Drugs for Heart Failure (Kruse) Flashcards
Heart failure occurs when
-cardiac output is inadequate to provide oxygen needed by the body
Causes of HF
- diminished coronary blood flow (CAD)
- Damaged heart valves
- External pressure around the heart
- Vitamin B deficiency
- Primary cardiac muscle disease
- Others
Compensatory changes associated with HF
- Decreased CO–>decreased carotid firing–>increased sympathetic discharge–>increased force and rate of contraction, increased preload and increased after load to try to increase CO
- Decreased CO–>decreased renal blood flow–>increased renin release—>increased Ang II–>increased sympathetic discharge and increased preload, after load and cardiac remodeling
Drug therapy of heart failure: historic focus on end point components
- volume overload (congestion)–>diuretics
- Myocardial dysfunction (heart failure)–>positive inotropic agents
- Does not reduce mortality in patients with HF
Drug therapy of heart failure: current therapies target organs/systems other than the heart
- Renin-angiotensin-aldosterone system
- Sympathetic NS
- Have been shown to reduce mortality
Hemodynamic responses to pharmacologic interventions in HF
-Combination of drugs (like diuretic, vasodilator and inotropic agents) are used to treat HF and can significantly improve low output symptoms and congestive symptoms
Which class of diuretics are the most efficacious for reducing volume overload?
-Loop diuretics
Loop diuretics prototype
-Furosomide and ethacrynic acid
MOA of loop diuretics
-Inhibit the luminal Na/K/2Cl cotransporter (NKCC2) in the TAL
Loop diuretics results in
- decreased intracellular K+ in TAL
- Decreased back diffusion of K+ and positive potential
- Decreased reabsorption of Ca2+ and Mg2+
- Increased diuresis
- Ion transport virtually non-existent; among the most efficacious diuretics available
Indications for Loop diuretics
- Edema
- Heart Failure
- Hypertension
- Acute renal failure
- Hypercalcemic states
Adverse effects of Loop diuretics
- Hypokalemia
- Alkalosis
- Hypocalcemia
- Hypomagnesemia
- Hyperuricemia
- Ototoxicity
- Sulfonamide hypersensitivity (not all)
Swollen tongue and nagging cough is associated with what drug?
-ACE inhibitors (e.g. Enalapril)
If patient cannot tolerate ACE inhibitor due to adverse effects (swollen tongue, caugh), an appropriate replacement would be what class of drug?
-Angiotensin Receptor Blocker (e.g. Losartan)
Effects of Angiotensin II
-Arterial vasoconstrictor
-Increases retention of sodium and water
-Increases aldosterone secretion
-Promotes catecholamine release from the adrenal medulla
-Promotes arrhythmias
Promotes vascular and cardiac hypertrophy and remodeling
-Stimulates myocyte death
Three key effects of ANG II
- Altered Peripheral resistance–>rapid pressor response
- Altered renal function–>Slow pressor response
- Altered Cardiovascular structure–>vascular and cardiac hypertrophy and remodeling
Ways to inhibit Angiotensin II
- Inhibit ACE (-prils)
- Inhibit AT receptors (sartans)
- Inhibit renin (aliskiren)
Drug used to treat palpitations, 3rd heart sound and its adverse effects include paroxysmal atrial tachycardia (atrial fibrillation) with block at toxic concentrations
-Digoxin
Cardiac glycosides prototype drug
-Digoxin
Uses of cardiac glycosides (digoxin)
- heart failure, tachyarrhytmias, shock
- well absorbed and widely distributed
Cardiac glycosides MOA
-inhibits the membrane-bound Na/K ATPase and increases myocardial contractility (50-100% in individuals with HF)
Cardiac glycosides composition
-a steroid nucleus, lactone ring, and sugar
Normal physiology: sarcolemmal exchange of Na and Ca during depolarization and repolarization
- Normally, AP comes in; that AP causes depolarization leading to flux of calcium into cell which interacts with ryanodine receptors which causes profound release of calcium leading to muscle contraction
- The SERCA pump releases Calcium back into the SR so that when the next AP comes down the process can start again
- The resting membrane potential is dependent on Na+/K+ ATPase (maintains high Na outside and high K inside)
Digoxin MOA
- blocks the Na/K ATPase so there is less Na outside of cell to be exchanged with calcium in order to sequester calcium from inside the cell
- The normal exchanging of calcium and sodium (3 sodium in for two calcium out) will not work (dependent on the Na/K gradient established by Na/K ATPase) so less calcium will be released out of the cell
- More calcium gets stored in SR so when AP comes down to activate cardiac myocyte, more Calcium is released resulting in increased force and strength of contraction
Electrical effects of digoxin at therapeutic levles
- Direct actions on the membranes of cardiac cells ultimately results in AP shortening
- Digoxin induced elected intracellular Calcium increases the activity of Ca-dependent K channels
- Increased Ca-dependent K channel activity promotes K efflux and a more rapid depolarization (shortened cardiac action potential)
______ effects predominate on cardiac tissue at therapeutic levels of digoxin
Parasympathomimetic
Parasympathomimetic effects involve
-sensitization of the baroreceptors, central vagal stimulation, and facilitation of muscarinic transmission at the cardiac muscle cell
Cholinergic innervation at therapeutic levels of digoxin is more concentrated in the
-atria, resulting in increased actions of digoxin on atrial and Av nodes compared to Purkinje or ventricular function
Effects of digoxin is inhibited by what drug?
Atropine
Electrical effects of digoxin at toxic levels
-Depolarization of the resting potential, marked shortening of the AP, and appearance of oscillatory depolarizing afxterpotentials following normally evoked AP
Digoxin at toxic levels–when afterpotentials reach threshold they
-elicit APs–premature depolarizations, ectopic beats
Most common cardiac manifestations of digoxin toxicity is
arrhythmia
If allowed to progress, the tachycardia caused by digoxin may deteriorate into
fibrillation that could be fatal unless corrected
Effects of digoxin at sinus node–theraputic vs. toxic dose
- Therapeutic: decreases rate
- Toxic: decreases rate
Effects of digoxin at atrial muscle–therapeutic vs toxic dose
- Therapeutic: decreases refractory period
- Toxic: decreases refractory period, arrhythmias
Effects of digoxin at AV node–therapeutic vs toxic dose
- Therapeutic: decreases conduction velocity, increases refractory period
- Toxic: decreases refractory period, arrhythmias
Effects of digoxin at Purkinje system, ventricular muscle
- Therapeutic: slight decrease in refractory period
- Toxic dose: extrasystoles, tachycardia, fibrillation
Effects of digoxin on ECG–therapeutic vs toxic dose
- Therapeutic: increased PR interval, decreased QT interval
- Toxic dose: tachycardia, fibrillation, arrest at extremely high dosage
Which drug potentiates the toxic effects of digoxin?
- Loop diuretics–furosomide
- Because K+ and digoxin bind to similar areas on the Na/K ATPase
Interactions of digoxin with K+, Ca and Mg
- Digoxin and potassium bind to competing sites on the Na/K ATPase
- Hyperkalemia can reduce the effects of digoxin (especially the toxic effects)
- Hypokalemia can potentiate the toxic effects of digoxin
Hyperkalemia and digoxin
- Hyperkalemia inhibits abnormal cardiac automaticity (i..e., hyperkalemia decreases pacemaker arrhythmogenesis)
- Moderately elevated extracellular K+ reduces the effects of digoxin, especially the toxic effects
Digoxin induced arrhythmia risk increases with
hypercalcemia and hypomagnesemia
Which drug both increases force of heart contraction and produces vasodilation?
-Bipyridines
ACE inhibitors, B-blockers, Cardiac glycosides, venodilators affects on vasodilation and force of contraction
-ACE inhibitors: increases vasodilation but does not affect force of contraction
-B blockers: decrease force of contraction but no affect on contractility force
-venodilators: increase vasodilation but does not affect force of contraction
-Cardiac glycosides: increase force of contraction but does not affect vasodilation
-
Bipyridines prototypes
- Milrinone
- Inamrinone (no longer available)
Bipyridines MOA
- cause selective inhibition of the PDE3 phosphodiesterase enzyme (PDE3 degrades cAMP)
- Increased concentration of cAMP in the heart result in direct stimulation of myocardial contractility and acceleration of myocardial relaxation
- Increased concentrations of cAMP in vasculature causes balanced arterial and venous dilation
Bypyridines clinical uses
- Ionotropic agents approved for SHORT-TERM support f circulation in advanced HF
- Chronic therapy does not show any improvement in quality or length of life
- Chronic therapy may increase mortality
Other agents that inhibit PDE
- Sildenafil, Tadalafil, Vardenafil inhibit PDE5
- Caffeine and theophylline are nonspecific PDE inhibitors
Steps in treatment of heart failure
1) control hypertension, hyperlipidemia, glucose metabolism (diabetes), obesity
2) Reduce workload of the heart (limit activity, put on bed rest)
3) Restrict sodium intake, give diuretics
4) Restrict water (rarely required)
5) Give ACE inhibitor or ARB
6) Give digoxin if systolic dysfunction with 3rd heart sound or atrial fibrillation present
7) Give B-blockers to patients with stable class II-IV HF
8) Give aldosterone blockers
9) Give vasodilators
10) Cardiac resynchronization if wide QRS is present in normal sinus rhythm
11) Cardiac transplant
