Heart Failure Drugs Flashcards
Digoxin MOA
Cardiac glycoside
Competes with K+ and blocks Na-K-ATPase, increasing intracellular Na+ concentration. Increased Na+ concentration inside the cell reduces the action of the Na-Ca2+ exchanger, increasing cytosolic Ca2+. This Ca2+ is sequestered in the SR (via SERCA) for use later during contraction (via RyR2).
Overall effect: increase in contractility
Which transporters move Ca2+ both into the SER and out of the SER?
SERCA brings Ca2+ into the SER
RyR2 releases Ca2+ into the cytosol from the SER for contraction
What is levosimendan?
Ca2+ sensitizer
Increases actin-troponin-tropomyosin sensitivity to Ca2+
What is the autonomic effect of digoxin at a low dose?
Parasympathomimetic: increased Ca2+ causes increased release of Ach from the synaptic terminals. Inhibits the SA and blocks A-V conduction due to the increased action of M2.
This is useful for treating A-fib
What is the autonomic effect of digoxin at a high dose?
Sympathomimetic: increased Ca2+ causes increased release of NE from the synaptic terminals. Increased heart contractility due to the action of B1 receptors
What effects does digoxin have in the GIT?
Anorexia, nausea, vomiting and diarrhea
Due to both smooth muscle contraction and through CNS chemoreceptor trigger zone stimulation
What effects does digoxin have in the CNS?
Vagal and chemoreceptor trigger zone stimulation
Disorientation, hallucination, visual disturbances (altered colour perception)
Gynecomastia (rare)
What characteristics does the ECG of someone taking digoxin have?
Early and brief shortening of the action potential due to increased K+ conductance caused by increased intracellular Ca2+
Increased PR interval caused by decrease in AV conduction velocity and flattening of T wave
Resting membrane potential is less negative, easy premature depolarization
What is the toxic response of digoxin?
Arrhythmia, including ventricular arrhythmia and AV blockage
Use of digoxin in congestive heart failure:
Effective but does not prolong life
Drug accumulates in the body and dosing regiments must be carefully designed and monitored
Use of digoxin in a-fib:
Unlike CCBs and BBs, digoxin does not have negative inotropic effects
Digoxin half life
1.5 days
Digoxin Vd
High - high tissue protein binding
Can be replaced by quinidine –> increasing serum digoxin levels
Interaction between K+ and digoxin
K+ and digoxin inhibit each other’s binding to Na-K ATPase (competitive)
Hypokalemia facilitates digoxin action
Hyperkalemia reduces digoxin action
Interaction between Ca2+ and digoxin
Ca2+ facilitates the toxic effects of digoxin
Hypercalcemia increases the risk of digoxin induced arrhythmia
Hypocalcemia renders digoxin less effective
Interaction between Mg2+ and digoxin
Mg2+ inhibits actions of digoxin
Digitalis-induced vomiting may deplete serum magnesium and facilitate toxicity
How does verapamil affect digoxin?
Lowers digoxin clearance in the liver and kidney (via p-glycoprotein efflux pump)
Replaces digoxin from tissue protein binding
Increases digoxin concentration in the blood
How to loop diuretics and thiazides affect digoxin?
May significantly reduce serum K+ and thus precipitate digitalis toxicity
Signs of digoxin toxicity
CNS: malaise, confusion, depression, vertigo, colour vision change
GI: anorexia, nausea, intestinal cramping, diarrhea
CVS: palpitations, syncope, arrhythmias, bigeminy ventricular premature contraction, bradycardia, cardiac affect (in very high doses)
How do you correct digoxin toxicity?
Correct potassium deficiencies (oral or IV)
Mild toxicities can be solved by omitting 1 or 2 doses of digitalis
Antiarrhythmic drugs: Lidocaine for ventricular arrhythmia, beta blocker or CCB for supraventricular arrythmia
Severe toxicity treated with Digibind, an anti-digoxin antibody (Fab fragments)
How are dobutamine and dopamine used in heart failure?
Useful in acute failure in which systolic function is markedly depressed
These drugs are not appropriate for chronic failure because of tolerance, lack of oral efficacy and significant arrhythmogenic effects
Inamrinone (amrinone) and milrinone MOA
Acts by inhibiting the enzyme phosphodiesterase-3
Leading to increased intracellular concentrations of cAMP-PKA
Phosphorylates L- Ca channels on plasma membrane, causing increased Ca++ entry into the cell, and phosphorylates ryanodine-Ca++ channel, leading to more calcium release. Heart contraction is increased
Phosphorylates MLCK and inactivates MLCK, causes vasodilation
How are inamrinone (amrinone) and milrinone used?
Only IV for short term therapy
Only for acute heart failure or severe exacerbation of CHF.
ADR of inamrinone (amrinone) and milrinone:
GI upset, arrhythmia, thrombocytopenia, liver toxicity. Milrinone is safer in term of bone marrow and liver toxicities
MOA of BNP
Released by ventricular myocytes when they are stretched. It is increased in heart failure.
BNP activates guanylyl cyclase, which increases cGMP causing vasodilation (arterioles AND veins)
Nesiritide
Recombinant human BNP used to treat acute decompensated congestive heart failure
T1/2 is 18 min
IV
What is the adverse effect of nesiritide?
Hypotension
How is furosemide used in heart failure?
Used to reduce volume immediately in pulmonary congestion and severe edema associated with acute heart failure
What do angiotensin II and aldosterone do locally in the heart?
Facilitate heart remodeling and fibrosis
How do B1 antagonists reduce mortality in heart failure?
Carvedolol, metoprolol
Decrease apoptosis
Decrease heart rate
Reduce remodeling by inhibiting mitogenic activity of catecholamine
Upregulate beta receptor
Effective in patients with hypertrophic cardiomyopathy
Not of value in acute failure (because they decrease heart contraction) and may be detrimental if systolic dysfunction is markedly decreased
Which drugs reduce mortality in heart failure?
ACEI, ARB
Spinorolactone, eplerenone
Carvedilol ( α and β blocker)
Metoprolol, bisoprolol, nebivolol (β1 blocker)
Ivabradine MOA
Inhibits SA node funny channel and reduces HR, but does not suppress contractility
Sacubitril MOA
ARNI ( ARB+ neprilysin inhibitor) (valsartan+ sacubitril)
Neprilysin is the enzyme to degrade natreuretic peptide (BNP) and bradykinin
Sacubitril is neprilysin inhibitor
Why use an ARNI ( ARB+ neprilysin inhibitor) (valsartan+ sacubitril)?
In patients with chronic symptomatic heart failure who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality
How do you manage chronic heart failure?
Limit physical activity Reduce weight Reduce water intake Control hypertension Na+ restriction Diuretics Angiotensin antagonists Digoxin Beta blockers Vasodilators
How do you manage acute left heart failure?
- O2
- Morphine IV or IH (calm down patient)
- Furosemide IV
- Digoxin IV (no repeat until 4 h later)
- Nitroprusside iv infusion, quickly reduce both artery and venous pressure (remember avoiding light, wrapping all tube and bag in foil paper)
- Life support
- Treat the cause (surgery to correct valvular disorders)
