Heart failure drugs week 3 Flashcards
mortality of heart failure
50% mortality after 5 years
Causes of HF
Causes of HF:
- CAD/myocardial infarction – loss of heart tissue
- Hypertension – pressure loading of heart causing decompensation
- Tachycardia chronic persistent – increase O2 consumption and damages myocytes.
- Valvular disease – Ex: aortic stenosis, increase myocardial work, heart hypertrophy and this causes slowly failing heart.
- Viral – myocarditis with myocyte death and ensuing failure.
- Toxic chemicals: cobalt – directly toxic to myocytes
- Drugs: adriamycin – myocyte toxin, cardiomyopathy due to chemotherapy.
- Congenital heart disease - volume or pressure overload to heart leading to failure.
- Volume overload – too much fluid (volume) – Aortic Insufficiency – blood leaks back into LV causing overload and failure.
- Genetic – Duchenne muscular dystrophy – hereditary myocyte abnormality – hypertrophied stiff heart that fails, associated K channel abnormalities.
- High output failure – Ex: shunts (arterial – venous connections), Beriberi heart disease – to compensate increased cardiac output, ↑O2 consumption, heart can’t compensate and fails.
Digoxin
MOA
effects
clinical uses
toxicities, what predisposes one to toxicities?
antidote
form of elmination
Inotropes: Drugs that increase contractility
Digitalis/Digoxin
- Plant derived – foxglove plant
MOA
- Inhibits Na+/K+ ATP’ase
- Increase in intracellular Na
- Reduction of calcium expulsion – by sodium – calcium exchanger (NCX)
- More Ca left intracellular to be released, Ca+ binds to tropomysin so more actin myosin cross bridges, greater tension - contractility
Therapeutic effects:
- shorten APD (action potential duration).
- ↑ vagal tone. Sensitizes baroreceptors – withdraw sympathetic neural activity – result slow HR (increase cardiac filling) and slows conduction through AV Node –blocks excessive electrical activity in atrium being conducted to ventricle
Clinical uses:
Digoxin: CHF therapy
- Does not prolong life, but reduces CHF hospitalization (especially at lower doses).
- Not shown useful in diastolic dysfunction
Digoxin in A Fib
- Increases AV node refractoriness (direct effect on AV node tissue)
- Increase AV node refractoriness by ↑ vagal tone (indirect)
- depresses SA node
- In A Flutter/Fib slows the ventricular response to rapid atrial electrical activity.
Toxicities:
- very low toxic to therapeutic ratio: TD50/ED50
- Cholinergic: nausea, vomiting, diarrhea
- blurry yellow vision (think van Gogh)
- arrhythmias-increases DADs due to increased intracellular Ca2+: can lead to ectopic beats, bigeminy, sustained tachycardia
- AV block
- ST depression: Tulane pharm: increased intracellular Ca2+ can also increase Ca-modulated K+ conductance. May contribute to shortening of AP and repolarization rate leading to ST segment changes.
- hyperkalemia: indicates poor prognosis
Factors predisposing to toxicity:
- Renal failure (decreased excretion)
- hypokalemia: permissive for digoxin binding at K+ site on Na+/K+ ATPase
- Verapamil, amiodarone, quinidine: decrease digoxin clearance, displaces digoxin from tissue binding sites
Antidote:
- Slowly normalize K+
- cardiac pacer
- anti-digoxin Fab fragments (Digibind)
- Mg2+
Note: Only drug that increases AV node conduction time (refractoriness increase) and not negatively inotropic. Thus, has a special niche in the treatment of AF & HF.
Inamrinone
MOA
clinical uses
form of administration
toxicities
Inamrinone
- Phosphodiesterase inhibitor (PD-3), ↑ Ca++ in cell.
- Actions: vasodilator, inotropic
- Used IV for acute decompensation
- Chronic administration increased mortality
- Symptomatic treatment, does not prolong life
- Causes cardiac arrhythmias
- Bone marrow & liver toxicity
Milrinone
MOA
clinical uses
toxicities
Milrinone
- Phosphodiesterase inhibitor (PD-3), ↑ Ca++
- Vasodilator & inotropic
- Chronic administration adverse, increase mortality
- Causes arrhythmias
- Less bone marrow & liver toxicity than inamrinone, preferred drug over inamrinone
Dobutamine
MOA
effects
clinical uses
form of administration
Dobutamine
- ß1 stimulator primary action (B1>B2, a)
- IV therapy
- Inotropic with vasodilation (ß2 stimulation)
- Less tachycardia than other catecholamines and thus less O2 consumption
- Used in acute HF. inotropic>chronotropic
- used in cardiac stress testing when pt cant increase HR during exercise
Dopamine
MOA
clinical uses
effects
Dopamine
- D1=D2>B>a
Clinical uses:
- Unstable bradycardia
- acute heart failure
- shock: D1 receptor agonist: increase renal blood flow, natriuresis-increase TPR while maintaining blood flow to kidneys!
Inotropic and chronotropic alpha effects predominate at high doses
Entresto
MOA
uses
toxicities
Entresto
- New HF drug, FDA approved in 2015
- Combination drug – combines two drugs: one agent is the ARB valsartan and the second is a neprilysin inhibitor.
- Neprilysin – a neutral endopeptidase, degrades several endogenous vasoactive peptides, including natriuretic peptides (vasodilate, increase
- Na+ excretion), bradykinin and adrenomedollin.
- Inhibition of neprilysin increases levels of natriuretic peptide, bradykinin and adrenomedullin causing further vasodilation: decreasing afterload and preload.
- The action of sacubitril – the neprilysin inhibitor counters the neurohormonal overactivation that contributes to vasoconstriction, sodium retention and remodeling seen in HF.
- In a large study, 8,000 patients entresto caused a reduction in hospitalization of 21% and all case mortality reduction of additional 17%. Entresto is superior to enalapril in reducing death and HF.
- Since this is a fixed dose combination difficult to adjust dose.
- Increased risk of hypotension, cough, and angioedema.
ISDN/Hydralazine
MOA
clinical use
isosorbide dinitrate + hydralazine
MOA: both agents are vasodilators. Hydralazine MOA: increase cGMP leading ot smooth muscle relaxation, vasodilates arterioles>veins (decreases afterload). Nitrates: vasodilate by increase NO in smooth muscle-in cGMP and smooth muscle relaztion-Dilates veins> arteries (decreases preload).
Clinical use: heart failure.
Reduces mortality in African Americans who are less benefited by ACE inhibitors & ARB’s (low plasma renin associated HF).
Clinical Pearl: ISDN/Hydralazine should be used before ACE/ARB in African American patients with HF.
Nesitiride
MOA
effects
clinical uses
half life
administration
Nesiritide
- A synthetic form of brain natriuretic peptide (BNP)
- Used IV for acute decompensation HF
- Causes natriuresis & diuresis
- Short half-life 18 min
- Not shown to provide long-term benefit, gives some symptomatic relief.
Bosentan
MOA
clinical use
Bosentan: blocks endothelin
- Competitive inhibitor of endothelin
- Used in pulmonary hypertension
- Not shown beneficial in heart failure, don’t know why since endothelin a local vasoconstrictor (good research topic).
Both ____ and ____ in clinical studies show
an absolute reduction in mortality – required therapies
in chronic HF therapy. Works best in systolic HF, but
also in diastolic HF.
Both carvedilol and metoprolol in clinical studies show
an absolute reduction in mortality – required therapies
in chronic HF therapy. Works best in systolic HF, but
also in diastolic HF.
Systolic heart failure treatment
Systolic heart failure
- Sodium removal – diuretic therapy and/or dietary
-
Angiotensin antagonism (use only one drug)
- ACE
- ARB
- Renin inhibitor
-
Inotropic augmentation with digoxin – withdraws neural/humoral activation
- Low dose digoxin (0.125 mg per day – blood level 0.8 – 1 ng/ml recommended)
-
ß blockers
- Carvedilol
- Metoprolol
- Can use others, but above two used in most studies, don’t use ß blockers with ISA, less benefit.
- Vasodilators: ISDN/Hydralazine – African Americans
- Cardiac resynchronisation therapy: QRS greater than 120-130 msec, synchronized pacemaker reduces mortality, paces the left and right ventricles to improve synchrony of heart depolarization that is off in HF.
- Left ventricular assist devices (LVAD’s) – partial mechanical heart supporting the left ventricle, can be a destination therapy.
- Cardiac transplant – limited by supply of donor hearts, problems with anti-rejection therapy, accelerated athrosclerosis, infection, question of increased malignancies.
Diastolic heart failure treatment
Diastolic Heart Failure
- ß blockers
- ACE inhibitors
- Aldosterone antagonists – eplerenone, controversial –recent study found no benefit of spironolactone overall both with benefit in US but not in Russia and Ukraine – selection of patients (?).
- All of above drugs reduce mortality.
Acute heart failure treatment
Acute Heart Failure Management
- Diuretics – Loop (furosemide IV) if Loop diuretic resistant add thiazide or metolazone.
Vasodilators/inotropics
- Nitroprusside (IV) – afterload reduction predominates
- Nitroglycerin (IV) – preload reduction predominates
- Dobutamine (IV) – afterload reduction & inotropic
- Dopamine (IV) – natriuretic (low dose)
- Inamrinone or milrinone (IV) – afterload reduction & inotropic, arrhythmogenic
- Nesiritide (IV) – preload reduction /natriuresis – no mortality benefit, reduces symptoms.
- Angiotensin antagonists – rarely used IV. ACE, ARB slow onset of action
-
Digoxin IV – not recommended!!!!!
- not effective
- arrhythmogenic
- Avoid!
- If hyponatremic may use conivaptan, a V1a antagonist, effective therapy for dilutional hyponatremia (alternative to severe fluid restriction)
- Intra aortic balloon counterpulsation – inflates in descending aorta during diastole, acute augmentation of cardiac function for a few days, invasive.
- Left ventricular assist device LVAD
- An assist pump that is in series with left ventricle that assists LV function.
- When heart recovers, can sometimes remove in weeks to months, can be a destination therapy or a bridge to transplant.
