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
