Drugs for Heart Failure - Kruse Flashcards
Cardiac glycosides
Inotropic agents
Digoxin
Digoxin immune fab (digoxin antibody)
Bipyridines
Inotropic agents
Inamrinone (no longer available)
Milrinone
Beta-adrenergic receptor agonists
Inotropic agents
Dobutamine
Dopamine
Agents without positive inotropic effects
Diuretics ACEI ARBs Vasodilators Beta-adrenergic receptor blockers Natriuretic peptide
Diuretics used in HF
Loop diuretics:
Bumetanide
Furosemide
Torsemide
Thiazide diuretics:
hydrochlorothiazide
Aldosterone antagonists:
Eplerenone
Spironolactone
Vasopressin (ADH) antagonists:
Conivaptan
Tolvaptan
ACEI used in HF
Captopril enalapril fosinopril lisinopril quinapril ramipril
ARBs used in HF
Candesartan
Losartan
valsartan
Vasodilators
Venodilators: Isosorbide denigrate
Arteriolar dilators: hydrazine
Combined arteriolar and venodilator: Nitroprusside
Beta-adrenergic receptor blockers
bisoprolol
carvedilol
metoprolol
nebivolol
Natriuretic peptide
Nesiritide
Pharmacokinetics of digoxin (cardiac glycosides)
1) 65-80% absorbed after oral administration
(2) Widely distributed to tissues, including the CNS
(3) For patients with normal renal function, the half life is 36-48 hours, permitting once-a-day dosing (66% Digoxin
is eliminated unchanged by the kidney)
(4) In patients with renal insufficiency (or elderly patients), the half life increases to 3.5-5
days and requires dosing adjustments
(5) In patients with HF who are taking vasodilators or sympathomimetic agents, cardiac output and renal blood flow are increased, which may increase renal digoxin clearance
MOA of digoxin
at the molecular level, digoxin causes inhibition of the membrane-bound (sarcolemma) Na+/K+ ATPase, ultimately causing an increase in the contraction of the cardiac sarcomere
The two desired effects of digoxin are (1) to improve contractility of the failing heart and (2) to prolong the refractory period of the atrioventricular node in patients with supraventricular arrhythmias (no effect on preload or afterload)
Mechanism of positive inotropic effect
(a) Inhibition of the Na+/K+ ATPase stops the cellular Na+ pump activity and reduces the
rate of active Na+ extrusion out of the cell, which results in a rise in intracellular Na+
concentrations
(b) Rising intracellular Na+ concentrations reduce the transmembrane Na+ gradient that
drives the extrusion of intracellular Ca2+ during myocyte repolarization by the
Na+/Ca2+ exchanger (NCX)
(c) With reduced Ca2+ efflux and repeated entry of Ca2+ with each action potential, Ca2+
accumulates in the myocyte
(d) Ca2+ uptake into the sarcoplasmic reticulum (SR) is increased and more Ca2+ becomes available for release from the SR during the next action potential, which
enhances myocardial contractility
(e) Therefore, cardiac glycosides increase myocardial contractility by ultimately increasing the releasable Ca2+ from the SR (see lecture slides for more information)
(f) The magnitude of the positive inotropic effect correlates with the degree of Na+/K+ ATPase inhibition
Electrical cardiac effects at therapeutic levels - digoxin
(a) Direct actions on the membranes of cardiac cells follow a well-defined progression: an early, brief prolongation of the action potential, followed by action potential shortening (especially the plateau phase)
(b) The decrease in action potential duration may be the result of increased potassium conductance that is caused by increased intracellular calcium
(i) Digoxin-induced elevated intracellular Ca2+ increases the activity of Ca2+- dependent K+ channels
(ii) Increased Ca2+-dependent K+ channel activity promotes K+ efflux and a more rapid repolarization (i.e., shortened cardiac action potential)
(c) Parasympathomimetic effects predominate on cardiac tissue at therapeutic levels of digoxin (see table below)
(i) Parasympathomimetic effects are inhibited by atropine
(ii) Parasympathomimetic effects involve sensitization of the baroreceptors, central
vagal stimulation, and facilitation of muscarinic transmission at the cardiac
muscle cell (unknown mechanism)
(iii) Cholinergic innervation is more concentrated in the atria, resulting in increased
actions of digoxin on atrial and atrioventricular nodes compared to Purkinje or
ventricular function
Electrical cardiac effects at toxic levels of digoxin
(a) Toxic levels are associated with depolarization of the resting potential (less negative), a marked shortening of the action potential, and the appearance of oscillatory depolarizing afterpotentials (delayed after depolarizations, DADs) following normally evoked action potentials (Figure 13-5, panel B on p. 215)
(i) Delayed after depolarizations are associated with overloading of the intracellular
Ca2+ stores and oscillations in free intracellular Ca2+ concentrations
(ii) When afterpotentials reach threshold, they elicit action potentials (premature
depolarizations, ectopic beats)
(b) Most common cardiac manifestations of digoxin toxicity include changes to
atrioventricular junctional rhythm, premature ventricular depolarization, bigeminal rhythm, and second-degree atrioventricular blockade (it is claimed that digoxin can cause virtually any arrhythmia)
(c) If allowed to progress, the tachycardia may deteriorate into fibrillation that could be fatal unless corrected
Digoxin toxicity
(1) Cardiac glycosides affect all excitable tissues due to its MOA and can cause adverse effects throughout the body (primarily GI and CNS)
(2) Heart: arrhythmias (see above)
(3) Gastrointestinal system (most common site of digoxin toxicity outside the heart)
(a) Anorexia, nausea, vomiting, and diarrhea
(b) Due to direct effects on the GI tract and CNS actions
(4) CNS: vagal and chemoreceptor trigger zone stimulation can cause GI symptoms; disorientation, hallucinations, and visual disturbances and/or changes
(5) Gynecomastia is a rare effect that can occur in men
(6) Antidigoxin immunotherapy (antidigoxin fab antibody) can be utilized in cases of digoxin
overdose
Interactions of digoxin with K, Ca, Mg
(1) Digoxin and potassium bind to competing sites on the Na+/K+ ATPase
(a) Hyperkalemia can reduce the effects of digoxin (especially the toxic effects) (b) Hypokalemia can potentiate the toxic effects of digoxin
(2) Hyperkalemia inhibits abnormal cardiac automaticity (i.e., hyperkalemia decreases pacemaker arrhythmogenesis)
(3) Hypercalcemia and hypomagnesemia increase the risk of a digoxin-induced arrhythmia
Digoxin in healthy heart vs chronically failing heart
little effect on individuals with a healthy heart, however, when administered to
individuals with a chronically failing heart, digoxin can increase the strength of contraction as much as 50-100%
Pharmacokinetics of bipyridines (inamrinone, milrinone)
(1) Elimination half-lives are 3-6 hours in patients with severe heart failure (approximately half that in healthy patients)
(2) 10-40% is excreted in the kidney
(3) Only available for parenteral administration
MOA for bipyridines
cause selective inhibition of phosphodiesterase isozyme 3 (PDE3), which increases cyclic adenosine monophosphate (cAMP) concentrations (phosphodiesterase enzymes degrade cellular cAMP and cGMP)
Pharmacodynamics of bipuridines
Increased concentrations of cAMP in the heart result in direct stimulation of myocardial contractility and acceleration of myocardial relaxation
(a) cAMP-dependent protein kinases in the heart phosphorylate and activate voltage-
gated Ca2+ channels, increasing the amount of Ca2+ entering the cell during an
action potential
(b) Increased concentrations of Ca2+ increase the force of contraction of the heart
Increased concentrations of cAMP in the vasculature cause balanced arterial and venous dilation with a consequent fall in systemic and pulmonary vascular resistances and left and right heart filling pressure
(a) cAMP-dependent protein kinases in smooth muscle phosphorylate and inactivate
myosin-light chain kinase
(b) Inactivation of myosin-light chain kinase causes smooth muscle relaxation
(vasodilation)
PDE3 inhibitors increase cardiac output due to the stimulation of myocardial contractility
and the decrease in left ventricular afterload (they are sometimes called ‘ino-dilators’)
Caffeine and theophylline are nonspecific PDE inhibitors and their use in HF is limited
by their lack of specificity and concomitant side effects
Toxicity of inamrinone
nausea, vomiting, arrhythmias, thrombocytopenia, and liver enzyme
changes
Toxicity of Milrinone
arrhythmias (bone-marrow suppression and liver toxicity is less likely
compared to inamrinone)
Bipyridines
Approved for the short-term support of the circulation in advanced heart failure
chronic parenteral
therapy does not show any signs of improving the quality or length of life and, in fact, may actually increase mortality
B-adrenergic and dopaminergic agonists
dobutamine (β-agonist) and dopamine (dopaminergic agonist)
MOA of B-adrenergic and dopaminergic agonists
act via stimulation of the cardiac myocyte dopamine D1 receptor (dopamine) and β1-adrenergic receptor (dobutamine)
(1) Receptor activation leads to stimulation of the GS-adenylyl cyclase-cAMP-protein kinase
A (PKA) pathway
(2) PKA phosphorylates a number of substrates that enhance Ca2+-dependent contraction and speed relaxation
Dobutamine
(1) Stimulates β1-receptors with little effect on β2- or α-receptors (β1 selective)
(2) The β agonist of choice for the management of patients with systolic dysfunction and HF
(3) Principal hemodynamic effect is an increase in stroke volume due to its positive
inotropic action and an increase in cardiac output
(4) The major side effects are excessive tachycardia and arrhythmias
(5) Parenteral administration
Dopamine
(1) Endogenous catecholamine with limited utility in the treatment of most patients with HF
(2) May be useful in patients if there is a need to raise blood pressure
(3) At low doses, dopamine causes vasodilation by stimulating dopaminergic receptors on
smooth muscle (causing cAMP-dependent relaxation) and by stimulating presynaptic D2 receptors on sympathetic nerves in the peripheral circulation (inhibiting norepinephrine release and reducing α-adrenergic stimulation of vascular smooth muscle)
(4) At intermediate doses, dopamine directly stimulates β receptors on the heart and vascular sympathetic neurons (enhancing cardiac contractility and neural norepinephrine release)
(5) At high doses, dopamine causes peripheral arterial and venous constriction via α- adrenergic receptor stimulation, which may be desirable in patients where circulatory failure is the result of vasodilation (e.g., sepsis, anaphylaxis)
(6) Tachycardia is more pronounced with dopamine than with dobutamine and may provoke ischemia in patients with coronary artery disease
(7) Parenteral administration
Loop diuretics
widely used in the treatment of heart failure (furosemide, bumetanide,
and torsemide are most commonly used)
Thiazide diuretics
most frequently used in the treatment of systemic hypertension and
have a more restricted role in the treatment of HF
Potassium-sparing diuretics
relatively weak diuretics and therefore are not effective
for volume reduction; however, aldosterone antagonists have been shown to improve survival in patients with advanced heart failure via a mechanism that is independent of diuresis
Aldosterone antagonists
(1) One of the principle features of HF is marked activation of the renin-angiotensin-
aldosterone system (some patients with HF have plasma aldosterone concentrations as
high as 20 times the normal level)
(2) Aldosterone not only is involved in increased sodium and water retention but may also
cause myocardial and vascular fibrosis (remodeling) and baroreceptor dysfunction
(3) Antagonism of the effects of aldosterone has been shown to improve survival in patients
with advanced HF
(4) Prototypes: spironolactone and eplerenone
Vasopressin (ADH) Antagonists
A variety of medical conditions (e.g., heart failure and syndrome of inappropriate ADH
(SIADH)) cause water retention as the result of ADH excess, which can result in
hyponatremia
Conivaptan
an ADH receptor antagonist and has been approved for use in the
above-mentioned cases
Conivaptan is administered parenterally with a half-life of 5-10 hours
MOA of vasopressin antagonists
antagonist at ADH receptors (V1a and V2) in the CCT
Vasopressin antagonist toxicity
conivaptan can cause hypernatremia, nephrogenic diabetes insipidus
Tolvaptan
selective antagonist of V2 ADH receptors that is given PO (use and
toxicity is similar to conivaptan)
