Pre HF)
Previous MI
LV systolic dusyfunction (hypertrophy)
Asymptomatic valvular disease
Stage C Symptomatic HF
Known structural heart disease
shortness of breath and fatigue
Reduced exercise tolerance
Stage D refractory end stage HF
Marked symotoms at rest despite maximal medical therapy
frequent hospitilizations
Stage A treatments
Ace inhibtior or ARB for vascular disease, hypertension, and or diabeties
Stage B treatments
- Ace inhibitor or ARB -Previous or remote MiI, asymptomatic LVD, hypertensive LDV
- Beta blockers-Previous or remote MiI, asymptomatic LVD
Stage C treatments
- Big guns
1. Ace inhibitor or ARB- all pateints unless contraindicated
2. Beta-blocker- all patients unless contraindicated
3. Diuretics- fluid retention
4. Aldosterone Antagonist (Spirnalactone)- symp LVD, post MI HF, LVD
5. Hydralazine and Nitrates- if nigger, symptomatic HF
6. ARB and ACE- symptomatic HF
7. Digoxin-symptomatic HF, atrial fib
Stafe D treatments
- Ace inhibitor or ARB- allunles not tolerated
- B-blocker
- diuretcis
- Digoxin- Atrial fib with rapid ventricular response
- Pos inotropes- bridge to transplantation or end of life
Ways to inc cardiac contractility
- Increase cytosolic Ca2+ using cardiac glycosides
- Increased myocardial c AMP concentration using Phosphodiesterase inhibitors (Amrinone, Milrinone)
- Agonism at β1 receptors using β adrenergic agonists (review Autonomic Pharmacology)
- Increase β1 receptor density using β receptor antagonist (review Autonomic Pharmacology)
cardiovascular effects digoxin
Positive inotropic effect
↓ EDV and ↓ESV
↓ pulmonary and systemic venous pressure
reflex ↓SANS (↓preload, afterload & ↓HR)
- Direct (+) vagal effect
↑ vagal tone decrease A-V conduction
↑ PR interval (longer ERP)
↓APD (shorter QT)
- ↑coronary flow (↓hypertrophy)
- ↓renal artery resistance (↑RBF ⇒ ↑GFR ⇒ ↑ UO)
- Proarrhythmic: digoxin can cause many types of
arrhythmias. Increased PR interval and ST depression
(typical hockey stick)* are common. More severe
arrhythmias can occur, especially in the presence of
hypokalemia.
antidote to digoxin overdose
cholestyramine
- digoxin immune Fab (des-IgG) [Digibind®]–
bind to both bound and free cardiac glycoside where it is sequestered in extracellular fluid and eliminated through the kidneys
administered IV, immediate onset of action
toxicity reversal within minutes
PHOSPHODIESTERASE INHIBITORS
INAMRINONE, MILRINONE
Digoxin effect on mortality rate
none
Diuretic effect o quality life and mortailty
mortality unknown, but improves quality og life more than any others!
ACE inhib effect mortality
20% lowest effect!
Aldosterone inhibit effect mortality
30%
B-blocker effect mortality
35%!!! largest reduction in mortality!!!
